WO2025082632A1

WO2025082632A1 - Method and composition for oligonucleotide synthesis

Info

Publication number: WO2025082632A1
Application number: PCT/EP2024/060228
Authority: WO
Inventors: Masaharu Saito
Original assignee: Bachem Holding AG
Current assignee: Bachem Holding AG
Priority date: 2023-10-16
Filing date: 2024-04-16
Publication date: 2025-04-24
Anticipated expiration: 2026-04-16

Abstract

The invention pertains to a method for the synthesis of oligonucleotides using pseudo solid-phase protecting groups, wherein said method comprises a step of subjecting a solution comprising a component (C-0)^# to one or more aqueous extractions, wherein the organic phase comprises the component (C-0)^#. Said component (C-0)^# is a nucleoside or an oligonucleotide, which is covalently bonded to a pseudo solid-phase protecting group and comprises a free backbone hydroxyl group. The aqueous phase of each of said one or more aqueous extractions has a pH-value in the range of 4-7.

Description

_{Bachem Holding AG} ^{April 16, 2024} BAC75082PC Method and composition for oligonucleotide synthesis The present invention generally pertains to the field of oligonucleotide synthesis at an industrial or laboratory scale. Improved methods for the synthesis of oligonucleotides are disclosed. Efficient methods for the manufacture of oligonucleotides at an industrial or laboratory scale as well as solvents for use in these methods are of significant pharmaceutical and commercial interest. The synthesis of oligonucleotides commonly relies on iterative coupling cycles, in which oligomeric or monomeric building blocks are added to a growing oligonucleotide chain. Solid-phase synthesis is characterized in that a growing oligonucleotide chain is assembled on a solid support, typically made of polymer resins or controlled pore glass. Solid-phase synthesis processes using the so-called phosphoramidite method have been optimized and automated. Thus, such solid-phase synthesis processes may be advantageous in terms of speed and are used most widely. However, the upscaling of solid-phase synthesis processes is difficult for several reasons, including excessive consumption of reagents and raw materials. A further disadvantage of solid-phase synthesis processes is that it is difficult to follow the progress of the reaction in real time and to analyze the structure of intermediates. More recently, liquid-phase synthesis processes have been developed, in which the growing oligonucleotide chain is bonded to a soluble support, also referred to as pseudo solid-phase protecting group or tag. These pseudo solid-phase protecting groups are typically hydrophobic and alter the solubility of the oligonucleotides. In consequence, oligonucleotides bonded to one or more such pseudo solid-phase protecting groups, herein also referred to as conjugates of oligonucleotides and pseudo solid-phase protecting groups, may be readily soluble in the organic solvents commonly used for oligonucleotide synthesis. In solid-phase synthesis, where the solid support is insoluble in the reaction solution(s) at all times, excess reagents and dissolved side-products or by-products may easily be removed by draining the reaction solution through a filter or frit or membrane of suitable pore sizes, thereby retaining the solid support carrying the growing oligonucleotide chains inside the reaction vessel or column. After draining of the liquids, new solvents and/or reagents and/or synthetic building blocks may be added. In contrast, in liquid-phase oligonucleotide synthesis using pseudo solid-phase protecting groups, these groups are typically selected so that the conjugates of the growing oligonucleotide chains and the pseudo solid-phase protecting groups are soluble in the reaction solvent(s). Thus, solid-liquid separation, typically filtration, may not readily be performed, and requires prior precipitation of the said conjugates. Such precipitation is typically achieved by addition of one or more polar solvents (e.g. water, acetonitrile, propionitrile, methanol, ethanol, 1-propanol, 2-propanol, and the like) and/or by concentrating the respective solution (e.g. in vacuo) and/or by decreasing the temperature of the respective solution. Each such sequence of precipitation and solid-liquid separation may be tedious, in particular since precipitating oligonucleotides in filterable form may not always be straight-forward. It may thus be desirable to reduce the number of such precipitation and solid-liquid separation steps required during liquid-phase oligonucleotide synthesis, e.g. to one such step per coupling cycle. Examples of precipitation and solid-liquid separation approaches to oligonucleotide synthesis using pseudo solid-phase protecting groups are e.g. disclosed in: US2015112053A1, EP3825300A1, EP2711370A1, EP3398955A1, US2018291056A1, EP3925964A1, EP2921499A1, EP3733680A1, EP3378869A1, WO2020227618A2, EP3263579A1, EP3950698A1, EP4006045A1, and EP3015467A1. Alternatively, or additionally, liquid-phase oligonucleotide synthesis using pseudo solid-phase protecting groups may rely on one or more (liquid-liquid) extraction steps, typically aqueous extraction steps, to remove excess reagents and/or side- products and/or by-products, thereby avoiding the need for precipitation. This strategy typically exploits the fact that the pseudo solid-phase protecting groups are usually quite hydrophobic. Thus, the conjugates of such pseudo solid-phase protecting groups and the growing oligonucleotide chains are typically (mostly) retained in an organic phase during aqueous extraction(s). Also in such approaches, at least one solid-liquid separation, typically filtration, step is usually performed per coupling cycle, either after evaporation to dryness and re-dissolution to achieve further purification, or prior to evaporation to dryness, if a drying agent such as sodium sulfate has been added, e.g. to the organic phase obtained from aqueous extraction. Examples of such approaches are e.g. disclosed in: M.C. de Koning et al., Organic Process Research & Development 2006, 10, 1238–1245; A. Schwenger et al., European Journal of Organic Chemistry 2017, 5852–5864; S. Kim et al., Chemistry – A European Journal 2013, 19, 8615–8620; X. Shi et al., Journal of Organic Chemistry 2022, 87(4), 2087−2110. An oligonucleotide synthesis process, which does not comprise any solid-liquid separation during and in between at least two consecutive coupling cycles, may be referred to as one-pot process. Such one- pot processes may be preferred, but have been reported very scarcely, namely in US2013267697A1, US2015080565A1, EP2816053A1, and EP3296306A1. A typical coupling cycle comprises a deprotection step, in which a temporary protecting group is removed from a hydroxyl moiety of a first nucleoside or oligonucleotide, so as to obtain a free hydroxyl group. This is followed by a coupling step, in which said free hydroxyl group engages in a condensation reaction with a phosphorus moiety of a second nucleoside or oligonucleotide, so as to obtain an elongated oligonucleotide. If the phosphorus moiety of said second nucleoside or oligonucleotide is a P(III) moiety, e.g., a phosphoramidite moiety, the coupling reaction is typically followed by a step of converting P(III) atoms to P(V) atoms by incubation with an oxidizing or sulfurizing agent. This step is also referred to as “oxidation step” or “sulfurization step”. Alternatively, P(III) moieties such as H- phosphonate diester moieties, may also be converted to P(V) moieties in the final coupling cycle only. A step of blocking unreacted hydroxyl groups (also referred to as “capping step”) is oftentimes carried out either after the coupling step or after the oxidation or sulfurization step. In extraction-based liquid-phase oligonucleotide synthesis using pseudo solid- phase protecting groups (see references cited above), there are two positions in the typical coupling cycles, where such extractions are performed: Usually after the oxidation or sulfurization step (in particular after the oxidation step with sodium thiosulfate solutions to reduce excess iodine-oxidizer) and, less common, after the deprotection step (i.e., after removal of a temporary hydroxyl protecting group). The structures of the oligonucleotide differ in these two extractions. After the oxidation/sulfurization step, the oligonucleotide does not comprise a free backbone hydroxyl group. The present invention specifically focusses on methods for liquid- phase oligonucleotide synthesis using pseudo solid-phase protecting groups comprising one or more aqueous extractions of a nucleoside or oligonucleotide having a free backbone hydroxyl group (i.e., after the deprotection step of the typical coupling cycle). So far, little to no attention has been paid to the pH-values of the aqueous phases of the aqueous extractions of nucleosides or oligonucleotides having a free backbone hydroxyl group (i.e., after the deprotection step) in liquid-phase oligonucleotide synthesis using pseudo solid-phase protecting groups. In the references cited above, at least one extraction was conducted with an alkaline aqueous solution (in particular hydrogen carbonate solutions). Strongly acidic solutions (in particular hydrogen sulfate solutions) have also been used. There is still a need for further methods for the liquid-phase synthesis of oligonucleotides using pseudo solid-phase protecting groups. Ideally, such methods would involve no or a minimum number of solid-liquid separations. Such methods will rely on one or more aqueous extractions. In general, optimized conditions for the aqueous extraction of solutions comprising nucleosides or oligonucleotides bound to a pseudo solid-phase protecting group are desirable. In particular, optimized conditions for the aqueous extraction of solutions comprising nucleosides or oligonucleotides bound to a pseudo solid-phase protecting group and having a free backbone hydroxyl group are desirable. Such extractions will be conducted after the deprotection step of the typical coupling cycle. Such optimized extraction conditions should ideally afford the target oligonucleotide of the respective synthesis with higher yield and/or higher purity. The present invention provides methods addressing the above needs. One aspect of the invention pertains to a method for the synthesis of a target oligonucleotide O^T, said method comprising a step of subjecting a solution comprising a component (C-0)^# selected from the group consisting of a nucleoside and an oligonucleotide to one or more aqueous extractions, wherein the organic phase comprises the component (C-0)^#, and wherein - said component (C-0)^# is covalently bonded to a pseudo solid-phase protecting group PG-s and is a compound of the following Formula I-C: (Formula I-C), wherein in Formula I-C: each oxygen atom O depicted within each nucleoside subunit x-0 to x-m represents the oxygen atom of a hydroxyl moiety of the respective nucleoside subunit; each of the nucleoside subunits x-0 to x-m may be the same or different; m is an integer equal to or larger than 0; Y¹ is selected independently for each repetitive unit m from the group consisting of O and S; Z¹ is selected independently for each repetitive unit m from the group consisting of O-R^z-1, S-R^z-1, and H; R^z-1 is a protecting group, which may be the same or different for each repetitive unit m; and PG-s is a pseudo solid-phase protecting group, and - each of said one or more aqueous extractions is carried out in the presence of one or more organic solvents S^O, wherein the one or more organic solvents S^O are selected so that an organic phase and an aqueous phase are formed during the aqueous extraction, and - the aqueous phase of each of said one or more aqueous extractions has a pH- value equal to or smaller than 7, preferably in the range of 4–7 or 4–6. The term “aqueous extraction” may, in the context of the aforementioned aspect of the invention, be understood in the broadest sense as any liquid-liquid extraction operation during which said solution comprising said component (C-0)^# is extracted with water or an aqueous solution in general. As defined herein, an “aqueous extraction” is further characterized in that it results in a mixture comprising at least one aqueous phase (preferably an aqueous layer) and at least one organic phase (preferably an organic layer), wherein the at least one aqueous phase (preferably layer) is then separated from the at least one organic phase (preferably layer). It will be understood that such phase separation is usually not complete, meaning that some (traces) of the aqueous phase may typically remain in the organic phase or vice versa. In case of more than one organic phases (either from a single aqueous extraction or from back-extraction of one or more aqueous phase), these more than one organic phases may be combined to obtain “the organic phase”. In general, the means of performing aqueous extractions are well-known to the skilled person. In the context of the above-mentioned aspect of the invention, to state that “each of said one or more aqueous extractions is carried out in the presence of one or more organic solvents S^O” means that at some point in time during each aqueous extraction, one or more organic solvents S^O are present in the vessel or separatory funnel or other receptacle, in which the respective extraction is carried out. One or more organic solvents S^O may preferably already be contained in said solution comprising the component (C-0)^#. Additionally, or alternatively, one or more organic solvents S^O may be added during the respective extraction. Preferably, to state that “each of said one or more aqueous extractions is carried out in the presence of one or more organic solvents S^O” means that in each aqueous extraction, one or more organic solvents S^O are comprised in the mixture from which an organic phase and an aqueous phase are to be obtained. In other words: The one or more organic solvents S^O are preferably present before the phase separation is completed. As used herein, an organic solvent is any solvent comprising in its chemical structure at least one carbon atom. As used herein, an organic solvent S^O is not particularly limited with regard to its chemical structure, except for that it is an organic solvent as defined herein. In the method of the invention, the one or more organic solvents S^O are selected so that an organic phase and an aqueous phase are formed during the respective aqueous extraction. The skilled person can easily identify one or more organic solvents which fulfill this criterion by routine experimentation. For example, the skilled person can simply add one or more organic solvents until an organic phase and an aqueous phase are formed during the respective aqueous extraction. In some embodiments of the method of the invention, each organic solvent S^O comprises in its chemical structure at least 4 carbon atoms or at least 5 carbon atoms. In some embodiments of the method of the invention, each organic solvent S^O comprises in its chemical structure 4–30 carbon atoms (i.e., not less than 4 carbon atoms and not more than 30 carbon atoms) or 5–30 carbon atoms. In some embodiments of the method of the invention, each organic solvent S^O comprises in its chemical structure 4–24 or 5–24 carbon atoms. In some embodiments of the method of the invention, each organic solvent S^O comprises in its chemical structure 4–18 or 5–18 carbon atoms. In some embodiments of the method of the invention, each organic solvent S^O comprises in its chemical structure 5–12 carbon atoms. In some embodiments of the method of the invention, each organic solvent S^O is selected from the group consisting of an amide solvent, an ether solvent, an alkane solvent, a heteroalkane solvent, and an aromatic solvent. The term “amide solvent” has been defined in another section of this text. Particularly preferred examples of such amide solvents are amide solvents S^A as defined herein. This is to say that amide solvents S^A as defined herein are organic solvents S^O as defined herein, unless indicated differently in specific embodiments. The term “ether solvent” has been defined in another section of this text. Particularly preferred examples of such ether solvents are ether solvents S^E as defined herein. As used herein, the term “alkane solvent” refers to any solvent, whose chemical structure consists only of atoms of the elements carbon (C) and hydrogen (H), with the proviso that the carbon atoms of an alkane may only be bonded to each other via direct single bonds. Preferred examples of such alkane solvents are pentanes, hexanes, and heptanes. Such alkane solvents may be linear, branched or cyclic, unless indicated differently in specific embodiments. n-Heptane is particularly preferred. As used herein, the term “heteroalkane solvent” refers to any solvent, whose chemical structure differs from that of an alkane solvent only in that one or more hydrogen atoms or carbon atoms are replaced by an atom of an element other than carbon (C) and hydrogen (H) (i.e., a “heteroatom”), wherein each heteroatom bonds to at least one carbon atom via a single bond (e.g., the oxygen atom of an alcohol group) or a double bond (e.g., the oxygen atom of a carbonyl group) or a triple bond (e.g., the nitrogen atom of a nitrile group). Preferred such heteroatoms are oxygen (O) and nitrogen (N) such as, e.g., in alcohols or amines or anhydrides or esters or nitriles. Alternative heteroatoms are halide atoms, in particular fluorine (F) or chlorine (Cl) such as, e.g., in dichloromethane and chloroform. As used herein, the term “aromatic solvent” refers to benzene or any solvent, in which one or more hydrogen residues of said benzene moiety are substituted. Preferred examples of substituents comprise alkyl groups as defined herein, heteroalkyl groups as defined herein, a nitrile group, an ether group, an ester group, an amide group, and a keto group. Alkyl groups and a nitrile group are most preferred. Examples of such aromatic solvents comprise benzonitrile, toluene, o-xylene, m-xylene, p-xylene, and mesitylene. In some embodiments of the method of the invention, each organic solvent S^O is selected from the group consisting of an ether solvent, an alkane solvent, a heteroalkane solvent, and an aromatic solvent. In some embodiments of the method of the invention, each organic solvent S^O is selected from the group consisting of an amide solvent S^A, an ether solvent S^E, an alkane solvent, and an aromatic solvent. In some embodiments of the method of the invention, each organic solvent S^O is selected from the group consisting of an ether solvent S^E, an alkane solvent, and an aromatic solvent. In some embodiments of the method of the invention, each organic solvent S^O is selected from the group consisting of an amide solvent S^A, an ether solvent S^E, an alkane solvent, and benzonitrile. In some embodiments of the method of the invention, each organic solvent S^O is selected from the group consisting of an ether solvent S^E, an alkane solvent, and benzonitrile. In some embodiments of the method of the invention, each organic solvent S^O is selected from the group consisting of an amide solvent S^A, an ether solvent S^E, a pentane, a hexane, a heptane, and benzonitrile. In some embodiments of the method of the invention, each organic solvent S^O is selected from the group consisting of an ether solvent S^E, a pentane, a hexane, a heptane, and benzonitrile. In some embodiments of the method of the invention, each organic solvent S^O is selected from the group consisting of an amide solvent S^A, 4-methyltetrahydropyran, cyclopentyl methyl ether, a pentane (linear, branched or cyclic), a hexane (linear, branched or cyclic), a heptane (linear, branched or cyclic), and benzonitrile. In some embodiments of the method of the invention, each organic solvent S^O is selected from the group consisting of 4-methyltetrahydropyran, cyclopentyl methyl ether, a pentane (linear, branched or cyclic), a hexane (linear, branched or cyclic), a heptane (linear, branched or cyclic), and benzonitrile. In some embodiments of the method of the invention, each organic solvent S^O is selected from the group consisting of N-octyl-2-pyrrolidone, N,N- dibutylformamide, N-cyclohexyl-2-pyrrolidone, N,N-diethyldodecaneamide, 4-methyltetrahydropyran, cyclopentyl methyl ether, a pentane (linear, branched or cyclic), a hexane (linear, branched or cyclic), a heptane (linear, branched or cyclic), and benzonitrile. In some embodiments of the method of the invention, each organic solvent S^O is selected from the group consisting of 4-methyltetrahydropyran, cyclopentyl methyl ether, a pentane (linear, branched or cyclic), a hexane (linear, branched or cyclic), a heptane (linear, branched or cyclic), and benzonitrile. In some embodiments of the method of the invention, each organic solvent S^O is selected from the group consisting of N-octyl-2-pyrrolidone, N,N-dibutylformamide, N- cyclohexyl-2-pyrrolidone, N,N-diethyldodecaneamide, 4-methyltetrahydropyran, cyclopentyl methyl ether, a hexane (linear, branched or cyclic), a heptane (linear, branched or cyclic), and benzonitrile. In some embodiments of the method of the invention, each organic solvent S^O is selected from the group consisting of 4-methyltetrahydropyran, cyclopentyl methyl ether, a hexane (linear, branched or cyclic), a heptane (linear, branched or cyclic), and benzonitrile. In some embodiments of the method of the invention, each organic solvent S^O is selected from the group consisting of N-octyl-2-pyrrolidone, N,N-dibutylformamide, N- cyclohexyl-2-pyrrolidone, N,N-diethyldodecaneamide, 4-methyltetrahydropyran, cyclopentyl methyl ether, a heptane (linear, branched or cyclic), and benzonitrile. In some embodiments of the method of the invention, each organic solvent S^O is selected from the group consisting of 4-methyltetrahydropyran, cyclopentyl methyl ether, a heptane (linear, branched or cyclic), and benzonitrile. In some embodiments of the method of the invention, each organic solvent S^O is selected from the group consisting of N-octyl-2-pyrrolidone, N,N-dibutylformamide, N-cyclohexyl-2- pyrrolidone, 4-methyltetrahydropyran, cyclopentyl methyl ether, n-heptane, and benzonitrile. In some embodiments of the method of the invention, each organic solvent S^O is selected from the group consisting of 4-methyltetrahydropyran, cyclopentyl methyl ether, n-heptane, and benzonitrile. In some embodiments of the method of the invention, each organic solvent S^O is selected from the group consisting of N-octyl-2-pyrrolidone, N,N-dibutylformamide, 4-methyltetrahydropyran, cyclopentyl methyl ether, n-heptane, and benzonitrile. In some embodiments of the method of the invention, each organic solvent S^O is selected from the group consisting of N-octyl-2-pyrrolidone, N,N-dibutylformamide, 4-methyltetrahydropyran, n-heptane, and benzonitrile. In some embodiments of the method of the invention, each organic solvent S^O is selected from the group consisting of 4-methyltetrahydropyran, n-heptane, and benzonitrile. In some embodiments of the method of the invention, each organic solvent S^O is selected from the group consisting of N-octyl-2-pyrrolidone, 4-methyltetrahydropyran, n-heptane, and benzonitrile. In some embodiments of the method of the invention, the one or more aqueous extractions are not carried out in the presence of an amide solvent S^A. In some embodiments of the method of the invention, the one or more aqueous extractions are not carried out in the presence of an amide solvent comprising equal to more than 6 carbon atoms. In some embodiments of the method of the invention, the one or more aqueous extractions are not carried out in the presence of an amide solvent comprising equal to more than 5 carbon atoms. In some embodiments of the method of the invention, the one or more aqueous extractions are not carried out in the presence of an amide solvent comprising equal to more than 4 carbon atoms. As used herein, an aqueous solution is a solution comprising water, preferably at least 10 vol-%, 20 vol-%, 30 vol-%, 40 vol-%, 50 vol-%, or 60 vol-% of water. Hence, water is herein also considered a specific aqueous solution, since it comprises more than 10 vol-%, 20 vol-%, 30 vol-%, 40 vol-%, 50 vol-%, or 60 vol-% of water. An aqueous solution may optionally comprise one or more water-miscible organic solvents. Non-limiting examples of such water-miscible organic solvents comprise: - alcohol solvents such as methanol, ethanol, and isopropyl alcohol (propan-2-ol, IPA), - nitrile solvents such as acetonitrile and propionitrile, - ketone solvents such as acetone and 2-butanone, - polar ether solvents such as tetrahydrofuran and 1,4-dioxane, - polar amide solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, and N-methyl-2-piperidone, - sulfoxide solvents such as dimethyl sulfoxide, and - mixtures thereof. An aqueous solution may optionally also comprise one or more dissolved components. Non-limiting examples of such dissolved components comprise: - inorganic salts such as alkali halides, in particular sodium chloride (e.g., typically used to facilitate and/or accelerate phase separation), - water-soluble protic acids such as acetic acid, - water-soluble organic or inorganic bases such as N-methylmorpholine (NMM), pyridine, sodium or potassium or ammonium carbonate or hydrogen carbonate, and sodium or potassium or ammonium phosphate or hydrogen phosphate or dihydrogen phosphate, and - mixtures thereof. The expression “the organic phase comprises the component (C-0)^#” may be understood in the broadest sense to mean that some of the molecules of said component (C-0)^# are dissolved in the organic phase. It is preferred that most molecules (e.g., more than 50 %, 60 %, 70 %, 80 %, or 90 % of the molecules) of the said component (C-0)^# are comprised in the organic phase (and thus not in the aqueous phase). Said “solution comprising a component (C-0)^#” may, for example, be a reaction mixture or it may, for example, be obtained from a reaction mixture by addition of one or more compounds and/or solvents. Examples of such compounds are bases, preferably bases having a pKa-value (determined in water, i.e., an aqueous solution of the base, at 25 °C) equal to or smaller than 9.0 or 8.0 or 7.0 or 6.5 or 6.0 or 5.5. Pyridine is an example of such a base. The protonated from of pyridine has a pKa- value smaller than 5.5. Pyridine is a weak base compared to, e.g., triethylamine, whose protonated from has a pKa-value larger than 9.0. Examples of solvents which may be added to a reaction mixture comprising the component (C-0)^# are non-polar solvents. Alternatively, or additionally, such non-polar solvents may also be added during or in between the one or more aqueous extractions. Non-limiting examples of non-polar solvents which may be added comprise: - ether solvents such as, e.g., alkylated derivatives of tetrahydropyran or tetrahydrofuran, in particular 4-methyltetrahydropyran (MTHP) and 2-methyltetrahydrofuran, cyclopentyl methyl ether (CPME), tert-butyl methyl ether, diethyl ether, and anisole; - aromatic solvents such as, e.g., benzene, benzonitrile, toluene, o- or m- or p- xylene, and mesitylene; - aliphatic hydrocarbon solvents such as, e.g., pentanes, hexanes, heptanes, octanes, nonanes, and cyclic derivatives thereof such as cyclohexane; - ester solvents such as, e.g., ethyl acetate and isopropyl acetate; - halogenated aliphatic hydrocarbon solvents such as, e.g., dichloromethane, 1,2-dichloroethane, and chloroform; and - mixtures thereof. 4-Methyltetrahydropyran (MTHP) is a preferred non-polar ether solvent which may be added prior to or during or in between the aqueous extraction(s). Additionally, or alternatively, one or more amide solvents S^A (as defined herein below) may be added prior to or during or in between the aqueous extraction(s). In some preferred embodiments of the method of the above-mentioned aspect of the invention, the one or more aqueous extractions are carried out in essentially halogen-free solvents. As used herein, the term “essentially halogen-free solvent” refers to a solvent which contains in total equal to or less than 3.0 vol-%, 2.0 vol-%, 1.0 vol-%, 0.1 vol-%, 0.01 vol-%, or 0.001 vol-% of halogenated solvents. As used herein, the term “halogenated solvent” refers to any solvent comprising in its chemical structure at least one halogen atom. Examples of halogenated solvents comprise dichloromethane, chloroform, 1,1-dichloroethane, and 1,2-dichloroethane. To state that “the one or more aqueous extractions are carried out in essentially halogen-free solvents” means that: - the solution comprising the component (C-0)^# comprises in total equal to or less than 3.0 vol-%, 2.0 vol-%, 1.0 vol-%, 0.1 vol-%, 0.01 vol-%, or 0.001 vol-% of halogenated solvents; and - only essentially halogen-free solvents may be added prior to, during or in between the one or more aqueous extractions. In some preferred embodiments of the method of the invention, each organic phase and each aqueous phase of the one or more aqueous extractions comprises in total less than 3.0 vol-%, 2.0 vol-%, 1.0 vol-%, 0.1 vol-%, 0.01 vol-%, or 0.001 vol-% of halogenated solvents. As used herein, the expression “in total less than 3.0 vol-%, 2.0 vol-%, 1.0 vol-%, 0.1 vol-%, 0.01 vol-%, or 0.001 vol-% of halogenated solvents” means that, if more than one halogenated solvents (e.g., dichloromethane and chloroform) are comprised, their vol-% are to be summed up to obtain the total vol- % which is to be less than 3.0 vol-%, 2.0 vol-%, 1.0 vol-%, 0.1 vol-%, 0.01 vol-%, or 0.001 vol-%. In some embodiments of the method of the above-mentioned aspect of the invention, said one or more aqueous extractions comprise a first aqueous extraction comprising the following steps (Ex-1) to (Ex-4): (Ex-1) Combining the solution comprising the component (C-0)^# with a first aqueous solution AS-1; (Ex-2) Agitating the mixture of step (Ex-1); (Ex-3) Allowing the phases to separate, so as to obtain a first organic phase OP-1 and a first aqueous phase AP-1, wherein the first organic phase OP-1 comprises the component (C-0)^#; and (Ex-4) Removing the first aqueous phase AP-1 from the first organic phase OP-1 or vice versa; wherein the solution comprising the component (C-0)^# of step (Ex-1) comprises one or more organic solvents S^O and/or one or more organic solvents S^O are added during any one of steps (Ex-1) and (Ex-2) and/or in between these steps. In some embodiments of the method of the above-mentioned aspect of the invention, said one or more aqueous extractions comprise a first aqueous extraction comprising the aforementioned steps (Ex-1) to (Ex-4), and a second aqueous extraction comprising the following steps (Ex-5) to (Ex-8): (Ex-5) Combining the first organic phase OP-1 with a second aqueous solution AS-2; (Ex-6) Agitating the mixture of step (Ex-5); (Ex-7) Allowing the phases to separate, so as to obtain a second organic phase OP-2 and a second aqueous phase AP-2, wherein the second organic phase OP-2 comprises the component (C-0)^#; and (Ex-8) Removing the second aqueous phase AP-2 from the second organic phase OP-2 or vice versa; wherein the first organic phase OP-1 comprises one or more organic solvents S^O and, optionally, one or more organic solvents S^O are added during any one of steps (Ex-5) and (Ex-6) and/or in between these steps. In some embodiments of the method of the above-mentioned aspect of the invention, said one or more aqueous extractions comprise a first aqueous extraction comprising the aforementioned steps (Ex-1) to (Ex-4), a second aqueous extraction comprising the aforementioned steps (Ex-5) to (Ex-8), and a third aqueous extraction comprising the following steps (Ex-9) to (Ex-12): (Ex-9) Combining the second organic phase OP-2 with a third aqueous solution AS-3; (Ex-10) Agitating the mixture of step (Ex-9); (Ex-11) Allowing the phases to separate, so as to obtain a third organic phase OP-3 and a third aqueous phase AP-3, wherein the third organic phase OP-3 comprises the component (C-0)^#; and (Ex-12) Removing the third aqueous phase AP-3 from the third organic phase OP-3 or vice versa; wherein the second organic phase OP-2 comprises one or more organic solvents S^O and, optionally, one or more organic solvents S^O are added during any one of steps (Ex-9) and (Ex-10) and/or in between these steps. The skilled artisan understands that one or more further aqueous extractions similar to the first, second, and third aqueous extraction comprising steps (Ex-1) to (Ex-4) or steps (Ex-5) to (Ex-8) or steps (Ex-9) to (Ex-12), respectively, may be carried out in addition. Such further aqueous extractions preferably comprise the following steps (Ex-A) to (Ex-D): (Ex-A) Combining the organic phase obtained from the previous aqueous extraction with an aqueous solution; (Ex-B) Agitating the mixture of step (Ex-A); (Ex-C) Allowing the phases to separate, so as to obtain an organic phase and an aqueous phase, wherein the organic phase comprises the component (C- 0)^#; and (Ex-D) Removing the aqueous phase from the organic phase or vice versa; wherein the organic phase obtained from the previous aqueous extraction comprises one or more organic solvents S^O and, optionally, one or more organic solvents S^O are added during any one of steps (Ex-A) and (Ex-B) and/or in between these steps. The skilled artisan understands that the aqueous solutions of two or more aqueous extractions, e.g., the aqueous solutions AS-1, AS-2, and AS-3, need not be identical, i.e., they may or may not comprise the same species/components/solvents and the amounts/volumes of said species/components/solvents may be the same or different, unless indicated differently in specific embodiments. According to the above-mentioned aspect of the invention, the aqueous phase of each, of said one or more aqueous extractions has a pH-value equal to or smaller than 7, preferably in the range of 4–7 or 4–6. As used herein, the pH-value of the aqueous phase of an aqueous extraction is to be determined from the respective aqueous phase after the aqueous extraction (i.e., after the phase separation, preferably after removing the aqueous phase from the organic phase or vice versa) and at a temperature in the range of 23–28 °C, preferably 25 °C. As used herein, the term “aqueous phase” of an aqueous extraction is distinct from the aqueous solution, which is initially combined with the solution comprising the component (C-0)^#, followed by extraction. The skilled artisan understands that the “aqueous phase” typically comprises species which have been extracted from the solution comprising the component (C-0)^#, e.g., water-soluble species. Hence, to say that the aqueous phase of an aqueous extraction has a certain pH-value is not the same as to say that the aqueous solution employed in the aqueous extraction has a certain pH-value. For example, pure water or any other aqueous solution may be used for an aqueous extraction, and during the aqueous extraction one or more protic acids may partition from said solution comprising the component (C-0)^# into the aqueous phase, so that the aqueous phase then has a pH-value which is lower than the pH-value of the water or other aqueous solution employed. In some embodiments of the method of the above-mentioned aspect of the invention, said one or more aqueous extractions comprise a first aqueous extraction comprising the following steps (Ex-1) to (Ex-4): (Ex-1) Combining the solution comprising the component (C-0)^# with a first aqueous solution AS-1; (Ex-2) Agitating the mixture of step (Ex-1); (Ex-3) Allowing the phases to separate, so as to obtain a first organic phase OP-1 and a first aqueous phase AP-1, wherein the first organic phase OP-1 comprises the component (C-0)^#; and (Ex-4) Removing the first aqueous phase AP-1 from the first organic phase OP-1 or vice versa; wherein - the solution comprising the component (C-0)^# of step (Ex-1) comprises one or more organic solvents S^O and/or one or more organic solvents S^O are added during any one of steps (Ex-1) and (Ex-2) and/or in between these steps; and - the first aqueous phase AP-1 has a pH-value equal to or smaller than 7, preferably in the range of 1.0–7.0, 2.0–7.0, 3.0–7.0, 3.5–7.0, 4.0–7.0, 4.0–6.0, 4.5–7.0, 4.5–6.5, 4.5–6.0, or 4.5−5.5. In some embodiments of the method of the above-mentioned aspect of the invention, said one or more aqueous extractions comprise a first aqueous extraction comprising the aforementioned steps (Ex-1) to (Ex-4), and a second aqueous extraction comprising the following steps (Ex-5) to (Ex-8): (Ex-5) Combining the first organic phase OP-1 with a second aqueous solution AS-2; (Ex-6) Agitating the mixture of step (Ex-5); (Ex-7) Allowing the phases to separate, so as to obtain a second organic phase OP-2 and a second aqueous phase AP-2, wherein the second organic phase OP-2 comprises the component (C-0)^#; and (Ex-8) Removing the second aqueous phase AP-2 from the second organic phase OP-2 or vice versa; wherein - the first organic phase OP-1 comprises one or more organic solvents S^O and, optionally, one or more organic solvents S^O are added during any one of steps (Ex-5) and (Ex-6) and/or in between these steps; and - the second aqueous phase AP-2 has a pH-value in the range of 4.0–7.0, 4.5–7.0, 5.0–7.0, 5.0–6.5, or 5.0–6.0. In some embodiments of the method of the above-mentioned aspect of the invention, said one or more aqueous extractions comprise a first aqueous extraction comprising the aforementioned steps (Ex-1) to (Ex-4), a second aqueous extraction comprising the aforementioned steps (Ex-5) to (Ex-8), and a third aqueous extraction comprising the following steps (Ex-9) to (Ex-12): (Ex-9) Combining the second organic phase OP-2 with a third aqueous solution AS-3; (Ex-10) Agitating the mixture of step (Ex-9); (Ex-11) Allowing the phases to separate, so as to obtain a third organic phase OP- 3 and a third aqueous phase AP-3, wherein the third organic phase OP-3 comprises the component (C-0)^#; and (Ex-12) Removing the third aqueous phase AP-3 from the third organic phase OP-3 or vice versa; wherein - the second organic phase OP-2 comprises one or more organic solvents S^O and, optionally, one or more organic solvents S^O are added during any one of steps (Ex-9) and (Ex-10) and/or in between these steps; and - the third aqueous phase AP-3 has a pH-value in the range of 5.0–7.0, 5.0–6.5, or 5.0–6.0. The skilled artisan understands that one or more further aqueous extractions similar to the first, second, and third aqueous extractions comprising steps (Ex-1) to (Ex-4) or steps (Ex-5) to (Ex-8) or steps (Ex-9) to (Ex-12), respectively, may be carried out in addition. Such further aqueous extractions preferably comprise the following steps (Ex-A) to (Ex-D): (Ex-A) Combining the organic phase obtained from the previous aqueous extraction with an aqueous solution; (Ex-B) Agitating the mixture of step (Ex-A); (Ex-C) Allowing the phases to separate, so as to obtain an organic phase and an aqueous phase, wherein the organic phase comprises the component (C- 0)^#; and (Ex-D) Removing the aqueous phase from the organic phase or vice versa; wherein - the organic phase obtained from the previous aqueous extraction comprises one or more organic solvents S^O and, optionally, one or more organic solvents S^O are added during any one of steps (Ex-A) and (Ex-B) and/or in between these steps; and - the aqueous phase obtained in each of steps (Ex-C) has a pH-value equal to or smaller than 7, preferably in the range of 4.0–7.0 or 4.0–6.0, in particular in the range of 5.0–7.0, 5.0–6.5, or 5.0–6.0 The expressions “the first organic phase OP-1 comprises the component (C-0)^#” and “the second organic phase OP-2 comprises the component (C-0)^#” and “the third organic phase OP-3 comprises the component (C-0)^#” will be understood based on the above explanation of the term “the organic phase comprises the component (C-0)^#”, since each of OP-1, OP-2, and OP-3 is an organic phase. In some embodiments of the method of the invention, in which said one or more aqueous extractions comprise said first aqueous extraction comprising steps (Ex-1) to (Ex-4), the first aqueous solution AS-1 has a pH-value in the range of 4.0–8.0, 5.0–8.0, 4.0–7.5, 4.5–7.0, 5.0–7.0, 5.0–6.5 or 5.0–6.0. In some embodiments of the method of the invention, in which said one or more aqueous extractions comprise said first aqueous extraction comprising steps (Ex-1) to (Ex-4), the first aqueous solution AS-1 does not comprise a compound having a pKa-value equal to or larger than 9.0, 8.5, 8.0, 7.5, 7.0, 6.5, 6.0 or 5.5. The pKa-value is to be determined in water (i.e., in an aqueous solution of the respective compound) at 25 °C. For example, pyridine is a base and its protonated form has a pKa value of 5.2 (cf., e.g., A. Fischer et al., J. Chem. Soc. 1964, 3591–3596; https://doi.org/10.1039/JR9640003591). Thus, pyridine is not a compound having a pKa-value equal to or larger than 5.5. As another example, 4-aminopyridine is also a base and its protonated form has a pKa-value of 9.1 (cf., e.g., A. Fischer et al., J. Chem. Soc. 1964, 3591–3596; https://doi.org/10.1039/JR9640003591). Hence, 4-aminopyridine is a compound having a pKa-value equal to or larger than 9.0. In some embodiments of the method of the invention, in which said one or more aqueous extractions comprise said first aqueous extraction comprising steps (Ex-1) to (Ex-4), and said second aqueous extraction comprising steps (Ex-5) to (Ex-8), each of the first aqueous solution AS-1 and the second aqueous solution AS-2 has a pH-value in the range of 5.0–8.0, 4.0–7.5, 4.5–7.0, 5.0–7.0, 5.0–6.5 or 5.0–6.0. In some embodiments of the method of the invention, in which said one or more aqueous extractions comprise said first aqueous extraction comprising steps (Ex-1) to (Ex-4), and said second aqueous extraction comprising steps (Ex-5) to (Ex-8), none of the first aqueous solution AS-1 and the second aqueous solution AS-2 comprises a compound having a pKa-value equal to or larger than 9.0, 8.5, 8.0, 7.5, 7.0, 6.5, 6.0 or 5.5. The pKa-value is to be determined in water (i.e., in an aqueous solution of the respective compound) at 25 °C. In some embodiments of the method of the invention, in which said one or more aqueous extractions comprise said first aqueous extraction comprising steps (Ex-1) to (Ex-4), and said second aqueous extraction comprising steps (Ex-5) to (Ex-8), and said third aqueous extraction comprising steps (Ex-9) to (Ex-12), each of the first aqueous solution AS-1, the second aqueous solution AS-2, and the third aqueous solution AS-3 has a pH-value in the range of 5.0–8.0, 4.0–7.5, 4.5–7.0, 5.0–7.0, 5.0–6.5 or 5.0–6.0. In some embodiments of the method of the invention, in which said one or more aqueous extractions comprise said first aqueous extraction comprising steps (Ex-1) to (Ex-4), and said second aqueous extraction comprising steps (Ex-5) to (Ex-8), and said third aqueous extraction comprising steps (Ex-9) to (Ex-12), none of the first aqueous solution AS-1, the second aqueous solution AS-2, and the third aqueous solution AS-3 comprises a compound having a pKa-value equal to or larger than 9.0, 8.5, 8.0, 7.5, 7.0, 6.5, 6.0 or 5.5. The pKa- value is to be determined in water (i.e., in an aqueous solution of the respective compound) at 25 °C. Step (Ex-1) is: Combining the solution comprising the component (C-0)^# with a first aqueous solution AS-1. This means that the solution comprising the component (C- 0)^# and the first aqueous solution AS-1 are combined in the vessel or funnel or other receptacle, in which the agitation of step (Ex-2) is to be performed. Step (Ex-5) is: Combining the first organic phase OP-1 with a second aqueous solution AS-2. This means that the first organic phase OP-1 and the second aqueous solution AS-2 are combined in the vessel or funnel or other receptacle, in which the agitation of step (Ex-6) is to be performed. Step (Ex-9) is: Combining the second organic phase OP-2 with a third aqueous solution AS-3. This means that the second organic phase OP-2 and the third aqueous solution AS-3 are combined in the vessel or funnel or other receptacle, in which the agitation of step (Ex-10) is to be performed. Step (Ex-A) is: Combining the organic phase obtained from the previous aqueous extraction with an aqueous solution. This means that the organic phase from the previous aqueous extraction and the aqueous solution are combined in the vessel or funnel or other receptacle, in which the agitation of step (Ex-B) is to be performed. The term “agitating” in steps (Ex-2), (Ex-6), (Ex-10), and (Ex-B) may be understood in the broadest sense to refer to any operation of inducing a movement of the respective mixture. This typically facilitates the extraction process. Suitable means of agitation are known to those skilled in the art and comprise, e.g., shaking, stirring, e.g., mechanical stirring, bubbling of an inert has such as nitrogen, and inversion of the vessel or funnel or other receptacle in which the one or more aqueous extractions may be carried out. More than one such means of agitation may be used in combination. On an industrial scale, a reaction vessel made of a suitable material, e.g., glass or stainless steel, equipped with a mechanical stirrer may preferably be used for the agitation step (Ex-2), (Ex-6), (Ex-10) or (Ex-B). In practice, it is usually most convenient, to carry out all steps of an aqueous extraction in the same vessel or funnel or other receptacle. Under the agitation of step (Ex-2), (Ex-6), (Ex-10), and (Ex-B) the respective organic phase and the respective aqueous phase usually form a dispersion. Under such conditions, one phase may typically not be removed from the other. For this purpose, phase separation is usually required. Hence: - Step (Ex-3) comprises “Allowing the phases to separate, so as to obtain a first organic phase OP-1 and a first aqueous phase AP-1”; - Step (Ex-7) comprises “Allowing the phases to separate, so as to obtain a second organic phase OP-2 and a second aqueous phase AP-2”; - Step (Ex-11) comprises “Allowing the phases to separate, so as to obtain a third organic phase OP-3 and a third aqueous phase AP-3”; and - Step (Ex-C) comprises “Allowing the phases to separate, so as to obtain an organic phase and an aqueous phase.” As used herein, the term “allowing the phases to separate so as to obtain an organic phase and an aqueous phase” may be understood in the broadest sense as establishing conditions under which the organic phase forms one or more, preferably one, layer (i.e., organic layer) and the aqueous phase forms one or more, preferably one, layer (i.e., aqueous layer). This definition likewise applies to the first, second, and third organic phase OP-1, OP-2, and OP-3 and the respective first, second, and third aqueous phase AP-1, AP-2, and AP-3. The skilled artisan understands that an organic layer formed from an organic phase may typically not be completely free of an aqueous phase and that an aqueous layer formed from an aqueous phase may typically not be completely free of an organic phase. Hence, an organic layer is mostly but not necessarily completely composed of an organic phase and an aqueous layer is mostly but not necessarily completely composed of an aqueous phase. “Establishing conditions under which the organic phase forms one or more, preferably one, layer (i.e., organic layer) and the aqueous phase forms one or more, preferably one, layer (i.e., aqueous layer)” may usually comprise stopping the agitation. This means that the shaking and/or stirring and/or inert gas bubbling and/or inversion of the vessel or funnel or other receptacle is stopped. It will be understood that some movement of the liquids may still occur. Hence, in some preferred embodiments, step (Ex-3) is: Stopping the agitation and allowing the phases to separate, so as to obtain a first organic phase OP-1 and a first aqueous phase AP-1, wherein the first organic phase OP-1 comprises the component (C-0)^#. In some preferred embodiments, step (Ex-7) is: Stopping the agitation and allowing the phases to separate, so as to obtain a second organic phase OP-2 and a second aqueous phase AP-2, wherein the second organic phase OP-2 comprises the component (C-0)^#. In some preferred embodiments, step (Ex- 11) is: Stopping the agitation and allowing the phases to separate, so as to obtain a third organic phase OP-3 and a third aqueous phase AP-3, wherein the third organic phase OP-3 comprises the component (C-0)^#. In some preferred embodiments, step (Ex-C) is: Stopping the agitation and allowing the phases to separate, so as to obtain an organic phase and an aqueous phase, wherein the organic phase comprises the component (C-0)^#. Typically, one may simply wait for the phases to separate. Phase separation may optionally be speeded up by addition of aqueous solutions comprising dissolved ions, e.g., by addition of brine (i.e., an aqueous solution of sodium chloride), as known to those skilled in the art. The expression “the organic phase comprises the component (C-0)^#” has been explained above. In steps (Ex-4), (Ex-8), (Ex-12), and (Ex-D), the respective aqueous phase is removed from the respective organic phase or vice versa. This means that at least one aqueous layer is physically removed from at least one organic layer or vice versa. This will be understood by the skilled artisan. This removal may typically comprise draining of one layer, typically the bottom layer, e.g., the aqueous layer from the vessel or funnel or other receptacle, in which the agitation has been carried out. It will be understood that this removal is not necessarily complete. In other words, “removing” in this context is not to mean “completely removing” but preferably means “mostly removing”. In this context, removing one phase from another phase may mean removing at least 51 vol-%, 60 vol-%, 70 vol-%, 80 vol- %, 90 vol-%, 95 vol-%, 96 vol-%, 97 vol-%, 98 vol-% or 99 vol-% of the respective phase to be removed. In practice, there will usually be a clearly recognizable phase boundary between the organic layer and the aqueous layer, so that removing the one from the other may simply be achieved by draining the bottom layer until the phase boundary is reached. According to the invention, the component (C-0)^# is a compound of the above- mentioned Formula I-C, which is a compound of Formula I below, wherein, PG-0 is absent, so that the hydroxyl moiety otherwise protected by PG-0 is a free hydroxyl group. It will be understood that any definitions and embodiments relating to the component C-0 of Formula I likewise apply to the component (C-0)^# of the above- mentioned Formula I-C, with the proviso that the protecting group PG-0 of Formula I is absent in the component (C-0)^# of Formula I-C, so that the hydroxyl moiety, which is protected by the protecting group PG-0 in Formula I is always a free hydroxyl group (OH) in the component (C-0)^# of Formula I-C. In some embodiments of the method of the invention, said solution comprising the component (C-0)^# further comprises one or more carbocation scavengers. As used herein, the term “carbocation scavenger” relates to a nucleophilic compound, which may be used to bind a carbocation or to consume a carbocation by formal donation of a hydride anion, thereby preventing unwanted side reactions of the carbocation. Examples of carbocation scavengers are given below for the deprotection mixtures M-(b-1), M-(b-2), and M-(b-x) and likewise apply to the aforementioned embodiments. In some embodiments, said solution comprising the component (C-0)^# further comprises one or more carbocation scavengers selected from the group consisting of - compounds comprising one or more sulfhydryl groups and one or more carboxyl groups, and - compounds comprising an indole residue and one or more carboxyl groups. Such carbocation scavengers are extractable carbocation scavengers, meaning that they partly or mostly partition into the aqueous phase during an aqueous extraction. If a carbocation scavenger is used, it is preferred that it is such an extractable carbocation scavenger, so that the scavenger itself does (mostly) not remain in the organic phase. Any molecules of the carbocation scavenger, which remain in the organic phase, may cause side reactions or consume staring materials, in particular nucleoside or oligonucleotide phosmoramidites, in the subsequent steps of the coupling cycle, in particular the coupling step. Nucleoside or oligonucleotide phosmoramidites are expensive and their consumption by the optionally employed carbocation scavenger is undesirable. In some embodiments, said solution comprising the component (C-0)^# further comprises one or more carbocation scavengers selected from the group consisting of compounds comprising one or more sulfhydryl groups and one or more carboxyl groups. In some embodiments, said solution comprising the component (C-0)^# further comprises one or more carbocation scavengers selected from the group consisting of compounds comprising one sulfhydryl groups and one or two carboxyl groups. In some embodiments, said solution comprising the component (C-0)^# further comprises one or more carbocation scavengers selected from the group consisting of glutathione, thiomalic acid, and 3-mercapropropionic acid. In some embodiments, said solution comprising the component (C-0)^# further comprises one or more carbocation scavengers selected from the group consisting of glutathione and thiomalic acid. In some preferred embodiments, said solution comprising the component (C-0)^# further comprises glutathione. In some embodiments of the method of the invention, the target oligonucleotide O^T comprises a first cycle oligonucleotide O-1, and the method comprises the following step (a-1), and a first coupling cycle comprising the following steps: (a-1) providing a component C-0 selected from the group consisting of a nucleoside and an oligonucleotide, wherein the component C-0 is covalently bonded to a pseudo solid-phase protecting group PG-s and comprises a backbone hydroxyl moiety protected by a protecting group PG-0 removable under acidic conditions, wherein the component C-0 is a compound of the following Formula I:

(Formula I), wherein in in Formula I: each oxygen atom O depicted within each nucleoside subunit x-0 to x-m represents the oxygen atom of a hydroxyl moiety of the respective nucleoside subunit; each of the nucleoside subunits x-0 to x-m may be the same or different; m is an integer equal to or larger than 0; PG-0 is a protecting group removable under acidic conditions; Y¹ is selected independently for each repetitive unit m from the group consisting of O and S; Z¹ is selected independently for each repetitive unit m from the group consisting of O-R^z-1, S-R^z-1, and H; R^z-1 is a protecting group, which may be the same or different for each repetitive unit m; and PG-s is a pseudo solid-phase protecting group; (b-1) incubating the component C-0 of step (a-1) with a deprotection mixture M-(b- 1), thereby cleaving the protecting group PG-0 from the component C-0, so as to obtain a component (C-0)^# having a free backbone hydroxyl group; (c-1) subjecting a solution comprising the component (C-0)^# to one or more aqueous extractions, wherein the organic phase comprises the component (C-0)^#; (d-1) optionally, reducing the water content of the organic phase comprising the component (C-0)^#; (e-1) reacting the component (C-0)^# with a building block B-1, wherein said building block B-1 is selected from the group consisting of a nucleoside and an oligonucleotide and comprises - a backbone hydroxyl moiety protected by a protecting group PG-1 removable under acidic conditions, and - a phosphorus moiety covalently bonded via its phosphorus atom to an oxygen atom of the backbone of the building block B-1, under conditions suitable to form a covalent bond between said free backbone hydroxyl group of the component (C-0)^# and the phosphorus atom of said phosphorus moiety of the building block B-1, thereby obtaining a first cycle oligonucleotide O-1; (f-1) optionally, incubating the first cycle oligonucleotide O-1 with an oxidizing or sulfurizing agent, thereby converting any P (III) atoms within said first cycle oligonucleotide O-1 to P (V) atoms; (g-1) optionally, subjecting a solution comprising the first cycle oligonucleotide O-1 to one or more aqueous extractions, wherein the organic phase comprises the first cycle oligonucleotide O-1; (h-1) if step (g-1) has been carried out, optionally reducing the water content of the organic phase comprising the first cycle oligonucleotide O-1; wherein during and in between steps (b-1) to (h-1) (as far as present), no solid-liquid separation is performed and steps (c-1) and (g-1) are carried out in the presence of one or more organic solvents S^O and, in each of the one or more aqueous extractions of step (c-1), the aqueous phase has a pH-value equal to or smaller than 7, preferably in the range of 4−7 or 4–6. In some embodiments of the method of the invention, no solid-liquid separation of the first cycle oligonucleotide O-1 or of any oligonucleotidic educts or intermediates involved in the synthesis of the first cycle oligonucleotide O-1 is performed during and in between steps (b-1) to (h-1) (as far as present) and steps (c-1) and (g-1) are carried out in the presence of one or more organic solvents S^O. In some embodiments of the method of the invention, steps (c-1) and (g-1) (as far as present) are not carried out in the presence of an amide solvent S^A. In some embodiments of the method of the invention, steps (c-1) and (g-1) (as far as present) are not carried out in the presence of an amide solvent comprising equal to more than 6 carbon atoms. In some embodiments of the method of the invention, steps (c-1) and (g-1) (as far as present) are not carried out in the presence of an amide solvent comprising equal to more than 5 carbon atoms. In some embodiments of the method of the invention, steps (c-1) and (g-1) (as far as present) are not carried out in the presence of an amide solvent comprising equal to more than 4 carbon atoms. In some embodiments of the method of the invention, the target oligonucleotide O^T comprises a second cycle oligonucleotide O-2, and the method further comprises performing a second coupling cycle comprising the following steps: (b-2) incubating the first cycle oligonucleotide O-1 obtained in the first coupling cycle with a deprotection mixture M-(b-2), thereby cleaving the protecting group PG-1 from the first cycle oligonucleotide O-1, so as to obtain a first cycle oligonucleotide (O-1)^# having a free backbone hydroxyl group; (c-2) subjecting a solution comprising the first cycle oligonucleotide (O-1)^# to one or more aqueous extractions, wherein the organic phase comprises the first cycle oligonucleotide (O-1)^#; (d-2) optionally, reducing the water content of the organic phase comprising the first cycle oligonucleotide (O-1)^#; (e-2) reacting the first cycle oligonucleotide (O-1)^# with a building block B-2, wherein said building block B-2 is selected from the group consisting of a nucleoside and an oligonucleotide and comprises - a backbone hydroxyl moiety protected by a protecting group PG-2 removable under acidic conditions, and - a phosphorus moiety covalently bonded via its phosphorus atom to an oxygen atom of the backbone of the building block B-2, under conditions suitable to form a covalent bond between said free backbone hydroxyl group of the first cycle oligonucleotide (O-1)^# and the phosphorus atom of said phosphorus moiety of the building block B-2, thereby obtaining a second cycle oligonucleotide O-2; (f-2) optionally, incubating the second cycle oligonucleotide O-2 with an oxidizing or sulfurizing agent, thereby converting any P (III) atoms within said second cycle oligonucleotide O-2 to P (V) atoms; (g-2) optionally, subjecting a solution comprising the second cycle oligonucleotide O-2 to one or more aqueous extractions, wherein the organic phase comprises the second cycle oligonucleotide O-2; (h-2) if step (g-2) has been carried out, optionally reducing the water content of the organic phase comprising the second cycle oligonucleotide O-2; wherein during and in between steps (b-1) to (h-2) (as far as present) no solid-liquid separation is performed and steps (c-1), (g-1), (c-2), and (g-2) are carried out in the presence of one or more organic solvents S^O, and in each of the one or more aqueous extractions of step (c-2), the aqueous phase has a pH-value equal to or smaller than 7, preferably in the range of 4−7 or 4–6. In some embodiments of the method of the invention, the target oligonucleotide O^T comprises a second cycle oligonucleotide O-2, and the method further comprises performing a second coupling cycle comprising the above steps (b-2) to (h-2) (as far as present), wherein: no solid-liquid separation of the second cycle oligonucleotide O-2 or of any oligonucleotidic educts or intermediates involved in the synthesis of the second cycle oligonucleotide O-2 is performed during and in between steps (b-1) to (h-2) (as far as present) and steps (c-1), (g-1), (c-2), and (g-2) are carried out in the presence of one or more organic solvents S^O. It will be readily understood in this context that, e.g. the first cycle oligonucleotide O-1 is an oligonucleotidic educt or intermediate involved in the in the synthesis of the second cycle oligonucleotide O- 2. In some embodiments of the method of the invention, the target oligonucleotide O^T comprises a second cycle oligonucleotide O-2, and the method further comprises performing a second coupling cycle comprising the above steps (b-2) to (h-2) (as far as present), wherein steps (c-1), (g-1), (c-2), and (g-2) (as far as present) are not carried out in the presence of an amide solvent S^A. In some embodiments of the method of the invention, the target oligonucleotide O^T comprises a second cycle oligonucleotide O-2, and the method further comprises performing a second coupling cycle comprising the above steps (b-2) to (h-2) (as far as present), wherein steps (c-1), (g-1), (c-2), and (g-2) (as far as present) are not carried out in the presence of an amide solvent comprising equal to more than 6 carbon atoms. In some embodiments of the method of the invention, the target oligonucleotide O^T comprises a second cycle oligonucleotide O-2, and the method further comprises performing a second coupling cycle comprising the above steps (b-2) to (h-2) (as far as present), wherein steps (c-1), (g-1), (c-2), and (g-2) (as far as present) are not carried out in the presence of an amide solvent comprising equal to more than 5 carbon atoms. In some embodiments of the method of the invention, the target oligonucleotide O^T comprises a second cycle oligonucleotide O-2, and the method further comprises performing a second coupling cycle comprising the above steps (b-2) to (h-2) (as far as present), wherein steps (c-1), (g-1), (c-2), and (g-2) (as far as present) are not carried out in the presence of an amide solvent comprising equal to more than 4 carbon atoms. In some embodiments of the method of the invention, the target oligonucleotide O^T comprises a n-th cycle oligonucleotide O-n, and the method further comprises performing performing (n−2) iterations of a coupling cycle comprising the following steps (b-x) to (h-x) (as far as present), wherein n is an integer in the range of 3 to 99, which denotes the total number of coupling cycles performed to obtain the n-th cycle oligonucleotide O-n, and each individual coupling cycle comprising the following steps (b-x) to (h-x) (as far as present) is identified by a serial number x, which runs in steps of 1 from 3 to n: (b-x) incubating the (x−1)-th cycle oligonucleotide O-(x−1) obtained in the previous coupling cycle with a deprotection mixture M-(b-x), thereby cleaving the protecting group PG-(x−1) from the (x−1)-th cycle oligonucleotide O-(x−1), so as to obtain a (x−1)-th cycle oligonucleotide (O-(x−1))^# having a free backbone hydroxyl group; (c-x) subjecting a solution comprising the (x−1)-th cycle oligonucleotide (O-(x−1))^# to one or more aqueous extractions, wherein the organic phase comprises the (x−1)-th cycle oligonucleotide (O-(x−1))^#; (d-x) optionally, reducing the water content of the organic phase comprising the (x−1)-th cycle oligonucleotide (O-(x−1))^#; (e-x) reacting the (x−1)-th cycle oligonucleotide (O-(x−1))^# with a building block B- x, wherein said building block B-x is selected from the group consisting of a nucleoside and an oligonucleotide and comprises - a backbone hydroxyl moiety protected by a protecting group PG-x removable under acidic conditions, and - a phosphorus moiety covalently bonded via its phosphorus atom to an oxygen atom of the backbone of the building block B-x, under conditions suitable to form a covalent bond between said free backbone hydroxyl group of the (x−1)-th cycle oligonucleotide (O-(x−1))^# and the phosphorus atom of said phosphorus moiety of the building block B-x, thereby obtaining a x-th cycle oligonucleotide O-x; (f-x) optionally, incubating the x-th cycle oligonucleotide O-x with an oxidizing or sulfurizing agent, thereby converting any P (III) atoms within said x-th cycle oligonucleotide O-x to P (V) atoms; (g-x) optionally, subjecting a solution comprising the x-th cycle oligonucleotide O-x to one or more aqueous extractions, wherein the organic phase comprises the x-th cycle oligonucleotide O-x; (h-x) if step (g-x) has been carried out, optionally reducing the water content of the organic phase comprising the x-th cycle oligonucleotide O-x; wherein during and in between steps (b-1) to (h-n) (as far as present) no solid-liquid separation is performed, and steps (c-1), (g-1), (c-2), and (g-2), as well as each iteration of steps (c-x) and (g-x) is carried out in the presence of one or more oranic solvents S^O, and in each of the one or more aqueous extractions of each step (c-x), the aqueous phase has a pH-value equal to or smaller than 7, preferably in the range of 4−7 or 4–6. In some embodiments of the method of the invention, the target oligonucleotide O^T comprises a n-th cycle oligonucleotide O-n, and the method further comprises performing (n−2) iterations of a coupling cycle comprising the above steps (b-x) to (h-x) (as far as present), wherein n is an integer in the range of 3 to 99, which denotes the total number of coupling cycles performed to obtain to obtain the n-th cycle oligonucleotide O-n, and each individual coupling cycle comprising the above steps (b-x) to (h-x) (as far as present) is identified by a serial number x, which runs in steps of 1 from 3 to n, wherein: no solid-liquid separation of the n-th cycle oligonucleotide O-n or of any oligonucleotidic educts or intermediates involved in the synthesis of the n-th cycle oligonucleotide O-n is performed during and in between steps (b-1) to (h-n) (as far as present), and steps (c-1), (g-1), (c-2), and (g-2), as well as each iteration of steps (c-x) and (g-x) is carried out in the presence of one or more organic solvents S^O, and in each of the one or more aqueous extractions of steps (c-1) and (c-2) and each step (c-x), the aqueous phase has a pH-value equal to or smaller than 7, preferably in the range of 4−7 or 4–6. It will be readily understood in this context that, e.g. any previous cycle oligonucleotide is an oligonucleotidic educt or intermediate involved in the synthesis of the n-th cycle oligonucleotide O-n. In some embodiments of the method of the invention, the target oligonucleotide O^T comprises a n-th cycle oligonucleotide O-n, and the method further comprises performing (n−2) iterations of a coupling cycle comprising the above steps (b-x) to (h-x) (as far as present), wherein steps (c-1), (g-1), (c-2), and (g-2) (as far as present) as well as each iteration of steps (c-x) and (g-x) (as far as present) are not carried out in the presence of an amide solvent S^A. In some embodiments of the method of the invention, the target oligonucleotide O^T comprises a n-th cycle oligonucleotide O-n, and the method further comprises performing (n−2) iterations of a coupling cycle comprising the above steps (b-x) to (h-x) (as far as present), wherein steps (c-1), (g-1), (c-2), and (g-2) (as far as present) as well as each iteration of steps (c-x) and (g-x) (as far as present) are not carried out in the presence of an amide solvent comprising equal to more than 6 carbon atoms. In some embodiments of the method of the invention, the target oligonucleotide O^T comprises a n-th cycle oligonucleotide O-n, and the method further comprises performing (n−2) iterations of a coupling cycle comprising the above steps (b-x) to (h-x) (as far as present), wherein steps (c-1), (g-1), (c-2), and (g-2) (as far as present) as well as each iteration of steps (c-x) and (g-x) (as far as present) are not carried out in the presence of an amide solvent comprising equal to more than 5 carbon atoms. In some embodiments of the method of the invention, the target oligonucleotide O^T comprises a n-th cycle oligonucleotide O-n, and the method further comprises performing (n−2) iterations of a coupling cycle comprising the above steps (b-x) to (h-x) (as far as present), wherein steps (c-1), (g-1), (c-2), and (g-2) (as far as present) as well as each iteration of steps (c-x) and (g-x) (as far as present) are not carried out in the presence of an amide solvent comprising equal to more than 4 carbon atoms. As used in the context of the present invention, expressions like “target oligonucleotide O^T” may be understood synonymously with “target oligonucleotide (O^T)”. This means “O^T“ and “(O^T)” may be understood as reference marks, which do not imply any further limitation, unless indicated differently. The same applies for similar expressions such as the first cycle oligonucleotides O-1 and (O-1)^#, the second cycle oligonucleotides O-2 and (O-2)^#, the (x−1)-th cycle oligonucleotides O-(x−1) and (O-(x−1))^#, the x-th cycle oligonucleotides O-x and (O-x)^#, and the n-th cycle oligonucleotides O-n and (O-n)^#. The number sign (i.e. hashtag, #) in superscript, i.e. "^#" is merely used to denote the absence of the protecting group PG-0, PG-1, PG-2, PG-(x−1), PG-x, or PG-n and thus the presence of a free backbone hydroxyl group. The numbers or integers 1, 2, (x−1), x, and n are merely used to denote the coupling cycle, in which the respective oligonucleotide is obtained or employed. The deprotection mixtures are referred to by a reference mark "M" followed by an indicator of the step in which the respective deprotection mixture is used. For example, the deprotection mixture used in step (b-1) is referred to as deprotection mixture M-(b-1). The same rationale applies to the deprotection mixtures M-(b-2) (used in step (b-2)), M-(b-x) (used in step (b-x)), M-(b-n) (used in step (b-x) of the last coupling cycle comprising steps (b-x) to (h-x), as far as present), M-(k-1) (used in step (k-1)), M-(k-2) (used in step (k-2)), and M-(k-n) (used in step (k-n)). In the building block B-1, "B" is a mere reference mark and "1" indicates the number of the coupling cycle in which said building block is used, e.g. the first coupling cycle in the case of B-1. The same rationale applies to the building blocks B-2, B-x, and B-n. The component C-0 is a specific component (a nucleoside or oligonucleotide), which may be used as starting material in the method of the invention. Since it is provided in step (a-1), which is performed prior to the first coupling cycle, a "0" has been added to its reference mark. This is not to be construed to be limiting in any kind. The component C is also a specific component (a nucleoside or oligonucleotide). The component (C-0)^# differs from the component C-0 in that the protecting group PG-0 is absent, so that (C-0)^# comprises a free backbone hydroxyl group. As used herein, the indefinite articles “a” and “an” may mean “one or more”, unless indicated differently. As used herein, the term “target oligonucleotide O^T” refers to any specific oligonucleotide which is to be synthesized by the method of the invention. In other words, the “target oligonucleotide O^T” is generally the final oligonucleotide product of the method of the invention. For example, the “target oligonucleotide O^T may have the same sequence as the n-th cycle oligonucleotide O-n, or may comprise one or more further nucleoside moieties, and/or may be obtained by conjugating the n-th cycle oligonucleotide O-n to another compound. Herein, the term “oligonucleotide” is used in a most general way to relate to any oligomers comprising at least two nucleoside subunits interconnected via an internucleosidic linkage group of any one of Formulae A and B:

(Formula A), wherein in Formula A: X¹ is selected from the group consisting of O and S; X² is selected from the group consisting of O-R¹, S-R¹, and H; and R¹ may be any conceivable residue, and is preferably selected from the group consisting of H and a protecting group (preferably a protecting group removable under alkaline conditions, in particular the 2-cyanoethyl group, i.e. CH2-CH2-CN));

(Formula B), wherein in Formula B: X³ is selected from the group consisting of O and S; and R² is a protecting group, preferably a protecting group removable under alkaline conditions, in particular the 2-cyanoethyl group; and wherein in Formulae A and B each of * and ** independently of each other denotes a binding site (i.e. the point of attachment) of a nucleoside subunit, which is to say that each of * and ** represents the atom of the respective nucleoside subunit with which said nucleoside subunit binds to the internucleosidic linkage group, wherein said atom represented by * and said atom represented by ** are both O. It will be understood that the internucleosidic linkage groups of Formulae A or B may be protonated (e.g. at a carbonyl or thiocarbonyl group) or deprotonated (e.g. hydroxyl or sulfhydryl groups may be deprotonated), without this being indicated specifically in Formulae A and B. Likewise, Formulae A and B will be understood to embrace any salts, stereoisomeric and tautomeric forms of the respective internucleosidic linkage groups, without this being indicated specifically in Formulae A and B. Internucleosidic linkage groups, also referred to as internucleoside linkage groups or linkage groups, may be classified depending on the oxidation state of the respective phosphorus (P) atom. Internucleosidic linkage groups typically comprise a P (III) atom or a P (V) atom. Throughout this text, the terms P (III) or phosphorus (III) atom are used interchangeably to denote a P atom of a certain oxidation state, namely with the oxidation state III (i.e. +3). Along the same lines, the terms P (V) or phosphorus (V) atom are used interchangeably to denote a P atom of a certain oxidation state, namely with the oxidation state V (i.e. +5). Internucleosidic linkage groups whose P atom is a P (III) atom are herein referred to as P (III) or phosphorus (III) linkage groups. Internucleosidic linkage groups whose P atom is a P (V) atom are herein referred to as P (V) or phosphorus (V) linkage groups. Examples of P (V) linkage groups are: - phosphate diester (i.e. a phosphodiester) groups (i.e. groups of Formula A with X¹ being O and X² being OH), - thiophosphate diester (i.e. a phosphorothioate) groups (i.e. groups of Formula A with X¹ being S and X² being OH), - dithiophosphate diester (i.e. a phosphorodithioate) groups (i.e. groups of Formula A with X¹ being S and X² being SH), - phosphate triester groups (i.e. groups of Formula A with X¹ being O and X² being OR¹, where R¹ is not H, and preferably is a protecting group such as the 2-cyanoethyl group), - thiophosphate triester groups (i.e. groups of Formula A with X¹ being S and X² being OR¹, where R¹ is not H, and preferably is a protecting group such as the 2-cyanoethyl group), and - dithiophosphate triester groups (i.e. groups of Formula A with X¹ being S and X² being SR¹, where R¹ is not H, and preferably is a protecting group such as the 2-cyanoethyl group). Examples of P (III) linkage groups are: - phosphite triester groups (i.e. groups of Formula B with X³ being O), - thiophosphite triester groups (i.e. groups of Formula B with X³ being S), and - H-phosphonate diester groups (i.e. groups of Formula A with X¹ being O and X² being H). It will be understood by those skilled in the art, that, if an oligonucleotide comprises more than one internucleosidic linkage groups, these internucleosidic linkage groups may be the same or different (i.e. have the same or different chemical structures). An oligonucleotide may also comprise one or more P(III) linkage groups and one or more P(V) linkage groups. As known to the skilled artisan, internucleosidic linkage groups may be modified in the course of oligonucleotide synthesis. For example, P(III) linkage groups may be converted to P (V) linkage groups by incubation with an oxidizing or sulfurizing agent, and/or protecting groups may be removed. Herein, the term “substituent” may be understood in the broadest sense and may denote any chemical residue or moiety. Thus, herein, unless indicated differently, the terms “substituent”, “residue” and “moiety” may be used interchangeably. The term “group” is also used to denote certain substituents (i.e. residues or moieties). However, the terms “substituent”, “moiety” or “residue” may be broader than the term “group” in the cases laid out below: Herein, the term hydroxyl group refers to a OH residue. In other words, a hydroxyl group is always a free hydroxyl group. However, the term hydroxyl moiety additionally encompasses a hydroxyl residue, which results from a reaction of a hydroxyl group with another chemical group, e.g. a hydroxyl residue involved in an internucleosidic linkage group or a hydroxyl residue bound to a protecting group. The expressions sulfhydryl group, SH, and sulfhydryl moiety are used analogously. Herein, the terms amino group and amine group are used interchangeably to denote a substituent bonded to the respective chemical structure via a nitrogen atom, wherein said nitrogen atom is further bonded to two or three residues selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, and heteroaryl. These residues may be further substituted and may be further specified, for example when denoting the amino group as di(C1−C6- alkyl)amino group (e.g. N(C1−C6-alkyl)2). Said di(C1−C6-alkyl)amino group may also be a cyclic amino group in which formally two alkyl residues are bonded to each other to form a cyclic structure. Examples of such cyclic amino groups comprise a pyrrolidine group and a piperidine group. The term amine moiety additionally encompasses an amine residue, which results from a reaction of an amine group with another chemical group, e.g. an amine residue involved in a bond to a protecting group. As used herein, the term “optionally substituted” may be understood in the broadest sense to mean that in the respective structure, which is optionally substituted, one or more hydrogen residues may optionally and independently of each other be substituted by another residue, also referred to as substituent. If a “substituent” (i.e. residue or moiety) is not further specified it may be any conceivable stable atom or atom group and may preferably be selected from the group consisting of an alkyl residue, O-alkyl, a halogen residue (F, Cl, Br, I), a cyano (i.e. CN) residue, a heteroalkyl residue, an alkenyl residue, a heteroalkenyl residue, an alkynyl residue, a heteroalkynyl residue, an aryl residue, a heteroaryl residue, a ketone residue (in particular C(O)alkyl), an aldehyde residue (CHO), a carboxylic acid residue or ester (in particular C(O)O-alkyl) or amide thereof, an amine group or moiety, a boryl residue (i.e. a substituent bonded via a B atom), a silyl residue (i.e. a substituent bonded via a silicon atom), a hydroxyl group or moiety, a sulfhydryl group or moiety, and combinations thereof. Unless indicated differently, these substituents may be further substituted, i.e. one or more hydrogen atoms in these substituents may be substituted by further substituents. As used throughout the present invention, the term “alkyl” may be understood in the broadest sense and may be used to denote any aliphatic group (in other words: residue, moiety or substituent) which is composed of atoms of the chemical elements carbon (C) and hydrogen (H), but does not comprise any heteroatoms. Additionally, an alkyl group as defined herein may be characterized in that it comprises at least one carbon atom and in that the one or more carbon atoms may only be bonded to each other via direct single bonds. Preferably, unless indicated differently in the context of specific embodiments, an alkyl group may comprise in total 1 to 40 carbon atoms (i.e. in total not less than 1 and not more than 40 carbon atoms). Unless stated differently, the term “alkyl” may generally embrace unbranched, branched, and cyclic groups. Non-limiting examples of alkyl groups comprise methyl, ethyl, n-propyl (propane-1-yl), isopropyl (propane-2-yl), n-butyl (butan-1-yl), sec-butyl (butan-2-yl), tert-butyl (2-methylpropan-2-yl), isobutyl (2-methylpropan-1-yl), cyclohexyl, cyclopentyl, and longer alkyl chains, in particular in pseudo solid-phase protecting groups, e.g. the pseudo solid-phase protecting group PG-s and amide solvents S^A. As used throughout the present invention, the term “heteroalkyl” may be understood in the broadest sense and may be used to denote any alkyl group, in which one or more carbon or hydrogen atoms are substituted by a heteroatom, with the proviso that a heteroalkyl group must comprise at least one carbon atom. A heteroatom in this context may be any atom of a chemical element other than carbon and hydrogen, and, unless indicated differently in the context of specific embodiments, may preferably be an atom which is at each occurrence independently selected from the group consisting of N (nitrogen), O, (oxygen), S (sulfur), P (phosphorus), F (fluorine), Cl (chlorine), Br (bromine), I (iodine), and Si (silicon). Preferably, unless indicated differently in the context of specific embodiments, a heteroalkyl group may comprise in total 1 to 40, 1 to 19, 1 to 6, or 1 to 5 carbon atoms. Unless stated differently, the term “heteroalkyl” may generally embrace unbranched, branched, and cyclic groups. Non-limiting examples of heteroalkyl groups comprise halogenated alkyl groups such as trifluoromethyl groups, oxygenated alkyl groups (i.e. alkyloxy groups), aminated alkyl groups (i.e. alkylamine groups, e.g. dimethylamine groups), and cyclic groups such as e.g. piperidine groups, pyrrolidine groups or morpholine groups. A heteroalkyl-substituent may typically be bonded via one or more of its carbon atoms. As used throughout the present invention, the term “alkenyl” may be understood in the broadest sense and may be used to denote any aliphatic group which may be derived from an alkyl group by introducing one or more C=C-double bonds between carbon atoms. The term “heteroalkenyl” may be understood in the broadest sense and may be used to denote any aliphatic group which may be derived from a heteroalkyl group by introducing one or more C=C-double bonds between carbon atoms. Herein, unless stated differently in the context of specific embodiments, the terms “alkenyl” and “heteroalkenyl” generally embrace both, the (E)- and the (Z)-isomers, and mixtures thereof. As used throughout the present invention, the term “alkynyl” may be understood in the broadest sense and may be used to denote any aliphatic group which may be derived from an alkyl group by introducing one or more C≡C-triple bonds between carbon atoms. The term “heteroalkynyl” may be understood in the broadest sense and may be used to denote any aliphatic group which may be derived from a heteroalkyl group by introducing one or more C≡C- triple bonds between carbon atoms. It will be understood that an alkenyl group, a heteroalkenyl group, an alkynyl group, and a heteroalkynyl group comprise at least two carbon atoms. As used throughout the present invention, the term “aryl” may be understood in the broadest sense and may be used to denote any mono- or polycyclic aromatic group, with the proviso that all aromatic ring atoms are carbon atoms. Unless indicted differently in the context of specific embodiments, an aryl group may preferably comprise in total 6 to 30, 6 to 20, or 6 to 15, in particular 6, aromatic carbon atoms. Benzene (i.e. the phenyl group, Ph) may be a preferred example of a monocyclic aromatic (i.e. aryl) group. It will be understood by those skilled in the art that the expression “polycyclic” in this regard may refer to condensed aromatic ring systems in which two or more aromatic rings are fused together. This is to say that the condensed aromatic rings share at least one bond between aromatic carbon atoms, so that this shared bond as well as the carbon atoms forming the bond are part of two or more monocyclic aromatic groups which build up the polycyclic aromatic group. Non-limiting examples of polycyclic aromatic (i.e. aryl) groups are naphthalene (i.e. napthyl), anthracene (i.e. anthracenyl), and phenanthrene (i.e. phenanthryl). As used throughout the present invention, the term “heteroaryl” may be understood in the broadest sense and may be used to denote any mono- or polycyclic heteroaromatic group, which differs from an aromatic (i.e. aryl) group in that at least one, preferably 1 to 5 or 1 to 3, aromatic ring atoms are heteroatoms. A heteroatom in this context is any atom of a chemical element other than carbon and hydrogen, and may, unless indicated differently in the context of specific embodiments, preferably be an atom which is at each occurrence independently selected from the group consisting of N, O, and S. Non-limiting examples of monocyclic heteroaromatic (i.e. heteroaryl) groups comprise pyridine (i.e. pyridyl), pyridazine (i.e. pyridazinyl), pyrimidine (i.e. pyrimidinyl), pyrazine (i.e. pyrazinyl), 1,2,3- triazine (i.e. 1,2,3-triazinyl), 1,2,4- triazine (i.e. 1,2,4-triazinyl), 1,3,5- triazine (i.e. 1,3,5- triazinyl), 1,2,3,4- tetrazine (i.e. 1,2,3,4-tetrazinyl), 1,2,4,5- tetrazine (i.e. 1,2,4,5- tetrazinyl), pyrrole (i.e. pyrrolyl), pyrazole (i.e. pyrazolyl), imidazole (i.e. imidazolyl), 1,2,3-triazole (i.e.1,2,3-triazolyl), 1,2,4-triazole (i.e.1,2,4-triazolyl), thiophene (i.e. thiophenyl), and furan (i.e. furanyl). Non-limiting examples of polycyclic heteroaromatic (i.e. heteroaryl) groups comprise quinoline (i.e. quinolinyl), quinazoline (i.e. quinazolinyl), quinoxaline (i.e. quinoxalinyl), benzofuran (i.e. benzofuranyl), benzothiophene (i.e. benzothiophenyl), benzimidazole (i.e. benzimidazolyl), benzothiazole (i.e. benzothiazolyl), benzoxazole (i.e. benzoxazolyl), dibenzofuran (i.e. dibenzofuranyl), and acridine (i.e. acridinyl). As used herein, the term “aliphatic” may be used to denote any residues or compounds which are not aromatic, i.e. which do not comprise an aromatic or heteroaromatic ring system. It is understood that such aliphatic compounds may be unbranched, branched or cyclic, unless indicated differently in the context of specific embodiments. For example, an aliphatic cyclic amine moiety may, e.g., be a piperidine moiety, a pyrrolidine moiety or a morpholine moiety, but may not be a pyridine moiety, which instead is a heteroaromatic amine moiety or, more general, a heteroaryl moiety or heteroaromatic moiety. Non-limiting examples of aliphatic moieties are aliphatic hydrocarbon groups. As used herein, the term "aliphatic hydrocarbon" may be understood in the broadest sense and may be used to denote any aliphatic residue which is composed of atoms of the chemical elements carbon (C) and hydrogen (H), but does not comprise any heteroatoms. The term “aliphatic hydrocarbon” embraces alkyl groups, alkenyl groups, and alkynyl groups as defined herein, unless indicated differently in the context of specific embodiments. In line with common practice, the names of substituents (i.e. residues or moieties and also groups) may herein typically be derived from the chemical name and indicated by the last syllable “-yl”. However, herein, this wording may be used interchangeably with the chemical name of the respective chemical atom or atom group as if it was not a substituent, with common abbreviations, and with the element symbol(s) themselves. For example, a CH3-substituent may also be referred to as methyl or Me, a Cl-substituent may also be referred to as chlorine or simply Cl, a phenyl substituent may also be denoted as Ph, and a cyano group may also be referred to as CN. If a substituent is denoted using element symbols, e.g. CN, O(C₁−C₆-alkyl), C(O)(C₁−C₆-alkyl), C(O)O(C₁−C₆-alkyl) and comprises more than one atom, the point of attachment of the respective residue (i.e. the atom from which the chemical bond to the parent structure originates) is herein generally the atom denoted to the very left, e.g. the carbon atom in CN and the oxygen atom in O(C₁−C₆-alkyl), unless indicated differently. The same rationale applies if a substituent is denoted using generic residues R such as in O-R^z-1, where the oxygen atom constitutes the point of attachment of the residue to the parent structure. Herein, unless stated differently in the context of specific embodiments, when referring to a specific substituent in general terms such as “butyl”, this wording embraces all isomers having a chemical structure falling under the respective general substituent name such as “butyl”, including for example regioisomers (such as n-butyl, sec-butyl, tert-butyl, isobutyl, and the like), diastereomers, and enantiomers, where applicable. As used throughout the present invention, the number of carbon atoms of residues (also moieties or substituents or groups) is occasionally indicated in the form of subscript numbers, for example in the form of C1−C24-alkyl or C6−C20-aryl. These subscript numbers refer to the range of allowable numbers of carbon atoms for the specific residue and in the context of the specific embodiment. When referring to aryl or heteroaryl residues, these subscript numbers refer to aromatic ring carbon atoms. For example, a C₁−C₂₄-alkyl group comprises in total 1 to 24 carbon atoms, but not less than 1 or more than 24 carbon atoms. Along the same lines, a C6−C20- aryl group comprises in total 6 to 20 aromatic ring carbon atoms, but not less than 6 or more than 20 aromatic ring carbon atoms. Herein, unless stated differently in the context of specific embodiments, when referring to an oligonucleotide, said oligonucleotide may generally be present as a mixture of isomers, in particular as a mixture of stereoisomers. A person skilled in the art understands that a molecule of an oligonucleotide may (typically) only be present in a single (stereo)isomeric form at a certain point in time. Thus, when referring to an oligonucleotide as optionally being present as a mixture of (stereo)isomers, this may refer to a population of oligonucleotide molecules having essentially the same nucleoside sequence, wherein the molecules of said population may be present in different (stereo)isomeric forms. Thus, said population of oligonucleotide molecules may be a mixture of numerous discrete stereoisomers, or may be enriched in one specific stereoisomeric form, or may essentially consist of molecules of a specific stereoisomeric form. It will be understood that certain groups, for example OH and SH groups within an oligonucleotide may be deprotonated. Likewise, it will be understood that certain groups, for example amino groups, within an oligonucleotide may be protonated. It will be understood by a person skilled in the art that an oligonucleotide as defined herein may optionally bear any counter ions known in the art, in particular cations such as sodium cations, potassium cations, magnesium cations, ammonium cations as well as in general cations derived from amines such as trimethylamine (TEA), diisopropylamine (DIPEA) or derived from heteroaromatics such as pyridine or collidine and/or anions such as chloride anions, bromide anions, acetate anions, trifluoroacetate anions, carbonate anions, hydrocarbonate anions, phosphate anions, hydrogen phosphate anions, dihydrogen phosphate anions, perchlorate anions, and combinations thereof. Deprotonation or protonation of an oligonucleotide as well as the (non-covalent) attachment of one or more cations and/or anions may for example occur during the synthesis, isolation, and purification of an oligonucleotide. In general, it will be understood by those skilled in the art that an oligonucleotide as defined herein may be non-covalently bonded or associated to/with species with whom the oligonucleotide was contacted in the course of its synthesis, isolation or purification, for example cations and/or anions or residuals of protecting groups as well as traces of one or more cation scavengers, such as, e.g., thiols or silanes. It will also be understood that such non-covalently bonded or associated species will typically not be depicted in chemical formulas, especially generic formulas, referring to the oligonucleotide or oligonucleotides. Non-limiting examples of oligonucleotides of the invention are 2´-deoxynucleic acids (DNA), ribonucleic acids (RNA), locked nucleic acids (LNA), constrained ethyl nucleic acid analogs (cET), bridged nucleic acids (BNA), tricycloDNA, unlocked nucleic acids (UNA), small interfering RNA (siRNA), microRNA, antisense oligonucleotides (ASO), gapmers, glycerol nucleic acids, phosphorothioate oligonucleotides, phosphorodithioate oligonucleotides, as well as derivatives and analogs thereof, all of which are known to those skilled in the art. An oligonucleotide preferably is a linear sequence of nucleoside subunits, wherein any two adjacent nucleoside subunits are interconnected by an internucleosidic linkage group as defined above. Such a linear sequence may also be referred to as an oligonucleotide strand. In line with common practice, the number of nucleoside subunits in an oligonucleotide may be denoted by a number (an integer equal to or larger than 2) followed by the syllable “mer” or by using a suitable prefix (e.g. di for 2, tri for 3, and the like). For example, an oligonucleotide comprising exactly two nucleoside subunits may be denoted as a 2mer or 2mer oligonucleotide or a dinucleotide and an oligonucleotide comprising exactly 20 nucleoside subunits may be denoted as a 20mer or a 20mer oligonucleotide. Such an oligonucleotide strand will comprise a first terminal nucleoside subunit and a second terminal nucleoside subunit, both of which only have exactly one adjacent nucleoside subunit. In case of a dinucleotide (i.e. a 2mer oligonucleotide) the two terminal nucleoside subunits are interconnected by a first and only internucleosidic linkage group. An oligonucleotide comprising more than two nucleoside subunits, will comprise exactly two terminal nucleoside subunits and one or more non-terminal nucleoside subunits, wherein non-terminal nucleoside subunits are characterized in that they have exactly two adjacent (i.e. one antecedent and one following) nucleoside subunits. The term “adjacent” when referring to nucleoside subunits of an oligonucleotide (strand) refers to any two nucleoside subunits which are interconnected by an internucleosidic linkage group. It is understood that a nucleoside moiety which forms part of an oligonucleotide is herein referred to as a nucleoside subunit of said oligonucleotide. Herein, the term nucleoside moiety embraces both, nucleosides as such and nucleoside subunits of an oligonucleotide as defined herein. The term “nucleoside” (without the addition “moiety” or “subunit”) is however only used to denote a mononucleoside, i.e. a nucleoside moiety which is not a nucleoside subunit of an oligonucleotide. The possible chemical structures of nucleoside moieties are known to those skilled in the art. A nucleoside moiety may be composed of: - a carbohydrate moiety (in other words: a sugar moiety), preferably a monosaccharide moiety, more preferably a pentose moiety, in particular a ribose moiety (such as typically present in RNA) or a 2´-deoxyribose moiety (such as typically present DNA); and - a nucleobase, wherein said carbohydrate moiety and said nucleobase may typically be covalently bonded to each other via a direct covalent bond, typically an N-glycosidic bond. The nature and the chemistry of carbohydrates and nucleobases form part of the common knowledge of those skilled in the art, who are able to select a carbohydrate moiety as well as a nucleobase for a nucleoside moiety depending on the structure of the oligonucleotide to be synthesized. Herein, unless indicated differently in the context of specific embodiments, the term “nucleoside moiety” may comprise naturally occurring nucleoside moieties as well as non-natural nucleoside moieties, in which the carbohydrate moiety and/or the nucleobase have been chemically modified or in which the nucleobase may even be absent (i.e. an abasic site). Non-limiting examples of naturally occurring nucleoside moieties may comprise adenosine, 2´-deoxyadenosine, guanosine, 2´-deoxyguanosine, cytidine, 2´-deoxycytidine, uridine, (2´-deoxy)thymidine, ribothymidine, inosine, and methylated derivatives thereof, all of which are known to those skilled in the art. Further examples may comprise queuosine, archaeosine, wybutosine, lysidine, and N⁶-threonylcarbamoyladenosine. The term “derivative” as used herein may be understood in the broadest sense and may refer to a compound obtainable from a first compound (i.e. a parent compound) by means of one or more, preferably one, chemical reaction. As a result, a derivative may differ from the first (parent) compound for example with regards to the substitutional pattern or with regards to the presence or absence of one or more atom, atom groups, functional groups, or protecting groups. For example, chemical modifications of (non-natural) nucleoside moieties may comprise modifications of the carbohydrate, in particular of the ribose or 2´-deoxyribose moiety. Such carbohydrate-modifications may exemplarily be selected from the group consisting of: - introducing an O−CH3 (i.e. O−methyl or OMe) group, an O−CH2−CH2−O−CH3 (i.e. O−methoxyethyl or O−MOE) group or an F-substituent (i.e. a fluorine substituent) at the 2´-carbon atom; - introducing a methylene or ethylene bridge between the 2′-oxygen and 4′-carbon (“locked” derivatives) of a ribose moiety; - interconnecting the 3´-carbon atom and the 5´-carbon atom of a ribose or 2´- deoxyribose moiety (e.g. in tricycloDNA, tcDNA); - replacing the ribose or 2´-deoxyribose moiety by another pentose such as arabinose or a hexose such as mannose; and - using the L-enantiomer of the carbohydrate instead of the naturally occurring D-enantiomer; and/or combinations of these modifications. Herein, the term “nucleobase” encompasses both non-natural nucleobases as well as naturally occurring nucleobases such as adenine, guanine, cytosine, thymine, and uracil. A person skilled in the art knows how to select a non-natural nucleobase suitable to replace a naturally occurring nucleobase in a nucleoside moiety, so that the non-natural nucleobase may still be capable of a specific interaction with a complementary nucleobase. The interaction between complementary nucleobases may be mediated by hydrogen bonds (cf. Watson-Crick base pairing). Non-natural nucleobases may preferably be derivatives of purine or pyrimidine, which are capable of a specific interaction with another nucleobase. Non-natural nucleoside moieties may for example be formed from a naturally occurring carbohydrate and a non-natural nucleobase or from a non-natural carbohydrate and a naturally occurring nucleobase or from a non-natural carbohydrate and a non-natural nucleobase. Examples of nucleoside moieties are nucleoside moieties of Formula C:

(Formula C), wherein in Formula C: B^N is a nucleobase which may carry one or more protecting groups; Q¹ is selected from the group consisting of OR³ (if the nucleoside moiety is the 3´-terminal nucleoside moiety of an oligonucleotide or if the nucleoside moiety is a nucleoside) and an oxygen atom covalently bonded to an internucleosidic linkage group (if the respective nucleoside moiety is part of an oligonucleotide and not the 3´-terminal nucleoside moiety thereof); R³ is selected from the group consisting of H, a protecting group, and a conjugated moiety which is not a nucleoside, nucleotide or oligonucleotide; Q² is selected from the group consisting of OR⁴ (if the nucleoside moiety is the 5´-terminal nucleoside moiety of an oligonucleotide or if the nucleoside moiety is a nucleoside) and an oxygen atom covalently bonded to an internucleosidic linkage group (if the respective nucleoside moiety is part of an oligonucleotide and not the 5´-terminal nucleoside moiety thereof); R⁴ is selected from the group consisting of H, a protecting group, and a conjugated moiety which is not a nucleoside, nucleotide or oligonucleotide; R^I is selected from the group consisting of H, F, and OR⁵, where R⁵ may be H, a protecting group, any conceivable substituent, or a conjugated moiety which is not a nucleoside, nucleotide or oligonucleotide; R^III is H or R^III and R^I are bonded together to form a cyclic structure; R^II, R^IV, and R^V may independently of each other be any conceivable substituent, wherein two or three of these residues may optionally be bonded together to form a cyclic structure. As laid out above, unless indicated differently in the context of specific embodiments, an oligonucleotide may herein generally be present as a mixture of isomers. No stereochemical information may be deduced from Formula C. In some preferred embodiments, a nucleoside moiety of Formula C is a nucleoside moiety of the following Formula C-a:

(Formula C-a; carbon atoms labelled from 1´ to 5´), wherein in Formula C-a, the carbon atoms have been numbered (in line with common practice) from 1´ to 5´, which merely serves illustrative purposes and should not be construed to be limiting in any kind. In Formula C-a, Q¹, Q², B^N, R^I, R^II, R^III, R^IV, R^V, R³, R⁴, and R⁵ are defined as for Formula C. It is understood that the carbon atom numbers will be identical in any ribose or 2´-deoxyribose based nucleoside moieties. From what has been laid out above, it will be understood that any nucleoside subunits comprising a ribose or 2´-deoxyribose moiety, e.g. nucleoside moieties of Formula C and/or C-a, will preferably all be incorporated into an oligonucleotide in 3´ → 5´ direction or 5´ → 3´direction (all in the same direction). Such nucleoside subunits will bond to one (if it is a terminal nucleoside subunit) or two (if it is a non- terminal nucleoside subunit) internucleosidic linkage groups, wherein, preferably, bonding to said internucleosidic linkage group(s) occurs through the 3´-hydroxyl moiety (i.e. the hydroxyl moiety bonded to the 3´-carbon atom) and/or the 5´-hydroxyl moiety (i.e. the hydroxyl moiety bonded to the 5´-carbon atom) exclusively. Since all nucleoside subunits are preferably incorporated in the same direction, any internucleosidic linkage groups between nucleoside subunits comprising a ribose or 2´-deoxyribose moiety are preferably bonded to the 5´-hydroxyl moiety of one nucleoside subunit and the 3´-hydroxyl moiety of another nucleoside subunit. Obviously, the 3´-hydroxyl moiety of the 3´-terminal nucleoside subunit does not engage in bonding to an internucleosidic linkage group. Likewise, the 5´-hydroxyl moiety of the 5´-terminal nucleoside subunit does not engage in bonding to an internucleosidic linkage group. It is understood from what has been laid out above, that an oligonucleotide comprises two or more nucleoside subunits (nucleoside moieties). It will further be understood that these two or more nucleoside subunits of an oligonucleotide may be the same or different (i.e. have the same or different chemical structures). As used herein, the term “nucleotide” may be understood in the broadest sense and may preferably refer to a conjugate of a nucleoside moiety and a phosphate group or derivative thereof, wherein a hydroxyl moiety of said nucleoside moiety bonds via its oxygen atom to the phosphorus atom of the phosphate moiety or derivative thereof. As will be understood by those skilled in the art, the internucleosidic linkage groups and any carbohydrate moieties, e.g. ribose- or 2´-deoxyribose moieties, are herein referred to as the “backbone” of an oligonucleotide. Thus, the term “backbone” of an oligonucleotide excludes the nucleobases. It will also be understood that in a (mono-)nucleoside, the backbone is the carbohydrate moiety, e.g. the ribose- or 2´-deoxyribose moiety, since a nucleoside does not contain any internucleosidic linkage groups. It forms part of the common knowledge of those skilled in the art that oligonucleotides may be conjugated to additional moieties, which are not a nucleoside, nucleotide or oligonucleotide as defined herein, for various purposes. In particular, free OH-groups (e.g. 3´-OH and/or 5´-OH groups of ribose or 2´-deoxyribose moieties), preferably at the terminal nucleosides of an oligonucleotide strand, may engage in such conjugation. For example, the 5’-OH group of the antisense strand of siRNA (small interfering RNA, known to those skilled in the art) may be modified by a vinyl phosphonate to inhibit cellular degradation and improve potency. A further example is conjugation to N-acetylgalactosamine (GalNAc), which may be of interest for targeted oligonucleotide delivery to hepatocytes. GalNAc structures, often branched to accommodate 3 or 4 GalNAc moieties, may be conjugated, e.g. to the 5’-OH group of an oligonucleotide (cf., e.g., WO2016055601), to the 3’-OH group (cf., e.g., WO2009073809), or monovalent GalNAc moieties may be conjugated via a linker to the 2’-position of subsequent ribose moieties within the oligonucleotide strand (cf., e.g., WO2019075419). For example, the target oligonucleotide O^T may be an oligonucleotide conjugate, unless indicated differently in the context of specific embodiments. A used herein, the term “oligonucleotide conjugate” may refer to any oligonucleotide comprising at least one nucleoside-subunit which is covalently bonded to another moiety, which is not a nucleoside, nucleotide or oligonucleotide, e.g. to a moiety comprising a peptide, protein, lipid, carbohydrate, or a hydrocarbon moiety, among which carbohydrate moieties may be preferred. In some embodiments of the method of the invention, the target oligonucleotide O^T is not an oligonucleotide conjugate. The expression “the target oligonucleotide O^T comprises a first cycle oligonucleotide O-1” herein means that the target oligonucleotide O^T comprises the nucleoside sequence of said first cycle oligonucleotide O-1. The expression “the target oligonucleotide O^T comprises a second cycle oligonucleotide O-2” herein means that the target oligonucleotide O^T comprises the nucleoside sequence of said second cycle oligonucleotide O-2. The expression “the target oligonucleotide O^T comprises a n-th cycle oligonucleotide O-n” herein means that the target oligonucleotide O^T comprises the nucleoside sequence of said n-th cycle oligonucleotide O-n. As used herein, the term “nucleoside sequence” refers to an array of the nucleoside subunits within an oligonucleotide. For a linear oligonucleotide, the nucleoside sequence is usually given starting from a first terminal nucleoside subunit, optionally continuing with one or more non-terminal nucleoside subunits, and ending with a second terminal nucleoside subunit. The nucleoside sequence of an oligonucleotide may be referred to as “sequence” of the oligonucleotide herein. Unless otherwise noted, the sequence of oligonucleotides with a phosphoribose backbone is written herein from the 5’ end (left) to the 3’ end (right). As used herein, the term “nucleoside sequence” does not specify one or more internucleosidic linkage groups and does not take into account the presence or absence of any protecting groups. Thus, two oligonucleotides comprising the same nucleoside subunits in the same order are herein considered to comprise the same nucleoside sequence, regardless of whether or not the internucleosidic linkage groups interconnecting these nucleoside subunits are the same or not (i.e. have the same chemical structure or not) and regardless of whether or not any atoms or functional groups within the carbohydrate moieties, the nucleobases, and the internucleosidic linkage groups are protected. A pseudo solid-phase protecting group is herein regarded a (permanent) protecting group and thus comprised in the general term “protecting group”, unless indicated differently in the context of specific embodiments. For example, the internucleosidic linkage groups may differ with regards to the oxidation state of the phosphorus atom and/or the presence or absence of protecting groups such as the 2-cyanoethyl group. As another example, the exocyclic amino groups of nucleobases such as cytosine, 5-methylcytosine, guanine, and adenine may be protected or may not be protected, and a 5´-terminal hydroxyl moiety may or may not be protected without having any impact on what is herein referred to as the nucleoside sequence. It will be understood that, unless indicated differently in the context of specific embodiments, the target oligonucleotide O^T may comprise more nucleoside subunits than the first cycle oligonucleotide O-1, for example, if the first coupling cycle comprising steps (b-1) to (h-1) (as far as present) is followed by further steps including further coupling cycles. It will be understood that, unless indicated differently in the context of specific embodiments, the target oligonucleotide O^T may comprise more nucleoside subunits than the second cycle oligonucleotide O-2, for example, if the second coupling cycle comprising steps (b-2) to (h-2) (as far as present) is followed by further steps including further coupling cycles. It will be understood that, unless indicated differently in the context of specific embodiments, the target oligonucleotide O^T may comprise more nucleoside subunits than the n-th cycle oligonucleotide O-n, for example, if said (n−2) iterations of the coupling cycle comprising steps (b-x) to (h-x) (as far as present) are followed by further steps including further coupling cycles. It will be understood that the term “further coupling cycles” embraces fragment coupling approaches, since a fragment coupling may be considered a coupling cycle in which two fragments are coupled. Additionally, or alternatively, the target oligonucleotide O^T may also be a conjugate as defined herein, i.e. covalently bonded to a moiety which is not a nucleoside, nucleotide or oligonucleotide, for example, to a carbohydrate moiety. Such conjugation may, for example, be achieved after the final iteration of the coupling cycle has been carried out. In some embodiments of the method of the invention, the target oligonucleotide O^T consists of the same nucleoside sequence as the first cycle oligonucleotide O-1. In such embodiments, the target oligonucleotide O^T may only differ from the first cycle oligonucleotide O-1 with regards to the internucleosidic linkage groups and the absence or presence of protecting groups. In some embodiments of the method of the invention, the target oligonucleotide O^T consists of the same nucleoside sequence as the second cycle oligonucleotide O-2. In such embodiments, the target oligonucleotide O^T may only differ from the second cycle oligonucleotide O-2 with regards to the internucleosidic linkage groups and the absence or presence of protecting groups. In some embodiments of the method of the invention, the target oligonucleotide O^T consists of the same nucleoside sequence as the n-th cycle oligonucleotide O-n. In such embodiments, the target oligonucleotide O^T may only differ from the n-th cycle oligonucleotide O-n with regards to the internucleosidic linkage groups and the absence or presence of protecting groups. For example, the target oligonucleotide may preferably only comprise phosphorus (V) linkage groups while the first cycle oligonucleotide O-1, the second cycle oligonucleotide O-2, or the n-th cycle oligonucleotide O-n may comprise one or more phosphorus (III) linkage groups. For example, the target oligonucleotide O^T may preferably not comprise any protecting groups, while the first cycle oligonucleotide O-1, the second-cycle oligonucleotide O-2, and the n-th cycle oligonucleotide O-n typically comprise several protecting groups and are at least covalently linked to a pseudo solid-phase protecting group, which is herein considered a (permanent) protecting group. In some embodiments of the method of the invention, the target oligonucleotide O^T comprises 2−200, 2−150, 2−100, 2−90, 2−80, 2−70, 2−60, 2−50, 3−50, 4−50, 5−50, 5−40, 5−30, 5−25, 5−20, 6−20 or 6−18 nucleoside subunits. As used herein, the term “protecting group” may be understood in the broadest sense as any group which is introduced into a molecule by means of chemical modification (i.e. through one or more, typically one, chemical reaction) of an atom or functional group (i.e. the atom or functional group which is to be protected) and which, once introduced, prevents said atom or functional group from engaging in one or more chemical reactions in subsequent process steps. The terms “protected” and “carrying a protecting group” are herein used interchangeably to denote an atom or functional group covalently bonded to a protecting group. A protecting group used for protecting an amine moiety may herein be referred to as an amine protecting group or amino protecting group. A protecting group used for protecting a hydroxyl moiety may herein be referred to as a hydroxyl protecting group. It will be understood by those skilled in the art that a protecting group may substitute a hydrogen residue from the atom or functional group to be protected. For example, a hydroxyl protecting group may covalently bind to the oxygen atom of the hydroxyl moiety to be protected, thereby substituting the hydrogen residue. As another example, an amine protecting group may covalently bind to the nitrogen atom of the amine moiety to be protected, thereby substituting a hydrogen residue. It will be understood that pseudo solid-phase protecting groups are also protecting groups as defined herein and embraced by the term “protecting group”, unless indicated differently in the context of specific embodiments. Oligonucleotide synthesis typically comprises one or more coupling steps (i.e. condensing steps or condensation steps), during each of which a free (i.e. unprotected) hydroxyl group of a first nucleoside or oligonucleotide is reacted with a phosphorus moiety of second nucleoside or oligonucleotide, which typically comprises a protected backbone hydroxyl moiety. Protection of this backbone hydroxyl moiety is required to avoid double insertion of said second nucleoside or oligonucleotide and/or multimerization. Prior to the next coupling step, this hydroxyl moiety is typicall deprotected to then engage in the next condensation reaction with the phosphorus moiety of a third nucleoside or oligonucleotide, and so on. The (hydroxyl) protecting groups cleaved prior to each condensation reaction (i.e. once per coupling cycle) are commonly referred to as temporary protecting groups. Typically, functional groups (e.g. exocyclic amino groups) in the nucleobases and other functional groups within the carbohydrate (e.g. ribose or 2-deoxyribose) moieties or internucleosidic linkage groups are also protected during chemical oligonucleotide synthesis. However, since these protecting groups are typically only removed once all coupling cycles have been performed, they are commonly referred to as permanent protecting groups. It will be understood that a pseudo solid-phase protecting group preferably is a permanent protecting group, since it shall typically influence the solubility of the growing oligonucleotide strand until it has been fully assembled (i.e. until all desired coupling cycles have been carried out). The temporary and the permanent protecting groups are typically orthogonal to each other, meaning that one type can be removed under conditions, which do not affect the other type of protecting group. Typically, the permanent protecting groups are removable (i.e. cleavable) under alkaline conditions and the temporary protecting groups are removable (i.e. cleavable) under acidic conditions. Herein, the terms “removing a protecting group”, “cleaving a protecting group”, and “deprotecting” a functional group are used interchangeably to denote a process, preferably a chemical reaction, of removing a protecting group from an atom or functional group, e.g. from a hydroxyl or amine moiety, so that the latter is again available in free form, e.g. as (free) hydroxyl group or (free) amine group. To expressly denote that a specific atom or functional group, e.g. a hydroxyl group, does not carry a protecting group, the adjective “free” may be used. Herein, the process of removing a protecting group comprising an optionally substituted triarylmethyl residue, e.g. a DMT group, may be referred to as “detritylation”. Herein, the terms “cleavage of a protecting group”, “removal of a protecting group”, and “deprotection” of a functional group are used interchangeably and also refer to a process, preferably a chemical reaction, of removing a protecting group from an atom or functional group. In the context of the invention, the term “pseudo solid-phase protecting group” refers to a protecting group, preferably a hydroxyl protecting group or an amine protecting group, in particular a hydroxyl protecting group, characterized in that it comprises one or more aliphatic hydrocarbon residues, with the proviso that all aliphatic hydrocarbon residues comprised in a pseudo solid-phase protecting group together comprise in total 18−200 carbon atoms. It will be understood by those skilled in the art, that such pseudo solid-phase protecting groups are typically quite non-polar and soluble in organic solvents commonly used in oligonucleotide synthesis. Their introduction to an otherwise quite polar nucleoside or oligonucleotide may thus increase the solubility of said nucleoside or oligonucleotide in typical organic solvents and decrease the solubility in water or aqueous solutions. Unless indicated differently in specific embodiments, a pseudo solid-phase protecting group is not limited with regard to the atom or functional group which it is bonded to (in other words: which it protects). As used herein, the term “oligonucleotide synthesis using pseudo solid-phase protecting groups” may be understood in the broadest sense to refer to any oligonucleotide synthesis characterized in that during at least one, preferably each, coupling cycle, a nucleoside or oligonucleotide to be elongated (i.e. which is coupled with another nucleoside or oligonucleotide) is covalently bonded to at least one pseudo solid-phase protecting group. As used herein, the term “coupling cycle” may be understood in the broadest sense and may refer to a sequence of two or more process steps, including a deprotection step used to provide a free hydroxyl group at a nucleoside or oligonucleotide, and a subsequent coupling step (also referred to as condensation step), in which said free hydroxyl group engages in a bond forming reaction with a phosphorus moiety of another nucleoside or oligonucleotide. Several iterations (i.e. rounds of) coupling cycles may be carried out. During each coupling cycle, an elongated oligonucleotide is obtained. A coupling cycle may be further characterized in aspects and embodiments of the method of the invention. For example, in some embodiments of the method of the invention, the first coupling cycle comprises steps (b-1) to (h- 1) (as far as present), i.e. steps (b-1), (c-1), (d-1), (e-1), (f-1), (g-1), and (h-1), which may preferably be carried out in this order, wherein any one of steps (d-1), (f-1), (g-1), and (h-1) is optional (i.e. may or may not be carried out), unless indicated differently in the context of specific embodiments. It will be understood that stating that the first coupling cycle comprises steps (b-1) to (h-1) (as far as present) does not alter the fact that any one of steps (d-1), (f-1), (g-1), and (h-1) is optional. It will be understood that stating that the first coupling cycle comprises steps (b-1) to (h-1) does not alter the fact that any one of steps (d-1), (f-1), (g-1), and (h-1) is optional. In some embodiments of the method of the invention, the first coupling cycle is followed by a second coupling cycle characterized in that it comprises the steps (b-2) to (h-2) (as far as present), i.e. steps (b-2), (c-2), (d-2), (e-2), (f-2), (g-2), and (h-2) as far as present, which may preferably be carried out in this order, wherein any one of steps (d-2), (f-2), (g-2), and (h-2) is optional (i.e. may or may not be carried out), unless indicated differently in the context of specific embodiments. It will be understood that stating that the second coupling cycle comprises steps (b-2) to (h-2) does not alter the fact that any one of steps (d-2), (f-2), (g-2), and (h-2) is optional. In some embodiments of the method of the invention, said second coupling cycle comprising steps (b-2) to (h-2) (as far as present) is followed by (n−2) iterations of a coupling cycle comprising steps (b-x) to (h-x) (as far as present), i.e. steps (b-x), (c-x), (d-x), (e-x), (f-x), (g-x), and (h-x), which may preferably be carried out in this order, wherein any one of steps (d-x), (f-x), (g-x), and (h-x) is optional (i.e. may or may not be carried out), unless indicated differently in the context of specific embodiments. It will be understood that said (n−2) iterations of a coupling cycle comprising steps (b-x) to (h-x) (as far as present) need not be identical with regards to which of the optional steps are carried out or are not carried out. For example, one or more of the optional steps may be carried out in one of said (n−2) iterations and may not be carried out in another of said (n−2) iterations. It will further be understood that a coupling cycle may comprise further steps, which may be inserted before, between, or after the steps specified. The "n" in the term "(n−2) iterations" is an integer in the range of 3 to 99. In some embodiments of the method of the invention, n is an integer in the range of 3−89, 3−79, 3−69, 3−59, 3−49, 3−39, 3−29, 3−19, 3−18, 3−17, 3−16, 3−15, 3−14, 3−13, 3−12, 3−11, 3−10, 3−9, 3−8, 3−7, 3−6, 3−5, or 3−4. It will be understood that to state that an integer is in the range of 3−5 means that said integer may be 3 or 4 or 5. Said integer n denotes the total number of coupling cycles performed to obtain the n-th cycle oligonucleotide O-n. This total number of performed coupling cycles denoted by the integer n includes the first coupling cycle comprising steps (b-1) to (h-1) (as far as present), the second coupling cycle comprising steps (b-2) to (h-2) (as far as present), as well as the (n−2) iterations of the coupling cycle comprising steps (b-x) to (h-x) (as far as present), but does not include any coupling cycles optionally performed, e.g. to prepare component C-0 or any of the building blocks used. Each coupling cycle comprising steps (b-x) to (h-x) (as far as present) is herein identified by a serial number x, which runs in steps of 1 from 3 to n, with n being said integer representing the total number of coupling cycles performed to obtain the n-th cycle oligonucleotide O-n. It will be understood that for, e.g. n=3, the method of the invention comprises a total of 3 coupling cycles: The first coupling cycle comprising the steps (b-1) to (h-1) (as far as present), the second coupling cycle comprising the steps (b-2) to (h-2) (as far as present), and (n−2), i.e.3−2=1, i.e. one, iteration of the coupling cycle comprising the steps (b-x) to (h-x) (as far as present) the latter being numbered with x=3=n. For n=30, the method of the invention comprises a total of 30 coupling cycles: The first coupling cycle comprising the steps (b-1) to (h-1) (as far as present), the second coupling cycle comprising the steps (b-2) to (h-2) (as far as present), and (n−2), i.e. 30−2=28, iterations of the coupling cycle comprising the steps (b-x) to (h-x) (as far as present), the latter being numbered with consecutive integers x running from 3 to 30. The final iteration of the coupling cycle comprising steps (b-x) to (h-x), (as far as present) is referred to as the the n-th cycle, i.e. x=n. The serial number x is herein used to identify any specific coupling cycle comprising the steps (b-x) to (h-x) (as far as present), and the building blocks employed in, as well as the oligonucleotides obtained from said coupling cycle. It will be understood that, for example, said building block B-x is, e.g., the building block B-5 in the fifth coupling cycle (x=5). It will also be understood that, for example, said x-th cycle oligonucleotide O-x is, e.g., the fifth cycle oligonucleotide O-5 in the fifth coupling cycle (x=5). One will readily understand that, as the first coupling cycle comprising the steps (b-1) to (h-1) (as far as present) as well as the second coupling cycle comprising the steps (b-2) to (h-2) (as far as present) are counted in the total number of coupling cycles, the fifth coupling cycle (x=5) is the third iteration of the coupling cycle comprising the steps (b-x) to (h-x) (as far as present). Thus, the serial number x does not denote the number of iterations of the coupling cycle comprising the steps (b-x) to (h-x) (as far as present). Instead, x is simply used to consecutively number the coupling cycles comprising the steps (b-x) to (h-x) (as far as present). In other words: x is used to consecutively number the coupling cycles from the third coupling cycle onwards. It will further be understood that, because x starts at 3 and runs in steps of 1, the coupling cycle previous to any given coupling cycle x (or x-th cycle) may be referred to as the coupling cycle (x−1) (or (x−1)-th cycle) and the oligonucleotide obtained in this previous coupling cycle may be referred to as the (x−1)-th cycle oligonucleotide O-(x−1). Thus, the x-th coupling cycle will start with removing the protecting group PG-(x−1) from the (x−1)-th-cycle oligonucleotide O-(x−1) of the previous coupling cycle. The x-th cycle oligonucleotide O-x of the coupling cycle x will then be obtained by reacting the deprotected (x−1)-th cycle oligonucleotide (O-(x−1))^# with the building block B-x. For example, in the third coupling cycle, the (x−1)-th cycle oligonucleotide O-(x−1) will be the second cycle oligonucleotide O-2 obtained in the second coupling cycle. As another example, in the fourth coupling cycle, the (x−1)-th cycle oligonucleotide O-(x−1) will be the third cycle oligonucleotide O-3 obtained in the third coupling cycle. It will further be understood that the n-th cycle is the final coupling cycle yielding the n-th cycle oligonucleotide O-n. Step (a-1) of some methods of the invention is not part of a coupling cycle and is carried out prior to the first coupling cycle comprising steps (b-1) to (h-1) (as far as present). Step (a-1) of some methods of the invention is: providing a component C-0 selected from the group consisting of a nucleoside and an oligonucleotide, wherein the component C-0 is covalently bonded to a pseudo solid-phase protecting group PG-s and comprises a backbone hydroxyl moiety protected by a protecting group PG-0 removable under acidic conditions. The terms “nucleoside” and “oligonucleotide” have been explained above. In some embodiments of the method of the invention, the component C-0 is a nucleoside. In some embodiments of the method of the invention, the component C-0 is an oligonucleotide. The term “backbone hydroxyl moiety” refers to a hydroxyl moiety which is part of the backbone of the component C-0 and will be understood based on the above explanations of the terms “hydroxyl moiety” and “backbone”. Preferably, said hydroxyl moiety is a hydroxyl moiety of a carbohydrate moiety, in particular of an optionally substituted and/or protected ribose or 2´-deoxyribose moiety. Preferably, said backbone hydroxyl moiety is comprised in a terminal nucleoside subunit of the component C-0. In some preferred embodiments, the component C-0 comprises exactly one protecting group PG-0. The protecting group PG-0 is a protecting group “removable under acidic conditions”. As used herein, a protecting group is “removable under acidic conditions”, if it can be cleaved by treatment with a protic acid. As used herein, the term “protic acid” may be understood in the broadest sense and may refer to any BrØnsted acid, also referred to as BrØnsted-Lowry acid. The terms “protic acid” and “BrØnsted acid” (or “BrØnsted-Lowry acid”) are well-known to those skilled in the art. Preferred examples protecting groups removable under acidic conditions are protecting groups comprising an optionally substituted triarylmethyl residue. As used herein, the two interchangeable terms “protecting group comprising an optionally substituted triarylmethyl residue” and “triarylmethyl type protecting group” may be understood in the broadest sense as any protecting group which covalently binds to the atom or functional group to be protected (e.g. to the oxygen atom of the hydroxyl moiety to be protected) via a carbon atom to which three optionally substituted aryl moieties are bonded. The basic triarylmethyl type protecting group is the triphenylmethyl group (i.e. the trityl group). As known to those skilled in the art, substituents, e.g. alkyl or alkoxy substituents, capable of stabilizing a triarylmethyl-cation formed during acid-catalyzed removal of a triarylmethyl type protecting group, may facilitate acid-catalyzed cleavage of the respective protecting group. Examples of triarylmethyl type protecting groups are the trityl group, the (p-methylphenyl)diphenylmethyl group (i.e. the 4-methyltrityl group), the di(p-methylphenyl)phenylmethyl group (i.e. the 4,4'-dimethyltrityl group), the tri(p-methylphenyl)methyl group (i.e. the 4,4',4"-trimethyltrityl group), the (p-methoxyphenyl)diphenylmethyl group (i.e. the MMT group), the di(p-methoxyphenyl)phenylmethyl group (i.e. the DMT or DMTr group), the tri(p-methoxyphenyl)methyl group (i.e. the TMT group), the 4,4'-dimethoxy-3''- [N-(imidazolylmethyl)]trityl group (i.e. the IDT group), the 4,4'-dimethoxy-3''-[N- (imidazolylethyl)carbamoyl]trityl group (i.e. the IET group), the bis(4-methoxyphenyl)-1'-pyrenylmethyl group (i.e. the Bmpm group), and the 4-(17- tetrabenzo[a,c,g,i]fluorenylmethyl)-4',4''-dimethoxytrityl group (i.e. the Tbf-DMT group). The trityl group, the MMT group, and the DMT group may be preferred. The DMT group is herein most preferred as temporary hydroxyl protecting group. As used herein, the terms DMT and DMTr are used interchangeably to denote a di(p-methoxyphenyl)phenylmethyl group. It will be understood that said protecting group PG-x may be the same or different (i.e. have the same or a different chemical structure) in each iteration x of the coupling cycle, unless indicated differently in the context of specific embodiments. In some embodiments of the method of the invention, said protecting group PG-0 is a protecting group comprising an optionally substituted triarylmethyl residue. In some embodiments of the method of the invention, said protecting group PG-0 is selected from the group consisting of the triphenylmethyl group (i.e. the trityl group), the (p-methylphenyl)diphenylmethyl group (i.e. the 4-methyltrityl group), the di(p-methylphenyl)phenylmethyl group (i.e. the 4,4'-dimethyltrityl group), the tri(p-methylphenyl)methyl group (i.e. the 4,4',4"-trimethyltrityl group), the (p-methoxyphenyl)diphenylmethyl group (i.e. the MMT group), and the di(p-methoxyphenyl)phenylmethyl group (i.e. the DMT group). In some embodiments of the method of the invention, said protecting group PG-0 is selected from the group consisting of the triphenylmethyl group, the (p-methoxyphenyl)diphenylmethyl group, and the di(p-methoxyphenyl)phenylmethyl group. In some embodiments of the method of the invention, said protecting group PG-0 is a di(p-methoxyphenyl)phenylmethyl group. In some preferred embodiments, the component C-0 comprises exactly one backbone hydroxyl moiety protected by a protecting group comprising an optionally substituted triarylmethyl residue, which is said protecting group PG-0. In some preferred embodiments, the component C-0 comprises exactly one protecting group comprising an optionally substituted triarylmethyl residue, which is said protecting group PG-0. The term “pseudo solid-phase protecting group” has been defined above and will be exemplified in more detail in a later section of this text. The expression “the component C-0 is covalently bonded to a pseudo solid-phase protecting group PG-s” means that there are one or more, preferably exactly one, covalent chemical bonds interconnecting the component C-0 and said pseudo solid-phase protecting group PG-s. It will be understood that the name “PG-s” has been assigned for illustrative purposes only and should not be construed to be limiting in any kind, unless indicated differently in the context of specific embodiments. In some embodiments of the method of the invention, the component C-0 is covalently bonded to exactly one pseudo solid-phase protecting group, which is said pseudo solid-phase protecting group PG-s. As stated above, a pseudo solid-phase protecting group as defined herein is not limited with regard to the atom or functional group of the respective nucleoside moiety to which it is covalently bonded, unless indicated differently in the context of specific embodiments. For example, a pseudo solid-phase protecting group may be covalently bonded to - a hydroxyl moiety of a carbohydrate moiety of a nucleoside moiety, preferably the 2´- or 3´-, in particular the 3´-hydroxyl moiety, of a ribose- or 2´-deoxyribose- type nucleoside moiety (e.g. of any one of Formulae C and C-a), or - an amine moiety of a nucleobase (e.g. an exocyclic amine moiety of adenine, guanine, cytosine or 5-methylcytosine or to the endocyclic amine (or rather amide) nitrogen atom in 3-position of thymine or uracil) of said component C-0 and of said component (C-0)^#. According to the invention, the component C-0 is a compound of the aforementioned Formula I. In some embodiments of the method of the invention, the component C-0 of Formula I, is a compound of the following Formula I-a:

(Formula I-a), wherein in Formula I-a: m, Y¹, Z¹, R^z-1, PG-0, and PG-s are defined as for Formula I; B^N is a nucleobase, which may be the same or different at each occurrence; R^VI is at each occurrence independently selected from the group consisting of H, F, O-(C1−C5-alkyl), O-(C1−C5-alkyl)-O-(C1−C5-alkyl), O-Si(C1−C5-alkyl)3, and O-CH2-O-Si(C1−C5-alkyl)3; R^VIII is independently at each occurrence H or R^VIII and R^VI of the same nucleoside subunit (i.e. bonded to the 4´- and 2´-C atom of the same carbohydrate moiety) together form a structure +–CH2-O−++, +–CH(CH3)-O−++, or +–CH2-CH2-O−++, where + is the point of attachment to the 4´-carbon atom (i.e. the carbon atom to which R^VIII is bonded) and ++ is the point of attachment to the 2´-carbon (i.e. the carbon atom to which R^VI is bonded); for each nucleoside subunit independently, R^VII, R^IX, and R^X are either all H or they are bonded together so that the respective nucleoside subunit has a structure of the following Formula I-a-tc:

(Formula I-a-tc), wherein in Formula I-a-tc: the oxygen atom from which the dashed line originates represents the oxygen atom bonded to the 3´-carbon atom, i.e. the carbon atom to which R^VII is bonded in Formula I-a; the dashed line indicates the covalent chemical bond interconnecting the respective oxygen atom of the nucleoside subunit of Formula I-a-tc and the pseudo solid-phase protecting group PG-s or P(Y¹)(Z¹) in Formula I-a; the oxygen atom from which the wavy line originates represents the oxygen atom bonded to the 5´-carbon atom, i.e. the carbon atom to which –C(R^IX)(R^X) is bonded in Formula I-a; and the wavy line indicates the covalent chemical bond interconnecting the respective oxygen atom of the nucleoside subunit of Formula I-a-tc and either PG-0 or P(Y¹)(Z¹) in Formula I-a. In some embodiments of the method of the invention, the component C-0 of any one of Formulae I, and I-a, is a compound of the following Formula I-b: (Formula I-b), wherein in Formula I-b: m, PG-0, PG-s, Y¹, Z¹, R^z-1, B^N, R^VI, and R^VIII are defined as for Formula I-a, and for each nucleoside subunit independently, R^VII, R^IX, and R^X are either all H or they are bonded together so that the respective nucleoside subunit has a structure of the following Formula I-b-tc:

(Formula I-b-tc), wherein in Formula I-b-tc: the oxygen atom from which the dashed line originates represents the oxygen atom bonded to the 3´-carbon atom, i.e. the carbon atom to which R^VII is bonded in Formula I-b; the dashed line indicates the covalent chemical bond interconnecting the respective oxygen atom of the nucleoside subunit of Formula I-b-tc and the pseudo solid-phase protecting group PG-s or P(Y¹)(Z¹) in Formula I-b; the oxygen atom from which the wavy line originates represents the oxygen atom bonded to the 5´-carbon atom, i.e. the carbon atom to which C(R^IX)(R^X) is bonded in Formula I-b; and the wavy line indicates the covalent chemical bond interconnecting the respective oxygen atom of the nucleoside subunit of Formula I-b-tc and either PG-0 or P(Y¹)(Z¹) in Formula I-b. In some embodiments, in the component C-0 of any one of Formulae I, I-a, and I-b, R^z-1 is a protecting group removable under alkaline conditions, wherein R^z-1 may be the same or different at each occurrence. As used herein, a protecting group is “removable under alkaline conditions”, if it can be cleaved by treatment with a base (wherein “a base” is not to be construed to mean any base, but specific bases adapted to the protecting group to be removed based on the common knowledge of those skilled in the art and routine experimentation). The term “base” may in this context be understood as proton acceptor in the sense of the BrØnsted-Lowry theory. Examples of such a base include ammonia, in particular an aqueous solution of ammonia (i.e. an aqueous ammonium hydroxide solution), methylamine, tert- butylamine, diethylamine, triethylamine, diisopropylethylamine, alkali hydroxides, and the like. In some embodiments, in the component C-0 of any one of Formulae I, I-a, and I-b, R^z-1 is for each repetitive unit m independently a protecting group of the chemical structure CH₂-CH₂-EWG, where EWG is an electron withdrawing group, preferably a cyano group. The electron withdrawing group may for example be selected from the group consisting of a cyano group, a halogen atom such as a chlorine, fluorine, or bromine atom, a formyl group, a keto group, a carboxyester group, and a carboxamide group. In some preferred embodiments, in the component C-0 of any one of Formulae I, I-a, and I-b, R^z-1 is for each repetitive unit m a 2-cyanoethyl group (i.e. CH2-CH2-CN). In some embodiments, in the component C-0 of any one of Formulae I, I-a, and I-b, Z¹ is selected independently for each repetitive unit m from the group consisting of O-R^z-1 and S-R^z-1. In some embodiments, in the component C-0 of any one of Formulae I, I-a, and I-b, Z¹ is selected independently for each repetitive unit m from the group consisting of O-R^z-1 and S-R^z-1, where R^z-1 is for each repetitive unit m a 2-cyanoethyl group. In such embodiments, Z¹ is selected independently for each repetitive unit m from the group consisting of O-CH₂-CH₂-CN and S-CH₂-CH₂-CN. In some embodiments, in the component C-0 of any one of Formulae I, I-a, and I-b, Z¹ is for each repetitive unit m O-R^z-1, where R^z-1 is for each repetitive unit m a 2-cyanoethyl group. In such embodiments, Z¹ is for each repetitive unit m O-CH2-CH2-CN. In some embodiments, in the component C-0 of any one of Formulae I, I-a, and I-b, Y¹ is for each repetitive unit m O. In some embodiments, in the component C-0 of any one of Formulae I, I-a, and I-b, Y¹ is for each repetitive unit m S. In some embodiments, in the component C-0 of any one of Formulae I-a, and I-b: R^VI is selected independently at each occurrence from the group consisting of H, F, O-CH3 (i.e. methoxy), O-CH2-CH2-O-CH3 (i.e. 2-methoxyethyl-1-oxy), O-Si(CH3)3 (i.e. trimethylsilyloxy), O-Si(CH3)2(C(CH3)3) (i.e. tert-butyl(dimethyl)silyloxy), and O- CH2-O-Si(C(CH3)3)3 (i.e. ((triisopropylsilyl)oxy)-methyloxy); R^VIII is independently at each occurrence H or R^VIII and R^VI of the same nucleoside subunit (i.e. bonded to the 4´- and 2´-C atom of the same carbohydrate moiety) together form a structure +–CH₂-O−++, +–CH(CH₃)-O−++, or +–CH₂-CH₂-O−++, where + is the point of attachment to the 4´-carbon atom (i.e. the carbon atom to which R^VIII is bonded) and ++ is the point of attachment to the 2´-carbon (i.e. the carbon atom to which R^VI is bonded); and for each nucleoside subunit independently, R^VII, R^IX, and R^X are either all H or they are bonded together so that the respective nucleoside subunit has a structure of the aforementioned Formula I-a-tc (in a component C-0 of Formula I-a) or Formula I-b-tc (in a component C-0 of Formula I-b). In some embodiments, in the component C-0 of any one of Formulae I-a, and I-b: R^VI is selected independently at each occurrence from the group consisting of H, F, O-CH3 (i.e. methoxy), and O-CH2-CH2-O-CH3 (i.e.2-methoxyethyl-1-oxy); and each of R^VII, R^VIII, R^IX, and R^X is at each occurrence H. In some embodiments, in the component C-0 of any one of Formulae I, I-a, and I-b, the integer m is an integer in the range of 0−49, 0−39, 0−29, 0−24, 0−19, 0−18, 0−17, 0−16, 0−15, 0−14, 0−13, 0−12, 0−11, 0−10, 0−9, 0−8, 0−7, 0−6, 0−5 or 0−4. It will be understood that to state than an integer is in the range of e.g.0−5 means that said integer may be 0, 1, 2, 3, 4, or 5. In some embodiments, in the component C-0 of any one of Formulae I, I-a, and I-b, the integer m is an integer in the range of 4−49, 4−39, 4−29, 4−24, 4−19, 4−18, 4−17, 4−16, 4−15, 4−14, 4−13, 4−12, 4−11, 4−10, or 4−9. In some preferred embodiments, in the component C-0 of any one of Formulae I, I-a, and I-b, the integer m is an integer equal to or larger than 5, in particular an integer in the range of 5–18 or 5–17. In some embodiments, in the component C-0 of any one of Formulae I, I-a, and I-b, the integer m is 0. The skilled person will understand that any kind of nucleobase B^N may be present in the component C-0 of any one of Formulae I, I-a, and I-b. Reference is e.g. made to the explanations relating to the nucleobase given above. In some embodiments, in the component C-0 of any one of Formulae I, I-a, and I-b, B^N is a nucleobase and at each occurrence independently selected from the group consisting of adenine, guanine, cytosine, 5-methylcytosine, thymine, and uracil. It will be understood by those skilled in the art, that any nucleobase B^N in any one of Formulae I, I-a, and I-b may optionally be protected, i.e. carry one or more protecting groups, without this being indicated specifically. Thus, when, for example, stating that B^N is adenine, guanine, cytosine, 5-methylcytosine, thymine, or uracil, this embraces the aforementioned nucleobases in protected form and in free form (i.e. with and without any protecting groups). The same rationale applies to nucleobases in general. The skilled artisan is familiar with nucleobase protecting groups and knows how to select, introduce, and remove them. In particular, the exocyclic amino groups in nucleobases such as in adenine, guanine, cytosine, and 5-methylcytosine may be protected. Non-limiting examples of protecting groups for exocyclic amino groups of nucleobases comprise the acetyl group, the benzoyl group, the isobutyryl group, the pivaloyl group, the pivaloyloxymethyl group, the trifluoroacetyl group, the phenoxyacetyl group, the 4-isopropylphenoxyacetyl group, the 4-tert- butylphenoxyacetyl group, and the dimethylformamidinyl group. Carbonyl groups present in nucleobases such as in thymine, uracil, and guanine may also be protected, for example, by reaction with phenol, 2,5-dichlorophenol, 3-chlorophenol, 3,5-dichlorophenol, 2-formylphenol, 2-naphthol, 4-methoxyphenol, 4-chlorophenol, 2-nitrophenol, 4-nitrophenol, 4-acetylaminophenol, pentafluorophenol, 4-pivaloyloxybenzyl alcohol, 4-nitrophenethyl alcohol, 2-(methylsulfonyl)ethanol, 2-(phenylsulfonyl)ethanol, 2-cyanoethanol, 2-(trimethylsilyl)ethanol, dimethylcarbamoyl chloride, diethylcarbamoyl chloride, ethylphenylcarbamoyl chloride, 1-pyrrolidinecarbonyl chloride, 4-morpholinecarbonyl chloride, diphenylcarbamoyl chloride, and the like. Examples of preferred nucleobase protecting groups are compiled in the following Table T-1. Table T-1: Non-limiting overview of preferred nucleobase protecting groups. protecting group typically used for Bz or bz = benzoyl; iBu or ibu = isobutyryl; exocyclic amino group of adenine PAC = phenoxyacetyl Ac = acetyl; Bz = benzoyl exocyclic amino group of cytosine or 5-methylcytosine iBu or ibu = isobutyryl; exocyclic amino group of guanine i-Pr-PAC = 4-isopropylphenoxyacetyl; dimethylformamidino In some embodiments of the method of the invention, each nucleobase of the component C-0, in particular each nucleobase B^N of the component C-0 of any one of Formulae I, I-a, and I-b is independently selected from the group consisting of - adenine, in which the exocyclic amino group is protected; - guanine, in which the exocyclic amino group is protected; - cytosine, in which the exocyclic amino group is protected; - 5-methylcytosine, in which the exocyclic amino group is protected; - thymine; and - uracil. In some embodiments of the method of the invention, each nucleobase of the component C-0, in particular each nucleobase B^N of the component C-0 of any one of Formulae I, I-a, and I-b is independently selected from the group consisting of - adenine, in which the exocyclic amino group is protected by a benzoyl group, an isobutyryl group or a phenoxyacetyl group; - guanine, in which the exocyclic amino group is protected by an isobutyryl group, a 4-isopropylphenoxyacetyl group or a dimethylformamidino group; - cytosine, in which the exocyclic amino group is protected by an acetyl group or a benzoyl group; - 5-methylcytosine, in which the exocyclic amino group is protected by an acetyl group or a benzoyl group; - thymine; and - uracil. In some embodiments, in the component C-0 of Formula I: m is an integer in the range of 0−49, 0−39, 0−29, 0−24, 0−19, 0−18, 0−17, 0−16, 0−15, 0−14, 0−13, 0−12, 0−11, 0−10, 0−9, 0−8, 0−7, 0−6, 0−5 or 0−4 or in the range of 4−49, 4−39, 4−29, 4−24, 4−19, 4−18, 4−17, 4−16, 4−15, 4−14, 4−13, 4−12, 4−11, 4−10, or 4−9; PG-0 is a protecting group comprising an optionally substituted triarylmethyl residue, preferably a di(p-methoxyphenyl)phenylmethyl (DMT) protecting group; Y¹ is selected independently for each repetitive unit m from the group consisting of O and S; Z¹ is selected independently for each repetitive unit m from the group consisting of O-R^z-1, S-R^z-1, and H; R^z-1 is for each repetitive unit m a 2-cyanoethyl group; and PG-s is a pseudo solid-phase protecting group. In some embodiments, in the component C-0 of Formula I: m is an integer in the range of 0−49, 0−39, 0−29, 0−24, 0−19, 0−18, 0−17, 0−16, 0−15, 0−14, 0−13, 0−12, 0−11, 0−10, 0−9, 0−8, 0−7, 0−6, 0−5 or 0−4 or in the range of 4−49, 4−39, 4−29, 4−24, 4−19, 4−18, 4−17, 4−16, 4−15, 4−14, 4−13, 4−12, 4−11, 4−10, or 4−9; PG-0 is a protecting group comprising an optionally substituted triarylmethyl residue, preferably a di(p-methoxyphenyl)phenylmethyl (DMT) protecting group; Y¹ is selected independently for each repetitive unit m from the group consisting of O and S; Z¹ is selected independently for each repetitive unit m from the group consisting of O-R^z-1 and S-R^z-1; R^z-1 is for each repetitive unit m a 2-cyanoethyl group; and PG-s is a pseudo solid-phase protecting group. In some embodiments, in the component C-0 of Formula I: m is an integer in the range of 0−49, 0−39, 0−29, 0−24, 0−19, 0−18, 0−17, 0−16, 0−15, 0−14, 0−13, 0−12, 0−11, 0−10, 0−9, 0−8, 0−7, 0−6, 0−5 or 0−4 or in the range of 4−49, 4−39, 4−29, 4−24, 4−19, 4−18, 4−17, 4−16, 4−15, 4−14, 4−13, 4−12, 4−11, 4−10, or 4−9; PG-0 is a protecting group comprising an optionally substituted triarylmethyl residue, preferably a di(p-methoxyphenyl)phenylmethyl (DMT) protecting group; Y¹ is selected independently for each repetitive unit m from the group consisting of O and S; Z¹ is for each repetitive unit m O-R^z-1; R^z-1 is for each repetitive unit m a 2-cyanoethyl group; and PG-s is a pseudo solid-phase protecting group. In some embodiments, in the component C-0 of any one of Formulae I-a and I-b: m is an integer in the range of 0−49, 0−39, 0−29, 0−24, 0−19, 0−18, 0−17, 0−16, 0−15, 0−14, 0−13, 0−12, 0−11, 0−10, 0−9, 0−8, 0−7, 0−6, 0−5 or 0−4 or in the range of 4−49, 4−39, 4−29, 4−24, 4−19, 4−18, 4−17, 4−16, 4−15, 4−14, 4−13, 4−12, 4−11, 4−10, or 4−9; PG-0 is a protecting group comprising an optionally substituted triarylmethyl residue, preferably a di(p-methoxyphenyl)phenylmethyl (DMT) protecting group; Y¹ is selected independently for each repetitive unit m from the group consisting of O and S; Z¹ is selected independently for each repetitive unit m from the group consisting of O-R^z-1, S-R^z-1, and H; R^z-1 is for each repetitive unit m a 2-cyanoethyl group; PG-s is a pseudo solid-phase protecting group; B^N is a nucleobase, which may be the same or different at each occurrence; R^VI is at each occurrence independently selected from the group consisting of H, F, O-(C₁−C₅-alkyl), O-(C₁−C₅-alkyl)-O-(C₁−C₅-alkyl), O-Si(C₁−C₅-alkyl)₃, and O-CH₂-O-Si(C₁−C₅-alkyl)₃; R^VIII is independently at each occurrence H or R^VIII and R^VI of the same nucleoside subunit (i.e. bonded to the 4´- and 2´-C atom of the same carbohydrate moiety) together form a structure +–CH₂-O−++, +–CH(CH₃)-O−++, or +–CH₂-CH₂-O−++, where + is the point of attachment to the 4´-carbon atom (i.e. the carbon atom to which R^VIII is bonded) and ++ is the point of attachment to the 2´-carbon (i.e. the carbon atom to which R^VI is bonded); and for each nucleoside subunit independently, R^VII, R^IX, and R^X are either all H or they are bonded together so that the respective nucleoside subunit has a structure of the aforementioned Formula I-a-tc (in a component C-0 of Fomula I-a) or the aforementioned Formula I-b-tc (in a component C-0 of Fomula I-b). In some embodiments, in the component C-0 of any one of Formulae I-a and I-b: m is an integer in the range of 0−49, 0−39, 0−29, 0−24, 0−19, 0−18, 0−17, 0−16, 0−15, 0−14, 0−13, 0−12, 0−11, 0−10, 0−9, 0−8, 0−7, 0−6, 0−5 or 0−4 or in the range of 4−49, 4−39, 4−29, 4−24, 4−19, 4−18, 4−17, 4−16, 4−15, 4−14, 4−13, 4−12, 4−11, 4−10, or 4−9; PG-0 is a protecting group comprising an optionally substituted triarylmethyl residue, preferably a di(p-methoxyphenyl)phenylmethyl (DMT) protecting group; Y¹ is selected independently for each repetitive unit m from the group consisting of O and S; Z¹ is selected independently for each repetitive unit m from the group consisting of O-R^z-1, and S-R^z-1; R^z-1 is for each repetitive unit m a 2-cyanoethyl group; PG-s is a pseudo solid-phase protecting group; B^N is a nucleobase, which may be the same or different at each occurrence; R^VI is at each occurrence independently selected from the group consisting of H, F, O-(C1−C5-alkyl), O-(C1−C5-alkyl)-O-(C1-C5-alkyl), O-Si(C1−C5-alkyl)3, and O-CH2-O-Si(C1−C5-alkyl)3; R^VIII is independently at each occurrence H or R^VIII and R^VI of the same nucleoside subunit (i.e. bonded to the 4´- and 2´-C atom of the same carbohydrate moiety) together form a structure +–CH2-O−++, +–CH(CH3)-O−++, or +–CH2-CH2-O−++, where + is the point of attachment to the 4´-carbon atom (i.e. the carbon atom to which R^VIII is bonded) and ++ is the point of attachment to the 2´-carbon (i.e. the carbon atom to which R^VI is bonded); and for each nucleoside subunit independently, R^VII, R^IX, and R^X are either all H or they are bonded together so that the respective nucleoside subunit has a structure of the aforementioned Formula I-a-tc (in a component C-0 of Fomula I-a) or the aforementioned Formula I-b-tc (in a component C-0 of Fomula I-b). In some embodiments, in the component C-0 any one of Formulae I-a and I-b: m is an integer in the range of 0−49, 0−39, 0−29, 0−24, 0−19, 0−18, 0−17, 0−16, 0−15, 0−14, 0−13, 0−12, 0−11, 0−10, 0−9, 0−8, 0−7, 0−6, 0−5 or 0−4 or in the range of 4−49, 4−39, 4−29, 4−24, 4−19, 4−18, 4−17, 4−16, 4−15, 4−14, 4−13, 4−12, 4−11, 4−10, or 4−9; PG-0 is a protecting group comprising an optionally substituted triarylmethyl residue, preferably a di(p-methoxyphenyl)phenylmethyl (DMT) protecting group; Y¹ is selected independently for each repetitive unit m from the group consisting of O and S; Z¹ is for each repetitive unit m O-R^z-1; R^z-1 is for each repetitive unit m a 2-cyanoethyl group; PG-s is a pseudo solid-phase protecting group; B^N is a nucleobase, which may be the same or different at each occurrence; R^VI is selected independently at each occurrence from the group consisting of H, F, O-CH₃ (i.e. methoxy), O-CH₂-CH₂-O-CH₃ (i.e. 2-methoxyethyl-1-oxy), O-Si(CH₃)₃ (i.e. trimethylsilyloxy)_, O-Si(CH₃)₂(C(CH₃)₃) (i.e. tert-butyl(dimethyl)silyloxy), and O-CH₂-O-Si(C(CH₃)₃)₃ (i.e. ((triisopropylsilyl)oxy)methyloxy); and each of R^VII, R^VIII, R^IX, and R^X is at each occurrence H. Any definitions and embodiments laid out herein for the component C-0 of Formula I likewise apply to the component (C-0)^# of Formula I-C, with the proviso that the protecting PG-0 is absent and the hydroxyl moiety, to which the protecting group PG-0 was bonded, is a free hydroxyl group (OH). In some embodiments of the method of the invention, the component (C-0)^# of Formula I-C, is a compound of Formula I-a, with the proviso that the protecting group PG-0 is absent and the hydroxyl moiety, to which the protecting group PG-0 was bonded, is a free hydroxyl group (OH). In such embodiments, any definitions and embodiments laid out herein for the component C-0 of Formula I-a are likewise applicable to the component (C-0)^# of Formula I-C, with the proviso that the protecting group PG-0 is absent and the hydroxyl moiety, to which the protecting group PG-0 was bonded, is a free hydroxyl group (OH). In some embodiments of the method of the invention, the component (C-0)^# of Formula I-C, is a compound of Formula I-b, with the proviso that the protecting group PG-0 is absent and the hydroxyl moiety, to which the protecting group PG-0 was bonded, is a free hydroxyl group (OH). In such embodiments, any definitions and embodiments laid out herein for the component C-0 of Formula I-b are likewise applicable to the component (C-0)^# of Formula I-C, with the proviso that the protecting group PG-0 is absent and the hydroxyl moiety, to which the protecting group PG-0 was bonded, is a free hydroxyl group (OH). The term “providing a component C-0” in step (a-1) may be understood in the broadest sense to refer to any means of obtaining a component C-0. The component C-0 may, for example, be obtained commercially, in particular, if it is a nucleoside. Alternatively, the component C-0 may be provided by means of chemical synthesis. Such means are well known to the skilled artisan and comprise, for example, solid-phase and liquid-phase oligonucleotide synthesis. As non-limiting examples, the following documents disclose means of providing components C-0 for use in the method of the invention: PCT/EP2022/059528, US2015112053A1, , EP3825300A1, EP2711370A1, EP3398955A1, US2018291056A1, EP3925964A1, EP2921499A1, EP3733680A1, EP3378869A1, WO2020227618A2, EP3263579A1, EP3950698A1, EP3015467A1, M.C. de Koning et al., Organic Process Research & Development 2006, 10, 1238–1245; A. Schwenger et al., European Journal of Organic Chemistry 2017, 5852–5864; S. Kim et al., Chemistry – A European Journal 2013, 19, 8615– 8620, US2015080565A1, US2013267697A1,and X. Shi et al., J. Org. Chem.2022, 87(4), 2087−2110. Step (b-1) of some methods of the invention is: incubating the component C-0 of step (a-1) with a deprotection mixture M-(b-1), thereby cleaving the protecting group PG-0 from the component C-0, so as to obtain a component (C-0)^# having a free backbone hydroxyl group. Step (b-2) of some methods of the invention is: incubating the first cycle oligonucleotide O-1 obtained in the first coupling cycle with a deprotection mixture M-(b-2), thereby cleaving the protecting group PG-1 from the first cycle oligonucleotide O-1, so as to obtain a first cycle oligonucleotide (O-1)^# having a free backbone hydroxyl group. Step (b-x) of some methods of the invention is: incubating the (x−1)-th cycle oligonucleotide O-(x−1) obtained in the previous coupling cycle with a deprotection mixture M-(b-x), thereby cleaving the protecting group PG-(x−1) from the (x−1)-th cycle oligonucleotide O-(x−1), so as to obtain a (x−1)-th cycle oligonucleotide (O- (x−1))^# having a free backbone hydroxyl group. The component C-0 and the protecting group PG-0 have been defined. The first cycle oligonucleotide O-1 is obtained in the first coupling cycle. It will be understood that, since the building block B-1 used to prepare said first cycle oligonucleotide O-1 comprises a backbone hydroxyl moiety protected by a protecting group PG-1 removable under acidic conditions, the first cycle oligonucleotide O-1 also comprises a backbone hydroxyl moiety protected by a protecting group PG-1 removable under acidic conditions. As laid out above, the term (x−1)-th cycle oligonucleotide O-(x−1) refers to the x-th cycle oligonucleotide obtained in the previous coupling cycle, and, in the case of the first coupling cycle comprising steps (b-x) to (h-x) (as far as present) (i.e. x = 3) refers to the second cycle oligonucleotide O-2. It will be understood that, since the building block B-2 used to prepare the second cycle oligonucleotide O-2 comprises a backbone hydroxyl moiety protected by a protecting group PG-2 removable under acidic conditions, the second cycle oligonucleotide O-2 also comprises a backbone hydroxyl moiety protected by a protecting group PG-2 removable under acidic conditions. It will be understood that, since each building block B-x comprises a backbone hydroxyl moiety protected by a protecting group PG-x removable under acidic conditions, each (x−1)-th cycle oligonucleotide O-(x−1) also comprises a backbone hydroxyl moiety protected by a protecting group PG-(x−1) removable under acidic conditions. The term “removable under acidic conditions” has been defined above in the context of the protecting group PG-0 and likewise applies to all protecting groups PG-1, PG-2, PG-x, PG-(x−1), and PG-n. In some embodiments of the method of the invention, each of the protecting groups PG-1, PG-2, PG-x, PG-(x−1), and PG-n is independently of each other a protecting group comprising an optionally substituted triarylmethyl residue. In some embodiments of the method of the invention, each of the protecting groups PG-1, PG-2, PG-x, PG-(x−1), and PG-n is independently of each other selected from the group consisting of the triphenylmethyl group (i.e. the trityl group), the (p-methylphenyl)diphenylmethyl group (i.e. the 4-methyltrityl group), the di(p-methylphenyl)phenylmethyl group (i.e. the 4,4'-dimethyltrityl group), the tri(p-methylphenyl)methyl group (i.e. the 4,4',4"-trimethyltrityl group), the (p-methoxyphenyl)diphenylmethyl group (i.e. the MMT group), and the di(p-methoxyphenyl)phenylmethyl group (i.e. the DMT group). In some embodiments of the method of the invention, each of the protecting groups PG-1, PG-2, PG-x, PG-(x−1), and PG-n is independently of each other selected from the group consisting of the triphenylmethyl group, the (p-methoxyphenyl)diphenylmethyl group, and the di(p-methoxyphenyl)phenylmethyl group. In some embodiments of the method of the invention, each of the protecting groups PG-1, PG-2, PG-x, PG- (x−1), and PG-n is a di(p-methoxyphenyl)phenylmethyl group. In some preferred embodiments, the first cycle oligonucleotide O-1 comprises exactly one backbone hydroxyl moiety protected by a protecting group comprising an optionally substituted triarylmethyl residue, which is said protecting group PG-1. In some preferred embodiments, the first cycle oligonucleotide O-1 comprises exactly one protecting group comprising an optionally substituted triarylmethyl residue, which is said protecting group PG-1. In some preferred embodiments, the second cycle oligonucleotide O-2 comprises exactly one backbone hydroxyl moiety protected by a protecting group comprising an optionally substituted triarylmethyl residue, which is said protecting group PG-2. In some preferred embodiments, the second cycle oligonucleotide O-2 comprises exactly one protecting group comprising an optionally substituted triarylmethyl residue, which is said protecting group PG-2. In some preferred embodiments, each (x−1)-th cycle oligonucleotide O-(x−1) comprises exactly one backbone hydroxyl moiety protected by a protecting group comprising an optionally substituted triarylmethyl residue, which is said protecting group PG-(x−1). In some preferred embodiments, each (x−1)-th cycle oligonucleotide O-(x−1) comprises exactly one protecting group comprising an optionally substituted triarylmethyl residue, which is said protecting group PG-(x−1). In some preferred embodiments of the method of the invention: - the component (C-0)^# differs from the component C-0 only in that the backbone hydroxyl moiety protected by the protecting group PG-0 in the component C-0 is a free backbone hydroxyl group in the component (C-0)^#; - the first cycle oligonucleotide (O-1)^# differs from the first cycle oligonucleotide O-1 only in that the backbone hydroxyl moiety protected by the protecting group PG-1 in the first cycle oligonucleotide O-1 is a free backbone hydroxyl group in the first cycle oligonucleotide (O-1)^#; - the second cycle oligonucleotide (O-2)^# differs from the second cycle oligonucleotide O-2 only in that the backbone hydroxyl moiety protected by the protecting group PG-2 in the second cycle oligonucleotide O-2 is a free backbone hydroxyl group in the second cycle oligonucleotide (O-2)^#; - each (x−1)-th cycle oligonucleotide (O-(x−1))^# differs from the respective (x−1)-th cycle oligonucleotide O-(x−1) only in that the backbone hydroxyl moiety protected by a protecting group PG-(x−1) in the (x−1)-th cycle oligonucleotide O-(x−1) is a free backbone hydroxyl group in the (x−1)-th cycle oligonucleotide (O-(x−1))^#. The term “free backbone hydroxyl group” refers to a free hydroxyl group, which is part of the backbone of the respective nucleoside or oligonucleotide. The term "deprotection mixture M-(b-1)" refers to any mixture which may be used to effect cleavage of the protecting group PG-0 from the component C-0. The term "deprotection mixture M-(b-2)" refers to any mixture which may be used to effect cleavage of the protecting group PG-1 from the first cycle oligonucleotide O-1. The term "deprotection mixture M-(b-3)" refers to any mixture which may be used to effect cleavage of the protecting group PG-2 from the second cycle oligonucleotide O-2. The term "deprotection mixture M-(b-x)" refers to any mixture which may be used to effect cleavage of the protecting group PG-(x−1) from the (x−1)-th cycle oligonucleotide O-(x−1). It will be understood that said deprotection mixture M-(b-x) may be the same or different (i.e. comprise the same or different components in the same or different ratios and/or concentrations) between different iterations of step (b-x). Per definition, each of the protecting groups PG-0, PG-1, PG-2, PG-(x−1), PG-x, and PG-n is a protecting group “removable under acidic conditions”, which has been explained above to mean that each of these protecting groups can be cleaved (i.e. removed) by treatment with a protic acid, also referred to as BrØnsted-Lowry acid. It is known to the skilled artisan that the acid strength, simply speaking, the tendency of a Br^Ønsted-Lowry acid to donate a proton, may be expressed in terms of a pKa value, wherein a strong acid has a lower (i.e. smaller) pKa value than a weak acid. The term “pKa value” as such and the means of determining the pKa value of a protic acid form part of the common knowledge of the skilled artisan. Additionally, pKa values for commonly used BrØnsted-Lowry acids (and many more) are available in tabulated form from the literature. As used herein, the pKa value is such determinable in water (i.e. aqueous solution) at 25 °C, unless indicated differently. In some embodiments of the method of the invention, the deprotection mixture M-(b-1), the deprotection mixture M-(b-2), and each deprotection mixture M-(b-x) comprise a protic acid. In some embodiments of the method of the invention, the deprotection mixture M-(b-1), the deprotection mixture M-(b-2), and each deprotection mixture M-(b-x) comprise a protic acid having a pKa equal to or smaller than 5, equal to or smaller than 4, equal to or smaller than 3.5, equal to or smaller than 3, equal to or smaller than 2.5, or equal to or smaller than 2. In some embodiments of the method of the invention, the deprotection mixture M-(b-1), the deprotection mixture M-(b-2), and each deprotection mixture M-(b-x) comprise a protic acid having a pKa in the range of 0−5, 0−4, 0−3.5, 0−3, 0−2.5, or 0−2. The protic acid is not particularly limited in terms of its chemical structure. For example, the protic acid may be a carboxylic acid, a sulfonic acid, a mineral acid or mixtures thereof. Examples of carboxylic acids comprise trifluoroacetic acid (TFA), dichloroacetic acid (DCA), trichloroacetic acid (TCA), and acetic acid (AcOH). A carboxylic acid such as acetic acid may, for example, also be employed in combination with trimethylsilyl chloride (TMSCl). Examples of sulfonic acids comprise methanesulfonic acid and p-toluenesulfonic acid. Examples of mineral acids comprise hydrochloric acid and sulfuric acid. It will be understood that the molar amount of the protic acid in each deprotection mixture M-(b-1), M-(b-2), and M-(b-x) is preferably higher than the molar amount of the respective component or oligonucleotide from which the respective protecting group is to be cleaved. For example, the total molar amount of the protic acid comprised in the respective deprotection mixture may be in the range of 1−100 mol, 1−90 mol, 1−80 mol, 1−70 mol, 1−60 mol, 1−50 mol, 1−40 mol, or 1−30 mol per 1 mol of the respective component or oligonucleotide from which the respective protecting group is to be cleaved. Besides the protic acid, each of the deprotection mixtures M-(b-1), M-(b-2), and M-(b-x) may further comprise one or more carbocation scavengers. As used herein, the term “carbocation scavenger” relates to a nucleophilic compound, which may be used to bind a carbocation or to consume a carbocation by formal donation of a hydride anion, thereby preventing unwanted side reactions of the carbocation. Typical examples of such carbocations are carbocations formed during the cleavage of protecting groups comprising an optionally substituted triarylmethyl residue. For example, the cleavage of a di(p-methoxyphenyl)phenylmethyl (DMT) protecting group may result in a DMT cation (i.e. a di(p-methoxyphenyl)phenylmethyl cation). Non-limiting examples of carbocation scavengers comprise: - compounds comprising one or more sulfhydryl groups (SH) and one or more carboxyl groups (C(O)OH or C(O)O⁻) such as, e.g., glutathione, thiomalic acid, 3-mercaptopropionic acid, cysteine, cysteinyl-glutamic acid, and cysteinyl-aspartic acid, wherein the N-terminal amino group in any one of cysteine, cysteinyl-glutamic acid, and cysteinyl aspartic acid may optionally be protected by a protecting group removable under alkaline conditions such as, e.g., the 9-fluorenylmethyloxycarbonyl (Fmoc) protecting group, - compounds comprising an indole residue and one or more carboxyl groups (C(O)OH or C(O)O⁻), such as, e.g., 1-(1H-indol-5-yl) butanedicarboxylate (CAS- RN: 1905473-95-1), tryptophan, tryptophanyl-glutamic acid, tryptophanyl-aspartic acid, wherein the N-terminal amino group in any one of tryptophan, tryptophanyl-glutamic acid, and tryptophanyl-aspartic acid may optionally be protected by a protecting group removable under alkaline conditions such as, e.g., the Fmoc protecting group, - pyrrole or derivatives thereof, in which one or more hydrogen residue have been substituted for a C₁−C₆-alkyl group, preferably a methyl group (CH₃), such as, e.g., pyrrole, 2-methylpyrrole, 3-methylpyrrole, 2,3-dimethylpyrrole, and 2,4-dimethylpyrrole, - indole or derivatives thereof, in which one or more hydrogen residue have been substituted for a C1−C6-alkyl group, preferably a methyl group (CH3), such as, e.g., indole, 2-methylindole, 3-methylindole, 4-methylindole, 5-methylindole, 6-methylindole, 7-methylindole, 5,6-dimethylindole, and 6,7-dimethylindole, - water, - aliphatic alcohols comprising 1 to 6 carbon atoms such as methanol, ethanol, propanol, and isopropyl alcohol, - phenol or derivatives thereof such as o-cresol, m-cresol, and p-cresol, - phenol ethers such as, e.g., anisole, 1,3-dimethoxybenzene, and 1,3,5- trimethoxybenzene, - thioethers such as, e.g., dimethyl sulfide, methyl ethyl sulfide, and thioanisole, - silanes such as, e.g., triisopropylsilane (TIS) and triethylsilane (TES), - thiols and thiophenols such as, e.g., 1,2-ethanedithiol (EDT), 1,4-dithioerythrol (DTE), 1,4-dithiothreitol (DTT), 3,6-dioxa-1,8-octanedithiol (DODT), 1,4-benzenedimethanthiol (BDMT), 1,4-butanedithiol, 2-mercaptoethanol, thiophenol, and p-thiocresol, - polyalkylbenzenes such as, e.g., 1,3,5-trimethylbenzene and pentamethylbenzene, and - mixtures thereof. The above-mentioned compounds comprising one or more sulfhydryl groups (SH) and one or more carboxyl groups (C(O)OH or C(O)O⁻) as well as the above-mentioned compounds comprising an indole residue and one or more carboxyl groups (C(O)OH or C(O)O⁻) may be preferred carbocation scavengers, and glutathione, thiomalic acid, and 3-mercaptopropionic acid may be a particularly preferred carbocation scavenger. Glutathione is most preferred. It will be understood that the molar amount of the optional carbocation scavenger in each deprotection mixture M-(b-1), M-(b-2), and M-(b-x) is preferably higher than the molar amount of the respective component or oligonucleotide from which the respective protecting group is to be cleaved. For example, the total molar amount of the carbocation scavenger optionally comprised in each deprotection mixture M-(b-1), M-(b-2), and M-(b-x) may be in the range of 1−60 mol, 1−50 mol, 1−40 mol, 1−35 mol, 1−30 mol, 5−30 mol, 10−30 mol, or 15−30 mol, per 1 mol of of the respective component or oligonucleotide from which the respective protecting group is to be cleaved. With glutathione as carbocation scavenger, 1–10 mol or 2–9 mol or 3–8 mol or 3–7 mol or 4–6 mor or 5 mol of glutathione per 1 mol of the respective component or oligonucleotide from which the respective protecting group is to be cleaved may preferably be used. TFA as protic acid may preferably be used alongside glutathione as carbocation scavenger. The skilled artisan understands that in the course of an iterative (i.e., stepwise) oligonucleotide synthesis, it may be unpractical to determine the molar amount of the component or oligonucleotide from which the protecting group is to be cleaved in each coupling cycle. Hence, in practice, one may assume that the molar amount of the respective component or oligonucleotide from which the respective protecting group is to be cleaved is essentially constant throughout the synthesis and equal to the molar amount of the component C-0 as provided in step (a-1). In some embodiments of the method of the invention, each deprotection mixture M-(b-1), M-(b-2), and M-(b-x) comprises: - a protic acid, preferably a protic acid having a pKa equal to or smaller than 5, 4, 3.5, 3, 2.5 or 2, and - one or more carbocation scavengers (as defined herein). In some embodiments of the method of the invention, each deprotection mixture M-(b-1), M-(b-2), and M-(b-x) comprises: - a protic acid, preferably a protic acid having a pKa equal to or smaller than 5, 4, 3.5, 3, 2.5 or 2, and - one or more carbocation scavengers selected from the group consisting of compounds comprising one or more sulfhydryl groups (SH) and one or more carboxyl groups (C(O)OH or C(O)O⁻) and compounds comprising one indole residue and one or more carboxyl groups (C(O)OH or C(O)O⁻). In some embodiments of the method of the invention, each deprotection mixture M-(b-1), M-(b-2), and M-(b-x) comprises: - a protic acid selected from the group consisting of a carboxylic acid, a sulfonic acid, a mineral acid, and mixtures thereof, and - one or more carbocation scavengers, each of which is a compound comprising one sulfhydryl group (SH) and one or two carboxyl groups (C(O)OH or C(O)O⁻). In some embodiments of the method of the invention, each deprotection mixture M-(b-1), M-(b-2), and M-(b-x) comprises: - a protic acid having a pKa equal to or smaller than 5, 4, 3.5, 3, 2.5 or 2 and being selected from the group consisting of a carboxylic acid, a sulfonic acid, a mineral acid, and mixtures thereof, and - one or more carbocation scavengers, each of which is a compound comprising one sulfhydryl group (SH) and one or two carboxyl groups (C(O)OH or C(O)O⁻). In some embodiments of the method of the invention, each deprotection mixture M-(b-1), M-(b-2), and M-(b-x) comprises: - a protic acid selected from the group consisting of trifluoroacetic acid, dichloroacetic acid, trichloroacetic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and mixtures thereof, and - one or more carbocation scavengers, each of which is a compound comprising one sulfhydryl group (SH) and one or two carboxyl groups (C(O)OH or C(O)O⁻). In some embodiments of the method of the invention, each deprotection mixture M-(b-1), M-(b-2), and M-(b-x) comprises: - a protic acid selected from the group consisting of trifluoroacetic acid, dichloroacetic acid, trichloroacetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and mixtures thereof, and - one or more carbocation scavengers selected from the group consisting of glutathione, thiomalic acid, 3-mercaptopropionic acid, cysteine, cysteinyl- glutamic acid, and cysteinyl-aspartic acid, wherein the N-terminal amino group in any one of cysteine, cysteinyl-glutamic acid, and cysteinyl aspartic acid may optionally be protected by a protecting group removable under alkaline conditions such as, e.g., the 9-fluorenylmethyloxycarbonyl (Fmoc) protecting group. In some embodiments of the method of the invention, each deprotection mixture M-(b-1), M-(b-2), and M-(b-x) comprises: - a protic acid selected from the group consisting of trifluoroacetic acid, dichloroacetic acid, and trichloroacetic acid, and - a carbocation scavenger selected from the group consisting of glutathione, thiomalic acid, and 3-mercaptopropionic acid. In some preferred embodiments of the method of the invention, each deprotection mixture M-(b-1), M-(b-2), and M-(b-x) comprises trifluoroacetic acid and glutathione. Each deprotection mixture M-(b-1), M-(b-2), and M-(b-x) may be a solution, i.e. may further comprise a solvent or mixed solvent capable of dissolving said protic acid, and, if present, also said one or more carbocation scavengers and/or said one or more further additives. Said solvent or mixed solvent may preferably comprise one or more non-polar solvents. Non-limiting examples of non-polar solvents comprise: - ether solvents such as, e.g., alkylated derivatives of tetrahydropyran or tetrahydrofuran, in particular 4-methyltetrahydropyran (MTHP) and 2-methyltetrahydrofuran, cyclopentyl methyl ether, tert-butyl methyl ether, diethyl ether, and anisole; - aromatic solvents such as, e.g., benzene, toluene, o- or m- or p-xylene, and mesitylene; - aliphatic hydrocarbon solvents such as, e.g., pentanes, hexanes, heptanes, octanes, nonanes, and cyclic derivatives thereof such as cyclohexane; - ester solvents such as, e.g., ethyl acetate and isopropyl acetate; - halogenated aliphatic hydrocarbon solvents such as, e.g., dichloromethane, 1,2-dichloroethane, and chloroform; and mixtures thereof. Optionally, said one or more non-polar solvents may be mixed with one or more polar solvents. Non-limiting examples of such polar solvents comprise: - nitrile solvents such as, e.g., acetonitrile and propionitrile; - amide solvents such as, e.g., N-N-dimethylformamide, N-N-dimethylacetamine, N-methyl-2-piperidone, and N-methyl-2-pyrrolidone; - ketone solvents such as, e.g., acetone and 2-butanone; - polar ether solvents such as, e.g., 1,4-dioxane and tetrahydrofuran; - sulfoxide solvents such as, e.g., dimethylsulfoxide; and - mixtures thereof. Alternatively, any one of the deprotection mixtures M-(b-1), M-(b-2), and M-(b-x) may be formed by adding said protic acid, and optionally the one or more carbocation scavengers and/or further additives directly into the respective reaction mixture or organic phase of the preceding step of the coupling cycle. The term “incubating” in steps (b-1), (b-2), and (b-x) may be understood in the broadest sense to refer to any process of contacting the respective component or oligonucleotide from which the respective protecting group is to be cleaved and the respective deprotection mixture, preferably inside the same reaction vessel or reactor. Typically, the respective component or oligonucleotide from which the respective protecting group is to be cleaved may already be contained in a reaction vessel or reactor, to which the respective deprotection mixture is then added. Alternatively, the components of the respective deprotection mixture may be added individually to the reaction vessel or reactor containing the respective component or oligonucleotide from which the respective protecting group is to be cleaved, so that the respective deprotection mixture may be formed directly within said reaction vessel or reactor containing the respective component or oligonucleotide from which the respective protecting group is to be cleaved. In other words: The term “incubating” does not imply that a preformed deprotection mixture is employed. Alternatively, the respective deprotection mixture may already be contained in a reaction vessel or reactor, to which the respective component or oligonucleotide from which the respective protecting group is to be cleaved is then added. Any one of steps (b-1), (b-2), and (b-x) may, for example, be performed at a temperature in the range of −15 to 90 °C, −10 to 90 °C, 0 to 90 °C, 5 to 90 °C, 10 to 70 °C, 15 to 60 °C, or 15 to 50 °C. For convenience, any one of steps (b-1), (b-2), and (b-x) may simply be performed at room temperature. Increased temperatures may result in shorter reaction times. The reaction time may also depend on the chemical structure of the reactants and will routinely be selected by a skilled person, for example based on reaction monitoring using, e.g., thin-layer chromatography and/or high performance liquid chromatography (HPLC), optionally coupled to mass spectrometry. After performing the deprotection reaction of any one of steps (b-1), (b-2), and (b-x), a base may be added to the reaction mixture to completely or partly neutralize any excess of the protic acid. Such neutralization may typically be achieved by addition of one or more bases or a solution thereof directly into the reaction mixture of the respective step (b-1), (b-2), and (b-x). Non-limiting examples of bases which may be used for such neutralization comprise pyridine, benzimidazole, 1,2,4-triazole, N- phenylimidazole, 2-amino-4,6-dimethylpyrimidine, 1,10-phenanthroline, imidazole, N-methylimidazole, 2-chlorobenzimidazole, 2-bromobenzimidazole, 2-methylimidazole, 2-phenylbenzimidazole, N-phenylbenzimidazole, and 5-nitrobenzimidazole, among which pyridine may be preferred. It will be understood that such neutralization may additionally or alternatively be achieved, if at least one of the one or more aqueous extractions of the subsequent step (c-1), (c-2), or (c-x) is performed with an alkaline aqueous solution. Step (c-1) of some methods of the invention is: subjecting a solution comprising the component (C-0)^# to one or more aqueous extractions, wherein the organic phase comprises the component (C-0)^#. Step (c-2) of some methods of the invention is: subjecting a solution comprising the first cycle oligonucleotide (O-1)^# to one or more aqueous extractions, wherein the organic phase comprises the first cycle oligonucleotide (O-1)^#. Step (c-x) of some methods of the invention is: subjecting a solution comprising the (x−1)-th cycle oligonucleotide (O-(x−1))^# to one or more aqueous extractions, wherein the organic phase comprises the (x−1)-th cycle oligonucleotide (O-(x−1))^#. Said solution comprising the component (C-0)^# of step (c-1) may, for example, be the reaction mixture obtained from carrying step (b-1). Said solution comprising the first cycle oligonucleotide (O-1)^# of step (c-2) may, for example, be the reaction mixture obtained from carrying step (b-2). Said solution comprising the (x−1)-th cycle oligonucleotide (O-(x−1))^# of step (c-x) may, for example, be the reaction mixture obtained from carrying step (b-x) of the same coupling cycle. Optionally, said solutions comprising the component (C-0)^# or the first cycle oligonucleotide (O-1)^# or the (x−1)-th cycle oligonucleotide (O-(x−1))^# may be obtained from the respective reaction mixture by addition of one or more non-polar solvents, for example in order to facilitate the phase separation. Alternatively, or additionally, such non-polar solvents may also be added during or in between the one or more aqueous extractions of any one of steps (c-1), (c-2), and (c-x). Non-limiting examples of non-polar solvents which may be added comprise: - ether solvents such as, e.g., alkylated derivatives of tetrahydropyran or tetrahydrofuran, in particular 4-methyltetrahydropyran (MTHP) and 2-methyltetrahydrofuran, cyclopentyl methyl ether, tert-butyl methyl ether, diethyl ether, and anisole; - aromatic solvents such as, e.g., benzene, benzonitrile, toluene, o- or m- or p- xylene, and mesitylene; - aliphatic hydrocarbon solvents such as, e.g., pentanes, hexanes, heptanes, octanes, nonanes, and cyclic derivatives thereof such as cyclohexane; - ester solvents such as, e.g., ethyl acetate and isopropyl acetate; - halogenated aliphatic hydrocarbon solvents such as, e.g., dichloromethane, 1,2-dichloroethane, and chloroform; and - mixtures thereof. 4-Methyltetrahydropyran (MTHP) may be a preferred non-polar ether solvent which may be added prior to or during or in between the aqueous extraction(s) of any one of steps (c-1), (c-2), and (c-x). Additionally, or alternatively, one or more amide solvents S^A (as defined herein below) may be added prior to or during or in between the aqueous extraction(s) of any one of steps (c-1), (c-2), and (c-x). The term “aqueous extraction” in steps (c-1), (c-2), and (c-x) of the method of the invention may be understood in the broadest sense as any liquid-liquid extraction operation during which the respective solution comprising the component (C-0)^# or the first cycle oligonucleotide (O-1)^# or the (x−1)-th cycle oligonucleotide (O-(x−1))^# is extracted with water or an aqueous solution. As used herein, an aqueous solution is a solution comprising water, preferably at least 10 vol-%, 20 vol-%, 30 vol-%, 40 vol-%, 50 vol-%, or 60 vol-% of water. Hence, water is herein also considered a specific aqueous solution, since it comprises more than 10 vol-%, 20 vol-%, 30 vol- %, 40 vol-%, 50 vol-%, or 60 vol-% of water. An aqueous solution may optionally comprise one or more water-miscible organic solvents. Non-limiting examples of such water-miscible organic solvents comprise: - alcohol solvents such as methanol, ethanol, and isopropyl alcohol (propan-2-ol, IPA), - nitrile solvents such as acetonitrile and propionitrile, - ketone solvents such as acetone and 2-butanone, - polar ether solvents such as tetrahydrofuran and 1,4-dioxane, - polar amide solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, and N-methyl-2-piperidone, - sulfoxide solvents such as dimethyl sulfoxide, and - mixtures thereof. An aqueous solution may optionally also comprise one or more dissolved components. Non-limiting examples of such dissolved components comprise: - inorganic salts such as alkali halides, in particular sodium chloride (e.g. typically used to facilitate and/or accelerate phase separation), - water-soluble protic acids (as defined herein) such as acetic acid, - water-soluble organic or inorganic bases such as N-methylmorpholine (NMM), pyridine, sodium or potassium or ammonium carbonate or hydrogen carbonate, and sodium or potassium or ammonium phosphate or hydrogen phosphate or dihydrogen phosphate, and - mixtures thereof. It will be understood that for each of the one or more aqueous extractions of a step (c-1) or (c-2) or (c-x), the aqueous solution may be the same or different (i.e. comprise the same or different components in the same or different ratios). It will also be understood that the aqueous solutions may be the same or different for different steps (c-x) of different coupling cycles. As used herein, an “aqueous extraction” is further characterized in that it results in a mixture comprising at least one aqueous phase (preferably an aqueous layer) and at least one organic phase (preferably an organic layer), wherein the at least one aqueous phase (preferably layer) is then separated from the at least one organic phase (preferably layer). In case of more than one organic phases (either from a single aqueous extraction or from back-extraction of one or more aqueous phase), these more than one organic phases may be combined to obtain “the organic phase” mentioned in steps (c-1), (c-2), and (c-x). In general, the means of performing aqueous extractions are well-known to the skilled person. The expression “the organic phase comprises the component (C-0)^#” in step (c-1) may be understood in the broadest sense to mean that some of the molecules of said component (C-0)^# are dissolved in the organic phase. The expression “the organic phase comprises the first cycle oligonucleotide (O-1)^#” in step (c-2) may be understood in the broadest sense to mean that some of the molecules of said first cycle oligonucleotide (O-1)^# are dissolved in the organic phase. The expression “the organic phase comprises the (x−1)-th cycle oligonucleotide (O-(x−1))^#” in step (c-x) may be understood in the broadest sense to mean that some of the molecules of said (x−1)-th cycle oligonucleotide (O-(x−1))^# are dissolved in the organic phase. It is preferred that most molecules (e.g. more than 50 %, 60 %, 70 %, 80 %, or 90 % of the molecules) of the said component (C-0)^# or said first cycle oligonucleotide (O-1)^#or said (x−1)-th cycle oligonucleotide (O-(x−1))^# are comprised in the organic phase (and thus not in the aqueous phase). As used herein, the pH-value of the aqueous phase of an aqueous extraction is to be determined from the respective aqueous phase after the aqueous extraction (i.e., after the phase separation, preferably after removing the aqueous phase from the organic phase or vice versa) and at a temperature in the range of 23–28 °C, preferably 25 °C. As used herein, the term “aqueous phase” of an aqueous extraction is distinct from the aqueous solution, which is initially combined with the solution comprising the component (C-0)^# (in step (c-1)) or the first cycle oligonucleotide (O-1)^# (in step (c- 2)) or the (x−1)-th cycle oligonucleotide (O-(x−1))^# (in a step (c-x)), followed by extraction. The skilled artisan understands that the “aqueous phase” typically comprises species which have been extracted from the solution comprising the component (C-0)^# (in step (c-1)) or the first cycle oligonucleotide (O-1)^# (in step (c- 2)) or the (x−1)-th cycle oligonucleotide (O-(x−1))^# (in a step (c-x)), e.g., water- soluble species. Hence, to say that the aqueous phase of an aqueous extraction has a certain pH-value is not the same as to say that the aqueous solution employed in the aqueous extraction has a certain pH-value. For example, pure water or any other aqueous solution may be used for an aqueous extraction, and during the aqueous extraction one or more protic acids may partition from said solution comprising the component (C-0)^# (in step (c-1)) or the first cycle oligonucleotide (O- 1)^# (in step (c-2)) or the (x−1)-th cycle oligonucleotide (O-(x−1))^# (in a step (c-x)) into the aqueous phase, so that the aqueous phase then has a pH-value which is lower than the pH-value of the water or other aqueous solution employed. In some embodiments of the method of the invention, said one or more aqueous extractions of steps (c-1), (c-2), and (c-x) comprise a first aqueous extraction comprising the following steps (Ex-I) to (Ex-IV): (Ex-I) Combining the solution comprising the component (C-0)^# (in step (c-1)) or the first cycle oligonucleotide (O-1)^# (in step (c-2)) or the (x−1)-th cycle oligonucleotide (O-(x−1))^# (in a step (c-x)) with a first aqueous solution AS-I; (Ex-II) Agitating the mixture of step (Ex-I); (Ex-III) Allowing the phases to separate, so as to obtain a first organic phase OP-I and a first aqueous phase AP-I, wherein the first organic phase OP-I comprises the component (C-0)^# (in step (c-1)) or the first cycle oligonucleotide (O-1)^# (in step (c-2)) or the (x−1)-th cycle oligonucleotide (O-(x−1))^# (in a step (c-x)); and (Ex-IV) Removing the first aqueous phase AP-I from the first organic phase OP-I or vice versa; wherein the solution comprising the component (C-0)^# (in step (c-1)) or the first cycle oligonucleotide (O-1)^# (in step (c-2)) or the (x−1)-th cycle oligonucleotide (O-(x−1))^# (in a step (c-x)) of step (Ex-I) comprises one or more oranic solvents S^O and/or one or more organic solvents S^O are added during any one of steps (Ex-I) and (Ex-II) and/or in between these steps. In such embodiments, the first aqueous phase AP-I preferably has a pH-value equal to or smaller than 7, preferably in the range of 1.0– 7.0, 2.0–7.0, 3.0–7.0, 3.5–7.0, 4.0–7.0, 4.0–6.0, 4.5–7.0, 4.5–6.5, 4.5–6.0, or 4.5−5.5. In some embodiments of the method of the invention, said one or more aqueous extractions of steps (c-1), (c-2), and (c-x) comprise a first aqueous extraction comprising the aforementioned steps (Ex-I) to (Ex-IV), and a second aqueous extraction comprising the following steps (Ex-V) to (Ex-VIII): (Ex-V) Combining the first organic phase OP-I with a second aqueous solution AS-II; (Ex-VI) Agitating the mixture of step (Ex-V); (Ex-VII) Allowing the phases to separate, so as to obtain a second organic phase OP-II and a second aqueous phase AP-II, wherein the second organic phase OP-II comprises the component (C-0)^# (in step (c-1)) or the first cycle oligonucleotide (O-1)^# (in step (c-2)) or the (x−1)-th cycle oligonucleotide (O-(x−1))^# (in a step (c-x)); and (Ex-VIII) Removing the second aqueous phase AP-II from the second organic phase OP-II or vice versa; wherein the first organic phase OP-I comprises one or more organic solvents S^O and, optionally, one or more organic solvents S^O are added during any one of steps (Ex-V) and (Ex-VI) and/or in between these steps. In such embodiments, the second aqueous phase AP-II preferably has a pH-value in the range of 4.0–7.0, 4.5–7.0, 5.0–7.0, 5.0–6.5, or 5.0–6.0. In some embodiments of the method of the invention, said one or more aqueous extractions of steps (c-1), (c-2), and (c-x) comprise a first aqueous extraction comprising the aforementioned steps (Ex-I) to (Ex-IV), a second aqueous extraction comprising the aforementioned steps (Ex-V) to (Ex-VIII), and a third aqueous extraction comprising the following steps (Ex-IX) to (Ex-XII): (Ex-IX) Combining the second organic phase OP-II with a third aqueous solution AS-III; (Ex-X) Agitating the mixture of step (Ex-IX); (Ex-XI) Allowing the phases to separate, so as to obtain a third organic phase OP-III and a third aqueous phase AP-III, wherein the third organic phase OP-III comprises the component (C-0)^# (in step (c-1)) or the first cycle oligonucleotide (O-1)^# (in step (c-2)) or the (x−1)-th cycle oligonucleotide (O-(x−1))^# (in a step (c-x)); and (Ex-XII) Removing the third aqueous phase AP-III from the third organic phase OP-III or vice versa; wherein the second organic phase OP-II comprises one or more organic solvents S^O and, optionally, one or more organic solvents S^O are added during any one of steps (Ex-IX) and (Ex-X) and/or in between these steps. In such embodiments, the third aqueous phase AP-III preferably has a pH-value in the range of 5.0–7.0, 5.0– 6.5, or 5.0–6.0. The skilled artisan understands that one or more further aqueous extractions similar to the first, second, and third aqueous extraction comprising steps (Ex-I) to (Ex-IV) or steps (Ex-V) to (Ex-VIII) or steps (Ex-IX) to (Ex-XII), respectively, may be carried out in addition in any one of steps (c-1), (c-2), and (c-x). Such further aqueous extractions preferably comprise the following steps (Ex-A´) to (Ex-D´): (Ex-A´) Combining the organic phase obtained from the previous aqueous extraction with an aqueous solution; (Ex-B´) Agitating the mixture of step (Ex-A´); (Ex-C´) Allowing the phases to separate, so as to obtain an organic phase and an aqueous phase, wherein the organic phase comprises the component (C- 0)^# (in step (c-1)) or the first cycle oligonucleotide (O-1)^# (in step (c-2)) or the (x−1)-th cycle oligonucleotide (O-(x−1))^# (in a step (c-x)); and (Ex-D´) Removing the aqueous phase from the organic phase or vice versa; wherein the organic phase obtained from the previous aqueous extraction comprises one or more organic solvents S^O and, optionally, one or more organic solvents ^O are added during any one of steps (Ex-A´) and (Ex-B´) and/or in between these steps. In such embodiments, the aqueous phase obtained in each step (Ex-C´) preferably has a pH-value equal to or smaller than 7, preferably in the range of 4.0–7.0 or 4.0–6.0, in particular in the range of 5.0–7.0, 5.0–6.5, or 5.0–6.0 The skilled artisan understands that the aqueous solutions of two or more aqueous extractions, e.g., the aqueous solutions AS-I, AS-I, and AS-III, need not be identical, i.e., they may or may not comprise the same species/components/solvents and the amounts/volumes of said species/components/solvents may be the same or different, unless indicated differently in specific embodiments. In some embodiments of the method of the invention, in which said one or more aqueous extractions of any one of steps (c-1), (c-2), and (c-x) comprise said first aqueous extraction comprising steps (Ex-I) to (Ex-IV), the first aqueous solution AS-I has a pH-value in the range of 5.0–8.0, 4.0–7.5, 4.5–7.0, 5.0–7.0, 5.0–6.5 or 5.0– 6.0. In some embodiments of the method of the invention, in which said one or more aqueous extractions of any one of steps (c-1), (c-2), and (c-x) comprise said first aqueous extraction comprising steps (Ex-I) to (Ex-IV), the first aqueous solution AS- I does not comprise a compound having a pKa-value equal to or larger than 9.0, 8.5, 8.0, 7.5, 7.0, 6.5, 6.0 or 5.5. The pKa-value is to be determined in water (i.e., in an aqueous solution of the respective compound) at 25 °C. In some embodiments of the method of the invention, in which said one or more aqueous extractions of any one of steps (c-1), (c-2), and (c-x) comprise said first aqueous extraction comprising steps (Ex-I) to (Ex-IV), and said second aqueous extraction comprising steps (Ex-V) to (Ex-VIII), each of the first aqueous solution AS-I and the second aqueous solution AS-II has a pH-value in the range of 5.0–8.0, 4.0–7.5, 4.5–7.0, 5.0–7.0, 5.0–6.5 or 5.0–6.0. In some embodiments of the method of the invention, in which said one or more aqueous extractions of any one of steps (c-1), (c-2), and (c-x) comprise said first aqueous extraction comprising steps (Ex-I) to (Ex-IV), and said second aqueous extraction comprising steps (Ex-V) to (Ex-VIII), none of the first aqueous solution AS-I and the second aqueous solution AS-II comprises a compound having a pKa-value equal to or larger than 9.0, 8.5, 8.0, 7.5, 7.0, 6.5, 6.0 or 5.5. The pKa-value is to be determined in water (i.e., in an aqueous solution of the respective compound) at 25 °C. In some embodiments of the method of the invention, in which said one or more aqueous extractions of any one of steps (c-1), (c-2), and (c-x) comprise said first aqueous extraction comprising steps (Ex-I) to (Ex-IV), and said second aqueous extraction comprising steps (Ex-V) to (Ex-VIII), and said third aqueous extraction comprising steps (Ex-IX) to (Ex-XII), each of the first aqueous solution AS-I, the second aqueous solution AS-II, and the third aqueous solution AS-III has a pH-value in the range of 5.0–8.0, 4.0–7.5, 4.5–7.0, 5.0–7.0, 5.0–6.5 or 5.0–6.0. In some embodiments of the method of the invention, in which said one or more aqueous extractions of any one of steps (c-1), (c-2), and (c-x) comprise said first aqueous extraction comprising steps (Ex-I) to (Ex-IV), and said second aqueous extraction comprising steps (Ex-V) to (Ex-VIII), and said third aqueous extraction comprising steps (Ex-IX) to (Ex-XII), none of the first aqueous solution AS-I, the second aqueous solution AS-II, and the third aqueous solution AS-III comprises a compound having a pKa-value equal to or larger than 9.0, 8.5, 8.0, 7.5, 7.0, 6.5, 6.0 or 5.5. The pKa-value is to be determined in water (i.e., in an aqueous solution of the respective compound) at 25 °C. Step (Ex-I) is: Combining the solution comprising the component (C-0)^# (in step (c- 1)) or the first cycle oligonucleotide (O-1)^# (in step (c-2)) or the (x−1)-th cycle oligonucleotide (O-(x−1))^# (in a step (c-x)) with a first aqueous solution AS-I. This means that the solution comprising the component (C-0)^# (in step (c-1)) or the first cycle oligonucleotide (O-1)^# (in step (c-2)) or the (x−1)-th cycle oligonucleotide (O-(x−1))^# (in a step (c-x)) and the first aqueous solution AS-I are combined in the vessel or funnel or other receptacle, in which the agitation of step (Ex-II) is to be performed. Step (Ex-V) is: Combining the first organic phase OP-I with a second aqueous solution AS-II. This means that the first organic phase OP-I and the second aqueous solution AS-II are combined in the vessel or funnel or other receptacle, in which the agitation of step (Ex-VI) is to be performed. Step (Ex-IX) is: Combining the second organic phase OP-II with a third aqueous solution AS-III. This means that the second organic phase OP-II and the third aqueous solution AS-III are combined in the vessel or funnel or other receptacle, in which the agitation of step (Ex-X) is to be performed. Step (Ex-A´) is: Combining the organic phase obtained from the previous aqueous extraction with an aqueous solution. This means that the organic phase from the previous aqueous extraction and the aqueous solution are combined in the vessel or funnel or other receptacle, in which the agitation of step (Ex-B´) is to be performed. The term “agitating” in steps (Ex-II), (Ex-VI), (Ex-X), and (Ex-B´) may be understood in the broadest sense to refer to any operation of inducing a movement of the respective mixture. This typically facilitates the extraction process. Suitable means of agitation are known to those skilled in the art and comprise, e.g., shaking, stirring, e.g., mechanical stirring, bubbling of an inert has such as nitrogen, and inversion of the vessel or funnel or other receptacle in which the one or more aqueous extractions may be carried out. More than one such means of agitation may be used in combination. On an industrial scale, a reaction vessel made of a suitable material, e.g., stainless steel, equipped with a mechanical stirrer may preferably be used for the agitation step (Ex-2), (Ex-6), (Ex-X) or (Ex-B´). In practice, it is usually most convenient, to carry out all steps of an aqueous extraction in the same vessel. Under the agitation of step (Ex-II), (Ex-VI), (Ex-X), and (Ex-B´) the respective organic phase and the respective aqueous phase usually form a dispersion. Under such conditions, one phase may typically not be removed from the other. For this purpose, phase separation is usually required. Hence: - Step (Ex-III) comprises “Allowing the phases to separate, so as to obtain a first organic phase OP-I and a first aqueous phase AP-I”; - Step (Ex-VII) comprises “Allowing the phases to separate, so as to obtain a second organic phase OP-II and a second aqueous phase AP-II”; - Step (Ex-XI) comprises “Allowing the phases to separate, so as to obtain a third organic phase OP-III and a third aqueous phase AP-III”; and - Step (Ex-C´) comprises “Allowing the phases to separate, so as to obtain an organic phase and an aqueous phase.” As used herein, the term “allowing the phases to separate so as to obtain an organic phase and an aqueous phase” may be understood in the broadest sense as establishing conditions under which the organic phase forms one or more, preferably one, layer (i.e., organic layer) and the aqueous phase forms one or more, preferably one, layer (i.e., aqueous layer). The skilled artisan understands that an organic layer formed from an organic phase may typically not be completely free of an aqueous phase and that an aqueous layer formed from an aqueous phase may typically not be completely free of an organic phase. Hence, an organic layer is mostly but not necessarily completely composed of an organic phase and an aqueous layer is mostly but not necessarily completely composed of an aqueous phase. “Establishing conditions under which the organic phase forms one or more, preferably one, layer (i.e., organic layer) and the aqueous phase forms one or more, preferably one, layer (i.e., aqueous layer)” may usually comprise stopping the agitation. This means that the shaking and/or stirring and/or inert gas bubbling and/or inversion of the vessel or funnel or other receptacle is stopped. It will be understood that some movement of the liquids may still occur. Hence, in some preferred embodiments, step (Ex-III) is: Stopping the agitation and allowing the phases to separate, so as to obtain a first organic phase OP-I and a first aqueous phase AP-I, wherein the first organic phase OP-I comprises the component (C-0)^# (in step (c-1)) or the first cycle oligonucleotide (O-1)^# (in step (c- 2)) or the (x−1)-th cycle oligonucleotide (O-(x−1))^# (in a step (c-x)). In some preferred embodiments, step (Ex-VII) is: Stopping the agitation and allowing the phases to separate, so as to obtain a second organic phase OP-II and a second aqueous phase AP-II, wherein the second organic phase OP-II comprises the component (C- 0)^# (in step (c-1)) or the first cycle oligonucleotide (O-1)^# (in step (c-2)) or the (x−1)- th cycle oligonucleotide (O-(x−1))^# (in a step (c-x)). In some preferred embodiments, step (Ex-XI) is: Stopping the agitation and allowing the phases to separate, so as to obtain a third organic phase OP-III and a third aqueous phase AP-III, wherein the third organic phase OP-III comprises the component (C-0)^# (in step (c-1)) or the first cycle oligonucleotide (O-1)^# (in step (c-2)) or the (x−1)-th cycle oligonucleotide (O-(x−1))^# (in a step (c-x)). In some preferred embodiments, step (Ex-C´) is: Stopping the agitation and allowing the phases to separate, so as to obtain an organic phase and an aqueous phase, wherein the organic phase comprises the component (C-0)^# (in step (c-1)) or the first cycle oligonucleotide (O-1)^# (in step (c- 2)) or the (x−1)-th cycle oligonucleotide (O-(x−1))^# (in a step (c-x)). Typically, one may simply wait for the phases to separate. Phase separation may optionally be speeded up by addition of aqueous solutions comprising dissolved ions, e.g., by addition of brine (i.e., an aqueous solution of sodium chloride), as known to those skilled in the art. The expression “the organic phase comprises the component C” has been explained above. In steps (Ex-IV), (Ex-VIII), (Ex-XII), and (Ex-D´), the respective aqueous phase is removed from the respective organic phase or vice versa. This means that at least one aqueous layer is physically removed from at least one organic layer or vice versa. This removal may typically comprise draining of one layer, typically the bottom layer, e.g., the aqueous layer. It will be understood that this removal is not necessarily complete. In other words, “removing” in this context is not to mean “completely removing” but preferably means “mostly removing”. In this context, removing one phase from another phase may mean removing at least 51 vol-%, 60 vol-%, 70 vol-%, 80 vol-%, 90 vol-%, 95 vol-%, 96 vol-%, 97 vol-%, 98 vol-% or 99 vol-% of the respective phase to be removed. In practice, there will usually be a clearly recognizable phase boundary between the organic layer and the aqueous layer, so that removing the one from the other may simply be achieved by draining the bottom layer until the phase boundary is reached. Step (d-1) of some methods of the invention is: optionally, reducing the water content of the organic phase comprising the component (C-0)^#. Step (d-2) of some of the methods of the invention is: optionally, reducing the water content of the organic phase comprising the first cycle oligonucleotide (O-1)^#. Step (d-x) of some of the methods of the invention is: optionally, reducing the water content of the organic phase comprising the (x−1)-th cycle oligonucleotide (O-(x−1))^#. The term “optionally” in steps (d-1), (d-2), and (d-x) denotes that the respective step may or may not be carried out in a given coupling cycle, unless indicated differently in the context of specific embodiments. In some embodiments of the method of the invention, step (d-1) is carried out (i.e. is not optional). In some embodiments of the method of the invention, in the second coupling cycle, step (d-2) is carried out (i.e. is not optional). In some embodiments of the method of the invention, in at least one, or each, coupling cycle comprising steps (b-x) to (h-x) (as far as present), step (d-x) is carried out (i.e. is not optional). The term “the organic phase” in steps (d-1), (d-2), and (d-x) refers to “the organic phase” of the respective step (c-1) or (c-2) or (c-x) of the same coupling cycle. The term “reducing the water content” may be understood in the broadest sense as any operation during which the concentration of water, preferably measured via standard Karl Fischer titration at 25 °C, is reduced. The set up may, for example, be as follows: The titration cell may be filled with HYDRANAL^TM -Coulomat Oil for anolyte reagent, and the inner burette may be filled with HYDRANAL^TM -Coulomat CG for catholyte reagent. After pretitration for dehydration, sample (100 µL) may be added to the titration sell and the measurement may be started. In line with common practice, the water content of solutions is herein reported in parts per million (ppm). Said reduction of the water content may be characterized by its end point. Preferably, the water content is reduced so that (i.e. until) it is equal to or less than 2000 ppm, 1900 ppm, 1800 ppm, 1700 ppm, 1600 ppm, 1500 ppm, 1400 ppm, 1300 ppm, 1200 ppm, 1100 ppm, 1000 ppm, 900 ppm, 800 ppm, 700 ppm, 600 ppm, 500 ppm, 400 ppm, 300 ppm, 250 ppm, 200 ppm, 150 ppm, or 100 ppm. In some embodiments of the method of the invention, step (d-1) is: optionally, reducing the water content of the organic phase comprising the component (C-0)^#, wherein the water content is adjusted to be equal to or less than 2000 ppm, 1900 ppm, 1800 ppm, 1700 ppm, 1600 ppm, 1500 ppm, 1400 ppm, 1300 ppm, 1200 ppm, 1100 ppm, 1000 ppm, 900 ppm, 800 ppm, 700 ppm, 600 ppm, 500 ppm, 400 ppm, 300 ppm, 250 ppm, 200 ppm, 150 ppm, or 100 ppm. In some embodiments of the method of the invention, step (d-2) is: optionally, reducing the water content of the organic phase comprising the first cycle oligonucleotide (O-1)^#, wherein the water content is adjusted to be equal to or less than 2000 ppm, 1900 ppm, 1800 ppm, 1700 ppm, 1600 ppm, 1500 ppm, 1400 ppm, 1300 ppm, 1200 ppm, 1100 ppm, 1000 ppm, 900 ppm, 800 ppm, 700 ppm, 600 ppm, 500 ppm, 400 ppm, 300 ppm, 250 ppm, 200 ppm, 150 ppm, or 100 ppm. In some embodiments of the method of the invention, step (d-x) is: optionally, reducing the water content of the organic phase comprising the (x−1)-th cycle oligonucleotide (O-(x−1))^#, wherein the water content is adjusted to be equal to or less than 2000 ppm, 1900 ppm, 1800 ppm, 1700 ppm, 1600 ppm, 1500 ppm, 1400 ppm, 1300 ppm, 1200 ppm, 1100 ppm, 1000 ppm, 900 ppm, 800 ppm, 700 ppm, 600 ppm, 500 ppm, 400 ppm, 300 ppm, 250 ppm, 200 ppm, 150 ppm, or 100 ppm. In some embodiments of the method of the invention: - step (d-1) is carried out (i.e. is not optional), if the organic phase comprising the component (C-0)^# of step (c-1) comprises more than 2000 ppm, 1900 ppm, 1800 ppm, 1700 ppm, 1600 ppm, 1500 ppm, 1400 ppm, 1300 ppm, 1200 ppm, 1100 ppm, 1000 ppm, 900 ppm, 800 ppm, 700 ppm, 600 ppm, 500 ppm, 400 ppm, 300 ppm, 250 ppm, 200 ppm, 150 ppm, or 100 ppm of water; - step (d-2) is carried out (i.e. is not optional), if the organic phase comprising the first cycle oligonucleotide (O-1)^# of step (c-2) comprises more than 2000 ppm, 1900 ppm, 1800 ppm, 1700 ppm, 1600 ppm, 1500 ppm, 1400 ppm, 1300 ppm, 1200 ppm, 1100 ppm, 1000 ppm, 900 ppm, 800 ppm, 700 ppm, 600 ppm, 500 ppm, 400 ppm, 300 ppm, 250 ppm, 200 ppm, 150 ppm, or 100 ppm of water; and - step (d-x) is carried out (i.e. is not optional), if the organic phase comprising the (x−1)-th cycle oligonucleotide (O-(x−1))^# of step (c-x) of the same coupling cycle comprises more than 2000 ppm, 1900 ppm, 1800 ppm, 1700 ppm, 1600 ppm, 1500 ppm, 1400 ppm, 1300 ppm, 1200 ppm, 1100 ppm, 1000 ppm, 900 ppm, 800 ppm, 700 ppm, 600 ppm, 500 ppm, 400 ppm, 300 ppm, 250 ppm, 200 ppm, 150 ppm, or 100 ppm of water. Any means of reducing the water content may be employed, preferred examples of which comprise azeotropic distillation and the use of a drying agent. In some embodiments of the method of the invention, in each of steps (d-1), (d-2), and (d-x), reducing the water content is achieved by means of azeotropic distillation (i.e. by subjecting said organic phase comprising the component (C-0)^# or the first cycle oligonucleotide (O-1)^# or the (x−1)-th cycle oligonucleotide (O-(x−1))^# to azeotropic distillation) and/or by means of contacting said organic phase comprising the component (C-0)^# or the first cycle oligonucleotide (O-1)^# or the (x−1)-th cycle oligonucleotide (O-(x−1))^# with a drying agent. In some embodiments of the method of the invention, in at least one or each of steps (d-1), (d-2), and (d-x), reducing the water content is achieved by means of azeotropic distillation. In some embodiments of the method of the invention, in at least one or each of steps (d-1), (d-2), and (d-x), reducing the water content is achieved by means of contacting said organic phase comprising the component (C-0)^# or the first cycle oligonucleotide (O-1)^# or the (x−1)-th cycle oligonucleotide (O-(x−1))^# with a drying agent. It will be understood that in any one of steps (d-1), (d-2), and (d-x), one or more solvents and/or further components may be added to said organic phase comprising the component (C-0)^# or the first cycle oligonucleotide (O-1)^# or the (x−1)-th cycle oligonucleotide (O-(x−1))^# prior to, during, and/or after reduction of the water content. The term “azeotropic distillation” may be understood in the broadest sense to refer to a distillation, in which an azeotrope of water and one or more organic solvents is distilled off. Said one or more organic solvents may already be comprised in the organic phase and/or may be added to the organic phase prior to and/or during azeotropic distillation. Preferably, said one or more organic solvents are selected so that the azeotrope with water has a lower boiling point than water itself and any one of the one or more organic solvents used to form said azeotrope. Preferred examples of said one or more organic solvents comprise toluene, benzene, and ether solvents, e.g. ether solvents S^E as defined herein (vide infra), in particular 4-methyltetrahydropyran (MTHP). A plethora of azeotropic data is available to the skilled artisan, e.g., in tabulated form, enabling him to select one or more suitable organic solvents for an azeotropic distillation. As used herein, the term “drying agent” may be understood in the broadest sense to refer to any salt or compound or macroscopic structure used to remove water from one or more organic solvents or solutions comprising one or more organic solvents. Any drying agent used for reducing the water content of organic solvents or solutions comprising organic solvents may be used in any one of steps (d-1), (d-2), and (d-x) of the method of the invention. Non-limiting examples of suitable drying agents comprise molecular sieves, in particular 3 Å (i.e.3 angstrom) or 4 Å molecular sieves, sulfuric acid, and inorganic salts such as sodium sulfate, magnesium sulfate, and calcium chloride. For example, the drying agent may be added to the organic phase, the water content of which is to be reduced. Alternatively, the organic phase, the water content of which is to be reduced, may be passed through a compartment, e.g. a column, packed with a drying agent, e.g. molecular sieves, as, for example, disclosed in X. Shi et al., The Journal of Organic Chemistry 2022, 87(4), 2087−2110 (cf., e.g., Figure 1 of the cited reference and explanations pertaining thereto). Step (e-1) of some methods of the invention is: reacting the component (C-0)^# with a building block B-1, wherein said building block B-1 is selected from the group consisting of a nucleoside and an oligonucleotide and comprises - a backbone hydroxyl moiety protected by a protecting group PG-1 removable under acidic conditions, and - a phosphorus moiety covalently bonded via its phosphorus atom to an oxygen atom of the backbone of the building block B-1, under conditions suitable to form a covalent bond between said free backbone hydroxyl group of the component (C-0)^# and the phosphorus atom of said phosphorus moiety of the building block B-1, thereby obtaining a first cycle oligonucleotide O-1. Step (e-2) of some of the methods of the invention is: reacting the first cycle oligonucleotide (O-1)^# with a building block B-2, wherein said building block B-2 is selected from the group consisting of a nucleoside and an oligonucleotide and comprises - a backbone hydroxyl moiety protected by a protecting group PG-2 removable under acidic conditions, and - a phosphorus moiety covalently bonded via its phosphorus atom to an oxygen atom of the backbone of the building block B-2, under conditions suitable to form a covalent bond between said free backbone hydroxyl group of the first cycle oligonucleotide (O-1)^# and the phosphorus atom of said phosphorus moiety of the building block B-2, thereby obtaining a second cycle oligonucleotide O-2. Step (e-x) of some of the methods of the invention is: reacting the (x−1)-th cycle oligonucleotide (O-(x−1))^# with a building block B-x, wherein said building block B-x is selected from the group consisting of a nucleoside and an oligonucleotide and comprises - a backbone hydroxyl moiety protected by a protecting group PG-x removable under acidic conditions, and - a phosphorus moiety covalently bonded via its phosphorus atom to an oxygen atom of the backbone of the building block B-x, under conditions suitable to form a covalent bond between said free backbone hydroxyl group of the (x−1)-th cycle oligonucleotide (O-(x−1))^# and the phosphorus atom of said phosphorus moiety of the building block B-x, thereby obtaining a x-th cycle oligonucleotide O-x. The terms “nucleoside and oligonucleotide” have been explained above. In some embodiments of the method of the invention, each of the building blocks B-1, B-2, and B-x is selected from the group consisting of a nucleoside and an oligonucleotide comprising not more than 50, 40, 30, 25, 20, 15, 10, or 5 nucleoside subunits. In some embodiments of the method of the invention, each of the building blocks B-1, B-2, and B-x is a nucleoside. In some embodiments of the method of the invention, each of the building blocks B-1, B-2, and B-x is an oligonucleotide. In some embodiments of the method of the invention, each of the building blocks B-1, B-2, and B-x is an oligonucleotide comprising not more than 50, 40, 30, 25, 20, 15, 10, or 5 nucleoside subunits. The term “backbone hydroxyl moiety” refers to a hydroxyl moiety which is part of the backbone of the respective building block B-1, B-2 or B-x and will be understood based on the above explanations of the terms “hydroxyl moiety” and “backbone”. The terms “protecting group” and “removable under acidic conditions” have been defined. The protecting groups PG-1, PG-2, and PG-x have been explained. It will be understood that said protecting group PG-x may be the same or different (i.e. have the same or a different chemical structure) in each coupling cycle comprising steps (b-x) to (h-x) (as far as present), unless indicated differently in the context of specific embodiments. Per definition, each of the building blocks B-1, B-2, and B-x further comprises a phosphorus moiety covalently bonded via its phosphorus atom to an oxygen atom of the backbone of the respective building block B-1, B-2, and B-x. The term “an oxygen atom of the backbone” refers to an oxygen atom which is part of the backbone of the respective building block B-1, B-2 or B-x and will be understood based on the above explanation of the term “backbone”. In some embodiments, each of the building blocks B-1, B-2, and B-x comprises: - exactly one backbone hydroxyl moiety protected by a protecting group PG-1 or PG-2 or PG-x removable under acidic conditions, and - exactly one phosphorus moiety covalently bonded via its phosphorus atom to an oxygen atom of the backbone of the respective building block B-1 or B-2 or B-x. In some embodiments of the method of the invention, each of the building blocks B-1, B-2, and B-x comprises: - exactly one protecting group removable under acidic conditions, which is said protecting group PG-1 or PG-2 or PG-x, and - exactly one phosphorus moiety covalently bonded via its phosphorus atom to an oxygen atom of the backbone of the respective building block B-1 or B-2 or B-x. In some embodiments of the method of the invention, each of the building blocks B- 1, B-2, and B-x comprises: - exactly one protecting group comprising an optionally substituted triarylmethyl residue, which is said protecting group PG-1 or PG-2 or PG-x, and - exactly one phosphorus moiety covalently bonded via its phosphorus atom to an oxygen atom of the backbone of the respective building block B-1 or B-2 or B-x. In some embodiments of the method of the invention, each of the building blocks B-1, B-2, and B-x is a compound of the following Formula II: wherein in Formula II: each oxygen atom (O) depicted within each nucleoside subunit y-0 to y-q represents the oxygen atom of a hydroxyl moiety of the respective nucleoside subunit; each nucleoside subunit y-0 to y-q may be the same or different (i.e. have the same or a different chemical structure); PM is a phosphorus moiety; PG is the protecting group PG-1 (for building block B-1) or PG-2 (for building block B-2) or PG-x (for a building block B-x) and is a protecting group removable under acidic conditions; q is an integer equal to or larger than 0; Y² is selected independently for each repetitive unit q from the group consisting of O and S; Z² is selected independently for each repetitive unit q from the group consisting of O-R^z-2, and S-R^z-2; and R^z-2 is a protecting group, which may be the same or different for each repetitive unit q. In some embodiments of the method of the invention, each of the building blocks B-1, B-2, and B-x is a compound of the following Formula II-a: (Formula II-a), wherein in Formula II-a: q, PG, Y², Z², R^Z-2, and PM are defined as for Formula II; B^N is a nucleobase, which may be the same or different (i.e. have the same or a different chemical structure) at each occurrence; R^XI is at each occurrence independently selected from the group consisting of H, F, O-(C₁−C₅-alkyl), O-(C₁−C₅-alkyl)-O-(C₁-C₅-alkyl), O-Si(C₁−C₅-alkyl)₃, and O-CH₂-O-Si(C₁−C₅-alkyl)₃; R^XIII is independently at each occurrence H or R^XIII and R^XI of the same nucleoside subunit (i.e. bonded to the 4´- and 2´-C atom of the same carbohydrate moiety) together form a structure +–CH2-O−++, +–CH(CH3)-O−++, or +–CH2-CH2-O−++, where + is the point of attachment to the 4´-carbon atom (i.e. the carbon atom to which R^XIII is bonded) and ++ is the point of attachment to the 2´-carbon (i.e. the carbon atom to which R^XI is bonded); and for each nucleoside subunit independently, R^XII, R^XIV, and R^XV are either all H or they are bonded together so that the respective nucleoside subunit has a structure of the following Formula II-a-tc:

(Formula II-a-tc), wherein in Formula II-a-tc: the oxygen atom from which the dashed line originates represents the oxygen atom bonded to the 3´-carbon atom, i.e. the carbon atom to which R^XII is bonded in Formula II-a; the dashed line indicates the covalent chemical bond interconnecting the respective oxygen atom of the nucleoside subunit of Formula II-a-tc and the phosphorus moiety PM or P(Y²)(Z²) in Formula II-a; the oxygen atom from which the wavy line originates represents the oxygen atom bonded to the 5´-carbon atom, i.e. the carbon atom to which C(R^XIV)(R^XV) is bonded in Formula II-a; and the wavy line indicates the covalent chemical bond interconnecting the respective oxygen atom of the nucleoside subunit of Formula II-a-tc and either PG or P(Y²)(Z²) in Formula II-a. In some embodiments of the method of the invention each of the building blocks B-1, B-2, and B-x is a compound of the following Formula II-b:

(Formula II-b), wherein in Formula II-b: q, PG, Y², Z², R^z-2, PM, B^N, R^XI, and R^XIII are defined as for Formula II-a, and for each nucleoside subunit independently, R^XII, R^XIV, and R^XV are either all H or they are bonded together so that the respective nucleoside subunit has a structure of the following Formula II-b-tc: (Formula II-b-tc), wherein in Formula II-b-tc: the oxygen atom from which the dashed line originates represents the oxygen atom bonded to the 3´-carbon atom, i.e. the carbon atom to which R^XII is bonded in Formula II-b; the dashed line indicates the covalent chemical bond interconnecting the respective oxygen atom of the nucleoside subunit of Formula II-b-tc and either the phosphorus moiety PM or P(Y²)(Z²) in Formula II-b; the oxygen atom from which the wavy line originates represents the oxygen atom bonded to the 5´-carbon atom, i.e. the carbon atom to which C(R^XIV)(R^XV) is bonded in Formula II-b; and the wavy line indicates the covalent chemical bond interconnecting the respective oxygen atom of the nucleoside subunit of Formula II-b-tc and either PG or P(Y²)(Z²) in Formula II-b. As used herein, the term “phosphorus moiety” may be understood in the broadest sense and may refer to any atom group comprising at least one, preferably exactly one, phosphorus atom, wherein the term “atom group” may refer to two or more atoms. In such an atom group, it is not required that each atom is covalently bonded to each further atom of said atom group, but that each atom is covalently bonded to at least one further atom of said atom group. From steps (e-1), (e-2), and (e-x) it is clear that said phosphorus moiety covalently bonded via its phosphorus atom to an oxygen atom of the backbone of the respective building block B-1 or B-2 or B-x, e.g. the phosphorus moiety PM of any one of Formulae II, II-a, and II-b, is a phosphorus moiety capable of engaging in a bond forming (condensation) reaction with a free hydroxyl group. The skilled artisan is aware of phosphorus moieties which fulfill this requirement and is able to select a suitable phosphorus moiety without undue experimentation. It is further known to those skilled in the art, that the phosphorus moiety which engages in such a bond forming reaction will typically form an internucleosidic linkage group of the elongated oligonucleotide formed via said bond forming reaction. Said phosphorus moiety covalently bonded via its phosphorus atom to an oxygen atom of the backbone of the respective building block B-1 or B- 2 or B-x, e.g. the phosphorus moiety PM of any one of Formulae II, II-a, and II-b, may be a phosphorus (III) moiety, also referred to as P (III) moiety, i.e. a phosphorus moiety comprising a P (III) atom as defined herein. Non-limiting examples of such P (III) moieties are phosphoramidite moieties, as e.g. disclosed in X. Wei et al., Tetrahedron 2013, 69, 3615–3637, and H-phosphonate monoester moieties, as e.g. disclosed in J. Stawinski and R. Strömberg (2005), Di- and Oligonucleotide Synthesis Using H-Phosphonate Chemistry, in Methods in Molecular Biology, vol. 288: Oligonucleotide Synthesis: Methods and Applications, edited by P. Herdewijn, Humana Press Inc., Totowa NJ, https://doi.org/10.1385/1-59259-823-4:081. Alternatively, said phosphorus moiety covalently bonded via its phosphorus atom to an oxygen atom of the backbone of the respective building block B-1 or B-2 or B-x, e.g. the phosphorus moiety PM of any one of Formulae II, II-a, and II-b, may be a phosphorus (V) moiety, also referred to as P (V) moiety, i.e. a phosphorus moiety comprising a P (V) atom as defined herein. Examples of such P (V) moieties comprise classical aryl phosphate diester moieties as e.g. exemplified by H. Lönneberg (Beilstein Journal of Organic Chemistry, 2017, 13, 1368–1387) and the P (V) moieties disclosed by Baran et al. (Science 2018, 361, 12341238 and ACS Central Science 2021, 7, 1473–1485). In some embodiments of the method of the invention, each of the building blocks B-1, B-2, and B-x is a compound of the following Formula II-1:

(Formula II-1), wherein in Formula II-1: each oxygen atom (O) depicted within each nucleoside subunit y-0 to y-q represents the oxygen atom of a hydroxyl moiety of the respective nucleoside subunit; each nucleoside subunit y-0 to y-q may be the same or different; PG is the protecting group PG-1 (for the building block B-1) or PG-2 (for the building block B-2) or PG-x (for a building block B-x) and is a protecting group removable under acidic conditions; q is an integer equal to or larger than 0; Y² is selected independently for each repetitive unit q from the group consisting of O and S; Z² is selected independently for each repetitive unit q from the group consisting of O-R^z-2 and S-R^z-2; R^z-2 is a protecting group, which may be the same or different for each repetitive unit q; Z³ is selected from the group consisting of O and S; and R^z-3 is a protecting group; each of R^a and R^b is a C1−C6-alkyl group, wherein R^a and R^b may be the same or different and may also bond to each other to form a 5-membered or 6-membered aliphatic cyclic amine moiety together with the nitrogen atom to which R^a and R^b are bonded; and wherein step (f-1) or (f-2) or (f-x) is carried out in each coupling cycle. In some embodiments of the method of the invention, each of the building blocks B-1, B-2, and B-x is a compound of the following Formula II-1-a:

(Formula II-1-a), wherein in Formula II-1-a: q, PG, Y², Z², R^z-2, Z³, R^z-3, R^a, and R^b are defined as for Formula II-1; and B^N, R^XI, R^XII, R^XIII, R^XIV, and R^XV are defined as for Formula II-a, and wherein step (f-1) or (f-2) or (f-x) is carried out in each coupling cycle. In some embodiments of the method of the invention, each of the building blocks B-1, B-2, and B-x is a compound of the following Formula II-1-b:

(Formula II-1-b), wherein in Formula II-1-b: q, PG, Y², Z², R^z-2, Z³, R^z-3, R^a, and R^b are defined as for Formula II-1, B^N, R^XI, R^XII, R^XIII, R^XIV, and R^XV are defined as for Formula II-b, and wherein step (f-1) or (f-2) or (f-x) is carried out in each coupling cycle. In some embodiments, in the building block B-1 or B-2 or B-x of any one of Formulae II, II-a, II-b, II-1, II-1-a, and II-1-b, the integer q is an integer in the range of 0−50, 0−35, 0−30, 0−25, 0−20, 0−15, 0−10, 0−5, 0−3, 0−2, 0−1 or q is 0. In some embodiments, in the building block B-1 or B-2 or B-x of any one of Formulae II, II-a, II-b, II-1, II-1-a, and II-1-b, the integer q is 0. It will be understood that, if the integer q in any one of Formulae II, II-a, II-b, II-1, II-1-a, and II-1-b is 0, the protecting group PG is bonded to the respective hydroxyl moiety of the then remaining nucleoside subunit carrying the phosphorus moiety (e.g. nucleoside subunit y-0 in Formulae II, II-1). In some embodiments, in the building block B-1 or B-2 or B-x of any one of Formulae II, II-a, II-b, II-1, II-1-a, and II-1-b, the protecting group PG is a protecting group comprising an optionally substituted triarylmethyl residue. In some embodiments, in the building block B-1 or B-2 or B-x of any one of Formulae II, II-a, II-b, II-1, II-1-a, and II-1-b, the protecting group PG is selected from the group consisting of the triphenylmethyl group (i.e. the trityl group), the (p-methylphenyl)diphenylmethyl group (i.e. the 4-methyltrityl group), the di(p-methylphenyl)phenylmethyl group (i.e. the 4,4'-dimethyltrityl group), the tri(p-methylphenyl)methyl group (i.e. the 4,4',4"- trimethyltrityl group), the (p-methoxyphenyl)diphenylmethyl group (i.e. the MMT group), and the di(p-methoxyphenyl)phenylmethyl group (i.e. the DMT group). In some embodiments, in the building block B-1 or B-2 or B-x of any one of Formulae II, II-a, II-b, II-1, II-1-a, and II-1-b, the protecting group PG is selected from the group consisting of the triphenylmethyl group, the (p-methoxyphenyl)diphenylmethyl group, and the di(p-methoxyphenyl)phenylmethyl group. In some embodiments, in the building block B-1 or B-2 or B-x of any one of Formulae II, II-a, II-b, II-1, II-1-a, and II-1-b, the protecting group PG is the di(p-methoxyphenyl)phenylmethyl group. In some embodiments, in the building block B-1 or B-2 or B-x of any one of Formulae II, II-a, II-b, II-1, II-1-a, and II-1-b, Y² is at each occurrence O. In some embodiments, in the building block B-1 or B-2 or B-x of any one of Formulae II, II-a, II-b, II-1, II-1- a, and II-1-b, Y² is at each occurrence S. In some embodiments, in the building block B-1 or B-2 or B-x of any one of Formulae II, II-a, II-b, II-1, II-1-a, and II-1-b, R^z-2 is a protecting group removable under alkaline conditions, wherein R^z-2 may be the same or different at each occurrence. The term “removable under alkaline conditions” has been explained above. In some embodiments, in the building block B-1 or B-2 or B-x of any one of Formulae II, II-a, II-b, II-1, II-1-a, and II-1-b, R^z-2 is for each repetitive unit q independently a protecting group of the chemical structure CH2-CH2-EWG, where EWG is an electron withdrawing group, preferably a cyano group. The electron withdrawing group may for example be selected from the group consisting of a cyano group, a halogen atom such as a chlorine, fluorine, or bromine atom, a formyl group, a keto group, a carboxyester group, or a carboxamide group. In some embodiments, in the building block B-1 or B-2 or B-x of any one of Formulae II, II-a, II-b, II-1, II-1-a, II-1-b, R^z-2 is for each repetitive unit q a 2-cyanoethyl group (i.e. CH₂-CH₂-CN). In some embodiments, in the building block B-1 or B-2 or B-x of any one of Formulae II, II-a, II-b, II-1, II-1-a, and II-1-b, Z² is selected independently for each repetitive unit q from the group consisting of O-R^z-2 and S-R^z-2. In some embodiments, in the building block B-1 or B-2 or B-x of any one of Formulae II, II-a, II-b, II-1, II-1-a, and II-1-b, Z² is selected independently for each repetitive unit q from the group consisting of O-R^z-2 and S-R^z-2, where R^z-2 is for each repetitive unit q a 2-cyanoethyl group (i.e. CH2-CH2-CN). In such embodiments, Z² is selected independently for each repetitive unit q from the group consisting of O-CH2-CH2-CN and S-CH2- CH2-CN. In some embodiments, in the building block B-1 or B-2 or B-x of any one of Formulae II, II-a, II-b, II-1, II-1-a, and II-1-b, Z² is for each repetitive unit q O-R^z-2, where R^z-2 is for each repetitive unit q a 2-cyanoethyl group (i.e. CH2-CH2-CN). In such embodiments, Z² is for each repetitive unit q O-CH2-CH2-CN. In some embodiments, in the building block B-1 or B-2 or B-x of any one of Formulae II, II-a, and II-b, Z² is for each repetitive unit q H. In some embodiments, in the building block B-1 or B-2 or B-x of any one of Formulae II, II-a, and II-b, Y² is for each repetitive unit q O and Z² is for each repetitive unit q H. The skilled person will understand that any kind of nucleobase B^N may be present in a building block B-1 or B-2 or B-x of any one of Formulae II-a, II-b, II-1-a, and II- 1-b. In some embodiments, in the building block B-1 or B-2 or B-x of any one of Formulae II-a, II-b, II-1-a, and II-1-b, B^N is a nucleobase and at each occurrence independently selected from the group consisting of adenine, guanine, cytosine, 5- methylcytosine, thymine, and uracil. It will be understood by those skilled in the art, that any nucleobase B^N in any one of Formulae II-a, II-b, II-1-a, and II-1-b may optionally be protected, i.e. carry one or more protecting groups, without this being indicated specifically. Thus, when, for example, stating that B^N is adenine, guanine, 5-methylcytosine, cytosine, thymine, or uracil, this embraces the aforementioned nucleobases in protected form and in free form (i.e. with and without any protecting groups). Nucleobase protecting groups are known to those skilled in the art and have also been explained above, including, for example, the preferred nucleobase protecting groups compiled in Table T-1. In some embodiments, each nucleobase of each building block B-1, B-2 and B-x, in particular each nucleobase B^N of each building block B-1, B-2 and B-x of any one of Formulae II-a, II-b, II-1-a, and II-1-b is independently selected from the group consisting of - adenine, in which the exocyclic amino group is protected; - guanine, in which the exocyclic amino group is protected; - cytosine, in which the exocyclic amino group is protected; - 5-methylcytosine, in which the exocyclic amino group is protected; - thymine; and - uracil. In some embodiments, each nucleobase of each building block B-1, B-2 and B-x, in particular each nucleobase B^N of each building block B-1, B-2 and B-x of any one of Formulae II-a, II-b, II-1-a, and II-1-b is independently selected from the group consisting of - adenine, in which the exocyclic amino group is protected by a benzoyl group, an isobutyryl group or a phenoxyacetyl group; - guanine, in which the exocyclic amino group is protected by an isobutyryl group, a 4-isopropylphenoxyacetyl group or a dimethylformamidino group; - cytosine, in which the exocyclic amino group is protected by an acetyl group or a benzoyl group; - 5-methylcytosine, in which the exocyclic amino group is protected by an acetyl group or a benzoyl group; - thymine; and - uracil. In some embodiments, in each building block B-1, B-2, and B-x of any one of Formulae II-a, II-b, II-1-a, and II-1-b: R^XI is at each occurrence independently selected from the group consisting of H, F, O-(C1−C5-alkyl), O-(C1−C5-alkyl)-O-(C1−C5-alkyl), O-Si(C1−C5-alkyl)3, and O-CH2-O-Si(C1−C5-alkyl)3; R^XIII is independently at each occurrence H or R^XIII and R^XI of the same nucleoside subunit (i.e. bonded to the 4´- and 2´-C atom of the same carbohydrate moiety) together form a structure +–CH2-O−++, +–CH(CH3)-O−++, or +–CH2-CH2-O−++, where + is the point of attachment to the 4´-carbon atom (i.e. the carbon atom to which R^XIII is bonded) and ++ is the point of attachment to the 2´-carbon (i.e. the carbon atom to which R^XI is bonded); and for each nucleoside subunit independently, R^XII, R^XIV, and R^XV are either all H or they are bonded together so that the respective nucleoside subunit has a structure of the aforementioned Formula II-a-tc (in a building block B-1 or B-2 or B-x of any one of Formulae II-a, II-1-a) or Formula II-b-tc (in a building block B-1 or B-2 or B-x of any one of Formula II-b, II-1-b). In some embodiments, in each building block B-1, B-2, and B-x of any one of Formulae II-a, II-b, II-1-a, and II-1-b: R^XI is at each occurrence independently selected from the group consisting of H, F, O-CH₃ (i.e. methoxy), O-CH₂-CH₂-O-CH₃ (i.e. 2-methoxyethyl-1-oxy), O-Si(CH3)3 (i.e. trimethylsilyloxy), O-Si(CH3)2(C(CH3)3) (i.e. tert- butyl(dimethyl)silyloxy), and O-CH2-O-Si(C(CH3)3)3 (i.e. ((triisopropylsilyl)oxy)- methyloxy); R^XIII is independently at each occurrence H or R^XIII and R^XI of the same nucleoside subunit (i.e. bonded to the 4´- and 2´-C atom of the same carbohydrate moiety) together form a structure +–CH2-O−++, +–CH(CH3)-O−++, or +–CH2-CH2-O−++, where + is the point of attachment to the 4´-carbon atom (i.e. the carbon atom to which R^XIII is bonded) and ++ is the point of attachment to the 2´-carbon (i.e. the carbon atom to which R^XI is bonded); and for each nucleoside subunit independently, R^XII, R^XIV, and R^XV are either all H or they are bonded together so that the respective nucleoside subunit has a structure of the aforementioned Formula II-a-tc (in a building block B-1 or B-2 or B-x of any one of Formulae II-a, II-1-a) or Formula II-b-tc (in a building block B-1 or B-2 or B-x of any one of Formula II-b, II-1-b). In some embodiments, in each building block B-1, B-2, and B-x of any one of Formulae II-a, II-b, II-1-a, and II-1-b: R^XI is selected independently at each occurrence from the group consisting of H, F, O-CH3 (i.e. methoxy), and O-CH2-CH2-O-CH3 (i.e.2-methoxyethyl-1-oxy); and each of R^XII, R^XIII, R^XIV, and R^XV is H at each occurrence. In some embodiments, in each building block B-1, B-2, and B-x of any one of Formulae II-1, II-1-a, and II-1-b, Z³ is O. In some embodiments, in each building block B-1, B-2, and B-x of any one of Formulae II-1, II-1-a, and II-1-b, Z³ is S. In some embodiments, in each building block B-1, B-2, and B-x of any one of Formulae II-1, II-1-a, and II-1-b, R^z-3 is a protecting group removable under alkaline conditions. The term “removable under alkaline conditions” has been explained above. In some embodiments, in each building block B-1, B-2, and B-x of any one of Formulae II-1, II-1-a, and II-1-b, R^z-3 is a protecting group of the chemical structure CH₂-CH₂-EWG, where EWG is an electron withdrawing group, preferably a cyano group. The electron withdrawing group may for example be selected from the group consisting of a cyano group, a halogen atom such as a chlorine, fluorine, or bromine atom, a formyl group, a keto group, a carboxyester group, or a carboxamide group. In some preferred embodiments, in each building block B-1, B-2, and B-x of any one of Formulae II-1, II-1-a, and II-1-b, R^z-3 is a 2-cyanoethyl group (i.e. CH₂-CH₂-CN). In some embodiments, in each building block B-1, B-2, and B-x of any one of Formulae II-1, II-1-a, and II-1-b, each of R^a and R^b is a C1–C6-alkyl group, wherein R^a and R^b may be the same or different, and wherein R^a and R^b may not bond to each other. In some embodiments, in each building block B-1, B-2, and B-x of any one of Formulae II-1, II-1-a, and II-1-b, each of R^a and R^b is an isopropyl group (i.e. CH(CH3)2). In some embodiments, in each building block B-1, B-2, and B-x of Formula II: PM is a phosphorus moiety, preferably a phosphorus moiety selected from the group consisting of a phosphoramidite moiety and a H-phosphonate monoester moiety; PG is the protecting group PG-1 (for building block B-1) or PG-2 (for building block B-2) or PG-x (for a building block B-x) and is a di(p-methoxyphenyl)phenylmethyl (DMT) protecting group; q is an integer in the range of 0−50, 0−35, 0−30, 0−25, 0−20, 0−15, 0−10, or 0−5, or q is 0; Y² is selected independently for each repetitive unit q from the group consisting of O and S; Z² is selected independently for each repetitive unit q from the group consisting of O-R^z-2, S-R^z-2, and H; and R^z-2 is at each occurrence a 2-cyanoethyl group. In some embodiments, in each building block B-1, B-2, and B-x of Formula II: PM is a phosphoramidite moiety; PG is the protecting group PG-1 (for building block B-1) or PG-2 (for building block B-2) or PG-x (for a building block B-x) and is a di(p-methoxyphenyl)phenylmethyl (DMT) protecting group; q is an integer in the range of 0−50, 0−35, 0−30, 0−25, 0−20, 0−15, 0−10, or 0−5, or q is 0; Y² is selected independently for each repetitive unit q from the group consisting of O and S; Z² is selected independently for each repetitive unit q from the group consisting of O-R^z-2 and S-R^z-2; and R^z-2 is at each occurrence a 2-cyanoethyl group. In some embodiments, in each building block B-1, B-2, and B-x of Formula II: PM is a phosphoramidite moiety; PG is the protecting group PG-1 (for building block B-1) or PG-2 (for building block B-2) or PG-x (for a building block B-x) and is a di(p-methoxyphenyl)phenylmethyl (DMT) protecting group; q is an integer in the range of 0−50, 0−35, 0−30, 0−25, 0−20, 0−15, 0−10, or 0−5, or q is 0; Y² is selected independently for each repetitive unit q from the group consisting of O and S; Z² is for each repetitive unit q O-R^z-2; and R^z-2 is at each occurrence a 2-cyanoethyl group. In some embodiments, in each building block B-1, B-2, and B-x of Formula II: PM is a H-phosphonate monoester moiety; PG is the protecting group PG-1 (for building block B-1) or PG-2 (for building block B-2) or PG-x (for a building block B-x) and is a di(p-methoxyphenyl)phenylmethyl (DMT) protecting group; q is an integer in the range of 0−50, 0−35, 0−30, 0−25, 0−20, 0−15, 0−10, or 0−5, or q is 0; Y² is selected independently for each repetitive unit q from the group consisting of O and S, and preferably is O; and Z² is for each repetitive unit q H. In some embodiments, in each building block B-1, B-2, and B-x of any one of Formulae II-a and II-b: PM is a phosphorus moiety, preferably a phosphorus moiety selected from the group consisting of a phosphoramidite moiety and a H-phosphonate monoester moiety; PG is the protecting group PG-1 (for building block B-1) or PG-2 (for building block B-2) or PG-x (for a building block B-x) and is a di(p-methoxyphenyl)phenylmethyl (DMT) protecting group; q is an integer in the range of 0−50, 0−35, 0−30, 0−25, 0−20, 0−15, 0−10, or 0−5, or q is 0; Y² is selected independently for each repetitive unit q from the group consisting of O and S; Z² is selected independently for each repetitive unit q from the group consisting of O-R^z-2, S-R^z-2, and H; R^z-2 is at each occurrence a 2-cyanoethyl group; R^XI is at each occurrence independently selected from the group consisting of H, F, O-(C₁−C₅-alkyl), O-(C₁−C₅-alkyl)-O-(C₁-C₅-alkyl), O-Si(C₁−C₅-alkyl)₃, and O-CH2-O-Si(C1−C5-alkyl)3; R^XIII is independently at each occurrence H or R^XIII and R^XI of the same nucleoside subunit (i.e. bonded to the 4´- and 2´-C atom of the same carbohydrate moiety) together form a structure +–CH2-O−++, +–CH(CH3)-O−++, or +–CH2-CH2-O−++, where + is the point of attachment to the 4´-carbon atom (i.e. the carbon atom to which R^XIII is bonded) and ++ is the point of attachment to the 2´-carbon (i.e. the carbon atom to which R^XI is bonded); and for each nucleoside subunit independently, R^XII, R^XIV, and R^XV are either all H or they are bonded together so that the respective nucleoside subunit has a structure of the aforementioned Formula II-a-tc (in a building block B-1, B-2 or B-x of Formula II-a) or Formula II-b-tc (in a building block B-1, B-2 or B-x of Formula II-b). In some embodiments, in each building block B-1, B-2, and B-x of any one of Formulae II-a and II-b: PM is a phosphorus moiety, preferably a phosphorus moiety selected from the group consisting of a phosphoramidite moiety and a H-phosphonate monoester moiety; PG is the protecting group PG-1 (for building block B-1) or PG-2 (for building block B-2) or PG-x (for a building block B-x) and is a di(p-methoxyphenyl)phenylmethyl (DMT) protecting group; q is an integer in the range of 0−50, 0−35, 0−30, 0−25, 0−20, 0−15, 0−10, or 0−5, or q is 0; Y² is selected independently for each repetitive unit q from the group consisting of O and S; Z² is selected independently for each repetitive unit q from the group consisting of O-R^z-2, S-R^z-2, and H; R^z-2 is at each occurrence a 2-cyanoethyl group; R^XI is at each occurrence independently selected from the group consisting of H, F, O-CH₃ (i.e. methoxy), O-CH₂-CH₂-O-CH₃ (i.e. 2-methoxyethyl-1-oxy), O-Si(CH₃)₃ (i.e. trimethylsilyloxy)_, O-Si(CH₃)₂(C(CH₃)₃) (i.e. tert-butyl(dimethyl)silyloxy), and O- CH₂-O-Si(C(CH₃)₃)₃ (i.e. ((triisopropylsilyl)oxy)-methyloxy); R^XIII is independently at each occurrence H or R^XIII and R^XI of the same nucleoside subunit (i.e. bonded to the 4´- and 2´-C atom of the same carbohydrate moiety) together form a structure +–CH2-O−++, +–CH(CH3)-O−++, or +–CH2-CH2-O−++, where + is the point of attachment to the 4´-carbon atom (i.e. the carbon atom to which R^XIII is bonded) and ++ is the point of attachment to the 2´-carbon (i.e. the carbon atom to which R^XI is bonded); and for each nucleoside subunit independently, R^XII, R^XIV, and R^XV are either all H or they are bonded together so that the respective nucleoside subunit has a structure of the aforementioned Formula II-a-tc (in a building block B-1, B-2 or B-x of Formula II-a) or Formula II-b-tc (in a building block B-1, B-2 or B-x of Formula II-b). In some embodiments, in each building block B-1, B-2, and B-x of any one of Formulae II-a and II-b: PM is a phosphoramidite moiety; PG is the protecting group PG-1 (for building block B-1) or PG-2 (for building block B-2) or PG-x (for a building block B-x) and is a di(p-methoxyphenyl)phenylmethyl (DMT) protecting group; q is an integer in the range of 0−50, 0−35, 0−30, 0−25, 0−20, 0−15, 0−10, or 0−5, or q is 0; Y² is selected independently for each repetitive unit q from the group consisting of O and S; Z² is for each repetitive unit q O-R^z-2; R^z-2 is at each occurrence a 2-cyanoethyl group; R^XI is selected independently at each occurrence from the group consisting of H, F, O-CH3 (i.e. methoxy), and O-CH2-CH2-O-CH3 (i.e.2-methoxyethyl-1-oxy); and each of R^XII, R^XIII, R^XIV, and R^XV is H at each occurrence. In some embodiments, in each building block B-1, B-2, and B-x of Formula II-1: PG is the protecting group PG-1 (for building block B-1) or PG-2 (for building block B-2) or PG-x (for a building block B-x) and is a di(p-methoxyphenyl)phenylmethyl (DMT) protecting group; q is an integer in the range of 0−50, 0−35, 0−30, 0−25, 0−20, 0−15, 0−10, or 0−5, or q is 0; Y² is selected independently for each repetitive unit q from the group consisting of O and S; Z² is selected independently for each repetitive unit q from the group consisting of O-R^z-2 and S-R^z-2, and Z² preferably is for each repetitive unit q O-R^z-2; R^z-2 is at each occurrence a 2-cyanoethyl group; Z³ is selected from the group consisting of O and S, and preferably is O; R^z-3 is a 2-cyanoethyl group; and each of R^a and R^b is a C1−C6-alkyl group, preferably an isopropyl group. In some embodiments, in each building block B-1, B-2, and B-x of Formula II-1: PG is the protecting group PG-1 (for building block B-1) or PG-2 (for building block B-2) or PG-x (for a building block B-x) and is a di(p-methoxyphenyl)phenylmethyl (DMT) protecting group; q is an integer in the range of 0−50, 0−35, 0−30, 0−25, 0−20, 0−15, 0−10, or 0−5, or q is 0; Y² is selected independently for each repetitive unit q from the group consisting of O and S; Z² is for each repetitive unit q O-R^z-2; R^z-2 is at each occurrence a 2-cyanoethyl group; Z³ is O; R^z-3 is a 2-cyanoethyl group; and each of R^a and R^b is an isopropyl group. In some embodiments, in each building block B-1, B-2, and B-x of any one of Formula II-1-a and II-1-b: PG is the protecting group PG-1 (for building block B-1) or PG-2 (for building block B-2) or PG-x (for a building block B-x) and is a di(p-methoxyphenyl)phenylmethyl (DMT) protecting group; q is an integer in the range of 0−50, 0−35, 0−30, 0−25, 0−20, 0−15, 0−10, or 0−5, or q is 0; Y² is selected independently for each repetitive unit q from the group consisting of O and S; Z² is selected independently for each repetitive unit q from the group consisting of O-R^z-2 and S-R^z-2, and Z² preferably is for each repetitive unit q O-R^z-2; R^z-2 is at each occurrence a 2-cyanoethyl group; Z³ is selected from the group consisting of O and S, and preferably is O; R^z-3 is a 2-cyanoethyl group; each of R^a and R^b is a C₁−C₆-alkyl group, preferably an isopropyl group; R^XI is at each occurrence independently selected from the group consisting of H, F, O-(C₁−C₅-alkyl), O-(C₁−C₅-alkyl)-O-(C₁−C₅-alkyl), O-Si(C₁−C₅-alkyl)₃, and O-CH₂-O-Si(C₁−C₅-alkyl)₃; R^XIII is independently at each occurrence H or R^XIII and R^XI of the same nucleoside subunit (i.e. bonded to the 4´- and 2´-C atom of the same carbohydrate moiety) together form a structure +–CH2-O−++, +–CH(CH3)-O−++, or +–CH2-CH2-O−++, where + is the point of attachment to the 4´-carbon atom (i.e. the carbon atom to which R^XIII is bonded) and ++ is the point of attachment to the 2´-carbon (i.e. the carbon atom to which R^XI is bonded); and for each nucleoside subunit independently, R^XII, R^XIV, and R^XV are either all H or they are bonded together so that the respective nucleoside subunit has a structure of the aforementioned Formula II-a-tc (in a building block B-1, B-2 or B-x of Formula II-1-a) or Formula II-b-tc (in a building block B-1, B-2 or B-x of Formula II-1-b). In some embodiments, in each building block B-1, B-2, and B-x of any one of Formula II-1-a and II-1-b: PG is the protecting group PG-1 (for building block B-1) or PG-2 (for building block B-2) or PG-x (for a building block B-x) and is a di(p-methoxyphenyl)phenylmethyl (DMT) protecting group; q is an integer in the range of 0−50, 0−35, 0−30, 0−25, 0−20, 0−15, 0−10, or 0−5, or q is 0; Y² is selected independently for each repetitive unit q from the group consisting of O and S; Z² is selected independently for each repetitive unit q from the group consisting of O-R^z-2 and S-R^z-2, and Z² preferably is for each repetitive unit q O-R^z-2; R^z-2 is at each occurrence a 2-cyanoethyl group; Z³ is selected from the group consisting of O and S and preferably is O; R^z-3 is a 2-cyanoethyl group; each of R^a and R^b is a C1−C6-alkyl group, preferably an isopropyl group; R^XI is at each occurrence independently selected from the group consisting of H, F, O-CH3 (i.e. methoxy), O-CH2-CH2-O-CH3 (i.e. 2-methoxyethyl-1-oxy), O-Si(CH3)3 (i.e. trimethylsilyloxy), O-Si(CH3)2(C(CH3)3) (i.e. tert-butyl(dimethyl)silyloxy), and O- CH2-O-Si(C(CH3)3)3 (i.e. ((triisopropylsilyl)oxy)-methyloxy); R^XIII is independently at each occurrence H or R^XIII and R^XI of the same nucleoside subunit (i.e. bonded to the 4´- and 2´-C atom of the same carbohydrate moiety) together form a structure +–CH2-O−++, +–CH(CH3)-O−++, or +–CH2-CH2-O−++, where + is the point of attachment to the 4´-carbon atom (i.e. the carbon atom to which R^XIII is bonded) and ++ is the point of attachment to the 2´-carbon (i.e. the carbon atom to which R^XI is bonded); and for each nucleoside subunit independently, R^XII, R^XIV, and R^XV are either all H or they are bonded together so that the respective nucleoside subunit has a structure of the aforementioned Formula II-a-tc (in a block B-1, B-2 or B-x of Formula II-1-a) or Formula II-b-tc (in a B-1, B-2 or B-x of Formula II-1-b). In some embodiments, in each building block B-1, B-2, and B-x of any one of Formula II-1-a and II-1-b: PG is the protecting group PG-1 (for building block B-1) or PG-2 (for building block B-2) or PG-x (for a building block B-x) and is a di(p-methoxyphenyl)phenylmethyl (DMT) protecting group; q is an integer in the range of 0−50, 0−35, 0−30, 0−25, 0−20, 0−15, 0−10, or 0−5, or q is 0; B^N is a nucleobase, which may be the same or different at each occurrence; Y² is selected independently for each repetitive unit q from the group consisting of O and S; Z² is selected independently for each repetitive unit q from the group consisting of O-R^z-2 and S-R^z-2, and Z² preferably is for each repetitive unit q O-R^z-2; R^z-2 is at each occurrence a 2-cyanoethyl group; Z³ is selected from the group consisting of O and S and preferably is O; R^z-3 is a 2-cyanoethyl group; each of R^a and R^b is a C₁−C₆-alkyl group, preferably an isopropyl group; R^XI is selected independently at each occurrence from the group consisting of H, F, O-CH₃ (i.e. methoxy), and O-CH₂-CH₂-O-CH₃ (i.e.2-methoxyethyl-1-oxy); and each of R^XII, R^XIII, R^XIV, and R^XV is H at each occurrence. In the method of the invention, the building block B-x may be the same or different (i.e. have the same or a different chemical structure) for each coupling cycle comprising steps (b-x) to (h-x) (as far as present), unless indicated differently in the context of specific embodiments. A building block B-1, B-2 or B-x for use in the method of the invention may, for example, be obtained commercially, in particular, if said phosphorus moiety is a phosphoramidite moiety or a H-phosphonate monoester moiety. Alternatively, a building block B-1, B-2 or B-x for use in the method of the invention may be obtained by means of chemical synthesis. The person skilled in the art is aware of methods of synthesizing such compounds, wherein the synthesis route will obviously depend on the chemical structure of said phosphorus moiety. Building blocks B-1, B-2 or B-x, e.g. of any one of Formulae II, II-a, and II-b, in which said phosphorus moiety, e.g. said phosphorus moiety PM, is a phosphoramidite moiety, in particular building blocks B-1, B-2 or B-x of any one of Formulae II-1, II-1-a, and II-1-b, may, for example, be synthesized as disclosed in, in K.V. Gothelf et al., Nature Communications 2021, 12, 2760, and in X. Wei et al., Tetrahedron 2013, 69, 3615−3637. Building blocks B-1, B-2 or B-x, e.g. of any one of Formulae II, II-a, and II-b, in which said phosphorus moiety, e.g. said phosphorus moiety PM, is a H-phosphonate monoester moiety, may, for example, be synthesized as disclosed in J. Stawinski and R. Strömberg (2005), Di- and Oligonucleotide Synthesis Using H-Phosphonate Chemistry, in Methods in Molecular Biology, vol. 288: Oligonucleotide Synthesis: Methods and Applications, edited by P. Herdewijn, Humana Press Inc., Totowa NJ, https://doi.org/10.1385/1-59259-823-4:081. Building blocks B-1, B-2 or B-x, e.g. of any one of Formulae II, II-a, and II-b, in which said phosphorus moiety, e.g. said phosphorus moiety PM, is a P (V) moiety suitable for chiral phosphorothioate synthesis may, for example, be synthesized as disclosed in P.S. Baran et al., Science 2018, 361, 1234−1238 (also see Supplementary Materials for this reference). The term “reacting” in step (e-1) may be understood in the broadest sense as any operation during which the component (C-0)^# and the building block B-1 are present in the same reaction vessel or reactor and engage in the bond forming reaction of step (e-1). The term “reacting” in step (e-2) may be understood in the broadest sense as any operation during which the first cycle oligonucleotide (O-1)^# and the building block B-2 are present in the same reaction vessel or reactor and engage in the bond forming reaction of step (e-2). The term “reacting” in step (e-x) may be understood in the broadest sense as any operation during which the (x−1)-th cycle oligonucleotide (O-(x−1))^# and the building block B-x are present in the same reaction vessel or reactor and engage in the bond forming reaction of step (e-x). Typically, the component (C-0)^#, the first cycle oligonucleotide (O-1)^# or the (x−1)-th cycle oligonucleotide (O-(x−1))^# may already be contained in a reaction vessel or reactor, to which the building block B-1, B-2 or B-x is then added. Alternatively, the building block B-1, B-2 or B-x or a solution thereof may already be contained in a reaction vessel or reactor, to which the component (C-0)^#, the first cycle oligonucleotide (O-1)^# or the (x−1)-th cycle oligonucleotide (O-(x−1))^# is then added. During each of steps (e-1), (e-2), and (e-x), a covalent (chemical) bond is formed between said free backbone hydroxyl group of the component (C-0)^#, the first cycle oligonucleotide (O-1)^# or the (x−1)-th cycle oligonucleotide (O-(x−1))^# and the phosphorus atom of said phosphorus moiety of the building block B-1, B-2 or B-x. The bond forming reaction of steps (e-1), (e-2), and (e-x) is herein also referred to as coupling or coupling reaction or condensation or condensation reaction, and steps (e-1), (e-2), and (e-x) are also referred to as coupling steps or condensation steps. The product obtained from the bond forming reaction of step (e-1) is the first cycle oligonucleotide O-1, which comprises the nucleoside sequence of the component (C-0)^# and of the building block B-1, wherein these two are now interconnected by an internucleosidic linkage group derived from the phosphorus moiety of the building block B-1. The product obtained from the bond forming reaction of step (e-2) is the second cycle oligonucleotide O-2, which comprises the nucleoside sequence of the first cycle oligonucleotide (O-1)^# and of the building block B-2, wherein these two are now interconnected by an internucleosidic linkage group derived from the phosphorus moiety of the building block B-2. The product obtained from the bond forming reaction of step (e-x) is the x-th cycle oligonucleotide O-x, which comprises the nucleoside sequence of the (x−1)-th cycle oligonucleotide (O-(x−1))^# and of the building block B-x, wherein these two are now interconnected by an internucleosidic linkage group derived from the phosphorus moiety of the building block B-x. The “conditions suitable” to form a covalent bond between said free backbone hydroxyl group of the component (C-0)^#, the first cycle oligonucleotide (O-1)^# or the (x−1)-th cycle oligonucleotide (O-(x−1))^# and the phosphorus atom of said phosphorus moiety of the building block B-1, B-2 or B-x form part of the common knowledge of those skilled in the art. These conditions may, for example, depend on the chemical structure of said phosphorus moiety which is to engage in the bond forming reaction. A bond forming reaction of step (e-1), (e-2) or (e-x), in which the phosphorus moiety engaging in said reaction is a phosphoramidite moiety, as e.g. present in building blocks B-1, B-2 or B-x of any one of Formulae II-1, II-1-a, and II-1-b, is herein also referred to as phosphoramidite coupling (reaction). Such phosphoramidite couplings may preferably be performed in the presence of an activator. Any activator used in oligonucleotide synthesis by the so-called phosphoramidite method may be used in the method of the invention. The activator may, for example, be selected from the group consisting of: - a tetrazole type activator such as 1H-tetrazole, 5-ethylthio-1H-tetrazole (ETT), 5-benzylthio-1H-tetrazole (BTT), 5-methylthio-1H-tetrazole (MTT), 1-methyl-5-mercaptotetrazole, 1-phenyl-5-mercaptotetrazole, and 5-(4-nitrophenyl)-1H-tetrazole, - an imidazole type activator such as 4,5-dicyanoimidazole (DCI) and 2-bromo- 4,5-dicyanoimidacole (2-Br-DCI), - a 1-hydroxybenzotriazole type activator such as 1-hydroxybenzotriazole, 1-hydroxy-6-trifluorobenzotriazole, and 1-hydroxy-6-trifluoro-4- nitrobenzotriazole, - a pyridinium salt type activator such as pyridinium hydrochloride, pyridinium p-toluenesulfonate, and pyridinium trifluoroacetate, and - a saccharin type activator, i.e. salts obtained from reacting saccharin with an organic base such as pyridine, collidine, lutidine, picoline, N-methylimidazole, and triethylamine. 5-Benzylthio-1H-tetrazole (BTT), 5-ethylthio-1H-tetrazole (ETT), 1H-tetrazole, and 4,5-dicyanoimidacole (DCI) may be preferred. N-methylimidazole (NMI) or pyridine may be added alongside the activator, which may help to adjust the acidity of the solution. For example, 1.0−100.0 mol, 1.0−50.0 mol, 1.0−40.0 mol, 1.0−30.0 mol, 1.0−20.0 mol, 1.0−15.0 mol, 1.0−10.0 mol, or 2.5−10.0 mol of the activator may be used per 1 mol of the building block B-1, B-2 or B-x engaging in the respective coupling reaction with its phosphoramidite moiety. As another example, NMI may be used alongside a protic acid, for example a carboxylic acid such as trifluoroacetic acid, without an additional activator. Acetonitrile may also be added. For example, a mixture of acetonitrile, NMI, and TFA (e.g. 7.5:2:2 v/v) may be added for the coupling reaction. In some preferred embodiments of the method of the invention, steps (e-1), (e-2), and (e-x) are carried out using a tetrazole-type activator, preferably ETT, most preferably in combination with a base, in particular pyridine. It will be understood that this does not imply that a step (e-2) and/or (e-x) must be performed. A bond forming reaction of step (e-1), (e-2) or (e-x), in which the phosphorus moiety engaging in said reaction is a H-phosphonate monoester moiety, is herein also referred to as H-phosphonate coupling (reaction). Such H-phosphonate couplings may typically be performed using a condensing agent. Any condensing agent used in oligonucleotide synthesis by the so-called H-phosphonate method may be used in the method of the invention. The condensing agent may, for example, be selected from the group consisting of pivaloyl chloride (PvCl), 1-adamantanecarbonyl chloride (AdCl), 2,2-dimethylbutyryl chloride, isobutyryl chloride, diphenyl chlorophosphate, 2,4,6-triisopropylbenzenesulfonyl chloride, bis(pentafluorophenyl) carbonate, 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphorinane 2-oxide (also referred to as 5,5-dimethyl-2-oxo-2-chloro-1,3,2-dioxaphosphinane, DMOCP), and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (OXP or BOP-Cl). The building block B-1, B-2 or B-x comprising said H-phosphonate monoester moiety may be pre-activated with (i.e. incubated with) said condensing agent, and then be combined with the component (C-0)^#, the first cycle oligonucleotide (O-1)^# or the (x−1)-th cycle oligonucleotide (O-(x−1))^#. Besides the condensing agent, a nucleophile such as pyridine may be added. For example, EP3378869A1 discloses suitable reaction conditions. A bond forming reaction of step (e-1), (e-2) or (e-x), in which the phosphorus moiety engaging in said reaction is an arylphosphate diester moiety, is herein also referred to as phosphotriester coupling (reaction). Briefly, the arylphosphate diester moieties may typically be activated with an arylsulfonyl chloride activator, such as mesitylene- 2-sulfonyl chloride (MsCl), usually in the presence of an auxiliary nucleophile such as 1-methylimidazole. Alternatively, pre-formed or in-situ generated 1-hydroxybenzotriazole-phosphotriesters may, for example, be used as phosphorus moiety instead of an aryl phosphate diester moiety in a phosphotriester coupling, again in the presence of an auxiliary nucleophile such as 1-methylimidazole. A bond forming reaction of step (e-1), (e-2) or (e-x), in which the phosphorus moiety engaging in said reaction is a P (V) moiety allowing for chiral phosphorothioate synthesis may, for example, be performed as disclosed in Baran et al.,Science 2018, 361, 1234−1238 (see also the Supplementary Materials of said publication) and ACS Central Science 2021, 7, 1473−1485), or in a similar fashion. Preferably, the solutions in which steps (e-1), (e-2), and (e-x) are carried out are substantially anhydrous, which may mean that they preferably comprise equal to or less than 2000 ppm, 1900 ppm, 1800 ppm, 1700 ppm, 1600 ppm, 1500 ppm, 1400 ppm, 1300 ppm, 1200 ppm, 1100 ppm, 1000 ppm, 900 ppm, 800 ppm, 700 ppm, 600 ppm, 500 ppm, 400 ppm, 300 ppm, 250 ppm, 200 ppm, 150 ppm, or 100 ppm of water. The water content may be determined by means of standard Karl Fischer titration at 25 °C, as known to those skilled in the art. The set up may, for example, be as follows: The titration cell may be filled with HYDRANAL^TM -Coulomat Oil for anolyte reagent, and the inner burette may be filled with HYDRANAL^TM - Coulomat CG for catholyte reagent. After pretitration for dehydration, sample (100 µL) may be added to the titration cell and the measurement may be started. In line with common practice, the water content of solutions is herein reported in parts per million (ppm). For example, 1.0−20.0 mol, 1.0−10.0 mol, 1.0−5.0 mol, 2.0−5.0 mol, or 2.0−4.0 mol, or 1.0−2.5 mol, or 1.0−2.0 mol of the building block B-1, B-2 or B-x may be used per mol of the component (C-0)^#, the first cycle oligonucleotide (O-1)^# or the (x−1)-th cycle oligonucleotide (O-(x−1))^#. Steps (e-1), (e-2), and (e-x) may, for example, be performed at a temperature in the range of 0−90 °C, 10−70 °C, 15−60 °C, 15−50 °C, or 20−50 °C. For convenience, steps (e-1), (e-2), and (e-x) may simply be performed at room temperature. Increased temperatures may result in shorter reaction times. The reaction time may also depend on the chemical structure of the reactants and will routinely be selected by a skilled person, for example based on reaction monitoring using, e.g., thin-layer chromatography and/or high performance liquid chromatography (HPLC), optionally coupled to mass spectrometry. If the internucleosidic linkage group formed in a bond forming reaction of a step (e-1), (e-2) or (e-x) is a P(III) linkage group as defined herein, e.g. a phosphite triester linkage group (as e.g. obtained from a phosphoramidite coupling), and supposed to be sulfurized (by incubation with a sulfurizing agent) to a P (V) linkage group, e.g. a phosphorothioate linkage group, in the subsequent step (f-1), (f-2) or (f-x), the respective step (e-1), (e-2) or (e-x) may be carried out in the presence of an antioxidant . Said antioxidant may suppress unwanted oxidation of a formed P(III) linkage group to a P (V) linkage group, which may not be amenable to sulfurization in the subsequent step. Examples of suitable antioxidants are, e.g., disclosed in EP3950698A1 and include inter alia triphenylphosphine, methyldiphenylphosphine, triethyl phosphite, ethoxydiphenylphosphine, diethoxyphenylphosphine, 9,10-dihydro-9-oxa-10-phosphaphenanthrene 10-oxide, and isobutylene sulfide. Alternatively, the solvents used may be controlled so that they contain no or a low level of oxidizing species. After the bond-forming reaction of step (e-1), (e-2) or (e-x) has been carried out, a quencher may optionally be added, wherein said quencher may be used to consume (i.e. react with) the phosphorus moiety of unreacted (excess) molecules of the building block B-1, B-2 or B-x employed. The quencher will typically be a nucleophilic compound capable of reacting with the phosphorus moiety. Water may, for example, be used as a quencher. Lactamide may, for example, also be used as a quencher. Step (f-1) of some methods of the invention is: optionally, incubating the first cycle oligonucleotide O-1 with an oxidizing or sulfurizing agent, thereby converting any P (III) atoms within said first cycle oligonucleotide O-1 to P (V) atoms. Step (f-2) of some of the methods of the invention is: optionally, incubating the second cycle oligonucleotide O-2 with an oxidizing or sulfurizing agent, thereby converting any P (III) atoms within said second cycle oligonucleotide O-2 to P (V) atoms. Step (f-x) of some of the methods of the invention is: optionally, incubating the x-th cycle oligonucleotide O-x with an oxidizing or sulfurizing agent, thereby converting any P (III) atoms within said x-th cycle oligonucleotide O-x to P (V) atoms. The terms “P (III) atom” and “P (V) atom” have been defined above. As used throughout this text, the “oxidation state” may be “the charge of an atom after its homonuclear bonds have been divided equally and heteronuclear bonds assigned to the bond partners according to Allen electronegativity, except when the electronegative atom is bonded reversibly as a Lewis-acid ligand, in which case it does not obtain that bonds electrons”, as described in the IUPAC Recommendations 2016 (P. Karen et al., Pure and Applied Chemistry 2016, 88(8), 831−839). The Allen electronegativities given in said reference may be used and the P−H bond electron pair is assigned to H. As an example, the phosphorus atom of the H-phosphonate monoester moiety has the oxidation state III. As another example, the phosphorus atom of the phosphoramidite moiety in any one of Formulae II-1, II-1-a, and II-1-b has the oxidation state III. As a third example, the phosphorus atoms in the phosphodiester linkage groups of DNA and RNA have the oxidation state V. The term “optionally” in step (f-1), (f-2), and (f-x) denotes that the respective step may or may not be carried out in a given coupling cycle, unless indicated differently in the context of specific embodiments. As known to those skilled in the art, most or even all phosphorus atoms of an oligonucleotide may typically be comprised in the backbone of said oligonucleotide, usually in the internucleosidic linkage group(s). The terms “P (III) linkage group” and “P (V) linkage group” have been defined above. As also known to those skilled in the art, oligonucleotides comprising one or more P (III) linkage groups are typically less stable than related oligonucleotides comprising only P (V) linkage groups (as e.g. present in DNA and RNA). In some embodiments of the method of the invention, the target oligonucleotide O^T comprises only P (V) linkage groups. If the first cycle oligonucleotide O-1 obtained in step (e-1) does not comprise any P (III) atoms, in particular not any P (III) linkage groups, it may not be necessary to carry out step (f-1). If the second cycle oligonucleotide O-2 obtained in step (e-2) does not comprise any P (III) atoms, in particular not any P (III) linkage groups, it may not be necessary to carry out step (f-2). If the x-th cycle oligonucleotide O-x obtained in step (e-x) of a coupling cycle does not comprise any P (III) atoms, in particular not any P (III) linkage groups, it may not be necessary to carry out step (f-x) in said coupling cycle. It is understood by those skilled in the art, that the oxidation state of the phosphorus atom within an internucleosidic linkage group formed in the bond forming reaction of a step (e-1), (e-2) or (e-x) will typically depend on the chemical structure of said phosphorus moiety of said building block B-1, B-2 or B-x, which engaged in the respective bond forming reaction. Typically, the oxidation state of the phosphorus atom within such a phosphorus moiety will be preserved in the course of the bond forming reaction of step (e-1), (e-2) or (e-x). For example, if a phosphotriester coupling as defined herein is carried out in a step (e-1), (e-2) or (e-x), the phosphorus atom of the resulting phosphotriester internucleosidic linkage group will typically be present as P (V) atom, i.e. the phosphotriester linkage group is a P (V) linkage group. The same principle applies, e.g., to the P (V) chemistry utilized by Baran et al. (Science 2018, 361, 1234−1238 and ACS Central Science 2021, 7, 1473−1485). On the other hand, if the phosphorus moiety of a component C-x engaging in a bond forming reaction of a step (e-1), (e-2) or (e-x) comprises a P (III) atom, the resulting internucleosidic linkage group will typically also comprise a P (III) atom, i.e. be a P (III) linkage group. For example, the bond forming reaction of a step (e-1), (e-2) or (e-x) may typically afford a phophite triester product (comprising a phosphite triester internucleosidic linkage group, i.e. a P (III) linkage group), if said phosphorus moiety covalently bonded via its phosphorus atom to an oxygen atom of the backbone of the building block B-1, B-2 or B-x, e.g. the phosphorus moiety PM of any one of Formulae II, II-a, and II-b, is a phosphoramidite moiety such as, e.g., present in any one of Formulae II-1, II-1-a, and II-1-b, while a H-phosphonate diester product (comprising a H-phosphonate diester internucleosidic linkage group, i.e. a P (III) linkage group) may typically be obtained, if said phosphorus moiety covalently bonded via its phosphorus atom to an oxygen atom of the backbone of the building block B-1, B-2 or B-x, e.g. the phosphorus moiety PM of any one of Formulae II, II-a, and II-b, is a H-phosphonate monoester moiety. H-phosphonate diester linkage groups may be more stable, e.g. under the conditions of steps (b-1), (b-2) or (b-x), than phosphite triester linkage groups, so that a step (f-1) or (f-2) or (f-x) may not need to be performed in each coupling cycle, in which said phosphorus moiety covalently bonded via its phosphorus atom to an oxygen atom of the backbone of the building block B-1, B-2 or B-x, e.g. the phosphorus moiety PM of any one of Formulae II, II-a, and II-b, is a H-phosphonate monoester moiety. However, at least in the final coupling cycle, step (f-1) or (f-2) or (f-x) may be carried out, so that any P (III) atoms are converted to P (V) atoms. In some embodiments of the method of the invention: - the phosphorus moiety of the building blocks B-1, B-2, and each building block B-x, e.g. the phosphorus moiety PM of any one of Formulae II, II, II-a, and II-b, is independently selected from the group consisting of a phosphoramidite moiety and a H-phosphonate monoester moiety; - in each coupling cycle, in which said phosphorus moiety of the building block B-1, B-2 or B-x is a phosphoramidite moiety, step (f-1) or (f-2) or (f-x) is carried out; and - at least in the final coupling cycle, step (f-1) or (f-2) or (f-x) is carried out. In some embodiments of the method of the invention: - the phosphorus moiety of the building blocks B-1, B-2, and each building block B-x, e.g. the phosphorus moiety PM of any one of Formulae II, II-a, and II-b, is a phosphoramidite moiety; and - in each coupling cycle, step (f-1) or (f-2) or (f-x) is carried out. In some embodiments of the method of the invention: - the phosphorus moiety of the building blocks B-1, B-2, and each building block B-x, e.g. the phosphorus moiety PM of any one of Formulae II, II-a, and II-b, is a H-phosphonate monoester moiety; and - at least in the final coupling cycle, step (f-1) or (f-2) or (f-x) is carried out. In some embodiments of the method of the invention: - each building block B-1, B-2, and B-x is independently a compound of Formula II-1, preferably of Formula II-1-a, in particular of Formula II-1-b; and - in each coupling cycle, step (f-1) or (f-2) or (f-x) is carried out. The “oxidizing agent” or the “sulfurizing agent” to be used in any one of steps (f-1), (f-2), and (f-x) are not particularly limited in terms of their chemical structure as long as the respective agent is capable of converting any P (III) atoms within said first cycle oligonucleotide O-1, said second cycle oligonucleotide O-2, and said x-th cycle oligonucleotide O-x to P (V) atoms. An “oxidizing agent” and a “sulfurizing agent” may differ in the means of how P (III) atoms are converted to P (V) atoms. An “oxidizing agent” may introduce one or more covalent bonds between the P (III) atom to be oxidized and an oxygen atom. A “sulfurizing agent” may introduce one or more covalent bonds between the P (III) atom to be sulfurized and a sulfur atom. As used herein, the term “oxidizing agent” preferably refers to any agent capable of converting a phosphite triester linkage group to a phosphate triester linkage group and a H-phosphonate diester linkage group to a phosphate diester (i.e. a phosphodiester) linkage group. As used herein, the term “sulfurizing agent” preferably refers to any agent capable of converting a phosphite triester linkage group to a thiophosphate triester linkage group and a H-phosphonate diester linkage group to a thiophosphate diester linkage group (i.e. a phosphorothioate) linkage group. Iodine may be a preferred oxidizing agent. For example, an aqueous solution of iodine may be used, preferably in combination with a co-solvent such as an ether solvent, e.g. an ether solvent S^E (vide infra), a nitrile solvent such as acetonitrile, a (hetero)aromatic solvent such as pyridine, or a mixture thereof. As one example, a solution of iodine (e.g. 1 mol/L) in a mixed solvent of 4-methyltetrahydropyran (MTHP), water, and, optionally, acetonitrile may be used. Alternatively, peroxides such as tert-butyl hydroperoxide, cumene hydroperoxides, bis-trimethylsilyl peroxide, 2-butanone peroxide, and hydrogen peroxide, or peroxy acids such as m-chloroperbenzoic acid (mCPBA) may, for example, be used as oxidizing agents. As one example, a solution of tert-butyl hydroperoxide in a non-polar solvent may be used. For example, a solution (e.g. 5−6 mol/L) of tert-butyl hydroperoxide in nonane may be used. As another example, an aqueous solution of hydrogen peroxide may be used. For example, an aqueous solution of hydrogen peroxide and, optionally, potassium iodide may be mixed with an aqueous phosphoric acid buffer (e.g. pH 6.8) to obtain an oxidizing agent. As another alternative, (1S)-(+)-(10- camphorsulfonyl)-oxaziridine (CSO) may, for example, be used as oxidizing agent, e.g. as a 0.5 M (i.e.0.5 mol/L) solution in, e.g., acetonitrile. In general, the oxidizing agent may, for example, be applied in form of a 0.005−10.0 M (i.e. mol/L) solution, preferably a 0.01−5.0 M solution in a suitable solvent. Alternatively, neat oxidizing agent may, for example, be added (i.e. the oxidizing agent need not be dissolved in a suitable solvent). Xanthane hydride (5-amino-3H-1,2,4-dithiazole-3-thione), 3H-1,2-benzodithiol-3- one, and 3-(N,N-dimethylamino-methylidene)amino)-3H-1,2,4-dithiazole-5-thione (CAS RN: 1192027-04-5, DDTT) may be preferred sulfurizing agents. Alternatively, 1,4-dithiothreitol (DTT), phenylacetyl disulfide (PADS) or 3H-1,2-benzodithiol-3-one 1,1-dioxide (Beaucage Reagent) may be used as sulfurizing agents. For example, neat sulfurizing agent (i.e. not in solution) may be added. As one example, neat DDTT may be added. As another example, neat xanthane hydride may be added. Alternatively, a solution of the sulfurizing agent in a suitable solvent may be added. The sulfurizing agent may, for example, be applied in form of a 0.005−5.0 M solution, preferably a 0.01−1.0 M solution in a suitable solvent, for example, selected from the group consisting of pyridine, acetonitrile, water, tetrahydrofuran, and mixtures thereof. As one example, a solution of xanthane hydride in pyridine may be used, optionally in combination with a co-solvent such as acetonitrile. As another example, a solution of xanthane hydride (e.g. 0.2 M) in pyridine may be used. As another example, a solution of xanthane hydride (e.g.0.1 M) in a mixture of pyridine and acetonitrile (e.g.1:1, v/v) may be used. Steps (f-1), (f-2), and (f-x) may, for example, be performed at a temperature in the range of 0−90 °C, 10−70 °C, 15−60 °C, or 15−50 °C. For convenience, steps (f-1), (f-2), and (f-x) may simply be performed at room temperature. Increased temperatures may result in shorter reaction times. The reaction time may also depend on the chemical structure of the reactants and will routinely be selected by a skilled person, for example, based on reaction monitoring using, e.g., thin-layer chromatography and/or high performance liquid chromatography (HPLC), optionally coupled to mass spectrometry. The term “incubating” in steps (f-1), (f-2), and (f-x) may be understood in the broadest sense to refer to any process of contacting the first cycle oligonucleotide O-1, the second cycle oligonucleotide O-2 or the x-th cycle oligonucleotide O-x, respectively, and the respective oxidizing or sulfurizing agent, preferably inside the same reaction vessel or reactor. Typically, the first cycle oligonucleotide O-1, the second cycle oligonucleotide O-2 or the x-th cycle oligonucleotide O-x may already be contained in a reaction vessel or reactor, to which the respective oxidizing or sulfurizing agent is then added. Alternatively, the first cycle oligonucleotide O-1, the second cycle oligonucleotide O-2 or the x-th cycle oligonucleotide O-x may be added to the reaction vessel or reactor containing the respective oxidizing or sulfurizing agent. After said conversion of any P (III) atoms to P (V) atoms of any one of steps (f-1), (f-2), and (f-x), excess oxidizing or sulfurizing agent may typically be quenched (i.e. reduced), e.g., by treatment with a reducing agent. For example, a reducing agent such as triethylphosphite or a solution thereof may be added directly into the reaction mixture of the respective step (f-1) or (f-2) or (f-x). Alternatively, if step (g-1) or (g-2) or (g-x) is carried out, a reducing agent may also be comprised in one or more of the one or more aqueous solutions used for the one or more aqueous extractions. Examples of such water-soluble reducing agents comprise thiosulfate salts such as sodium thiosulfate. Step (g-1) of some methods of the invention is: optionally, subjecting a solution comprising the first cycle oligonucleotide O-1 to one or more aqueous extractions, wherein the organic phase comprises the first cycle oligonucleotide O-1. Step (g-2) of some of the methods of the invention is: optionally, subjecting a solution comprising the second cycle oligonucleotide O-2 to one or more aqueous extractions, wherein the organic phase comprises the second cycle oligonucleotide O-2. Step (g-x) of some of the methods of the invention is: optionally, subjecting a solution comprising the x-th cycle oligonucleotide O-x to one or more aqueous extractions, wherein the organic phase comprises the x-th cycle oligonucleotide O-x. The term “optionally” in steps (g-1), (g-2), and (g-x) denotes that the respective step may or may not be carried out in a given coupling cycle, unless indicated differently in the context of specific embodiments. Steps (g-1), (g-2), and (g-x) may, for example, be carried out to (at least partly) remove one or more side products and/or by-products and/or excess reagents and/or water-miscible solvents. In some embodiments of the method of the invention, step (g-1) is carried out (i.e. is not optional). In some embodiments of the method of the invention, in the second coupling cycle, step (g-2) is carried out (i.e. is not optional). In some embodiments of the method of the invention, in at least one, or each, coupling cycle comprising steps (b-x) to (h-x) (as far as present), step (g-x) is carried out (i.e. is not optional). The skilled artisan will understand that said solution comprising the first cycle oligonucleotide O-1 in step (g-1) may refer to the reaction mixture obtained from carrying out step (e-1), if step (f-1) is not performed, or may refer to the reaction mixture obtained from carrying out step (f-1) (wherein one or more quenchers or reducing agents may, for example, have been added beforehand as explained above). The skilled artisan will also understand that said solution comprising the second cycle oligonucleotide O-2 in step (g-2) may refer to the reaction mixture obtained from carrying out step (e-2), if step (f-2) is not performed, or may refer to the reaction mixture obtained from carrying out step (f-2) (wherein one or more quenchers or reducing agents may, for example, have been added beforehand as explained above). The skilled artisan will also understand that said solution comprising the x-th cycle oligonucleotide O-x in step (g-x) may refer to the reaction mixture obtained from carrying out step (e-x), if step (f-x) is not performed, or may refer to the reaction mixture obtained from carrying out step (f-x) (wherein one or more quenchers or reducing agents may, for example, have been added beforehand as explained above). Optionally, said solutions comprising the first cycle oligonucleotide O-1, the second cycle oligonucleotide O-2 or the x-th cycle oligonucleotide O-x may be obtained from the respective reaction mixture by addition of one or more non-polar solvents, for example, in order to facilitate the phase separation. Alternatively, or additionally, such non-polar solvents may also be added during or in between the one or more aqueous extractions of any one of steps (g-1), (g-2), and (g-x). Non-limiting examples of non-polar solvents comprise those listed above in the context of steps (c-1), (c-2), and (c-x). 4-Methyltetrahydropyran (MTHP) may be a preferred non-polar ether solvent which may be added prior to or during or in between the aqueous extraction(s) of any one of steps (g-1), (g-2), and (g-x). Additionally, or alternatively, one or more amide solvents S^A may be added prior to or during or in between the aqueous extraction(s) of any one of steps (g-1), (g-2), and (g-x). The term “aqueous extraction” in steps (g-1), (g-2), and (g-x) of the method of the invention may be understood in the broadest sense as any liquid-liquid extraction operation during which the respective solution comprising the first cycle oligonucleotide O-1, the second cycle oligonucleotide O-2 or the x-th cycle oligonucleotide O-x is extracted with water or an aqueous solution. The term “aqueous solution” has been defined above. It will be understood that for each of the one or more aqueous extractions of a step (g-1) or (g-2) or (g-x), the aqueous solution may be the same or different (i.e. comprise the same or different components in the same or different ratios). It will also be understood that the aqueous solutions may be the same or different for different steps (g-x) of different coupling cycles. In case of more than one organic phases (either from a single aqueous extraction or from back-extraction of one or more aqueous phase), these more than one organic phases may be combined to obtain “the organic phase” mentioned in steps (g-1), (g-2), and (g-x). In general, the means of performing aqueous extractions are well-known to the skilled person. The expression “the organic phase comprises the first cycle oligonucleotide O-1” in step (g-1) may be understood in the broadest sense to mean that some of the molecules of said first cycle oligonucleotide O-1 are dissolved in the organic phase. The expression “the organic phase comprises the second cycle oligonucleotide O-2” in step (g-2) may be understood in the broadest sense to mean that some of the molecules of said second cycle oligonucleotide O-2 are dissolved in the organic phase. The expression “the organic phase comprises the x-th cycle oligonucleotide O-x” in step (g-x) may be understood in the broadest sense to mean that some of the molecules of said x-th cycle oligonucleotide O-x are dissolved in the organic phase. It is preferred that most molecules (e.g. more than 50 %, 60 %, 70 %, 80 %, or 90 % of the molecules) of the said first cycle oligonucleotide O-1 or said second cycle oligonucleotide O-2 or said x-th cycle oligonucleotide O-x are comprised in the organic phase (and thus not in the aqueous phase). Step (h-1) of some methods of the invention is: if step (g-1) has been carried out, optionally reducing the water content of the organic phase comprising the first cycle oligonucleotide O-1. Step (h-2) of some of the methods of the invention is: if step (g-2) has been carried out, optionally reducing the water content of the organic phase comprising the second cycle oligonucleotide O-2. Step (h-x) of some of the methods of the invention is: if step (g-x) has been carried out, optionally reducing the water content of the organic phase comprising the x-th cycle oligonucleotide O-x. The expression “if step (g-1) has been carried out” in step (h-1) means that in the first coupling cycle, step (h-1) may only be carried out, if step (g-1) has been carried out. The expression “if step (g-2) has been carried out” in step (h-2) means that in the second coupling cycle, step (h-2) may only be carried out, if step (g-2) has been carried out. The expression “if step (g-x) has been carried out” in step (h-x) means that in a given coupling cycle comprising steps (b-x) to (h-x) (as far as present), step (h-x) may only be carried out, if step (g-x) has been carried out (in the same coupling cycle). The term “optionally” in steps (h-1), (h-2), and (h-x) denotes that, even if the respective step (g-1), (g-2) or (g-x) has been carried out, the respective step (h-1), (h-2) or (h-x) may or may not be carried, unless indicated differently in the context of specific embodiments. In some embodiments of the method of the invention, step (h-1) is carried out (i.e. is not optional), if step (g-1) has been carried out. In some embodiments of the method of the invention, in the second coupling cycle, step (h- 2) is carried out (i.e. is not optional), if step (g-2) has been carried out. In some embodiments of the method of the invention, in at least one, or each, coupling cycle comprising steps (b-x) to (h-x) (as far as present), step (h-x) is carried out (i.e. is not optional), if step (g-x) has been carried out in the same coupling cycle. The term “the organic phase” in steps (h-1), (h-2), and (h-x) refers to “the organic phase” of the respective step (g-1) or (g-2) or (g-x) of the same coupling cycle. The term “reducing the water content” has been defined above. In some embodiments of the method of the invention, step (h-1) is: if step (g-1) has been carried out, optionally reducing the water content of the organic phase comprising the first cycle oligonucleotide O-1, wherein the water content is adjusted to be equal to or less than 2000 ppm, 1900 ppm, 1800 ppm, 1700 ppm, 1600 ppm, 1500 ppm, 1400 ppm, 1300 ppm, 1200 ppm, 1100 ppm, 1000 ppm, 900 ppm, 800 ppm, 700 ppm, 600 ppm, 500 ppm, 400 ppm, 300 ppm, 250 ppm, 200 ppm, 150 ppm, or 100 ppm. In some embodiments of the method of the invention, step (h-2) is: if step (g-2) has been carried out, optionally reducing the water content of the organic phase comprising the second cycle oligonucleotide O-2, wherein the water content is adjusted to be equal to or less than 2000 ppm, 1900 ppm, 1800 ppm, 1700 ppm, 1600 ppm, 1500 ppm, 1400 ppm, 1300 ppm, 1200 ppm, 1100 ppm, 1000 ppm, 900 ppm, 800 ppm, 700 ppm, 600 ppm, 500 ppm, 400 ppm, 300 ppm, 250 ppm, 200 ppm, 150 ppm, or 100 ppm. In some embodiments of the method of the invention, step (h-x) is: if step (g-x) has been carried out, optionally reducing the water content of the organic phase comprising the x-th cycle oligonucleotide O-x, wherein the water content is adjusted to be equal to or less than 2000 ppm, 1900 ppm, 1800 ppm, 1700 ppm, 1600 ppm, 1500 ppm, 1400 ppm, 1300 ppm, 1200 ppm, 1100 ppm, 1000 ppm, 900 ppm, 800 ppm, 700 ppm, 600 ppm, 500 ppm, 400 ppm, 300 ppm, 250 ppm, 200 ppm, 150 ppm, or 100 ppm. In some embodiments of the method of the invention: - step (h-1) is carried out (i.e. is not optional), if the organic phase comprising the first cycle oligonucleotide O-1 of step (g-1) comprises more than 2000 ppm, 1900 ppm, 1800 ppm, 1700 ppm, 1600 ppm, 1500 ppm, 1400 ppm, 1300 ppm, 1200 ppm, 1100 ppm, 1000 ppm, 900 ppm, 800 ppm, 700 ppm, 600 ppm, 500 ppm, 400 ppm, 300 ppm, 250 ppm, 200 ppm, 150 ppm, or 100 ppm of water; - step (h-2) is carried out (i.e. is not optional), if the organic phase comprising the second cycle oligonucleotide O-2 of step (g-2) comprises more than 2000 ppm, 1900 ppm, 1800 ppm, 1700 ppm, 1600 ppm, 1500 ppm, 1400 ppm, 1300 ppm, 1200 ppm, 1100 ppm, 1000 ppm, 900 ppm, 800 ppm, 700 ppm, 600 ppm, 500 ppm, 400 ppm, 300 ppm, 250 ppm, 200 ppm, 150 ppm, or 100 ppm of water; and - step (h-x) is carried out (i.e. is not optional), if the organic phase comprising the x-th cycle oligonucleotide O-x of step (g-x) of the same coupling cycle comprises more than 2000 ppm, 1900 ppm, 1800 ppm, 1700 ppm, 1600 ppm, 1500 ppm, 1400 ppm, 1300 ppm, 1200 ppm, 1100 ppm, 1000 ppm, 900 ppm, 800 ppm, 700 ppm, 600 ppm, 500 ppm, 400 ppm, 300 ppm, 250 ppm, 200 ppm, 150 ppm, or 100 ppm of water. Any means of reducing the water content may be employed, preferred examples of which comprise azeotropic distillation and the use of a drying agent, both of which have been explained above. In some embodiments of the method of the invention, in at least one or each of steps (h-1), (h-2), and (h-x), reducing the water content is achieved by means of azeotropic distillation and/or by contacting said organic phase comprising the first cycle oligonucleotide O-1, the second cycle oligonucleotide O-2 or the x-th cycle oligonucleotide O-x with a drying agent. In some embodiments of the method of the invention, in at least one or each of steps (h-1), (h-2), and (h-x), reducing the water content is achieved by means of azeotropic distillation. In some embodiments of the method of the invention, in at least one or each of steps (h-1), (h-2), and (h-x), reducing the water content is achieved by means of contacting said organic phase comprising the first cycle oligonucleotide O-1, the second cycle oligonucleotide O-2 or the x-th cycle oligonucleotide O-x with a drying agent. It will be understood that in any one of steps (h-1), (h-2), and (h-x), one or more solvents and/or further components may be added to said organic phase comprising the first cycle oligonucleotide O-1, the second cycle oligonucleotide O-2 or the x-th cycle oligonucleotide O-x prior to, during, and/or after reduction of the water content. In some embodiments of the method of the invention, in at least one or each of steps (d-1), (d-2), (d-x), (h-1), (h-2), and (h-x), reducing the water content is achieved by means of azeotropic distillation. In some embodiments of the method of the invention: - the first coupling cycle further comprises a step (i-1) of reacting free hydroxyl groups with a blocking agent, wherein step (i-1) is carried out after step (e-1) or after step (f-1); and/or - the second coupling cycle further comprises a step (i-2) of reacting free hydroxyl groups with a blocking agent, wherein step (i-2) is carried out after step (e-2) or after step (f-2); and/or - at least one coupling cycle comprising steps (b-x) to (h-x) (as far as present) further comprises a step (i-x) of reacting free hydroxyl groups with a blocking agent, wherein step (i-x) is carried out after step (e-x) or after step (f-x). The free backbone hydroxyl group present in the component (C-0)^#, the first cycle oligonucleotide (O-1)^#, and the (x−1)-th cycle oligonucleotide (O-(x−1))^# is supposed to engage in the bond forming reaction of step (e-1), (e-2) or (e-x) (of the same coupling cycle), which consumes said free backbone hydroxyl group in the sense of incorporating it into a newly-formed internucleosidic linkage group. However, a (typically very small, e.g. < 1 %, < 0.5 % or < 0.1 %) fraction of the free backbone hydroxyl groups may not engage in the bond forming reaction at the first occasion, i.e. in the same coupling cycle, in which the respective free hydroxyl group has been generated by cleaving a protecting group. Such free hydroxyl groups are herein also referred to as unreacted free hydroxyl groups. These groups would be available to participate in the bond forming reactions of the coupling steps of following coupling cycles. This may not be desirable, since it would afford an oligonucleotide product lacking one nucleoside subunit. Such oligonucleotide products may be difficult to remove from the target oligonucleotide O^T later on. As used herein, the terms “blocking agent” and “capping agent” are used interchangeably to denote any chemical reagent capable of acylating, preferably acetylating, a free hydroxyl group. Capping agents for oligonucleotide synthesis form part of the common knowledge of those skilled in the art. Any blocking (i.e. capping) agents known from oligonucleotide synthesis may be used in the method of the invention. Preferred examples of such blocking agents comprise anhydrides of carboxylic acids, in particular acetic anhydride. It is known to those skilled in the art that free carboxylic acids may also be used in combination with activating agents such as carbodiimides (e.g. dicyclohexylcarbdiimide or diisopropylcarbodiimide) and additives such as, e.g., 4-dimethylaminopyridine (DMAP). For example, acetylation may be achieved by treating the growing oligonucleotide chains with neat acetic anhydride or a solution thereof. An organic base such as pyridine, lutidine (e.g.2,6-lutidine), collidine, N-methylimidazole, or a mixture thereof may be added. For example, acetic anhydride (e.g.4 moles of acetic anhydride per 1 mol of employed component (C-0)^#) may be used, preferably in combination with a base such as pyridine (e.g.5 moles of base per 1 mol of employed component (C-0)^#). The blocking agents may be added directly into the reaction vessel or reactor, in which step (e-1), (e-2), (e-x), (f-1), (f-2) or (f-x) was carried out. The term “reacting” in step (i-1), (i-2), and (i-x) may be understood in the broadest sense as any operation during which the growing oligonucleotide chains and the blocking agent are present in the same reaction vessel or reactor and engage in the blocking reaction. In some embodiments of the method of the invention, the method further comprises - a step (k-1) of incubating the first cycle oligonucleotide O-1 with a deprotection mixture M-(k-1), thereby cleaving the protecting group PG-1 from the first cycle oligonucleotide O-1, so as to obtain a first cycle oligonucleotide (O-1)^# having a free backbone hydroxyl group; and/or - a step (m-1) of incubating the first cycle oligonucleotide O-1 or (O-1)^# with a base, thereby cleaving the pseudo solid-phase protecting group PG-s and, optionally, one or more further protecting groups from the first cycle oligonucleotide O-1 or (O-1)^#; and/or - a step (p-1) of modifying the first cycle oligonucleotide O-1 or (O-1)^#; wherein, if more than one of steps (k-1), (m-1), and (p-1) are performed, they may be performed in any order. It will be understood that any one of steps (k-1), (m-1), and (p-1) may only be carried out after all steps of the first coupling cycle (optionally excluding steps indicated as optional) have been performed. It will also be understood that, if any one of steps (k-1), (m-1), and (p-1) is carried out, the second coupling cycle comprising steps (b-2) to (h-2) and thus any further coupling cycles comprising steps (b-x) to (h-x) (as far as present) may not be carried out. In some embodiments of the method of the invention, the method further comprises - a step (k-2) of incubating the second cycle oligonucleotide O-2 with a deprotection mixture M-(k-2), thereby cleaving the protecting group PG-2 from the second cycle oligonucleotide O-2, so as to obtain a second cycle oligonucleotide (O-2)^# having a free backbone hydroxyl group; and/or - a step (m-2) of incubating the second cycle oligonucleotide O-2 or (O-2)^# with a base, thereby cleaving the pseudo solid-phase protecting group PG-s and, optionally, one or more further protecting groups from the second cycle oligonucleotide O-2 or (O-2)^#; and/or - a step (p-2) of modifying the second cycle oligonucleotide O-2 or (O-2)^#; wherein, if more than one of steps (k-2), (m-2), and (p-2) are performed, they may be performed in any order. It will be understood that any one of steps (k-2), (m-2), and (p-2) may only be carried out after all steps of the second coupling cycle (optionally excluding steps indicated as optional) have been performed. It will also be understood that, if any one of steps (k-2), (m-2), and (p-2) is carried out, further coupling cycles comprising steps (b-x) to (h-x) (as far as present) may not be carried out. In some embodiments of the method of the invention, the method further comprises - a step (k-n) of incubating the n-th cycle oligonucleotide O-n with a deprotection mixture M-(k-n), thereby cleaving the protecting group PG-n from the n-th cycle oligonucleotide O-n, so as to obtain a n-th cycle oligonucleotide (O-n)^# having a free backbone hydroxyl group; and/or - a step (m-n) of incubating the n-th cycle oligonucleotide O-n or (O-n)^# with a base, thereby cleaving the pseudo solid-phase protecting group PG-s and, optionally, one or more further protecting groups from the n-th cycle oligonucleotide O-n or (O-n)^#; and/or - a step (p-n) of modifying the n-th cycle oligonucleotide O-n or (O-n)^#; wherein, if more than one of steps (k-n), (m-n), and (p-n) are performed, they may be performed in any order. It will be understood that any one of steps (k-n), (m-n), and (p-n) may only be carried out after all steps of the (n−2)-th iteration of the coupling cycle comprising steps (b- x) to (h-x) (optionally excluding steps indicated as optional) have been performed. The term "deprotection mixture M-(k-1)" refers to any mixture which may be used to effect cleavage of the protecting group PG-1 from the first cycle oligonucleotide O-1. Any definitions and embodiments pertaining to the deprotection mixture M-(b-2) may also apply to the deprotection mixture M-(k-1). The term "deprotection mixture M-(k-2)" refers to any mixture which may be used to effect cleavage of the protecting group PG-2 from the second cycle oligonucleotide O-2. Any definitions and embodiments pertaining to the deprotection mixture M-(b-3) (i.e. a deprotection mixture M-(b-x) with x=3) may also apply to the deprotection mixture M-(k-2). The term "deprotection mixture M-(k-n)" refers to any mixture which may be used to effect cleavage of the protecting group PG-n from the n-th cycle oligonucleotide O-n. Any definitions and embodiments pertaining to the deprotection mixture M-(b-x) may also apply to the deprotection mixture M-(k-n). The term “base” in steps (m-1), (m-2), and (m-n) may be understood in the broadest sense to refer to any base (a proton acceptor in the sense of the BrØnsted-Lowry theory), unless indicated differently in the context of specific embodiments. Non- limiting examples of such a base comprise ammonia, a (C1−C6-alkyl)NH2 monoalkylamine, in particular methylamine, ethylamine or tert-butylamine, a (C₁−C₆-alkyl)₂NH dialkylamine, in particular dimethylamine or diethylamine, a source of hydroxide ions, and mixtures thereof. As known to the skilled artisan, such bases will typically not be employed as such in a step (m-1), (m-2) or (m-n), but rather in form of a solution of the base in a suitable solvent, in particular water, i.e. as an aqueous solution of the respective base. Such an aqueous solution may further comprise one or more water-miscible organic solvents such as, e.g., acetonitrile, tetrahydrofuran, methanol, ethanol, and the like. As used herein, the term “a source of hydroxide ions” may refer to a salt which comprises hydroxide ions, wherein sodium hydroxide, potassium hydroxide, and ammonium hydroxide may be preferred examples. The person skilled in the art knows that an aqueous solution of ammonia may also be referred to as an ammonium hydroxide solution, since it comprises ammonium ions and hydroxide ions. The skilled artisan understands that a solution comprising a source of hydroxide anions may comprise said source of hydroxide ions in solvated form. In some embodiments, said base of any one of steps (m-1), (m-2), and (m-n) is an aqueous solution of one or more compounds selected from the group consisting of ammonia, a (C₁−C₆-alkyl)NH₂ monoalkylamine, a (C₁−C₆-alkyl)₂NH dialkylamine, sodium hydroxide, potassium hydroxide, and mixtures thereof. In some embodiments, said base of any one of steps (m-1), (m-2), and (m-n) is an aqueous solution of one or more compounds selected from the group consisting of ammonia, methylamine, ethylamine, tert-butylamine, sodium hydroxide, potassium hydroxide, and mixtures thereof. For example, said base of any one of steps (m-1), (m-2), and (m-n) may be an aqueous solution of ammonia, e.g.25−30 wt-% aqueous ammonia. As another example, said base of any one of steps (m-1), (m-2), and (m-n) may be an aqueous solution of tert-butylamine, e.g. a 1:1 (v:v) mixture of water and tert-butylamine. As another example, said base of any one of steps (m-1), (m-2), and (m-n) may be an aqueous solution of methylamine, e.g. a 1:1 (v:v) mixture of water and methylamine. As another example, said base of any one of steps (m-1), (m-2), and (m-n) may be a solution of sodium hydroxide (e.g.1 mol/L) in a mixture of water and tetrahydrofuran (e.g. 1:3, v:v). Alternatively, hydrazine (e.g. used in form of its hydrate) may, for example, be used as nucleophilic base. In some embodiments of the method of the invention, the method comprises exactly one step selected from the group consisting of step (m-1), step (m-2), and step (m-n), and wherein - step (m-1) is carried out by incubating the first cycle oligonucleotide O-1 or (O-1)^# with an aqueous solution of an organic amine, preferably an aliphatic amine, more preferably a primary or secondary aliphatic amine, in particular a primary aliphatic amine such as tert-butylamine, and an aliphatic alcohol, preferably an aliphatic alcohol comprising 1−6 carbon atoms, in particular methanol; - step (m-2) is carried out by incubating the second cycle oligonucleotide O-2 or (O-2)^# with an aqueous solution of an organic amine, preferably an aliphatic amine, more preferably a primary or secondary aliphatic amine, in particular a primary aliphatic amine such as tert-butylamine, and an aliphatic alcohol, preferably an aliphatic alcohol comprising 1−6 carbon atoms, in particular methanol; and - step (m-n) is carried out by incubating the n-th cycle oligonucleotide O-n or (O-n)^# with an aqueous solution of an organic amine, preferably an aliphatic amine, more preferably a primary or secondary aliphatic amine, in particular a primary aliphatic amine such as tert-butylamine, and an aliphatic alcohol, preferably an aliphatic alcohol comprising 1−6 carbon atoms, in particular methanol. In such embodiments, the respective oligonucleotide, i.e., the first cycle oligonucleotide O-1 or (O-1)^# in a step (m-1) and the second cycle oligonucleotide O-2 or (O-2)^# in a step (m-2) and the n-th cycle oligonucleotide O-n or (O-n)^# in a step (m-n) preferably comprises at least one internucleosidic linkage group selected from the group consisting of a thiophosphate triester group and a thiophosphate diester group, preferably a linkage group of Formula B, where X¹ is S and X² is either OH or O-CH2-CH2-CN. In some embodiments of the method of the invention, the method comprises exactly one step selected from the group consisting of step (m-1), step (m-2), and step (m-n), and wherein - step (m-1) is carried out by incubating the first cycle oligonucleotide O-1 or (O-1)^# with an aqueous solution of a (C₁−C₆-alkyl)NH₂ monoalkylamine, in particular tert-butylamine, and an aliphatic alcohol comprising 1−6 carbon atoms, in particular methanol; - step (m-2) is carried out by incubating the second cycle oligonucleotide O-2 or (O-2)^# with an aqueous solution of a (C1−C6-alkyl)NH2 monoalkylamine, in particular tert-butylamine, and an aliphatic alcohol comprising 1−6 carbon atoms, in particular methanol; and - step (m-n) is carried out by incubating the n-th cycle oligonucleotide O-n or (O-n)^# with an aqueous solution of a (C₁−C₆-alkyl)NH₂ monoalkylamine, in particular tert-butylamine, and an aliphatic alcohol comprising 1−6 carbon atoms, in particular methanol. In such embodiments, the respective oligonucleotide, i.e., the first cycle oligonucleotide O-1 or (O-1)^# in a step (m-1) and the second cycle oligonucleotide O-2 or (O-2)^# in a step (m-2) and the n-th cycle oligonucleotide O-n or (O-n)^# in a step (m-n) preferably comprises at least one internucleosidic linkage group selected from the group consisting of a thiophosphate triester group and a thiophosphate diester group, preferably a linkage group of Formula B, where X¹ is S and X² is either OH or O-CH₂-CH₂-CN. In some embodiments of the method of the invention, the method comprises exactly one step selected from the group consisting of step (m-1), step (m-2), and step (m-n), and wherein - step (m-1) is carried out by incubating the first cycle oligonucleotide O-1 or (O-1)^# with an aqueous solution of a (C₁−C₆-alkyl)NH₂ monoalkylamine, in particular tert-butylamine, and an aliphatic alcohol comprising 1−6 carbon atoms, in particular methanol, wherein the volume-ratio of monoalkylamine to aliphatic alcohol to water is 1:1:2 (v:v:v); - step (m-2) is carried out by incubating the second cycle oligonucleotide O-2 or (O-2)^# with an aqueous solution of a (C1−C6-alkyl)NH2 monoalkylamine, in particular tert-butylamine, and an aliphatic alcohol comprising 1−6 carbon atoms, in particular methanol, wherein the volume-ratio of monoalkylamine to aliphatic alcohol to water is 1:1:2 (v:v:v); and - step (m-n) is carried out by incubating the n-th cycle oligonucleotide O-n or (O-n)^# with an aqueous solution of a (C1−C6-alkyl)NH2 monoalkylamine, in particular tert-butylamine, and an aliphatic alcohol comprising 1−6 carbon atoms, in particular methanol, wherein the volume-ratio of monoalkylamine to aliphatic alcohol to water is 1:1:2 (v:v:v). In such embodiments, the respective oligonucleotide, i.e., the first cycle oligonucleotide O-1 or (O-1)^# in a step (m-1) and the second cycle oligonucleotide O-2 or (O-2)^# in a step (m-2) and the n-th cycle oligonucleotide O-n or (O-n)^# in a step (m-n) preferably comprises at least one internucleosidic linkage group selected from the group consisting of a thiophosphate triester group and a thiophosphate diester group, preferably a linkage group of Formula B, where X¹ is S and X² is either OH or O-CH2-CH2-CN. The use of an aqueous solution of a (C₁−C₆-alkyl)NH₂ monoalkylamine, in particular tert-butylamine, and an aliphatic alcohol comprising 1−6 carbon atoms, in particular methanol is particularly preferred, if the pseudo solid-phase protecting group PG-s is a protecting group of Formula P-1-a below, in particular, with the integer a being 1. Steps (m-1), (m-2), and (m-n) may, for example, be performed at a temperature in the range of 5−95 °C, 10−95 °C, 15−95 °C, 20−95 °C, 25−95 °C, 30−95 °C, 35−95 °C, 50−90 °C, 55−90 °C, 60−85 °C, or 60−80 °C. Lower temperatures, e.g., in the range of 45–70 °C or 50–60 °C, in particular 55 °C, may be preferred when using an aqueous solution of a (C₁−C₆-alkyl)NH₂ monoalkylamine, in particular tert-butylamine, and an aliphatic alcohol comprising 1−6 carbon atoms, in particular methanol. It will be understood that steps (m-1), (m-2), and (m-n) may preferably be performed in a sealed reaction vessel or reactor, e.g. in an autoclave, when operating at elevated temperatures. Under the alkaline conditions of steps (m-1), (m-2), and (m-n), “one or more further protecting groups” (i.e. other than said pseudo solid-phase PG-s) may optionally be cleaved from the respective oligonucleotide. In fact, as will be understood by the skilled artisan, any common protecting groups removable under alkaline conditions will typically be removed during the incubation with said base in steps (m-1), (m-2), and (m-n). Such protecting groups removable under alkaline conditions, e.g. under the conditions of steps (m-1), (m-2), and (m-n), may, for example, be the typical nucleobase protecting groups, non-limiting examples of which comprise the protecting groups listed in Table T-1 above. Additionally, protecting groups at the internucleosidic linkage groups, e.g. any protecting groups R^Z-1 and R^Z-2, in particular any 2-cyanoethyl protecting groups, may typically be removed under the conditions of steps (m-1), (m-2), and (m-n). In the context of steps (p-1), (p-2), and (p-n) of the method of the invention, the term “modifying” may be understood in the broadest sense to embrace “chemically modifying” and/or “biotechnologically modifying” the respective oligonucleotides. In the context of steps (p-1), (p-2), and (p-n), “chemically modifying” is defined as subjecting the respective oligonucleotide (which is to be chemically modified) to one or more chemical reactions. Non-limiting examples of such chemical reactions are - the removal of one or more protecting groups (including any pseudo solid-phase protecting groups); - conjugation with one or more compounds selected from the group consisting of a nucleoside, an oligonucleotide, a carbohydrate such as a monosaccharide or a polysaccharide, an amino acid, a peptide, a lipid, an active pharmaceutical ingredient, or the like; and - an intramolecular bond forming reaction resulting in cyclization. It will be understood that more than one such chemical reactions may be performed in the course of said chemical modification. In the context of steps (p-1), (p-2), and (p-n), “biotechnologically modifying” is defined as subjecting the respective oligonucleotide (which is to be biotechnologically modified) to one or more enzymatic reactions. As used herein, the term “enzymatic reaction” refers to any reaction which is enabled by and/or catalyzed by one or more enzymes. A preferred example is enzymatic ligation. In some embodiments, the method of the invention further comprises a step (z) of isolating the target oligonucleotide O^T. The means of isolating oligonucleotides upon oligonucleotide synthesis form part of the common knowledge of those skilled in the art. Typically, such a step of isolating an oligonucleotide comprises one or more purification steps and one or more steps aiming at obtaining the oligonucleotide in solid form. For oligonucleotide purification, chromatographic methods may typically be used, in particular ion exchange (especially anion exchange) chromatography and reversed phase (RP) HPLC, e.g. in form of hydrophobic interaction HPLC. These techniques are known to those skilled in the art. Additionally, a step of isolating an oligonucleotide may comprise ultrafiltration and/or desalting steps. Typically, the target oligonucleotide to be isolated may be dissolved in a reaction mixture. It may then be preferable to first obtain a crude product either by precipitating the target oligonucleotide to be purified from the respective reaction mixture or by evaporation to dryness (e.g. in vacuo). Precipitation may for example be achieved by (partly) removing one or more solvents and/or by addition of one or more antisolvents (in which the target oligonucleotide is not soluble or poorly soluble) and/or by cooling the reaction mixture from which the target oligonucleotide to be isolated. The so-obtained crude product may, for example be washed with one or more solvents and/or aqueous solutions. The crude product may then be dissolved, so as to obtain a solution, preferably an aqueous solution of the target oligonucleotide to be isolated. Alternatively, the reaction mixture containing the target oligonucleotide as such may be used without precipitation or evaporation to dryness. For example, a solution, preferably an aqueous solution, containing the target oligonucleotide O^T to be isolated may be submitted to ultrafiltration and/or desalting, ion exchange chromatography, and another round of ultrafiltration and/or desalting. Alternatively, a crude product containing the target oligonucleotide O^T to be isolated may be submitted to reversed phase (RP) HPLC, e.g. in form of hydrophobic interaction HPLC. The latter method may preferably be performed, if the oligonucleotides still carry the 5´-terminal hydroxyl protecting group, e.g. the DMT group. Said 5´-protecting group may even be removed on the RP-HPLC column by passing an acidic solution through the column. If the 5´-terminal protecting group has been removed prior to purification, ion exchange chromatography may be preferred. Purification is typically followed by one or more steps aiming at obtaining the oligonucleotide in solid form. Lyophilization or spray drying may, for example, be used. In some cases, it may be desirable to obtain the oligonucleotide in form of a salt with certain counter ions. In such cases, salt exchange may be performed, typically prior to lyophilization or spray drying. In some embodiments of the method of the invention, during and in between steps (b-1) to (h-1) (as far as present), no solid-liquid separation is performed and steps (c-1) and (g-1) are carried out in the presence of one or more organic solvents S^O, wherein the one or more organic solvents S^O are selected so that an organic phase and an aqueous phase are formed during the aqueous extraction. It will be understood that the expression “steps (c-1) and (g-1) are carried out in the presence of one or more organic solvents S^O” does not imply that step (g-1) must be carried out, i.e., is not optional. However, if step (g-1) is carried out, it is carried out in the presence of one or more organic solvents S^O. If the method of the invention comprises performing a second coupling cycle comprising steps (b-2) to (h-2) (as far as present) , during and in between steps (b- 1) to (h-2) (as far as present), no solid-liquid separation is performed and steps (c- 1), (g-1), (c-2), and (g-2) are carried out in the presence of one or more organic solvents S^O, wherein the one or more organic solvents S^O are selected so that an organic phase and an aqueous phase are formed during the aqueous extraction . It will be understood that the expression “steps (c-1), (g-1), (c-2), and (g-2) are carried out in the presence of one or more organic solvents S^O” does not imply that steps (g-1) and (g-2) must be carried out, i.e., are not optional. However, if one or both of steps (g-1) and (g-2) are carried out, they are carried out in the presence of one or more organic solvents S^O. If the method of the invention comprises performing (n−2) iterations of a coupling cycle comprising the following steps (b-x) to (h-x) (as far as present), wherein n is an integer in the range of 3 to 99, which denotes the total number of coupling cycles performed to obtain to obtain the n-th cycle oligonucleotide O-n, during and in between steps (b-1) to (h-n) (as far as present), no solid-liquid separation is performed, and steps (c-1), (g-1), (c-2), and (g-2), as well as each iteration of steps (c-x) and (g-x) is carried out in the presence of one or more organic solvents S^O, wherein the one or more organic solvents S^O are selected so that an organic phase and an aqueous phase are formed during the aqueous extraction. It will be understood that the expression “steps (c-1), (g-1), (c-2), and (g-2), as well as each iteration of steps (c-x) and (g-x) are carried out in the presence of one or more organic solvents S^O” does not imply that steps (g-1), (g-2), and (g-x) must be carried out, i.e., are not optional. However, if one or more of steps (g-1), (g-2) and (g-x) are carried out, they are carried out in the presence of one or more organic solvents S^O. As used herein, the term “amide solvent” may be understood in the broadest sense to refer to any solvent characterized in that in its chemical structure, at least one carbonyl carbon atom (C=O) is covalently bonded directly to a nitrogen atom which may be further substituted or protected. As used herein, the term “solid-liquid separation” refers to any operation during which a solid is separated from a liquid. Most commonly, solid-liquid separation will be filtration or centrifugation, preferably filtration. It will be understood that such solid-liquid separation may typically not be complete, meaning that some residual liquid may typically be attached to the solid after solid-liquid separation, as known to those skilled in the art. It will be understood that the term “solid-liquid separation” does not embrace evaporation of the liquid. Hence, as used herein, a step of, e.g., evaporating a solution to dryness is not considered a “solid-liquid separation”. It will further be understood that pumping or circulating a liquid through a column packed with a solid, e.g., a drying agent such as molecular sieves as, as, e.g., disclosed in in X. Shi et al., Journal of Organic Chemistry 2022, 87(4), 2087−2110 (cf., e.g., Figure 1 of the cited reference and explanations pertaining thereto), is not a solid- liquid separation as defied herein. In some embodiments of the present invention, the process does not comprise any solid-liquid separation during or in between at least at least 3, 4, 5, 6, 7, 8, 9 consecutive coupling cycles. In some embodiments of the present invention, the process does not comprise any solid-liquid separation of the n-th cycle oligonucleotide O-n or of any oligonucleotidic educts or intermediates involved in the synthesis of the n-th cycle oligonucleotide O-n during or in between at least at least 3, 4, 5, 6, 7, 8, 9 consecutive coupling cycles. The term “during and in between steps (b-1) to (h-1)” means that - none of the steps (b-1), (c-1), (d-1), (e-1), (f-1), (g-1), and (h-1) comprises a solid-liquid separation (each of steps (d-1), (f-1), (g-1), and (h-1) may or may not be carried out as explained above), - if carried out, step (i-1) does not comprise a solid-liquid separation, and - no solid-liquid separation is performed in between any two of these steps. The term “during and in between steps (b-1) to (h-2)” means that - none of the steps (b-1), (c-1), (d-1), (e-1), (f-1), (g-1), (h-1), (b-2), (c-2), (d-2), (e-2), (f-2), (g-2), and (h-2) (as far as present, each of steps (d-1), (f-1), (g-1), (h-1), (d-2), (f-2), (g-2), (h-2) may or may not be carried out as explained above), comprises a solid-liquid separation, - if carried out, step (i-1) does not comprise a solid-liquid separation, - if carried out, step (i-2) does not comprise a solid-liquid separation, and - no solid-liquid separation is performed in between any two of these steps. The term “during and in between steps (b-1) to (h-n)” means that - none of the steps (b-1), (c-1), (d-1), (e-1), (f-1), (g-1), (h-1), (b-2), (c-2), (d-2), (e-2), (f-2), (g-2), and (h-2)(each of steps (d-1), (f-1), (g-1), (h-1), (d-2), (f-2), (g- 2), (h-2) may or may not be carried out as explained above) comprises a solid-liquid separation, - no iteration of step (b-x), no iteration of step (c-x), no iteration of step (d-x), no iteration of step (e-x), no iteration of step (f-x), no iteration of step (g-x), and no iteration of step (h-x) (each of steps (d-x), (f-x) (g-x) and (h-x) may or may not be carried out in a given coupling cycle) comprises a solid-liquid separation, - if carried out, step (i-1) does not comprise a solid-liquid separation, - if carried out, step (i-2) does not comprise a solid-liquid separation, - if carried out, no iteration of step (i-x) comprises a solid-liquid separation, and - no solid-liquid separation is performed in between any two of these steps. As used herein, the term “ether solvent” may be understood in the broadest sense to refer to any solvent characterized in that its chemical structure comprises at least one oxygen atom covalently bonded to exactly two residues independently selected from the group consisting of an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group, a heteroalkynyl group, an aryl group, and a heteroaryl group, wherein each of these two residues engages in a covalent chemical bond to said oxygen atom via a carbon atom (C), and wherein these two residues may optionally bond to each other to form a cyclic structure. Unless indicated differently in the context of specific embodiments, an ether solvent S^E may be any ether solvent. Examples and further embodiments pertaining to an ether solvent S^E will be laid out in a later section of this text. In some embodiments of the method of the invention, steps (b-1) to (h-1) (i.e. any one of steps (b-1), (c-1), (d-1), (e-1), (f-1), (g-1), and (h-1) as far as present) are carried out in essentially halogen-free solvents. It will be understood that this does not imply that any optional step must be carried out. In some embodiments of the method of the invention, if the second coupling cycle comprising steps (b-2) to (h-2) (as far as present) is performed, steps (b-1) to (h-2) (i.e. any one of steps (b-1), (c-1), (d-1), (e-1), (f-1), (g-1), (h-1), (b-2), (c-2), (d-2), (e-2), (f-2), (g-2), and (h-2) as far as present) are carried out in essentially halogen- free solvents. It will be understood that this does not imply that any optional step must be carried out. In some embodiments of the method of the invention, if (n−2) iterations of the coupling cycle comprising steps (b-x) to (h-x) (as far as present) are performed, all of steps (b-1) to (h-n) (i.e. any one of steps (b-1), (c-1), (d-1), (e-1), (f-1), (g-1), (h- 1), (b-2), (c-2), (d-2), (e-2), (f-2), (g-2), and (h-2), as far as present, as well as each iteration of any one of steps (b-x), (c-x), (d-x), (e-x), (f-x), (g-x), and (h-x)) are carried out in essentially halogen-free solvents. It will be understood that this does not imply that any optional step must be carried out. In some embodiments of the method of the invention, steps (b-1) to (h-1) (as far as present) are carried out in essentially halogen-free solvents, and further wherein: - if a second coupling cycle comprising steps (b-2) to (h-2) (as far as present) is performed, steps (b-1) to (h-2) (as far as present) are carried out in essentially halogen-free solvents; and - if (n−2) iterations of the coupling cycle comprising steps (b-x) to (h-x) (as far as present) are performed, any steps (b-1) to (h-n) (as far as present) are carried out in essentially halogen-free solvents. As used herein, the term “essentially halogen-free solvent” refers to a solvent which contains in total equal to or less than 3.0 vol-%, 2.0 vol-%, 1.0 vol-%, 0.1 vol-%, 0.01 vol-%, or 0.001 vol-% of halogenated solvents. As used, the term “halogenated solvent” refers to any solvent comprising in its chemical structure at least one halogen atom. Examples of halogenated solvents comprise dichloromethane, chloroform, and 1,1-dichloroethane, and 1,2-dichloroethane. To state that a step “is carried out in essentially halogen-free solvents” means that only essentially halogen-free solvents are used in the respective step. In some embodiments of the method of the invention: - said component C-0 comprises exactly one pseudo solid-phase protecting group, which is the pseudo solid-phase protecting group PG-s; and - the building block B-1 does not comprise any pseudo solid-phase protecting groups. In some embodiments of the method of the invention: - said component C-0 comprises exactly one pseudo solid-phase protecting group, which is the pseudo solid-phase protecting group PG-s; and - none of the building block B-1 and B-2 comprise any pseudo solid-phase protecting groups. In some embodiments of the method of the invention: - said component C-0 comprises exactly one pseudo solid-phase protecting group, which is the pseudo solid-phase protecting group PG-s; and - none of the building block B-1, B-2, and B-x comprise any pseudo solid-phase protecting groups. In some embodiments of the method of the invention, the sum of nucleoside subunits comprised in the component C-0 and all building blocks B-1, B-2, and B-x together is in the range of 5−100, 5−90, 5−80, 5−70, 5−60, 5−50, 5−40, 5−30, 5−20, 6−20 or 6−18. It will be understood that in the component C-0 of any one of Formulae I, I-a, I-b, the amount of nucleoside subunits is determined as 1 + m, where m is the integer m. It will be understood that in each building block B-1, B-2, and B-x of any one of Formulae II, II-a, II-b, II-1, II-1-a, and II-1-b, the amount of nucleoside subunits is determined as 1 + q, where q is the integer q. In some embodiments of the method of the invention: - said component C-0 comprises exactly one pseudo solid-phase protecting group, which is the pseudo solid-phase protecting group PG-s; - none of the building blocks B-1, B-2, and B-x comprises any pseudo solid-phase protecting groups; and - the sum of nucleoside subunits comprised in the component C-0 and all building blocks B-1, B-2, and B-x together is in the range of 5−100, 5−90, 5−80, 5−70, 5−60, 5−50, 5−40, 5−30, 5−20, 6−20 or 6−18. In some embodiments of the method of the invention; - the first cycle oligonucleotide O-1 comprises exactly one pseudo solid-phase protecting group, which is the pseudo solid-phase protecting group PG-s, and - the first cycle oligonucleotide comprises in total 5−100, 5−90, 5−80, 5−70, 5−60, 5−50, 5−40, 5−30, 5−20, 6−20 or 6−18 nucleoside subunits. In some embodiments of the method of the invention; - the second cycle oligonucleotide O-2 comprises exactly one pseudo solid-phase protecting group, which is the pseudo solid-phase protecting group PG-s, and - the second cycle oligonucleotide O-2 comprises in total 5−100, 5−90, 5−80, 5−70, 5−60, 5−50, 5−40, 5−30, 5−20, 6−20 or 6−18 nucleoside subunits. In some embodiments of the method of the invention; - the n-th cycle oligonucleotide O-n comprises exactly one pseudo solid-phase protecting group, which is the pseudo solid-phase protecting group PG-s, and - the n-th cycle oligonucleotide O-n comprises in total 5−100, 5−90, 5−80, 5−70, 5−60, 5−50, 5−40, 5−30, 5−20, 6−20 or 6−18 nucleoside subunits. As used herein, an amide solvent S^A is an amide solvent comprising one or more alkyl groups, wherein these one or more alkyl groups together comprise in total 6−48, 8−48, 6−47, 8−47, 6−46, 8−46, 6−45, 8−45, 6−44, 8−44, 6−43, 8−43, 6−42, 8−42, 6−41, 8−41, 6−40, 8−40, 6−39, 8−39, 6−38, 8−38, 6−37, 8−37, 6−36, 8−36, 6−35, 8−35, 6−34, 8−34, 6−33, 8−33, 6−32, 8−32, 6−31, 8−31, 6−30, 8−30, 6−29, 8−29, 6−28, 8−28, 6−27, 8−27, 6−26, 8−26, 6−25, 8−25, 6−24, 8−24, 6–23, 8–23, 6–22, 8–22, 6–21, 8–21, 6–20, 8–20, 6–19, 8–19, 6–18, 8–18, 6–17, 8–17, 6−16, 8−16, 6–15, 8–15, 6–14, 8–14, 6–13, 8–13, 6−12, or 8−12, 6−48 carbon atoms. Preferably, an amide solvent S^A is an amide solvent comprising one or more alkyl groups, wherein these one or more alkyl groups together comprise in total 6−24 carbon atoms. In some embodiments of the method of the invention, each amide solvent S^A is at each occurrence selected independently from the group consisting of the following Formulae S^A-1, S^A-2, and S^A-3:

wherein in Formula S^A-1: R^A-1 is selected from the group consisting of H and a C1−C24-alkyl group, in which exactly one hydrogen residue may optionally be substituted by a C(O)O(C1−C5-alkyl) group; and each of R^A-2 and R^A-3 is independently a C1−C24-alkyl group; with the proviso that R^A-1, R^A-2 and R^A-3 together comprise in total 6−48 carbon atoms; wherein in Formula S^A-2: o is an integer of 1 or 2; and R^A-4 is a C6–C24-alkyl group; and wherein in Formula S^A-3: p is an integer of 1 or 2; X^A is selected from the group consisting of CH₂, O, and NC(O)R^A-6, with the proviso that, if p is 1, X^A is CH₂; R^A-5 is a C1–C24-alkyl group; and R^A-6 is a C1–C24-alkyl group; with the proviso that R^A-5 and R^A-6 together comprise in total 6–48 carbon atoms. In some embodiments of the method of the invention, each amide solvent S^A is at each occurrence selected independently from the group consisting of the following Formulae S^A-1, S^A-2, and S^A-3: wherein in Formula S^A-1: R^A-1 is selected from the group consisting of H and a C₁−C₂₂-alkyl group, in which exactly one hydrogen residue may optionally be substituted by a C(O)O(C₁−C₅-alkyl) group; and each of R^A-2 and R^A-3 is independently a C₁−C₂₃-alkyl group; with the proviso that R^A-1, R^A-2 and R^A-3 together comprise in total 6−24 carbon atoms; wherein in Formula S^A-2: o is an integer of 1 or 2; and R^A-4 is a C6–C24-alkyl group; and wherein in Formula S^A-3: p is an integer of 1 or 2; X^A is selected from the group consisting of CH2, O, and NC(O)R^A-6, with the proviso that, if p is 1, X^A is CH2; R^A-5 is a C1–C24-alkyl group; and R^A-6 is a C1–C23-alkyl group; with the proviso that R^A-5 and R^A-6 together comprise in total 6–24 carbon atoms. Herein, when denoting residues comprising heteroatoms, brackets are occasionally used for illustrative purposes, as, e.g., exemplified in the following residue: C(O)O(C₁C₅-alkyl). Such brackets are not to be construed to indicate that the group in brackets is only optionally comprised in the respective residue. If an oxygen atom of a chemical residue is depicted in brackets, this indicates that said oxygen atom is covalently bonded only to the carbon atom depicted to the left in the chemical formula of the respective residue. If a hydrocarbon group such as, e.g., a C1–C5-alkyl group forms part of a residue comprising further atoms, said hydrocarbon group may be presented in brackets to highlight the fact that it is a separate group within said residue. This will easily be understood based on the common general knowledge. For example, a C(O)O(C1–C5-alkyl) residue is an ester residue, bonded via the carboxyl carbon atom to the respective parent structure, wherein the C₁–C₅-alkyl moiety is bonded to the oxygen atom not depicted in brackets. As another example, a O(C1–C40-alkyl) residue denotes an alkoxy residue in which the alkyl moiety comprises at least one and not more than 40 carbon atoms. As another example, a C(O)(C1–C40-alkyl) residue denotes an alkanoyl residue bonded to the respective parent structure via a carbonyl carbon atom, wherein the C1–C40-alkyl moiety is bonded directly to the carbonyl carbon atom and not to the oxygen atom depicted in brackets. The skilled artisan is capable of identifying and obtaining amide solvents S^A fulfilling the aforementioned structural requirements and such amide solvents may also be commercially available. Examples of amide solvents S^A of Formula S^A-1 comprise N,N-dibutylformamide (DBF), N,N-dibutylacetamide, methyl 5-(dimethylamino)-2- methyl-5-oxopentanoate (CAS-RN 1174627-68-9), N,N-dimethyloctanamide, N,N-dimethyldecanamide, N,N-diethyldodecanamide, and N,N-bis(1- methylpropyl)acetamide. Examples of amide solvents S^A of Formula S^A-2 comprise N-octyl-2-pyrrolidone (NOP), N-octyl-2-piperidone, and 1-cyclohexyl-2-pyrrolidone (CAS RN: 6837-24-7). Examples of amide solvents S^A of Formula S^A-3 comprise N-nonanoylpyrrolidine (CAS-RN 20308-70-7), N-nonanoylpiperidine (CAS-RN 20368-13-2), N-nonanoylmorpholine (CAS-RN 5299-64-9), and 1,4-dipentanoylpiperazine (CAS RN 18903-08-7). In some embodiments of the method of the invention, each amide solvent S^A independently of each other is selected from the group consisting of N,N-dibutylformamide (DBF) and N-octyl-2- pyrrolidone (NOP). In some embodiments of the method and the composition of the invention, each amide solvent S^A is independently of each other selected from the group consisting of, N-octyl-2-pyrrolidone (NOP), N,N-dibutylformamide (DBF), N,N-diethyldodecanamide, and 1-cyclohexyl-2-pyrrolidone. In some embodiments of the method of the invention, each ether solvent S^E is at each occurrence selected independently from the group consisting of the following Formulae S^E-1 and S^E-2:

(Formula S^E-2), wherein in Formula S^E-1: s is an integer of 0 or 1, and each of R^E-1, R^E-2, R^E-3, R^E-4, R^E-5, R^E-6, R^E-7, R^E-8, R^E-9, and R^E-10 is independently selected from the group consisting of H and a C1−C5-alkyl group, with the proviso that at least one of R^E-1, R^E-2, R^E-3, R^E-4, R^E-5, R^E-6, R^E-7, R^E-8, R^E-9, and R^E-10 is a C1−C5-alkyl group; and wherein in Formula S^E-2: each of R^E-11 and R^E-12 is independently a C1−C6-alkyl group, with the proviso that R^E-11 and R^E-12 together comprise in total 5−12 carbon atoms (i.e. not less than 5 and not more than 12 carbon atoms). In some embodiments of the method of the invention, each ether solvent S^E is independently of each other a solvent of any one of the aforementioned Formulae S^E-1 and S^E-2, wherein in Formula S^E-1: s is an integer of 0 or 1, and each of R^E-1, R^E-2, R^E-3, R^E-4, R^E-5, R^E-6, R^E-7, R^E-8, R^E-9, and R^E-10 is independently selected from the group consisting of H and a C₁−C₅-alkyl group, with the proviso that exactly one, exactly two or exactly three of R^E-1, R^E-2, R^E-3, R^E-4, R^E-5, R^E-6, R^E-7, R^E-8, R^E-9, and R^E-10 are a C1−C5-alkyl group; and wherein in Formula S^E-2: each of R^E-11 and R^E-12 is independently a C1−C6-alkyl group, with the proviso that R^E-11 and R^E-12 together comprise in total 6−12 carbon atoms. In some embodiments of the method of the invention, each ether solvent S^E is independently of each other a solvent of any one of the aforementioned Formulae S^E-1 and S^E-2, wherein in Formula S^E-1: s is an integer of 0 or 1, and each of R^E-1, R^E-2, R^E-3, R^E-4, R^E-5, R^E-6, R^E-7, R^E-8, R^E-9, and R^E-10 is independently selected from the group consisting of H and CH₃ (i.e. a methyl group, Me), with the proviso that exactly one or exactly two of R^E-1, R^E-2, R^E-3, R^E-4, R^E-5, R^E-6, R^E-7, R^E-8, R^E-9, and R^E-10 are CH₃; and wherein in Formula S^E-2: each of R^E-11 and R^E-12 is independently a C1−C6-alkyl group, with the proviso that R^E-11 and R^E-12 together comprise in total 6−12 carbon atoms. In some embodiments of the method of the invention, each ether solvent S^E is independently of each other a solvent of any one of the aforementioned Formulae S^E-1 and S^E-2, wherein in Formula S^E-1: s is an integer of 0 or 1, and each of R^E-1, R^E-2, R^E-3, R^E-4, R^E-5, R^E-6, R^E-7, R^E-8, R^E-9, and R^E-10 is independently selected from the group consisting of H and CH3 (i.e. a methyl group, Me), with the proviso that exactly one of R^E-1, R^E-2, R^E-3, R^E-4, R^E-5, R^E-6, R^E-7, R^E-8, R^E-9, and R^E-10 is CH3; and wherein in Formula S^E-2: each of R^E-11 and R^E-12 is independently a C₁−C₆-alkyl group, with the proviso that R^E-11 and R^E-12 together comprise in total 6−12 carbon atoms. In some embodiments of the method of the invention, each ether solvent S^E is independently of each other a solvent of the aforementioned Formula S^E-1, wherein in Formula S^E-1: s is an integer of 0 or 1, and each of R^E-1, R^E-2, R^E-3, R^E-4, R^E-5, R^E-6, R^E-7, R^E-8, R^E-9, and R^E-10 is independently selected from the group consisting of H and CH3 (i.e. a methyl group, Me), with the proviso that exactly one of R^E-1, R^E-2, R^E-3, R^E-4, R^E-5, R^E-6, R^E-7, R^E-8, R^E-9, and R^E-10 is CH3. The skilled artisan is capable of identifying and obtaining ether solvents S^E fulfilling the aforementioned structural requirements and such ether solvents may also be commercially available. Examples of ether solvents S^E of Formula S^E-1 comprise 4-methyltetrahydropyran (MTHP), 3-methyltetrahydropyran, 2-methyltetrahydropyran, 2-methyltetrahydrofuran, 3-methyltetrahydrofuran, 2,5-dimethyltetrahydrofuran, 2,2-dimethyltetrahydrofuran, 2,2,5,5-tetramethyltetrahydrofuran, and the like. Examples of ether solvents S^E of Formula S^E-2 comprise cyclopentyl methyl ether (CPME), cyclohexyl methyl ether, dibutyl ether, isoamyl ether, methyl tert-butyl ether (MTBE), diisopropyl ether, and the like. In some embodiments of the method and the composition of the invention each ether solvent S^E is independently selected from the group consisting of 4-methyltetrahydropyran (MTHP) and cyclopentyl methyl ether (CPME). In some embodiments of the method and the composition of the invention each ether solvent S^E is 4-methyltetrahydropyran (MTHP). In some embodiments of the method and the composition of the invention, each pseudo solid-phase protecting group, e.g. the pseudo solid-phase protecting group PG-s, is a protecting group of the following Formula P-1:

(Formula P-1), wherein in Formula P-1: the asterisk indicates the point of attachment of the pseudo solid-phase protecting group to a hydroxyl or amine moiety of the respective nucleoside moiety (in other words: the asterisk represents the oxygen atom of the protected hydroxyl moiety or the nitrogen atom of the protected amine moiety); a is an integer of 0 or 1; b is an integer of 0 or 1; L^P is a linker moiety; i is an integer of 1 to 5, preferably 1 to 3, in particular 2 to 3; and R^P-1 is at each occurrence independently selected from the group consisting of O(C1−C40-alkyl), O(C2−C40-alkenyl), O(C2−C40-alkynyl), a C1−C40-alkyl group, a C2−C40-alkenyl group, a C2−C40-alkynyl group, C(O)(C1−C40-alkyl), C(O)(C2−C40-alkenyl), and C(O)(C2−C40-alkynyl); wherein all present residues R^P-1 together comprise in total 18−200 or 30−200 or 36−120 carbon atoms. Unless indicated differently in the context of specific embodiments, a pseudo solid-phase protecting group of Formula P-1 may be bonded to any position of a nucleoside or oligonucleotide, with the proviso that said point of attachment indicated by the asterisk in Formula P-1 (i.e. the atom of the nucleoside or oligonucleotide to which said pseudo solid-phase protecting group is covalently bonded) must be the oxygen atom of a hydroxyl moiety or the nitrogen atom of an amine moiety. Preferred examples of hydroxyl moieties to which a pseudo solid-phase protecting group of Formula P-1 may be covalently bonded are hydroxyl moieties of the backbone of a nucleoside or oligonucleotide, e.g. any hydroxyl moieties available in the carbohydrate (preferably ribose or 2´-deoxyribose) moiety of a nucleoside moiety as well as any hydroxyl moieties present in an internucleosidic linkage group. Preferred examples of amine moieties to which a pseudo solid-phase protecting group of Formula P-1 may be covalently bonded are amine moieties of nucleobases, in particular the exocyclic amine moieties of adenine, guanine, cytosine, and 5-methylcytosine. The component C-0 of any one of Formulae I, I-a, and I-b comprises a pseudo solid-phase protecting group PG-s which is bonded to a hydroxyl moiety. If said protecting group PG-s in the component C-0 of any one of Formulae I, I-a, and I-b is a protecting group of the aforementioned Formula P-1, the asterisk of Formula P-1 indicates the oxygen atom in the respective Formula I, I-a, and I-b, to which the protecting group PG-s is bonded and the covalent bond between the protecting group PG-s and said oxygen atom in any one of Formulae I, I-a, and I-b is the covalent bond interconnecting the carbonyl carbon atom and the asterisk in Formula P-1 (in other words: only one and not two covalent chemical bonds interconnect the carbonyl carbon atom shown in Formula P-1 and the respective oxygen atom of the respective Formula I, I-a, and I-b). It will be understood that, if the integer a in Formula P-1 is 0, the oxygen atom in brackets will be absent and the carbonyl carbon atom depicted to its right will be covalently bonded directly to the linker moiety L^P, if the integer b is 1, or to the phenyl moiety, if the integer b is 0. It will also be understood that if the integer b in Formula P-1 is 0, the linker moiety L^P will be absent and the phenyl moiety depicted to its left will be covalently bonded directly to the oxygen atom, if the integer a is 1, or to the carbonyl carbon atom, if the integer a is 0. This rationale is applicable to any atoms, atom groups or residues depicted in brackets having an integer which may be 0. In some embodiments of the invention, the integer a in Formula P-1 is 0. In some embodiments of the invention, the integer a in Formula P-1 is 1. In some embodiments of the invention, the integer b in Formula P-1 is 1. In some embodiments of the invention, the integer a in Formula P-1 is 0. In some embodiments of the invention, the integer b in Formula P-1 is 0. In some embodiments of the invention, the integer a in Formula P-1 is 0 and the integer b in Formula P-1 is 1. In some embodiments of the invention, the integer a in Formula P-1 is 1 and the integer b in Formula P-1 is 1. In some embodiments of the invention, the integer a in Formula P-1 is 1 and the integer b in Formula P-1 is 0. In some embodiments of the invention, the integer a in Formula P-1 is 0 and the integer b in Formula P-1 is 0. The linker moiety L^P in a pseudo solid-phase protecting group of Formula P-1 may be any chemical residue which interconnects the oxygen atom, if the integer a is 1, or the carbonyl carbon atom, if the integer a is 0, with the phenyl residue to which R^P-1 is bonded. For example, said linker moiety may be a C₁−C₄₀-alkylene moiety, in which alkylene moiety one or more carbon atoms and/or one or more hydrogen residues may optionally be substituted for a heteroatom selected from the group consisting of O and N. As used herein, the term “alkylene group (or moiety or residue)” may be understood in the broadest sense to be similar to an alkyl residue, with the sole difference, that an alkylene residue mandatorily comprises two or more, preferably exactly two, chemical bonds (for the avoidance of doubt: a double bond is not the same as two chemical bonds) to the parent structure comprising said alkylene group. In other words: An alkylene group may preferably be an alkanediyl residue. This will be understood by the skilled person and may be exemplified as follows: A methyl group (i.e. –CH₃) is a classical alkyl group, which bonds to the respective parent structure via exactly one covalent chemical bond (indicated via the hyphen). The corresponding alkylene group would be a methylene group (i.e. –CH₂−) and differs from the alkyl group in that is bonds to the parent structure via exactly two covalent chemical bonds (indicated by the hyphens; both bonds originate from the methylene carbon atom). Unless indicated differently in the context of specific embodiments, an alkylene group may be branched, unbranched (i.e. linear) or cyclic. In some embodiments of the method and the composition of the invention, each pseudo solid-phase protecting group, e.g. the pseudo solid-phase protecting group PG-s, is a protecting group of any one of the following Formulae P-1-a, P-1-b, P-1-c,

(Formula P-1-a), wherein in Formula P-1-a: the integers a and i, the asterisk, and R^P-1 are defined as for Formula P-1; and L¹ is a C1−C12-alkylene group, preferably a C1−C3-alkylene group;

(Formula P-1-b), wherein in Formula P-1-b: the integers a and i, the asterisk, and R^P-1 are defined as for Formula P-1; L¹ is a C₁−C₁₂-alkylene group, preferably a C₁−C₄-alkylene group, in particular a C1−C2-alkylene group; and X^P-2 is selected from the group consisting of ++C(O)+, ++C(O)N(R^P-C)+, ++C(O)O+, and ++C(O)S+, where R^P-C is selected from the group consisting of H and a C1−C6-alkyl group, and where + is the point of attachment to L¹ and ++ is the point of attachment to the phenyl moiety substituted with R^P-1;

wherein in Formula P-1-c: the integers a and i, the asterisk, and R^P-1 are defined as for Formula P-1; c is an integer of 0 or 1 and preferably is 1; L¹ is a C1−C12-alkylene group, preferably a C1−C4-alkylene group, in particular a C2-alkylene group (i.e. an ethylene group, CH2-CH2); X^P-1 is selected from the group consisting of +C(O)N(R^P-B)++, +C(O)O++, and +C(O)S++, where R^P-B is selected from the group consisting of H and a C₁−C₆-alkyl group, and where + is the point of attachment to L¹ or O or the carbonyl carbon atom and ++ is the point of attachment to L²; L² is a C₁−C₁₂-alkylene group, preferably a C₁−C₄-alkylene group; X^P-2 is selected from the group consisting of ++C(O)N(R^P-C)+, ++C(O)O+, and ++C(O)S+, where R^P-C is selected from the group consisting of H and a C1−C6-alkyl group, and where + is the point of attachment to L² and ++ is the point of attachment to the phenyl moiety substituted with R^P-1; and may optionally together represent the following structure

which the dashed line represents the covalent bond to L¹ or O or the carbonyl carbon, and the wavy line represents the covalent bond to the phenyl moiety substituted with R^P-1;

(Formula P-1-d), wherein in Formula P-1-d: the integers a and i, the asterisk, and R^P-1 are defined as for Formula P-1; L¹ is a C1−C12-alkylene group, preferably a C1−C4-alkylene group, in particular a C2-alkylene group (i.e. an ethylene group, CH2-CH2); X^P-1 is selected from the group consisting of +C(O)N(R^P-B)++, +C(O)O++, and +C(O)S++, where R^P-B is selected from the group consisting of H and a C1−C6-alkyl group, and where + is the point of attachment to L¹ and ++ is represents the carbon atom to which R^P-D is bonded in CHR^P-D; and R^P-D is selected from the group consisting of H and a residue of the following Formula P-1-L**:

(Formula P-1-L**), wherein in Formula P-1-L**: the hashtag (#) represents the carbon atom to which R^P-D is bonded in CHR^P-D, k is an integer of 0 to 4; R^P-3 is defined as R^P-1 (i.e. the same definitions apply to R^P-3 of Formula P-1-L** and R^P-1 of Formula P-1); and R^P-2 is H or R^P-2 and a residue R^P-1 may optionally together represent a covalent chemical bond or O so as to form a fluoreny or xanthenyl moiety comprising the phenyl residue to which R^P-2 is bonded and the phenyl residue to which R^P-1 is bonded;

(Formula P-1-e), wherein in Formula P-1-e: the integers a and i, the asterisk, and R^P-1 are defined as for Formula P-1; L¹ is a C₁−C₁₂-alkylene group, preferably a C₁−C₄-alkylene group, in particular a C₂-alkylene group (i.e. an ethylene group, CH₂-CH₂); X^P-1 is selected from the group consisting of +C(O)++, +C(O)N(R^P-B)++, +C(O)O++, and +C(O)S++, where R^P-B is selected from the group consisting of H and a C₁−C₆-alkyl group, and where + is the point of attachment to L¹ and ++ is the point of attachment to L²; L² is a C₁−C₁₂-alkylene group, preferably a C₁−C₄-alkylene group, in particular a C₁−C₄-alkylene group; and X^P-3 is selected from the group consisting of ++C(O)N(R^P-E)+, and ++C(O)O+ where + denotes the point of attachment to L² and ++ is the point of attachment to the phenyl moiety substituted with R^P-1, and where R^P-E is selected from the group consisting of H and a C1C6-alkyl group; and wherein in any one of Formulae P-1-a, P-1-b, P-1-c and P-1-e, all present residues R^P-1 together comprise in total 18−200 or 30−200 or 36−120 carbon atoms; and wherein in Formula P-1-d, all present residues R^P-1 and R^P-3 together comprise in total 18−200 or 30−200 or 36−120 carbon atoms. In some embodiments of the method and the composition of the invention, each pseudo solid-phase protecting group, e.g. the pseudo solid-phase protecting group PG-s, is a protecting group of any one of the aforementioned Formulae P-1-a, P-1-b, P-1-c, P-1-d, and P-1-e, wherein in Formula P-1-a: the asterisk and R^P-1 are defined as for Formula P-1; a is an integer of 0 or 1; i is an integer of 1 to 3, preferably 2 to 3; and L¹ is a C1−C3-alkylene group (i.e. selected from the group consisting of CH2, CH2-CH2, and CH2-CH2-CH2); wherein in Formula P-1-b: the asterisk and R^P-1 are defined as for Formula P-1; the integer a is 0 (i.e. the oxygen atom is absent and L¹ bonds directly to the carbonyl carbon atom); i is an integer of 1 to 3, preferably 2 to 3; L¹ is a C1−C4-alkylene group, in particular a C1−C2-alkylene group; and X^P-2 is selected from the group consisting of ++C(O)N(R^P-C)+ and ++C(O)O+, where R^P-C is selected from the group consisting of H and a C1−C6-alkyl group, and where + is the point of attachment to L¹ and ++ is the point of attachment to the phenyl moiety substituted with R^P-1; wherein in Formula P-1-c: the asterisk and R^P-1 are defined as for Formula P-1; the integer a is 0; i is an integer of 1 to 3, preferably 2 to 3; c is an integer of 0 or 1 and preferably is 1; L¹ is a C₁−C₄-alkylene group, in particular a C₂-alkylene group (i.e. an ethylene group, CH₂-CH₂); X^P-1 is selected from the group consisting of +C(O)N(R^P-B)++ and +C(O)O++, where R^P-B is selected from the group consisting of H and a C1−C6-alkyl group, and where + is the point of attachment to L¹ or the carbonyl carbon atom and ++ is the point of attachment to L²; L² is a C1−C4-alkylene group; X^P-2 is selected from the group consisting of ++C(O)N(R^P-C)+ and ++C(O)O+, where R^P-C is selected from the group consisting of H and a C1−C6-alkyl group, and where + is the point of attachment to L² and ++ is the point of attachment to the phenyl moiety substituted with R^P-1; and may optionally together represent the following structure

which the dashed line represents the covalent bond to L¹ or the carbonyl carbon atom, and the wavy line represents the covalent bond to the phenyl moiety substituted with R^P-1; wherein in Formula P-1-d: the asterisk and R^P-1 are defined as for Formula P-1; the integer a is 0; i is an integer of 1 to 3, preferably 2 to 3; L¹ is a C₁−C₄-alkylene group, in particular a C₂-alkylene group; X^P-1 is selected from the group consisting of +C(O)N(R^P-B)++ and +C(O)O++, where R^P-B is selected from the group consisting of H and a C₁−C₆-alkyl group, and where + is the point of attachment to L¹ or the carbonyl carbon atom and ++ represents the carbon atom to which R^P-D is bonded in CHR^P-D; and R^P-D is selected from the group consisting of H and a residue of the aforementioned Formula P-1-L**, wherein in Formula P-1-L**: the hashtag (#) represents the carbon atom to which R^P-D is bonded in CHR^P-D, k is an integer of 0 to 3; R^P-3 is defined as R^P-1 (i.e. the same definitions apply to R^P-3 of Formula P-1-L** and R^P-1 of Formula P-1); and R^P-2 is H; and wherein in Formula P-1-e: the integer a is 0; i is an integer of 1 to 3, preferably 2 to 3; L¹ is a C₁−C₄-alkylene group, in particular a C₂-alkylene group; X^P-1 is selected from the group consisting of +C(O)++, +C(O)N(R^P-B)++, and +C(O)O++, where R^P-B is selected from the group consisting of H and a C1−C6-alkyl group, and where + is the point of attachment to L¹ and ++ is the point of attachment to L²; L² is a C1−C4-alkylene group, in particular a C1−C2-alkylene group; and X^P-3 is selected from the group consisting of ++C(O)N(R^P-E)+, and ++C(O)O+, where R^P-E is selected from the group consisting of H and a C1−C6-alkyl group, and where + denotes the point of attachment to L² and ++ is the point of attachment to the phenyl moiety substituted with R^P-1; and wherein in any one of Formulae P-1-a, P-1-b, P-1-c, and P-1-e, all present residues R^P-1 together comprise in total 18−200 or 30−200 or 36−120 carbon atoms; and wherein in Formula P-1-d, all present residues R^P-1 and R^P-3 together comprise in total 18−200 or 30−200 or 36−120 carbon atoms. In some embodiments of the method and the composition of the invention, each pseudo solid-phase protecting group, e.g. the pseudo solid-phase protecting group PG-s, is a protecting group of any one of the aforementioned Formulae P-1-a, P-1- b, P-1-c, P-1-d, and P-1-e, wherein in Formula P-1-a: the asterisk and R^P-1 are defined as for Formula P-1; a is an integer of 0 or 1; i is an integer of 1 to 3, preferably 2 to 3; and L¹ is C1−C3-alkylene group; wherein in Formula P-1-b: the asterisk and R^P-1 are defined as for Formula P-1; the integer a is 0; i is an integer of 1 to 3, preferably 2 to 3; L¹ is a C₁−C₄-alkylene group, in particular a C₁−C₂-alkylene group; and X^P-2 is selected from the group consisting of ++C(O)N(R^P-C)+ and ++C(O)O+, where R^P-C is selected from the group consisting of H and CH₃, and where + is the point of attachment to L¹ and ++ is the point of attachment to the phenyl moiety substituted with R^P-1; wherein in Formula P-1-c: the asterisk and R^P-1 are defined as for Formula P-1; the integer a is 0; i is an integer of 1 to 3, preferably 2 to 3; the integer c is 1; L¹ is a C1−C4-alkylene group, in particular a C2-alkylene group (i.e. an ethylene group, CH2-CH2); X^P-2 together represent the following structure

which the dashed line represents the covalent bond to L¹ and the wavy line represents the covalent bond to the phenyl moiety substituted with R^P-1; and wherein in Formula P-1-d: the asterisk and R^P-1 are defined as for Formula P-1; the integer a is 0; i is an integer of 1 to 3, preferably 2 to 3; L¹ is a C1−C4-alkylene group, in particular a C2-alkylene group; X^P-1 is selected from the group consisting of +C(O)N(R^P-B)++ and +C(O)O++, where R^P-B is selected from the group consisting of H and a CH3, and where + is the point of attachment to L¹ and ++ represents the carbon atom to which R^P-D is bonded in CHR^P-D; and R^P-D is selected from the group consisting of H and a residue of the aforementioned Formula P-1-L**, wherein in Formula P-1-L**: the hashtag (#) represents the carbon atom to which R^P-D is bonded in CHR^P-D, k is an integer of 0 to 3; R^P-3 is defined as R^P-1 (i.e. the same definitions apply to R^P-3 of Formula P-1-L** and R^P-1 of Formula P-1); and R^P-2 is H; and wherein in Formula P-1-e: the integer a is 0; i is an integer of 1 to 3, preferably 2 to 3; L¹ is a C1−C4-alkylene group, in particular a C2-alkylene group; X^P-1 is selected from the group consisting of +C(O)++, +C(O)N(R^P-B)++, and +C(O)O++, where R^P-B is selected from the group consisting of H and CH3, and where + is the point of attachment to L¹ and ++ is the point of attachment to L²; L² is a C1−C4-alkylene group, in particular a C1−C2-alkylene group; and X^P-3 is selected from the group consisting of ++C(O)N(R^P-E)+, and ++C(O)O+, where R^P-E is selected from the group consisting of H and a CH3, and where + denotes the point of attachment to L² and ++ is the point of attachment to the phenyl moiety substituted with R^P-1; and wherein in any one of Formulae P-1-a, P-1-b, P-1-c, and P-1-e all present residues R^P-1 together comprise in total 36−120 carbon atoms; and wherein in Formula P-1-d, all present residues R^P-1 and R^P-3 together comprise in total 36−120 carbon atoms. In some embodiments of the invention, R^P-1 in any one of Formulae P-1, P-1-a, P-1-b, P-1-c, P-1-d, and P-1-e as well as R^P-3 in any one of Formulae P-1 and P-1-d is at each occurrence independently selected from the group consisting of O(C₁−C₄₀-alkyl), O(C₂−C₄₀-alkenyl), a C₁−C₄₀-alkyl group, a C₂−C₄₀-alkenyl group, C(O)(C₁−C₄₀-alkyl), and C(O)(C₂−C₄₀-alkenyl). In some embodiments of the invention, R^P-1 in any one of Formulae P-1, P-1-a, P-1-b, P-1-c, P-1-d, and P-1-e as well as R^P-3 in any one of Formulae P-1 and P-1-d is at each occurrence independently selected from the group consisting of O(C₁−C₃₀-alkyl), O(C₂−C₃₀- alkenyl), a C₁−C₃₀-alkyl group, a C₂−C₃₀-alkenyl group, C(O)(C₁−C₃₀-alkyl), and C(O)(C2−C30-alkenyl). In some embodiments of the invention, R^P-1 in any one of Formulae P-1, P-1-a, P-1-b, P-1-c, P-1-d, and P-1-e as well as R^P-3 in any one of Formulae P-1 and P-1-d is at each occurrence independently selected from the group consisting of O(C1−C30-alkyl), O(C2−C30-alkenyl), C(O)(C1−C30-alkyl), and C(O)(C2−C30-alkenyl). In some embodiments of the invention, R^P-1 in any one of Formulae P-1, P-1-a, P-1-b, P-1-c, P-1-d, and P-1-e as well as R^P-3 in any one of Formulae P-1 and P-1-d is at each occurrence independently selected from the group consisting of O(C1−C30-alkyl) and C(O)(C1−C30-alkyl). In some embodiments of the invention, R^P-1 in any one of Formulae P-1, P-1-a, P-1-b, P-1-c, P-1-d, and P- 1-e as well as R^P-3 in any one of Formulae P-1 and P-1-d is at each occurrence independently O(C1−C30-alkyl). In some embodiments of the invention, R^P-1 in any one of Formulae P-1, P-1-a, P-1-b, P-1-c, P-1-d, and P-1-e as well as R^P-3 in any one of Formulae P-1 and P-1-d is at each occurrence independently O(C₁−C₃₀- alkyl), wherein said C₁−C₃₀-alkyl in O(C₁−C₃₀-alkyl) is a linear (i.e. unbranched and non-cyclic) alkyl residue. Pseudo solid-phase protecting groups of the aforementioned Formula P-1-a, methods for their preparation, introduction into nucleosides or oligonucleotides as well as cleavage from oligonucleotides are, e.g., disclosed in PCT/EP2022/059528 published as WO 2022/214692 A1, wherein reference is in particular made to Formulae II, II-a, and III to VII of said reference as well as to Examples 1 to 40 of said reference. Pseudo solid-phase protecting groups of the aforementioned Formula P-1-b are, e.g., disclosed in EP3825300A1. Pseudo solid-phase protecting groups of the aforementioned Formula P-1-c are, e.g., disclosed in S. Kim et al., Chemistry – A European Journal 2013, 19, 8615−8620 (DOI: 10.1002/chem.201300655), wherein reference is also made to the Supporting Information belonging to said reference and comprising the experimental protocols. Pseudo solid-phase protecting groups of the aforementioned Formula P-1-d are, e.g., disclosed in US2013267697A1, EP2711370A1, and EP3398955A1. Examples of pseudo solid-phase protecting groups of Formula P-1-d comprise protecting groups of the following structures:

, wherein in any one of these structures, the asterisk, R^P-1, and R^P-3 are defined as for Formula P-1. R^P-1 and R^P-3 may, e.g., be at each occurrence a C22H45-alkyl group, a C21H43-alkyl group, a C20H41-alkyl group, a C19H39-alkyl group or a C18H37-alkyl group. In some embodiments of the method and the composition of the invention, each pseudo solid-phase protecting group, e.g. the pseudo solid-phase protecting group PG-s, is a protecting group of the aforementioned Formula P-1-a. The following Figures and Examples, including the experiments conducted and the results achieved, are provided for illustrative purposes only and are not to be construed as limiting the scope of the claims.

Description of the Figure Figure 1 illustrates the one or more coupling cycles which may be performed as part of the method of the invention. The method of the invention may comprise a first coupling cycle comprising steps (b-1) to (h-1) (as far as present), wherein steps (d-1), (f-1), (g-1), and (h-1) are optional, which is indicated in Figure 1 by embracing these steps in brackets. Prior to the first coupling cycle, a component C-0 is provided [step (a-1)]. In the first coupling cycle, the protecting group PG-0 is removed from said component C-0 [step (b-1)] which yields the component (C-0)^#. This is followed by one or more aqueous extractions [step (c-1)], optionally followed by reducing the water content of the organic phase which comprises the component (C-0)^# [step (d-1)]. The component (C-0)^# is reacted with a provided first building block B-1 [step (e-1)] which yields a first cycle oligonucleotide O-1. Optionally, any P (III) atoms within O-1 may be converted to P (V) atoms by incubation with an oxidizing or sulfurizing agent [step (f-1)], optionally followed by one or more aqueous extractions [step (g-1)], optionally followed by reducing the water content of the organic phase which comprises the first cycle oligonucleotide O-1 [step (h-1)]. The method of the invention may further comprise a second coupling cycle comprising steps (b-2) to (h-2), wherein steps (d-2), (f-2), (g-2), and (h-2) are optional, which is indicated in Figure 1 by embracing these steps in brackets. The first cycle oligonucleotide O-1 may serve as the educt of the second coupling cycle. The protecting group PG-1 is removed from the first cycle O-1 [step (b-2)] which yields the first cycle oligonucleotide (O-1)^#. This is followed by one or more aqueous extractions [step (c-2)], optionally followed by reducing the water content of the organic phase which comprises the first cycle oligonucleotide (O-1)^# [step (d-1)]. The first cycle oligonucleotide (O-1)^# is reacted with a provided second building block B-2 [step (e-2)] which yields a second cycle oligonucleotide O-2. Optionally, any P (III) atoms within O-2 may be converted to P (V) atoms by incubation with an oxidizing or sulfurizing agent [step (f-2)], optionally followed by one or more aqueous extractions [step (g-2)], optionally followed by reducing the water content of the organic phase which comprises the second cycle oligonucleotide O-2 [step (h-2)]. The method of the invention may further comprise (n−2) iterations of a coupling cycle comprising steps (b-x) to (h-x) (as far as present), which are referred to as “further coupling cycles” in Figure 1. Steps (d-x), (f-x), (g-x), and (h-x) are optional in each of these further coupling cycles, which is indicated in Figure 1 by embracing these steps in brackets. The second cycle oligonucleotide O-2 will then be used as educt O-(x−1), of the third coupling cycle (x=3). The protecting group PG-(x−1), i.e. PG-2, is removed [step (b-x)] which yields oligonucleotide (O-(x−1))^#, i.e. (O-2)^# (x=3). This is followed by one or more aqueous extractions [step (c-x)], optionally followed by reducing the water content of the organic phase which comprises the oligonucleotide (O-(x−1))^#, i.e. (O-2)^# (x=3) [step (d-1)]. The oligonucleotide (O-(x−1))^#, i.e. (O-2)^#, is reacted with a provided building block B-x, i.e. B-3 (x=3) [step (e-x)] which yields an oligonucleotide O-x, i.e. O-3 (x=3). Optionally, any P (III) atoms within O-3 may be converted to P (V) atoms by incubation with an oxidizing or sulfurizing agent [step (f-x)], optionally followed by one or more aqueous extractions [step (g-x)], optionally followed by reducing the water content of the organic phase which comprises the oligonucleotide O-x, i.e. O-3 (x=3) [step (h-x)]. Up to (n−2) coupling cycles comprising steps (b-x) to (h-x) (as far as present) [“further coupling cycles”] may be performed, in each of which the oligonucleotide O-x of the previous coupling cycle is used as educt O-(x−1). The fact that the first cycle oligonucleotide O-1 need not be subjected to the second coupling cycle, the fact that the second cycle oligonucleotide O-2 need not be subjected to the third coupling cycle, and the fact that each x-th cycle oligonucleotide O-x need not be subjected to another coupling cycle are indicated in Figure 1 by the dashed "exit" arrows.

Examples General information and methods Target oligonucleotides of the syntheses presented herein The following Examples pertain to the synthesis of target oligonucleotides, wherein these target oligonucleotides are summarized in the following Table T-2. Table T-2: Target oligonucleotides of the oligonucleotide syntheses presented herein. name of target Example sequence of target oligonucleotide oligonucleotide 1 T MG(ib)s-MMeC(bz)s-MMeUs-MG(ib)s-MG(ib)-(Kc- 2 O -1 C1-carbonate) 3 O^T-2 5´-dA-dT-dC-dA-dT-3’ T 5´-MAs-MMeUs-MAs-MAs-MMeUs-MGs-MMeCs- 4 O -3 MMeUs-MGs-MG-3´ a) "(Kc-C1-carbonate)" in the sequence of target oligonucleotide O^T-1 denotes a specific pseudo solid-phase protecting group bonded to the 3´-hydroxyl moiety of the 3´-terminal MG(ib) nucleoside subunit. The structure of this pseudo solid-phase protecting group is, for example, depicted in compound (2) below. The following notation is herein used to denote oligonucleotide sequences, unless indicated differently: A = adenosine dA = 2´-doexyadenosine G = guanosine dG = 2´-doexyguanosine C = cytidine dC = 2´-doexycytidine MeC or meC = 5-methylcytidine (the nucleobase is 5-methylcytosine) T or dT = thymidine (meaning 2´-deoxythymidine and not ribothymidine) U = uridine MeU or meU = 5-methyluridine (the nucleobase is 5-methyluracil, i.e. thymine) “M” indicates that the nucleoside subunit denoted to the right of said letter “M” comprises a 2´-O-(2-methoxyethyl) residue (2´-O-MOE, i.e. the 2´-carbon atom of the carbohydrate moiety is substituted with O-CH2-CH2-O-CH3). The presence of protecting groups at the nucleobases is indicated in brackets to the right of the nucleoside symbol: “(bz)” and “(Bz)” interchangeably denote a benzoyl protecting group at the exocyclic amine moiety of the respective nucleobase; “(ac)” and “(Ac)” interchangeably denote an acetyl protecting group at the exocyclic amine moiety of the nucleobase; “(ib)” denotes an isobutyryl protecting group at the exocyclic amine moiety of the nucleobase. Unless indicated differently, all internucleosidic linkage groups are phosphodiester linkage groups. The letter "s" to the right of a nucleoside symbol indicates that the internucleosidic linkage group in 3´-position of the respective nucleoside-subunit is a phosphorothioate linkage group instead of a phosphodiester linkage group. Nucleoside subunits are separated by hyphens to enhance readability. Herein, unless indicated differently, all oligonucleotides are denoted in 5´ to 3´ direction (i.e. the nucleoside subunit denoted to the very left is the 5´-terminal nucleoside subunit). Nonetheless, to enhance readability, the 5´- and the 3´-termnini are herein typically indicated as such. For example, 5´-MMeUs-MMeC-3´ herein denotes a dinucleotide, in which the 3´-hydroxyl moiety of a 2´-O-MOE substituted 5-methyluridine and the 5´-hydroxyl moiety of a 2´-O-MOE substituted 5-methylcytidine are interconnected by a phosphorothioate linkage group. As another example, 5´-dA(bz)-dT-3´ denotes a dinucleotide, in which the 3´-hydroxyl moiety of a benzyol-protected 2´- deoxyadenosine and the 5´-hydroxyl moiety of a (2´-deoxy)thymidine are interconnected by a phosphodiester linkage group. HPLC methods Method A Solid phase: YMC-Triart C18, 12 nm, 3.0 μm, 4.6×150 mm; Mobile phase A: 0.1 % AcOH aq.; Mobile Phase B: THF; Flow rate: 1.0 mL/min; Gradient (mobile phase B %): 0.0-10.0 min; 75 to 90 %, 10.0-15.0 min; 90 %, 15.0-15.1 min; 90 to 75 %, 15.1- 20.0 min; 75 %; Column temperature: 40 °C; Detection wavelength: 220 nm. Method B Solid phase: YMC-Pack Pro C18, 3 μm, 4.6×100 mm; Mobile phase A: AcOH aq.; Mobile phase B: THF; Flow rate: 1.0 mL/min; Gradient (mobile phase B %): 0-10.0 min; 65 to 90 %, 10.0-15.0 min; 90 %, 15.0-15.1 min; 90 to 65 %, 15.01-20.0 min; 65 %; Column temperature: 40 °C; Detection wavelength: 220 nm. Method C Solid phase: Waters ACQUITY peptide BEH, 1.7 um, 2.1×100 mm; Mobile phase A: 50 mM di-n-butylammonium acetate aq.; Mobile phase B: Acetonitril:H2O (90:10 v/v) ; Flow rate: 0.2 mL/min; Gradient (mobile phase B %): 0-30 min; 15 to 35 %, 30-31 min; 35 to 90 %, 31-33 min; 90 %, 33-33.1 min; 90 to 15 %, 33.1-45 min; 15 %; Column temperature: 60 °C; Detection wavelength: 260 nm. Method D Solid phase: YMC-Triart C18, 12 nm, 1.9 μm, 2.1×150 mm; Mobile phase A: 0.1% AcOH aq.; Mobile phase B: THF; Flow rate: 0.3 mL/min; Gradient (mobile phase B %): 0.0-15.0 min; 65% to 75 %, 15.0-15.1 min; 75 to 90 %, 15.1-20.1 min; 90%, 20.0-20.1 min; 90 to 65%, 20.1-30.0 min; 65%; Detected wavelength: 260 nm. Method ESolid phase: Waters ACQUITY BEH, 1.7 um, 2.1×100 mm; Mobile phase A: 50 mM di-n- butylammonium acetate aq.; Mobile phase B: Acetonitril:H2O (90:10 v/v) ; Flow rate: 0.2 mL/min; Gradient (mobile phase B %): 0-30 min; 25 to 45 %, 30-31 min; 45 to 90 %, 31-33 min; 90 %, 33-33.1 min; 90 to 25 %, 33.1-45 min; 25 %; Column temperature: 60 °C; Detection wavelength: 260 nm HPLC-MS methods Method 1 Solid phase: Waters ACQUITY peptide BEH, 1.7 um, 2.1×100 mm; Mobile phase A: 50 mM di-n- butylammonium acetate aq.; Mobile phase B: Acetonitril:H2O (90:10 v/v) ; Flow rate: 0.2 mL/min; Gradient (mobile phase B %): 0-30 min; 15 to 35 %, 30-31 min; 35 to 90 %, 31-33 min; 90 %, 33-33.1 min; 90 to 15 %, 33.1-45 min; 15 %; Column temperature: 60 °C; Detection wavelength: 260 nm.; Acquisition range: 250-3500 m/z. MS conditions (general) Ion source: Dual ESI; Ionization mode: positive or negative; Vcap: 3500 V, 20; Gas temp: 325 °C; Gas Flow: 8 L/min; Nebulizer: 50 psi. Pre-treatment of N-octyl-2-pyrrolidone N-octyl-2-pyrrolidone (NOP) was obtained commercially. Prior to use, it was treated as follows: L-Ascorbic acid (1 wt-%) and 2,6-di-tert-butyl-p-cresol (1 wt-%) were added, followed by stirring at room temperature (i.e. approximately 25 °C) for 30 min. The so-obtained solution was washed four times: first and second wash with 0.5 M NaHCO₃ aq. (1:1 v/v), third wash with 1 vol-% acetic acid aq. (1:1 v/v), and fourth wash with H2O (1:1 v/v). Determination of the water content Throughout the examples presented herein, reference is occasionally made to the water content of solutions. Unless indicated differently, the water content was determined by means of standard Karl Fischer titration at room temperature (i.e. approximately 25 °C). The titration cell was filled with HYDRANAL^TM -Coulomat Oil for anolyte reagent, and the inner burette was filled with HYDRANAL^TM -Coulomat CG for catholyte reagent. After pretitration for dehydration, sample (100 µL) was added to the titration cell and the measurement started. In line with common practice, the water content of solutions is herein reported in parts per million (ppm). Analysis of solvent composition after azeotropic distillation Throughout the examples presented herein, reference is occasionally made to the composition of mixed solvents after azeotropic distillation. This content is herein provided in form of volume-% (vol-%) and was, unless indicated differently, determined by gas chromatography. Samples were analyzed by the following method: Column: SH-Rxi-624Sil MS (30 m × 0.32 mm ID, 1.8 µm), Injection volume: 1 µL, Inlet: Split (5/1), Injection temperature: 230 °C, Column flow: 35 cm/s Helium, Column temperature program: 40 °C(2 min)-10 °C/min-240 °C (20 min) total 42 min, Detector: FDI at 250 °C. Then, the content of solvent was calculated by using a calibration curve. Determination of pH-values Throughout the examples presented herein, reference is occasionally made to the pH-values of aqueous phases or solutions. Unless indicated differently, the pH value was determined using a pH-electrode at rt. The pH electrode was calibrated by pH buffers (pH 4.01, 6.86, 9.18). A LAQUA D-72 water quality meter by HORIBA equipped with a 9680S-10D Long ToupH electrode by HORIBA was used for the pH-measurements in the Examples presented herein. Room temperature (rt) As used herein, unless indicated differently, the terms room temperature (rt) and ambient temperature are used interchangeably to denote a temperature of approximately 25 °C. Unless indicated differently, all reactions were performed at rt. Reaction setup Unless indicated differently, all oligonucleotide syntheses presented in the following were carried out in an eggplant flask made of glass equipped with a magnetic stir bar. All aqueous extractions were carried out in a common separatory funnel. All azeotropic distillations were carried out using a common rotary evaporator. Base treatment to effect cleavage of the pseudo solid-phase protecting groups and other base-labile protecting groups was carried out in an ACE Pressure Tube by OSAKA CHEMICAL Co., Ltd., which is a pressure-resistant sealed glass tube. Synthesis and introduction of pseudo solid-phase protecting groups Pseudo solid-phase protecting groups of Formula P-1-a may be synthesized and introduced into the starting nucleoside by methods disclosed in the prior art. In particular, the methods disclosed in WO 2022/214692 A1 and in PCT/EP2023/078683 may be used. Synthesis of DMTr-dT-(Kc-C1-carbonate) (1)

To a solution of DMTr-dT (CAS-RN: 40615-39-2, i.e.5´-DMTr-protected dT, 5.39 g, 9.90 mmol) and 1,1'-carbonyldiimidazole (3.22 g, 19.86 mmol) in 2-methyltetrahydrofuran (150 mL) stirred at rt was added 1-methylimidazole (1.58 mL, 19.24 mmol). The resulting reaction mixture was stirred at rt for 100 min (monitored by HPLC, Method A) and subsequently washed twice with saturated aqueous NH4Cl (150 mL and 75 mL) and then with saturated aqueous NaCl (75 mL).2-Methyltetrahydrofuran (100 mL) was added to the organic phase followed by concentration in vacuo to a volume of 100 mL. 3,5-Bis(docosyloxy)benzenemethanol (CAS-RN: 955095-32-6, 5.01 g, 6.62 mmol), DBU (1.48 mL, 9.92 mmol) and 1-methylimidazole (790 µL, 9.91 mmol) were added to the solution (water content: 239.1 ppm) of DMT-dT-1H-imidazole-1-carboxyl. The resulting reaction mixture was stirred at rt for 205 min, followed by addition of DMTr- dT (3.58 g, 6.57 mmol) and stirring at rt for 17.5 h (monitored by HPLC, Method A). Acetic anhydride (7.5 mL, 75.67 mmol), pyridine (8.0 mL, 99.12 mmol) and 1-methylimidazole (7.9mL, 99.11 mmol) were added. After stirring at rt for 30 min, methanol (12 mL, 44.7 mmol) was added. After stirring 30 min at rt, the reaction mixture was concentrated in vacuo, followed by addition of acetonitrile (250 mL). The resulting precipitate was filtrated and washed twice with acetonitrile (100 mL × 2) to give DMTr-dT-(Kc-C1-carbonate) (7.92 g, 90.3 % yield based on 3,5-bis(docosyloxy)benzenemethanol) as a white solid. Synthesis A of DMTr-MG(ib)-(Kc-C1-carbonate) (2)

1-Methylimidazole (631 µL, 7.92 mmol) was added to a stirred solution of DMTr- MG(ib) (CAS-RN: 251647-55-9, i.e. 5´-DMTr-protected guanosine with 2´-O-(2- methoxyethyl) residue, 4.24 g, 5.94 mmol) and 1,1´-carbonyldiimidazole (1.71 g, 10.55 mmol) in 2-methyltetrahydrofuran (90 mL) at rt. The resulting reaction mixture was stirred at rt for 133 min (monitored by HPLC, Method A) and subsequently washed twice with saturated aqueous NH₄Cl (90mL and 45 mL) and then with saturated aqueous NaCl (45 mL). 2-Methyltetrahydrofuran (60 mL) was added to the organic phase followed by concentration in vacuo to a volume of 60 mL. 3,5-Bis(docosyloxy)benzenemethanol (CAS-RN: 955095-32-6, 2.99 g, 3.95 mmol), DBU (887 µL, 5.94 mmol) and 1-methylimidazole (474 µL, 5.95 mmol) were added to the solution (water content: 366.9 ppm) of DMT-MG(ib)-1H-imidazole-1-carboxyl. The resulting reaction mixture was stirred at rt for 3.5 h, followed by addition of DMTr-MG(ib) (2.81 g, 3.94 mmol) and stirring the reaction mixture at rt for 17.5 h (monitored by HPLC, Method A). Isobutyric anhydride (7.9 mL, 47.44 mmol), pyridine (4.8 mL, 59.47 mmol) and 1-methylimidazole (4.7 mL, 58.96 mmol) were added. After stirring at rt for 30 min, methanol (7.2 mL, 177.53 mmol) was added. After stirring for 30 min at rt, the reaction mixture was concentrated in vacuo, followed by addition of acetonitrile (150 mL). The resulting precipitate was filtrated and washed twice with acetonitrile (60 mL × 2) to give DMTr-MG(ib)-(Kc-C1- carbonate) (2, 5.29 g, yield 81.6 % based on 3,5-bis(docosyloxy)benzenemethanol) as a white solid. Synthesis B of DMTr-MG(ib)-(Kc-C1-carbonate) (2) 1-Methylimidazole (1.57 mL, 19.12 mmol, 2.9 eq.) was added to a stirred solution of DMTr-MG(ib) (CAS-RN: 251647-55-9, 7.07 g, 9.91 mmol) and 1,1´- carbonyldiimidazole (3.21 g, 19.80 mmol, 3.0 eq.) in 2-methyltetrahydrofuran (150 mL) at rt. The resulting reaction mixture was stirred at rt for 120 min and subsequently washed twice with saturated aqueous NH4Cl (150mL and 75 mL) and then with saturated aqueous NaCl (75 mL).2- methyltetrahydrofuran (200 mL) was added to the organic phase followed by concentration in vacuo to a volume of 100 mL. 3,5-bis(docosyloxy)benzenemethanol (CAS-RN: 955095-32-6, 5.00 g, 6.60 mmol, 1.0 eq.), DBU (1.48 mL, 9.92 mmol, 1.5 eq.) and 1-methylimidazole (789 µL, 9.90 mmol, 1.5 eq.) were added to the solution (water content: 108.9 ppm) of DMT- MG(ib)-1H-imidazole-1-carboxyl. The resulting reaction mixture was stirred at rt for 19 h (monitored by HPLC, Method B), followed by addition of DMTr-MG(ib) (4.71 g, 6.60 mmol, 1.0 eq.) and stirring the reaction mixture at rt for 24 h (monitored by HPLC, Method B). Isobutyric anhydride (13.19 mL, 79.21 mmol, 12.0 eq.), pyridine (7.98 mL, 98.87 mmol, 15.0 eq.) and 1-methylimidazole (7.89 mL, 98.99 mmol, 15.0 eq.) were added. After stirring at rt for 30 min, methanol (12.05 mL, 297.11 mmol, 45 eq.) was added. After stirring 30 min at rt, the reaction mixture was concentrated in vacuo to 44 g followed by addition of acetonitrile (250 mL). The resulting precipitate was filtrated and washed twice with acetonitrile (100 mL × 2) to give crude DMTr-MG(ib)-(Kc-C1-carbonate) (9.69 g), which was dissolved in pyridine (200 mL) (water content of the obtained solution: 249.3 ppm). Isobutyryl chloride (3.52 mL, 33.37 mmol, 5.1 eq.) was added under ice cooling, followed by stirring for 30 min at rt (monitored by HPLC, Method B). Water (3.57 mL, 198.17 mmol, 30.0 eq.) was added to the solution under ice-cooling. After stirring for 15 min, 2- methyltetrahydrofuran (200 mL), n-heptane (40 mL) and water (200 mL) were added to the solution, followed by extraction and phase separation. The resulting organic phase was stirred for 17 h at rt. The organic phase was washed with water (200 mL), 15 wt-% aqueous sodium chloride (10 mL) and acetone (10 mL), followed by concentration to 5.9 g. Acetonitrile (200 mL) was added to the so-obtained solution. The resulting precipitate was filtrated and washed twice with acetonitrile (100 mL × 2) to give crude DMTr-MG(ib)-(Kc-C1-carbonate) (8.55 g), which was added to acetone (500 mL). After stirring for 30 min, the solution was filtrated and the so- obtained filtrate was concentrated to 16.25 g, followed by precipitation by addition of acetonitrile (500 mL). The resulting precipitate was filtrated, then washed twice with acetonitrile (200 mL × 2) to give DMTr-MG(ib)-(Kc-C1-carbonate) (2, 6.98 g, 70.7 % yield based on 3,5-bis(docosyloxy)benzenemethanol) as a white solid. Syntheses of oligonucleotides Example 1: Synthesis A of target oligonucleotide OT-1 (see Table T-2) Providing DMTr-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (4) as an exemplary component C-0 Dichloroacetic acid (DCA, 30 mL) was added at rt to a stirred solution of DMTr- MG(ib)-(Kc-C1-carbonate) (2, 5.29 g, 3.53 mmol) obtained from Synthesis A laid out above, and thiomalic acid (2.99 g, 19.91 mmol, 5.6 eq.) in cyclopentyl methyl ether (CPME, 90 mL), and the mixture was stirred at rt until reaction monitoring by HPLC (Method D) indicated completion of the DMTr-deprotection. N-methylmorpholine (NMM, 38 mL), acetone (15 mL) and water (60 mL) were added, followed by extraction. The organic phase was separated and washed twice with water (45 mL × 2). The so-obtained organic phase was concentrated, followed by precipitation by addition of acetonitrile (300 mL). The resulting precipitate was filtrated, then washed twice with acetonitrile (120 mL × 2) to give MG(ib)-(Kc-C1-carbonate) (3, 3.86 g, 81.6 % yield for 2 steps from 3,5 bis(docosyloxy)benzenemethanol). A solution of MG(ib)-(Kc-C1-carbonate) (3, 787 mg, 0.66 mmol) in a mixture of 4-methyltetrahydropyran (MTHP) and NOP (1:1 v/v, 7.5 mL) was subjected to 2 rounds of azeotropic distillation, during each of which MTHP (7.5 mL) was added, followed by concentration in vacuo to a volume of 7.5 mL (bath temperature 45 °C, pressure 40−100 hPa; water content: 155.1 ppm). DMTr-MG(ib) phosphoramidite (CAS-RN: 251647-55-9, 1.20 g, 1.31 mmol, 2.0 eq.) and MTHP (5 mL) were added to the so-obtained solution comprising MG(ib)-(Kc-C1-carbonate) (3), followed by concentration in vacuo (bath temperature 45 °C, pressure 40 hPa) to a volume of 7.5 mL.5-Ethylthio-1H-tetrazole (859 mg, 6.60 mmol, 10.0 eq.) and pyridine (1.6 mL, 19.82 mmol, 30.0 eq.) were added and the mixture was stirred at rt until reaction monitoring by HPLC (Method C) indicated completion of the coupling. Lactamide (CAS-RN: 2043-43-8, 119 mg, 1.34 mmol, 2.0 eq.) was added, followed by stirring for 30 min. 3-(N,N-dimethylaminomethylidene)amino)-3H-1,2,4-dithiazole-5-thione (CAS-RN: 1192027-04-5, DDTT, 407 mg, 1.98 mmol, 3.0 eq) was added. After stirring for 30 min at rt, triethylphosphite (343 µL, 3.0 eq) was added. After stirring for 10 min at rt, propan-2-ol (1.0 mL) was added, followed by stirring for 10 min at rt. The so-obtained solution comprising DMTr-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (4) was used directly in the subsequent step (without any precipitation, filtration or purification steps in between). Synthesis of DMTr-MMeUs-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (6) in an exemplary first coupling cycle using MG(ib)s-MG(ib)-(Kc-C1-carbonate) (5) as an exemplary component (C-0)^# A mixture of glutathione (CAS-RN: 70-18-8,1.01 g, 3.29 mmol.5.0 eq.), acetonitrile (5 mL) and trifluoroacetic acid (TFA, 5 mL) was added to the so-obtained solution comprising DMTr-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (4) at 0 °C, followed by stirring at rt until reaction monitoring by HPLC (Method C) indicated complete DMTr-deprotection. Pyridine (6.8 mL), n-heptane (7.5 mL), MTHP (7.5 mL), acetone (10 mL) and 15 wt-% aqueous (aq.) sodium chloride solution (brine, 45 mL, pH-value = 4.7) were added to the reaction mixture comprising MG(ib)s-MG(ib)-(Kc-C1-carbonate) (5) as an exemplary component (C-0)^#, followed by extraction (the first aqueous extraction) and phase separation. The aqueous phase had a pH-value of 4.5. The organic phase was extracted with a mixture of, 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 45 mL, pH-value = 5.1, the second aqueous extraction), followed by phase separation. The aqueous phase had a pH-value of 5.0. The organic phase was extracted with a mixture of 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 45 mL, pH-value = 5.2, the third aqueous extraction), followed by phase separation. The aqueous phase had a pH-value of 5.1. MTHP (7.5 mL) was added to the so-obtained organic phase comprising MG(ib)s- MG(ib)-(Kc-C1-carbonate) (5), followed by concentration in vacuo to a volume of 7.5 mL (bath temperature 35−45 °C, pressure 40-200 hPa). The MTHP (7.5 mL) addition and subsequent concentration was repeated four times (final volume: 7.5 mL; water content: 160.1 ppm). DMTr-MMeU phosphoramidite (CAS-RN: 163878- 63-5, 1.08 g, 1.32 mmol, 2.0 eq.) and MTHP (5 mL) were added to the so-obtained solution comprising MG(ib)s-MG(ib)-(Kc-C1-carbonate) (5), followed by concentration in vacuo (bath temperature 45 °C, pressure 40 hPa) to a volume of 7.5 mL.5-Ethylthio-1H-tetrazole (861 mg, 6.61 mmol, 10.0 eq.) and pyridine (1.6 mL, 19.82 mmol, 30.0 eq.) were added and the mixture was stirred at rt until reaction monitoring by HPLC (Method C) indicated completion of the coupling. Lactamide (118 mg, 1.33 mmol, 2.0 eq.) was added, followed by stirring for 30 min at rt. DDTT (407 mg, 1.98 mmol, 3.0 eq) was added. After stirring for 30 min at rt, triethylphosphite (343 µL, 3.0 eq) was added. After stirring for 10 min at rt, propan- 2-ol (1.0 mL) was added, followed by stirring for 10 min at rt. The so-obtained solution comprising DMTr-MMeUs-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (6) was used directly in the subsequent step (without any precipitation, filtration or purification steps in between). Synthesis of DMTr-MMeC(bz)s-MMeUs-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (8) in an exemplary second coupling cycle using MMeUs-MG(ib)s-MG(ib)-(Kc-C1- carbonate) (7) as an exemplary component (C-0)^# A mixture of glutathione (1.01 g, 3.29 mmol.5.0 eq.), acetonitrile (5 mL) and TFA (5 mL) was added to the so-obtained solution comprising DMTr-MMeUs-MG(ib)s- MG(ib)-(Kc-C1-carbonate) (6) at 0 °C, followed by stirring at rt until reaction monitoring by HPLC (Method C) indicated complete DMTr-deprotection. Pyridine (6.8 mL), n-heptane (7.5 mL), MTHP (7.5 mL), acetone (10 mL) and 15 wt-% aqueous (aq.) sodium chloride solution (brine, 45 mL, pH-value = 4.7) were added to the reaction mixture comprising MMeUs-MG(ib)s-MG(ib)-(Kc-C1- carbonate) (7) as an exemplary component (C-0)^#, followed by extraction and phase separation. The aqueous phase had a pH-value of 4.5. NOP (1.0 mL) was added to the organic phase, followed by extraction with a mixture of, 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 45 mL, pH-value =5.1), followed by phase separation. The aqueous phase had a pH-value of 5.0. The organic phase was extracted with a mixture of 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 45 mL, pH-value = 5.2), followed by phase separation. The aqueous phase had a pH-value of 5.1. MTHP (7.5 mL) was added to the so-obtained organic phase comprising MMeUs- MG(ib)s-MG(ib)-(Kc-C1-carbonate) (7), followed by concentration in vacuo to a volume of 7.5 mL (bath temperature 35−45 °C, pressure 40-200 hPa). The MTHP (7.5 mL) addition and subsequent concentration was repeated four times (final volume: 7.5 mL; water content: 189.4 ppm). DMTr-MMeC(bz) phosphoramidite (CAS-RN: 163759-94-2, 1.21 g, 1.31 mmol, 2.0 eq.) and MTHP (5 mL) were added to the so-obtained solution comprising MMeUs-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (7), followed by concentration in vacuo (bath temperature 45 °C, pressure 40 hPa) to a volume of 7.5 mL.5-Ethylthio-1H-tetrazole (860 mg, 6.61 mmol, 10.0 eq.) and pyridine (1.6 mL, 19.82 mmol, 30.0 eq.) were added and the mixture was stirred at rt until reaction monitoring by HPLC (Method C) indicated completion of the coupling. Lactamide (116 mg, 1.30 mmol, 2.0 eq.) was added, followed by stirring for 30 min at rt. DDTT (410 mg, 2.00 mmol, 3.0 eq) was added. After stirring for 30 min at rt, triethylphosphite (343 µL, 3.0 eq) was added. After stirring for 10 min at rt, propan-2-ol (1.0 mL) was added, followed by stirring for 10 min at rt. The so-obtained solution comprising DMTr-MMeC(bz)s-MMeUs-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (8) was used directly in the subsequent step (without any precipitation, filtration or purification steps in between). Synthesis of DMTr-MG(ib)s-MMeC(bz)s-MMeUs-MG(ib)s-MG(ib)-(Kc-C1- carbonate) (10) in an exemplary third coupling cycle using MMeC(bz)s-MMeUs- MG(ib)s-MG(ib)-(Kc-C1-carbonate) (9) as an exemplary component (C-0)^# A mixture of glutathione (1.02 g, 3.32 mmol.5.0 eq.), acetonitrile (5 mL) and TFA (5 mL) was added to the so-obtained solution comprising DMTr-MMeC(bz)s-MMeUs- MG(ib)s-MG(ib)-(Kc-C1-carbonate) (8) at 0 °C, followed by stirring at rt until reaction monitoring by HPLC (Method C) indicated complete DMTr-deprotection. Pyridine (6.8 mL), n-heptane (7.5 mL), MTHP (7.5 mL), acetone (10 mL) and 15 wt-% aqueous (aq.) sodium chloride solution (brine, 45 mL, pH-value = 4.6) were added to the reaction mixture comprising MMeC(bz)s-MMeUs-MG(ib)s-MG(ib)-(Kc- C1-carbonate) (9) as an exemplary component (C-0)^#, followed by extraction and phase separation. The aqueous phase had a pH-value of 4.2. NOP (1.0 mL) was added to the organic phase, followed by extraction with a mixture of, 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 45 mL, pH-value =5.2), followed by phase separation. The aqueous phase had a pH-value of 4.6. The organic phase was extracted with a mixture of 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 45 mL, pH-value = 5.2), followed by phase separation. The aqueous phase had a pH-value of 4.7. MTHP (7.5 mL) was added to the so-obtained organic phase comprising MMeC(bz)s-MMeUs-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (9), followed by concentration in vacuo to a volume of 7.5 mL (bath temperature 35−45 °C, pressure 40-200 hPa). The MTHP (7.5 mL) addition and subsequent concentration was repeated four times (final volume: 7.5 mL; water content: 189.4 ppm). DMTr-MG(ib) phosphoramidite (CAS-RN: 251647-55-9, 1.20 g, 1.31 mmol, 2.0 eq.) and MTHP (5 mL) were added to the so-obtained solution comprising MMeC(bz)s-MMeUs- MG(ib)s-MG(ib)-(Kc-C1-carbonate) (9), followed by concentration in vacuo (bath temperature 45 °C, pressure 40 hPa) to a volume of 7.5 mL.5-Ethylthio-1H-tetrazole (858 mg, 6.59 mmol, 10.0 eq.) and pyridine (1.6 mL, 19.82 mmol, 30.0 eq.) were added and the mixture was stirred at rt until reaction monitoring by HPLC (Method C) indicated completion of the coupling. Lactamide (118 mg, 1.33 mmol, 2.0 eq.) was added, followed by stirring for 30 min at rt. DDTT (407 mg, 1.98 mmol, 3.0 eq) was added. After stirring for 30 min at rt, triethylphosphite (343 µL, 3.0 eq) was added. After stirring for 10 min at rt, propan-2-ol (1.0 mL) was added, followed by stirring for 10 min at rt. The so-obtained solution comprising DMTr-MG(ib)s- MMeC(bz)s-MMeUs-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (10) was used directly in the subsequent step (without any precipitation, filtration or purification steps in between). MG(ib)s-MMeC(bz)s-MMeUs-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (OT-1) A mixture of glutathione (1.05 g, 3.42 mmol.5.2 eq.), acetonitrile (5 mL) and TFA (5 mL) was added to the so-obtained solution comprising DMTr-MG(ib)s-MMeC(bz)s- MMeUs-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (10) at 0 °C, followed by stirring at rt until reaction monitoring by HPLC (Method C) indicated complete DMTr-deprotection. Pyridine (6.8 mL), n-heptane (7.5 mL), MTHP (7.5 mL), acetone (10 mL) and 15 wt-% aqueous (aq.) sodium chloride solution (brine, 45 mL, pH-value = 4.7) were added to the reaction mixture comprising MG(ib)s-MMeC(bz)s-MMeUs-MG(ib)s- MG(ib)-(Kc-C1-carbonate) (OT-1), followed by extraction and phase separation. The aqueous phase had a pH-value of 4.2. NOP (1.0 mL) was added to the organic phase, followed by extraction with a mixture of 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 45 mL, pH-value =5.1), followed by phase separation. The aqueous phase had a pH-value of 4.5. The organic phase was extracted with a mixture of 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 45 mL, pH-value = 5.2), followed by phase separation. The aqueous phase had a pH-value of 4.6. MTHP (7.5 mL) was added to the so-obtained organic phase comprising MG(ib)s- MMeC(bz)s-MMeUs-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (OT-1), followed by concentration in vacuo to a weight of 11.6 g (bath temperature 35−45 °C, pressure 40-200 hPa), followed by addition of methanol (120 mL). The resulting precipitate was filtered and washed twice with methanol (30 mL × 2) to give MG(ib)s- MMeC(bz)s-MMeUs-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (OT-1, 1.59 g, 73.6 % crude yield from MG(ib)-(Kc-C1-carbonate) (3), 92.80 % purity (HPLC, Method C)). Note that, if a carbocation scavenger should be used in the steps of removing the DMTr-protecting group, it should best be extractable into the aqueous phase. Otherwise, the carbocation scavenger molecules, which remain in the organic phase, will react with and thereby consume molecules of the phosphoramidite building block in the subsequent coupling reaction. The phosphoramidite building block is an expensive starting material. Briefly, when using a non-extractable carbocation scavenger such as 1-dodecanethiol instead of an extractable carbocation scavenger such as glutathione (present Example), the excess of the phosphoramidite building block in the coupling reaction needs to be increased, which is undesirable. Additionally, if a carbocation scavenger should be used in the steps of removing the DMTr-protecting group, better yields and/or purities are obtained when using a carbocation scavenger, which is extractable into the aqueous phase. Example 2: (comparative Example): Synthesis B of target oligonucleotide OT-1 (see Table T-2) Present Example 2 is a comparative Example, which differs from the Example 1 according to the present invention only with regard to the aqueous extractions, in particular with regard to the pH-values of the aqueous phases of the aqueous extractions. Providing DMTr-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (4) as an exemplary component C-0 The protocol was as described above for Example 1. The so-obtained solution comprising DMTr-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (4) was used directly in the subsequent step (without any precipitation, filtration or purification steps in between). Synthesis of DMTr-MMeUs-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (6) in an exemplary first coupling cycle using MG(ib)s-MG(ib)-(Kc-C1-carbonate) (5) as an exemplary component (C-0)^# The protocol was as described above for Example 1, with the sole difference that the aqueous extractions were conducted as follows: n-Heptane (7.5 mL), MTHP (7.5 mL), acetone (10 mL) and 10 wt-% aqueous (aq.) sodium hydrogen sulfate solution (45 mL, pH-value = 0.5) were added to the reaction mixture comprising MG(ib)s-MG(ib)-(Kc-C1-carbonate) (5) as an exemplary component (C-0)^#, followed by extraction (the first aqueous extraction) and phase separation. The aqueous phase had a pH-value of 0.8. NOP (1.0 mL) and acetone (10 mL) were added to the organic phase, followed by extraction with 10 wt-% aqueous sodium hydrogen carbonate solution (45 mL, pH-value = 8.0, the second aqueous extraction), followed by phase separation. The aqueous phase had a pH-value of 6.3. Acetone (10 mL) was added to the organic phase, followed by extraction with 10 wt-% aqueous sodium hydrogen carbonate solution (45 mL, pH- value = 8.1, the third aqueous extraction), followed by phase separation. The aqueous phase had a pH-value of 8.2. The organic phase was extracted with a mixture of 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 45 mL, pH-value = 5.2, fourth aqueous extraction), followed by phase separation. The aqueous phase had a pH-value of 8.2. Synthesis of DMTr-MMeC(bz)s-MMeUs-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (8) in an exemplary second coupling cycle using MMeUs-MG(ib)s-MG(ib)-(Kc-C1- carbonate) (7) as an exemplary component (C-0)^# The protocol was as described above for Example 1, with the sole difference that the aqueous extractions were conducted as follows: n-Heptane (7.5 mL), MTHP (7.5 mL), acetone (10 mL) and 10 wt-% aqueous (aq.) sodium hydrogen sulfate solution (45 mL, pH-value = 0.6) were added to the reaction mixture comprising MMeUs-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (7) as an exemplary component (C-0)^#, followed by extraction (the first aqueous extraction) and phase separation. The aqueous phase had a pH-value of 0.7. NOP (1.0 mL) and acetone (10 mL) were added to the organic phase, followed by extraction with 10 wt-% aqueous sodium hydrogen carbonate solution (45 mL, pH-value = 8.2, the second aqueous extraction), followed by phase separation. The aqueous phase had a pH-value of 6.8. Acetone (10 mL) was added to the organic phase, followed by extraction with 10 wt-% aqueous sodium hydrogen carbonate solution (45 mL, pH- value = 8.2, the third aqueous extraction), followed by phase separation. The aqueous phase had a pH-value of 8.0. The organic phase was extracted with a mixture of 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 45 mL, pH-value = 5.0, fourth aqueous extraction), followed by phase separation. The aqueous phase had a pH-value of 7.5.

carbonate) (10) in an

third coupling cycle using MMeC(bz)s-MMeUs-

The protocol was as described above for Example 1, with the sole difference that the aqueous extractions were conducted as follows: n-Heptane (7.5 mL), MTHP (7.5 mL), acetone (10 mL) and 10 wt-% aqueous (aq.) sodium hydrogen sulfate solution (45 mL, pH-value = 0.5) were added to the reaction mixture comprising MMeC(bz)s-MMeUs-MG(ib)s-MG(ib)-(Kc-C1- carbonate) (9) as an exemplary component (C-0)^#, followed by extraction (the first aqueous extraction) and phase separation. The aqueous phase had a pH-value of 0.7. NOP (1.0 mL) and acetone (10 mL) were added to the organic phase, followed by extraction with 10 wt-% aqueous sodium hydrogen carbonate solution (45 mL, pH-value = 8.3, the second aqueous extraction), followed by phase separation. The aqueous phase had a pH-value of 6.6. Acetone (10 mL) was added to the organic phase, followed by extraction with 10 wt-% aqueous sodium hydrogen carbonate solution (45 mL, pH-value = 8.3, the third aqueous extraction), followed by phase separation. The aqueous phase had a pH-value of 7.8. The organic phase was extracted with a mixture of 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 45 mL, pH-value = 5.0, fourth aqueous extraction), followed by phase separation. The aqueous phase had a pH-value of 7.3.

The protocol was as described above for Example 1, with the sole difference that the aqueous extractions were conducted as follows: n-Heptane (7.5 mL), MTHP (7.5 mL), acetone (10 mL) and 10 wt-% aqueous (aq.) sodium hydrogen sulfate solution (45 mL, pH-value = 0.5) were added to the reaction mixture comprising MG(ib)s-MMeC(bz)s-MMeUs-MG(ib)s-MG(ib)-(Kc-C1- carbonate) (OT-1), followed by extraction and phase separation. The aqueous phase had a pH-value of 0.6. NOP (1.0 mL) and acetone (10 mL) were added to the organic phase, followed by extraction with 10 wt-% aqueous sodium hydrogen carbonate solution (45 mL, pH-value = 8.1), followed by phase separation. The aqueous phase had a pH-value of 6.8. Acetone (10 mL) was added to the organic phase, followed by extraction with 10 wt-% aqueous sodium hydrogen carbonate solution (45 mL, pH-value = 8.1), followed by phase separation. The aqueous phase had a pH-value of 8.2. The organic phase was extracted with a mixture of 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 45 mL, pH-value = 5.7), followed by phase separation. The aqueous phase had a pH-value of 8.2. MG(ib)s-MMeC(bz)s-MMeUs-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (OT-1, 1.35 g, 62.4 % crude yield from MG(ib)-(Kc-C1-carbonate) (3), 64.8 % purity (HPLC, Method C)). Example 1 according to the present invention afforded the target oligonucleotide O^T-1 in higher yield (73.6% for Example 1 instead of 62.4% for comparative Example 2) and higher purity (92.8% for Example 1 instead of 64.8% for comparative Example 2) as compared to the comparative Example 2. Example 3: Synthesis of target oligonucleotide OT-2 (see Table T-2) Providing DMTr-dA(bz)-dT-(Kc-C1-carbonate) (12) as an exemplary component C-0 Dichloroacetic acid (DCA, 50 mL) was added at rt to a stirred solution of DMTr-dT- (Kc-C1-carbonate) (1, 7.92 g, 5.96 mmol) obtained as laid out above, and thiomalic acid (4.97 g, 33.10 mmol, 5.5 eq.) in cyclopentyl methyl ether (CPME, 150 mL), and the mixture was stirred at rt until reaction monitoring by HPLC (Method D) indicated completion of the DMTr-deprotection. N-methylmorpholine (NMM, 62 mL), acetone and water (100 mL) were added, followed by extraction. The organic phase was separated and washed twice with water (75 mL × 2). The so-obtained organic phase was concentrated to 9.5 g, followed by precipitation by addition of acetonitrile (440 mL). The resulting precipitate was filtrated, then washed twice with acetonitrile (175 mL × 2) to give dT-(Kc-C1-carbonate) (11, 6.26 g, quantitative yield from DMTr-dT- (Kc-C1-carbonate) (1)). A solution of dT-(Kc-C1-carbonate) (11, 677 mg, 0.66 mmol) in a mixture of MTHP and benzonitrile (CAS-RN: 100-47-0) (2:1 v/v, 15 mL) was subjected to 2 rounds of azeotropic distillation, during each of which MTHP (10 mL) was added, followed by concentration in vacuo to a volume of 15 mL (bath temperature 45 °C, pressure 40−100 hPa; water content: 233.9 ppm). DMTr-dA(bz) phosphoramidite (CAS-RN: 98796-53-3,1.16 g, 1.35 mmol, 2.0 eq.) and MTHP (5 mL) were added to the so- obtained solution comprising dT-(Kc-C1-carbonate) (11), followed by concentration in vacuo (bath temperature 45 °C, pressure 40 hPa) to a volume of 15 mL. 5- Ethylthio-1H-tetrazole (860 mg, 6.61 mmol, 10.0 eq.) and pyridine (1.6 mL, 19.82 mmol, 30.0 eq.) were added and the mixture was stirred at rt until reaction monitoring by HPLC (Method C) indicated completion of the coupling. Lactamide (120 mg, 1.35 mmol, 2.0 eq.) was added, followed by stirring for 30 min at rt. 1 M I₂ in MTHP (1.45 mL, 1.45 mmol, 2.2 eq.), H₂O (36 µL), and acetonitrile (1.5 mL) were added. After stirring for 10 min at rt, the reaction mixture was extracted twice: first with 0.5 N Na₂S₂O₃ aq. (10 mL), then with 0.5 N Na₂S₂O₃ aq. (10 mL). The so- obtained organic phase comprising DMTr-dA(bz)-dT-(Kc-C1-carbonate) (12) was used directly in the subsequent step (without any precipitation, filtration or purification steps in between). Synthesis of DMTr-dC(bz)-dA(bz)-dT-(Kc-C1-carbonate) (14) in an exemplary first coupling cycle using dA(bz)-dT-(Kc-C1-carbonate) (13) as an exemplary component (C-0)^# A mixture of glutathione (1.01 g, 3.29 mmol.5.0 eq.), acetonitrile (5 mL) and TFA (5 mL) was added to the so-obtained solution comprising DMTr-dA(bz)-dT-(Kc-C1- carbonate) (12) at 0 °C, followed by stirring at rt until reaction monitoring by HPLC (Method C) indicated complete DMTr-deprotection. Pyridine (6.8 mL), n-heptane (7.5 mL), MTHP (15 mL), acetone (10 mL) and 15 wt-% aqueous (aq.) sodium chloride solution (brine, 45 mL, pH-value = 5.0) were added to the reaction mixture comprising dA(bz)-dT-(Kc-C1-carbonate) (13) as an exemplary component (C-0)^#, followed by extraction (the first aqueous extraction) and phase separation. The aqueous phase had a pH-value of 4.4. Benzonitrile (1.0 mL) was added to the organic phase, followed by extraction with a mixture of, 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 45 mL, pH-value = 5.2, the second aqueous extraction), followed by phase separation. The aqueous phase had a pH-value of 5.1. The organic phase was extracted with a mixture of 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 45 mL, pH-value = 5.2, the third aqueous extraction), followed by phase separation. The aqueous phase had a pH-value of 5.6. MTHP (10 mL) was added to the so-obtained organic phase comprising dA(bz)-dT- (Kc-C1-carbonate) (13), followed by concentration in vacuo to a volume of 15 mL (bath temperature 35−45 °C, pressure 40-200 hPa). The MTHP (10 mL) addition and subsequent concentration was repeated four times (final volume: 15 mL; water content: 136.2 ppm). DMTr-dC(bz) phosphoramidite (CAS-RN: 102212-98-6, 1.08 g, 1.32 mmol, 2.0 eq.) and MTHP (5 mL) were added to the so-obtained solution comprising dA(bz)-dT-(Kc-C1-carbonate) (13), followed by concentration in vacuo (bath temperature 45 °C, pressure 40 hPa) to a volume of 15 mL.5-Ethylthio-1H- tetrazole (860 mg, 6.61 mmol, 10.0 eq.) and pyridine (1.6 mL, 19.82 mmol, 30.0 eq.) were added and the mixture was stirred at rt until reaction monitoring by HPLC (Method C) indicated completion of the coupling. Lactamide (120 mg, 1.35 mmol, 2.0 eq.) was added, followed by stirring for 30 min at rt.1 M I₂ in MTHP (1.45 mL, 1.45 mmol, 2.2 eq.), H₂O (36 µL), and acetonitrile (1.5 mL) were added. After stirring for 10 min at rt, the reaction mixture was extracted twice: first with 0.5 N Na2S2O3 aq. (10 mL), then with 0.5 N Na2S2O3 aq. (10 mL). The so-obtained organic phase comprising DMTr-dC(bz)-dA(bz)-dT-(Kc-C1-carbonate) (14) was used directly in the subsequent step (without any precipitation, filtration or purification steps in between). Synthesis of DMTr-dT-dC(bz)-dA(bz)-dT-(Kc-C1-carbonate) (16) in an exemplary second coupling cycle using dC(bz)-dA(bz)-dT-(Kc-C1-carbonate) (15) as an exemplary component (C-0)^# A mixture of glutathione (1.01 g, 3.29 mmol.5.0 eq.), acetonitrile (5 mL) and TFA (5 mL) was added to the so-obtained solution comprising DMTr-dC(bz)-dA(bz)-dT- (Kc-C1-carbonate) (14) at 0 °C, followed by stirring at rt until reaction monitoring by HPLC (Method C) indicated complete DMTr-deprotection. Pyridine (6.8 mL), n-heptane (7.5 mL), MTHP (7.5 mL), acetone (10 mL) and 15 wt-% aqueous (aq.) sodium chloride solution (brine, 45 mL, pH-value = 4.8) were added to the reaction mixture comprising dC(bz)-dA(bz)-dT-(Kc-C1-carbonate) (15) as an exemplary component (C-0)^#, followed by extraction (the first aqueous extraction) and phase separation. The aqueous phase had a pH-value of 4.5. Benzonitrile (1.0 mL) and MTHP (5 mL) were added to the organic phase, followed by extraction with a mixture of, 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 45 mL, pH-value = 5.4, the second aqueous extraction), followed by phase separation. The aqueous phase had a pH-value of 5.1. The organic phase was extracted with a mixture of 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 45 mL, pH-value = 5.4, the third aqueous extraction), followed by phase separation. The aqueous phase had a pH-value of 5.6. MTHP (10 mL) was added to the so-obtained organic phase comprising dC(bz)- dA(bz)-dT-(Kc-C1-carbonate) (15), followed by concentration in vacuo to a volume of 15 mL (bath temperature 35−45 °C, pressure 40-200 hPa). The MTHP (10 mL) addition and subsequent concentration was repeated four times (final volume: 15 mL; water content: 236.2 ppm). DMTr-dT phosphoramidite (CAS-RN: 98796-51-1, 0.99 g, 1.32 mmol, 2.0 eq.) and MTHP (5 mL) were added to the so-obtained solution comprising dC(bz)-dA(bz)-dT-(Kc-C1-carbonate) (15), followed by concentration in vacuo (bath temperature 45 °C, pressure 40 hPa) to a volume of 15 mL.5-Ethylthio-1H-tetrazole (857 mg, 6.58 mmol, 10.0 eq.) and pyridine (1.6 mL, 19.82 mmol, 30.0 eq.) were added and the mixture was stirred at rt until reaction monitoring by HPLC (Method C) indicated completion of the coupling. Lactamide (118 mg, 1.33 mmol, 2.0 eq.) was added, followed by stirring for 30 min at rt.1 M I2 in MTHP (1.45 mL, 1.45 mmol, 2.2 eq.), H2O (36 µL), and acetonitrile (1.5 mL) were added. After stirring for 10 min at rt, the reaction mixture was extracted twice: first with 0.5 N Na2S2O3 aq. (10 mL), then with 0.5 N Na2S2O3 aq. (10 mL). The organic phase was concentrated in vacuo to a volume of 15 mL (bath temperature 35−45 °C, pressure 40-200 hPa). The so-obtained organic phase comprising DMTr-dT- dC(bz)-dA(bz)-dT-(Kc-C1-carbonate) (16) was used directly in the subsequent step (without any precipitation, filtration or purification steps in between). Synthesis of DMTr-dA(bz)-dT-dC(bz)-dA(bz)-dT-(Kc-C1-carbonate) (18) in an exemplary third coupling cycle using dT-dC(bz)-dA(bz)-dT-(Kc-C1-carbonate) (17) as an exemplary component (C-0)^# A mixture of glutathione (1.02 g, 3.32 mmol.5.0 eq.), acetonitrile (5 mL) and TFA (5 mL) was added to the so-obtained solution comprising DMTr-dT-dC(bz)-dA(bz)- dT-(Kc-C1-carbonate) (16) at 0 °C, followed by stirring at rt until reaction monitoring by HPLC (Method C) indicated complete DMTr-deprotection. Pyridine (6.8 mL), n-heptane (7.5 mL), MTHP (7.5 mL), acetone (10 mL) and 15 wt-% aqueous (aq.) sodium chloride solution (brine, 45 mL, pH-value = 4.9) were added to the reaction mixture comprising dT-dC(bz)-dA(bz)-dT-(Kc-C1-carbonate) (17) as an exemplary component (C-0)^#, followed by extraction (the first aqueous extraction) and phase separation. The aqueous phase had a pH-value of 4.4. Benzonitrile (1.0 mL) and MTHP (5 mL) were added to the organic phase, followed by extraction at 40 °C with a mixture of, 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 45 mL, pH-value = 5.6, the second aqueous extraction), followed by phase separation. The aqueous phase had a pH-value of 5.2. The organic phase was extracted at 40 °C with a mixture of 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 45 mL, pH-value = 5.2, the third aqueous extraction), followed by phase separation. The aqueous phase had a pH-value of 5.7. MTHP (10 mL) was added to the so-obtained organic phase comprising dT-dC(bz)- dA(bz)-dT-(Kc-C1-carbonate) (17), followed by concentration in vacuo to a volume of 15 mL (bath temperature 35−45 °C, pressure 40-200 hPa). The MTHP (10 mL) addition and subsequent concentration was repeated four times (final volume: 15 mL; water content: 204.0 ppm). DMTr-dA(bz) phosphoramidite (CAS-RN: 98796- 53-3, 1.13 g, 1.32 mmol, 2.0 eq.) and MTHP (5 mL) were added to the so-obtained solution comprising dT-dC(bz)-dA(bz)-dT-(Kc-C1-carbonate) (17), followed by concentration in vacuo (bath temperature 45 °C, pressure 40 hPa) to a volume of 15 mL.5-Ethylthio-1H-tetrazole (858 mg, 6.59 mmol, 10.0 eq.) and pyridine (1.6 mL, 19.82 mmol, 30.0 eq.) were added and the mixture was stirred at rt until reaction monitoring by HPLC (Method C) indicated completion of the coupling. Lactamide (118 mg, 1.33 mmol, 2.0 eq.) was added, followed by stirring for 30 min at rt.1 M I2 in MTHP (1.45 mL, 1.45 mmol, 2.2 eq.), H2O (36 µL), and acetonitrile (1.5 mL) were added. After stirring for 10 min at rt, the reaction mixture was extracted twice at 40 °C: first with 0.5 N Na2S2O3 aq. (10 mL), then with 0.5 N Na2S2O3 aq. (10 mL). The organic phase was concentrated in vacuo to a volume of 15 mL (bath temperature 35−45 °C, pressure 40-200 hPa). The so-obtained organic phase comprising DMTr- dA(bz)-dT-dC(bz)-dA(bz)-dT-(Kc-C1-carbonate) (18) was used directly in the subsequent step (without any precipitation, filtration or purification steps in between). 5’-dA-dT-dC-dA-dT-3’ (OT-2) A mixture of glutathione (1.02 g, 3.32 mmol.5.0 eq.), acetonitrile (5 mL) and TFA (5 mL) was added to the so-obtained solution comprising DMTr-dA(bz)-dT-dC(bz)- dA(bz)-dT-(Kc-C1-carbonate) (18) at 0 °C, followed by stirring at rt until reaction monitoring by HPLC (Method C) indicated complete DMTr-deprotection. Pyridine (6.8 mL), n-heptane (7.5 mL), MTHP (7.5 mL), acetone (10 mL) and 15 wt-% aqueous (aq.) sodium chloride solution (brine, 45 mL, pH-value = 5.1) were added to the reaction mixture comprising dA(bz)-dT-dC(bz)-dA(bz)-dT-(Kc-C1- carbonate) (19) as an exemplary component (C-0)^#, followed by extraction (the first aqueous extraction) and phase separation. The aqueous phase had a pH-value of 4.4. Benzonitrile (1.0 mL) was added to the organic phase, followed by extraction with a mixture of, 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 45 mL, pH-value = 5.5, the second aqueous extraction), followed by phase separation. The aqueous phase had a pH-value of 5.0. The organic phase was extracted with a mixture of 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 45 mL, pH-value = 5.5, the third aqueous extraction), followed by phase separation. The aqueous phase had a pH-value of 5.5. MTHP (7.5 mL) was added to the so-obtained organic phase comprising dA(bz)-dT- dC(bz)-dA(bz)-dT-(Kc-C1-carbonate) (19), followed by concentration in vacuo to a volume of 9.0 g (bath temperature 35−45 °C, pressure 40-200 hPa), followed by addition of methanol (120 mL). The resulting precipitate was filtered and washed twice with methanol (15 mL × 2) to give dA(bz)-dT-dC(bz)-dA(bz)-dT-(Kc-C1- carbonate) (19, 895 mg, 48.9 % crude yield based on dT-(Kc-C1-carbonate) (11)) as a white solid. dA(bz)-dT-dC(bz)-dA(bz)-dT-(Kc-C1-carbonate) (19, 100 mg, 0.036 mmol) was added into a mixture of H2O, methanol and tert-butylamine (2:1:1 v/v, 6.3 mL). The mixture was stirred at 45 °C for 18.5 h. The reaction mixture was cooled to rt and filtrated using a glass filter, followed by washing of the residue with water (1 mL). The filtrate was concentrated in vacuo (bath temperature 45 °C, pressure 35 hPa) to give 5’-dA-dT-dC-dA-dT-3’ (OT-2, 68.4 mg, quantitative from dA(bz)-dT-dC(bz)- dA(bz)-dT-(Kc-C1-carbonate) (19), 49.39 % purity, HPLC Method C). MS (Method 1) m/z: [M - H]- calcd for C49H62N17O28P4-, 1460.2906; found 1460.2875. Example 4: Synthesis of target oligonucleotide OT-3 (see Table T-2) Providing DMTr-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (4) as an exemplary component C-0 Dichloroacetic acid (DCA, 50 mL) was added at rt to a stirred solution of DMTr- MG(ib)-(Kc-C1-carbonate) (2, 6.98 g, 4.66 mmol) obtained from Synthesis B laid out above, and thiomalic acid (4.96 g, 33.03 mmol, 7.1 eq.) in cyclopentyl methyl ether (CPME, 150 mL), and the mixture was stirred at rt until reaction monitoring by HPLC (Method D) indicated completion of the DMTr-deprotection. N-methylmorpholine (NMM, 80 mL), acetone (25 mL) and water (100 mL) were added, followed by extraction. The organic phase was separated and washed twice with water (75 mL × 2). The so-obtained organic phase was concentrated to 9.72 g, followed by precipitation by addition of acetonitrile (500 mL). The resulting precipitate was filtrated, then washed twice with acetonitrile (200 mL × 2) to give MG(ib)-(Kc-C1- carbonate) (3, 4.65 g, 58.9 % yield for 2 steps from 3,5-bis(docosyloxy)benzenemethanol). A solution of MG(ib)-(Kc-C1-carbonate) (3, 1.58 g, 1.32 mmol, 1.0 eq) in a mixture of 4-methyltetrahydropyran (MTHP) and N-octylpyrrolidone (NOP) (2:1 v/v, 22.5 mL) was concentrated in vacuo to a volume of 7.5 mL (bath temperature 35−45 °C, pressure 40-200 hPa). DMTr-MG(ib) phosphoramidite (CAS-RN: 251647-55-9, 2.41 g, 2.64 mmol, 2.0 eq.) and MTHP (10 mL) were added (water content of the so- obtained solution: 180.3 ppm), followed by concentration in vacuo (bath temperature 45 °C, pressure 40 hPa), then adjustment a volume to 15 mL by addition of MTHP (7.5 mL). Molecular sieves 4A (0.1 g), 5-Ethylthio-1H-tetrazole (1.72 g, 13.21 mmol, 10.0 eq.) and pyridine (3.20 mL, 39.65 mmol, 30.0 eq.) were added, and the mixture was stirred at rt until reaction monitoring by HPLC (Method D) indicated completion of the coupling. Lactamide (237 mg, 2.66 mmol, 2.0 eq.) was added, followed by stirring at rt for 30 min. 3-(N,N-dimethylaminomethylidene)amino)-3H-1,2,4- dithiazole-5-thione (CAS-RN: 1192027-04-5, DDTT, 814 mg, 3.96 mmol, 3.0 eq) was added. After stirring for 30 min at rt, triethylphosphite (686 µL, 3.96 mmol, 3.0 eq) was added. After stirring for 10 min at rt, propan-2-ol (2.0 mL) was added, followed by stirring for 10 min at rt. The so-obtained solution comprising DMTr- MG(ib)s-MG(ib)-(Kc-C1-carbonate) (4) was used directly in the subsequent step (without any precipitation, filtration or purification steps in between). Synthesis of DMTr-MMeUs-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (6) in an exemplary first coupling cycle using MG(ib)s-MG(ib)-(Kc-C1-carbonate) (5) as an exemplary component (C-0)^# A mixture of glutathione (2.03 g, 6.60 mmol, 5.0 eq.), acetonitrile (10 mL) and TFA (10 mL) was added to the aforementioned solution comprising DMTr-MG(ib)s- MG(ib)-(Kc-C1-carbonate) (4) at 0 °C, followed by stirring at rt until reaction monitoring by HPLC (Method D) indicated complete DMTr-deprotection. The liquid contents of the flask were transferred into a separatory funnel, thereby leaving the molecular sieves inside the flask. Pyridine (20 mL), n-heptane (15 mL), MTHP (15 mL), acetone (20 mL) and 15 wt-% aqueous (aq.) sodium chloride solution (brine, 90 mL, pH-value = 4.9) were added into the separatory funnel, followed by extraction and phase separation. The pH- value of the aqueous phase was 4.6. NOP (2.0 mL) was added to the organic phase inside the separatory funnel, followed by extraction with a mixture of 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 90 mL, pH-value = 5.2) and phase separation. The pH-value of the aqueous phase was 5.1. The organic phase was extracted with a mixture of 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 90 mL, pH-value = 5.2), followed by phase separation. The pH-value of the aqueous phase was 5.5. In an eggplant flask, MTHP (7.5 mL) was added to the so-obtained organic phase comprising MG(ib)s-MG(ib)-(Kc-C1-carbonate) (5), followed by concentration in vacuo to a volume of 7.5 mL (bath temperature 35−45 °C, pressure 40-200 hPa). The MTHP (7.5 mL) addition and subsequent concentration was repeated four times (final volume: 7.5 mL; water content: 247.8 ppm). Molecular sieves 4A (0.1 g), DMTr- MMeU phosphoramidite (CAS-RN: 163878-63-5, 2.16 g, 2.64 mmol, 2.0 eq.) and MTHP (10 mL) were added to the so-obtained solution comprising MG(ib)s-MG(ib)- (Kc-C1-carbonate) (5), followed by concentration in vacuo (bath temperature 45 °C, pressure 40 hPa) then adjustment to a volume to 15 mL by addition of MTHP.5- Ethylthio-1H-tetrazole (1.72 g, 13.21 mmol, 10.0 eq.) and pyridine (3.20 mL, 39.65 mmol, 30.0 eq.) were added, and the mixture was stirred at rt until reaction monitoring by HPLC (Method D) indicated completion of the coupling. Lactamide (235 mg, 2.64 mmol, 2.0 eq.) was added, followed by stirring for 30 min at rt. DDTT (813 mg, 3.96 mmol, 3.0 eq) was added. After stirring for 30 min at rt, triethylphosphite (686 µL, 3.96 mmol, 3.0 eq) was added. After stirring for 10 min at rt, propan-2-ol (2.0 mL) was added, followed by stirring for 10 min at rt. The so- obtained solution comprising DMTr-MMeUs-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (6) was used directly in the subsequent step (without any precipitation, filtration or purification steps in between). Exemplary second coupling cycle and exemplary further coupling cycles The second coupling cycle and all further coupling cycles were performed according to the following general protocol, unless indicated differently. The starting materials and products of each coupling cycle are listed in Table E-1 below. The terms “starting material” and “product” are not to be construed to indicate any precipitation and/or isolation steps in between the coupling cycles, unless indicated differently. Table E-1: Overview of iterations 2 to 8 of the coupling cycle of Examples 4 number of the starting product coupling material cycle 2 DMTr-MMeC(bz)s-MMeUs-MG(ib)s-MG(ib)-(Kc-C1- 6 carbonate) (8) DMTr-MG(ib)s-MMeC(bz)s-MMeUs-MG(ib)s-MG(ib)- 3 8 (Kc-C1-carbonate) (10) DMTr-MMeUs-MG(ib)s-MMeC(bz)s-MMeUs-MG(ib)s- 4 10 MG(ib)-(Kc-C1-carbonate) (20) 5 DMTr-MA(bz)s-MMeUs-MG(ib)s-MMeC(bz)s-MMeUs- 20 MG(ib)s-MG(ib)-(Kc-C1-carbonate) (21) DMTr-MA(bz)s-MA(bz)s-MMeUs-MG(ib)s-MMeC(bz)s- 6 21 MMeUs-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (22) DMTr-MMeUs-MA(bz)s-MA(bz)s-MMeUs-MG(ib)s- 7 22 MMeC(bz)s-MMeUs-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (23) DMTr-MA(bz)s-MMeUs-MA(bz)s-MA(bz)s-MMeUs- 8 23 MG(ib)s-MMeC(bz)s-MMeUs-MG(ib)s-MG(ib)-(Kc-C1- carbonate) (24) General protocol for coupling cycles In a typical coupling cycle, the following steps were performed in the presented order. If equivalents (eq) of materials are listed, they are given relative to MG(ib)- (Kc-C1-carbonate) (3). DMTr-deprotection (including neutralization with pyridine) A mixture of TFA (10 mL), glutathione (5 eq.) and acetonitrile (10 mL) was added under ice-cooling at a temperature in the range of 5−25 °C directly to the solution obtained from the preceding sulfurization step. The mixture was stirred at rt until reaction monitoring by HPLC (Method D) indicated completion of the DMTr- deprotection. Pyridine (20 mL) was added under ice-cooling at a temperature in the range of 10-25 °C directly to the reaction mixture obtained from carrying out the DMTr-deprotection. Aqueous extractions The so-obtained solution was transferred into a separatory funnel, thereby leaving the molecular sieves inside the flask, and subjected to three aqueous extractions as summarized in Table E-2 below for each of the coupling cycles. Table E-2: Overview of aqueous extractions conducted in the second coupling cycle and the further coupling cycles as defined in Table E-1 above. number of the Extraction Conditions coupling cycle n-Heptane (15 mL), MTHP (15 mL), acetone (20 mL), and 15 wt-% aqueous sodium chloride solution (90 mL, pH-value = 4.9) were added into the separatory funnel, followed by extraction and phase separation. The aqueous phase had a pH-value of 4.6. NOP (2.0 mL) was added to the organic phase in the separatory funnel, followed by extraction with a mixture of, 5 wt-% aqueous 2 sodium chloride solution and acetone (1:1 v/v, 90 mL, pH-value = 5.2, pH) and phase separation. The aqueous phase had a pH-value of 5.1. The organic phase was extracted with a mixture of 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 90 mL, pH-value = 5.2), followed by phase separation. The aqueous phase had a pH-value of 5.5. n-Heptane (15 mL), MTHP (15 mL), acetone (20 mL), and 15 wt-% aqueous sodium chloride solution (90 mL, pH-value = 4.9) were added 3 into the separatory funnel, followed by extraction and phase separation. The aqueous phase had a pH-value of 4.6. NOP (2.0 mL) was added to the organic phase in the separatory funnel, followed by extraction with a mixture of, 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 90 mL, pH-value = 5.2, pH) and phase separation. The aqueous phase had a pH-value of 5.1. The organic phase was extracted with a mixture of 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 90 mL, pH-value = 5.2), followed by phase separation. The aqueous phase had a pH- value of 5.5. n-Heptane (15 mL), MTHP (15 mL), acetone (20 mL), and 15 wt-% aqueous sodium chloride solution (90 mL, pH-value = 4.9) were added into the separatory funnel, followed by extraction and phase separation. The aqueous phase had a pH-value of 4.6. NOP (2.0 mL) was added to the organic phase in the separatory funnel, followed by extraction with a mixture of, 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 90 mL, pH-value = 5.2, pH) and phase separation. The aqueous phase had a pH-value of 5.0. The organic phase was extracted with a mixture of 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 90 mL, pH-value = 5.2), followed by phase separation. The aqueous phase had a pH- value of 5.5. n-Heptane (15 mL), MTHP (15 mL), acetone (20 mL), and 15 wt-% aqueous sodium chloride solution (90 mL, pH-value = 4.9) were added into the separatory funnel, followed by extraction and phase separation. The aqueous phase had a pH-value of 4.6. NOP (2.0 mL) was added to the organic phase in the separatory funnel, followed by extraction with a mixture of, 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 90 mL, pH-value = 5.2, pH) and phase separation. The aqueous phase had a pH-value of 5.1. The organic phase was extracted with a mixture of 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 90 mL, pH-value = 5.2), followed by phase separation. The aqueous phase had a pH- value of 5.4. n-Heptane (15 mL), MTHP (15 mL), and 15 wt-% aqueous sodium chloride solution (90 mL, pH-value = 4.9) were added into the separatory funnel, followed by extraction and phase separation. The aqueous phase had a pH-value of 4.6. NOP (2.0 mL) and MTHP (15 mL) was added to the organic phase in the separatory funnel, followed by extraction with a mixture of, 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 90 mL, pH- value = 5.2, pH) and phase separation. The aqueous phase had a pH- value of 5.1. The organic phase was extracted with a mixture of 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 90 mL, pH-value = 5.2), followed by phase separation. The aqueous phase had a pH- value of 5.4. n-Heptane (15 mL), MTHP (15 mL), and 15 wt-% aqueous sodium chloride solution (90 mL, pH-value = 4.9) were added into the separatory funnel, followed by extraction and phase separation. The aqueous phase had a pH-value of 4.6. NOP (2.0 mL) and MTHP (15 mL) was added to the organic phase in the separatory funnel, followed by extraction with a mixture of, 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 90 mL, pH- value = 5.2, pH) and phase separation. The aqueous phase had a pH- value of 5.1. The organic phase was extracted with a mixture of 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 90 mL, pH-value = 5.2), followed by phase separation. The aqueous phase had a pH- value of 5.3. n-Heptane (15 mL), MTHP (15 mL), acetone (20 mL), and 15 wt-% aqueous sodium chloride solution (90 mL, pH-value = 4.9) were added into the separatory funnel, followed by extraction and phase separation. The aqueous phase had a pH-value of 4.5. NOP (2.0 mL) was added to the organic phase in the separatory funnel, followed by extraction with a mixture of, 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 90 mL, pH-value = 5.2, pH) and phase separation. The aqueous phase had a pH-value of 5.0. The organic phase was extracted with a mixture of 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 90 mL, pH-value = 5.2), followed by phase separation. The aqueous phase had a pH- value of 5.4. Azeotropic distillation In an eggplant flask, MTHP (15 mL) was added to the organic phase obtained from the preceding aqueous extractions, followed by concentration in vacuo (bath temperature 35−45 °C, pressure 40-200 hPa). This MTHP addition and concentration step was typically repeated. The water content was adjusted to be less than 400 ppm. MTHP (10 mL) and the 5’-DMTr-protected phosphoramidite (2.0 eq.) which to be coupled in the subsequent coupling reaction were added to the solution, followed by concentration in vacuo (bath temperature 45 °C, pressure 40- 100 hPa) to a volume of 15 mL. If needed to arrive at a final volume of 15 mL, additional MTHP (dried over 4A molecular sieves) was added. Coupling reaction (including quenching with Lactamide) Molecular sieves 4A (0.1 g), Pyridine (30 eq.) and 5-Ethylthio-1H-tetrazole (10 eq.) were added, and the mixture was stirred at rt until reaction monitoring by HPLC (Method D) indicated completion of the coupling reaction. Lactamide (1.0 eq.) was added, and the mixture was stirred for 30 min at rt. Sulfurization (including quenching with triethyl phosphite and isopropyl alcohol) DDTT (3.0 eq.) was added, and the mixture was stirred for 30 min at rt. Triethyl phosphite (3.0 eq.) was added and the mixture was stirred for 10 min at rt. Isopropyl alcohol (2-PrOH, 2.0 mL) was added and the mixture was stirred for 10 min at rt. Precipitation of MG(ib)s-MMeC(bz)s-MMeUs-MG(ib)s-MG(ib)-(Kc-C1-carbonate) In the fourth coupling cycle (cf. Table E-1 above), the organic phase obtained from the final aqueous extraction was concentrated in vacuo to a weight of 17.10 g, followed by addition of methanol (240 mL) under ice-cooling. The resulting precipitate was filtered and washed twice with methanol (30 mL × 2) to give MG(ib)s- mMeC(bz)s-mMeUs-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (3.71 g, 85.8 % crude yield from MG(ib)-(Kc-C1-carbonate) (3)). NOP (7.5 mL) was added to this precipitate, and the so-obtained solution was then subjected instead of the organic phase to the subsequent azeotropic distillation step according to the general protocol. Steps following the completion of the 8^th coupling cycle as defined in Table E-1 above At 0 °C, a mixture of glutathione (2.03 g, 6.60 mmol.5.0 eq.), acetonitrile (10 mL) and TFA (10 mL) were added to the solution comprising DMTr-MA(bz)s-MMeUs- MA(bz)s-MA(bz)s-MMeUs-MG(ib)s-MMeC(bz)s-MMeUs-MG(ib)s-MG(ib)-(Kc-C1- carbonate) (24) as obtained from the sulfurization step of the 8^th coupling cycle (as defined in Table E-1 above), followed by stirring at rt until reaction monitoring by HPLC (Method D) indicated complete DMTr-deprotection. The so-obtained solution was transferred into a separatory funnel, thereby leaving the molecular sieves inside the flask. Pyridine (20 mL), n-heptane (15 mL), MTHP (15 mL), acetone (20 mL) and 15 wt-% aqueous (aq.) sodium chloride solution (brine, 90 mL, pH-value = 4.9) were added into the separatory funnel, followed by extraction and phase separation. The aqueous phase had a pH-value of 4.5. NOP (2.0 mL) was added to the organic phase in the separatory funnel, followed by extraction with a mixture of, 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 90 mL, pH-value = 5.2, pH) and phase separation. The aqueous phase had a pH-value of 5.1. The organic phase was extracted with a mixture of 5 wt-% aqueous sodium chloride solution and acetone (1:1 v/v, 90 mL, pH-value = 5.2), followed by phase separation. The aqueous phase had a pH-value of 5.4. In an eggplant flask, MTHP (15 mL) was added to the so-obtained organic phase comprising MA(bz)s-MMeUs-MA(bz)s- MA(bz)s-MMeUs-MG(ib)s-MMeC(bz)s-MMeUs-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (25), followed by concentration in vacuo to a weight of 11.6 g (bath temperature 35−45 °C, pressure 40-200 hPa), followed by addition of methanol (120 mL), and stirring for 30 min under ice-cooling. The resulting precipitate was filtered and washed twice with methanol (30 mL × 2) to give MA(bz)s-MMeUs-MA(bz)s- MA(bz)s-MMeUs-MG(ib)s-MMeC(bz)s-MMeUs-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (25, 5.85 g, 75.7 % crude yield from MG(ib)-(Kc-C1-carbonate) (3)) The so-obtained MA(bz)s-MMeUs-MA(bz)s-MA(bz)s-MMeUs-MG(ib)s-MMeC(bz)s- MMeUs-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (25, 1.0 g, 0.171 mmol) and dithiothreitol (DTT, 263 mg, 1.71 mmol, 10 eq.) were added into a mixture of H2O, methanol and tert-butylamine (2:1:1 v/v, 30 mL). The mixture was stirred at rt for 1 h, then heated to 45 °C and stirred at 45 °C for 17.5 h. The reaction mixture was cooled to rt and filtrated using a glass filter, followed by washing of the residue with water (10 mL). The filtrate was concentrated in vacuo (bath temperature 45 °C, pressure 35 hPa) to give a solid. This solid was dissolved in methanol (1.7 mL), followed by dilution with a mixture of methanol and propan-2-ol (1:1, 1.7 mL). The so-obtained solution was added into tetrahydrofuran (THF, 140 mL). The resulting precipitate was filtrated and washed twice with THF (20 mL and 10 mL) to give 5´- MAs-MMeUs-MAs-MAs-MMeUs-MGs-MMeCs-MMeUs-MGs-MG-3´ (OT-3, 736.9 mg, quantitative yield from MA(bz)s-MMeUs-MA(bz)s-MA(bz)s-MMeUs-MG(ib)s- MMeC(bz)s-MMeUs-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (25), 82.39 % purity, HPLC Method E). MS (Method 1) m/z: [M-3H]^3- calc. for C130H184N39O69P9S9^3-, 1320.2384, found 1320.2317.

Claims

Bachem Holding AG April 16, 2024 BAC75082PC Claims 1. A method for the synthesis of a target oligonucleotide O^T, said method comprising a step of subjecting a solution comprising a component (C-0)^# selected from the group consisting of a nucleoside and an oligonucleotide to one or more aqueous extractions, wherein the organic phase comprises the component (C-0)^#, and wherein - said component (C-0)^# is covalently bonded to a pseudo solid-phase protecting group PG-s and is a compound of the following Formula I-C:

(Formula I-C), wherein in Formula I-C: each oxygen atom O depicted within each nucleoside subunit x-0 to x-m represents the oxygen atom of a hydroxyl moiety of the respective nucleoside subunit; each of the nucleoside subunits x-0 to x-m may be the same or different; m is an integer equal to or larger than 0; Y¹ is selected independently for each repetitive unit m from the group consisting of O and S; Z¹ is selected independently for each repetitive unit m from the group consisting of O-R^z-1, S-R^z-1, and H; R^z-1 is a protecting group, which may be the same or different for each repetitive unit m; and PG-s is a pseudo solid-phase protecting group, and - each of said one or more aqueous extractions is carried out in the presence of one or more organic solvents S^O, wherein the one or more organic solvents S^O are selected so that an organic phase and an aqueous phase are formed during the aqueous extraction, and - the aqueous phase of each of said one or more aqueous extractions has a pH-value in the range of 4–7. 2. The method according to claim 1, wherein the target oligonucleotide O^T comprises a first cycle oligonucleotide O-1, and the method comprises the following step (a-1), and a first coupling cycle comprising the following steps: (a-1) providing a component C-0 selected from the group consisting of a nucleoside and an oligonucleotide, wherein the component C-0 is covalently bonded to a pseudo solid-phase protecting group PG-s and comprises a backbone hydroxyl moiety protected by a protecting group PG-0 removable under acidic conditions, wherein the component C-0 is a compound of the following Formula I:

(Formula I), wherein in in Formula I: each oxygen atom O depicted within each nucleoside subunit x-0 to x-m represents the oxygen atom of a hydroxyl moiety of the respective nucleoside subunit; each of the nucleoside subunits x-0 to x-m may be the same or different; m is an integer equal to or larger than 0; PG-0 is a protecting group removable under acidic conditions; Y¹ is selected independently for each repetitive unit m from the group consisting of O and S; Z¹ is selected independently for each repetitive unit m from the group consisting of O-R^z-1, S-R^z-1, and H; R^z-1 is a protecting group, which may be the same or different for each repetitive unit m; and PG-s is a pseudo solid-phase protecting group; (b-1) incubating the component C-0 of step (a-1) with a deprotection mixture M-(b-1), thereby cleaving the protecting group PG-0 from the component C-0, so as to obtain a component (C-0)^# having a free backbone hydroxyl group; (c-1) subjecting a solution comprising the component (C-0)^# to one or more aqueous extractions, wherein the organic phase comprises the component (C-0)^#; (d-1) optionally, reducing the water content of the organic phase comprising the component (C-0)^#; (e-1) reacting the component (C-0)^# with a building block B-1, wherein said building block B-1 is selected from the group consisting of a nucleoside and an oligonucleotide and comprises - a backbone hydroxyl moiety protected by a protecting group PG-1 removable under acidic conditions, and - a phosphorus moiety covalently bonded via its phosphorus atom to an oxygen atom of the backbone of the building block B-1, under conditions suitable to form a covalent bond between said free backbone hydroxyl group of the component (C-0)^# and the phosphorus atom of said phosphorus moiety of the building block B-1, thereby obtaining a first cycle oligonucleotide O-1; (f-1) optionally, incubating the first cycle oligonucleotide O-1 with an oxidizing or sulfurizing agent, thereby converting any P (III) atoms within said first cycle oligonucleotide O-1 to P (V) atoms; (g-1) optionally, subjecting a solution comprising the first cycle oligonucleotide O-1 to one or more aqueous extractions, wherein the organic phase comprises the first cycle oligonucleotide O-1; (h-1) if step (g-1) has been carried out, optionally reducing the water content of the organic phase comprising the first cycle oligonucleotide O-1; wherein during and in between steps (b-1) to (h-1), no solid-liquid separation is performed and steps (c-1) and (g-1) are carried out in the presence of one or more organic solvents S^O as defined in claim 1, and in each of the one or more aqueous extractions of step (c-1), the aqueous phase has a pH-value in the range of 4−7. 3. The method according to claim 2, wherein the target oligonucleotide O^T comprises a second cycle oligonucleotide O-2, and the method further comprises performing a second coupling cycle comprising the following steps: (b-2) incubating the first cycle oligonucleotide O-1 obtained in the first coupling cycle with a deprotection mixture M-(b-2), thereby cleaving the protecting group PG-1 from the first cycle oligonucleotide O-1, so as to obtain a first cycle oligonucleotide (O-1)^# having a free backbone hydroxyl group; (c-2) subjecting a solution comprising the first cycle oligonucleotide (O-1)^# to one or more aqueous extractions, wherein the organic phase comprises the first cycle oligonucleotide (O-1)^#; (d-2) optionally, reducing the water content of the organic phase comprising the first cycle oligonucleotide (O-1)^#; (e-2) reacting the first cycle oligonucleotide (O-1)^# with a building block B-2, wherein said building block B-2 is selected from the group consisting of a nucleoside and an oligonucleotide and comprises - a backbone hydroxyl moiety protected by a protecting group PG-2 removable under acidic conditions, and - a phosphorus moiety covalently bonded via its phosphorus atom to an oxygen atom of the backbone of the building block B-2, under conditions suitable to form a covalent bond between said free backbone hydroxyl group of the first cycle oligonucleotide (O-1)^# and the phosphorus atom of said phosphorus moiety of the building block B-2, thereby obtaining a second cycle oligonucleotide O-2; (f-2) optionally, incubating the second cycle oligonucleotide O-2 with an oxidizing or sulfurizing agent, thereby converting any P (III) atoms within said second cycle oligonucleotide O-2 to P (V) atoms; (g-2) optionally, subjecting a solution comprising the second cycle oligonucleotide O-2 to one or more aqueous extractions, wherein the organic phase comprises the second cycle oligonucleotide O-2; (h-2) if step (g-2) has been carried out, optionally reducing the water content of the organic phase comprising the second cycle oligonucleotide O-2; wherein during and in between steps (b-1) to (h-2), no solid-liquid separation is performed and steps (c-1), (g-1), (c-2), and (g-2) are carried out in the presence of one or more organic solvents S^O as defined in claim 1, and in each of the one or more aqueous extractions of step (c-2), the aqueous phase has a pH-value in the range of 4−7. 4. The method according to claim 3, wherein the target oligonucleotide O^T comprises a n-th cycle oligonucleotide O-n, and the method further comprises performing (n−2) iterations of a coupling cycle comprising the following steps (b-x) to (h-x), wherein n is an integer in the range of 3 to 99, which denotes the total number of coupling cycles performed to obtain the n-th cycle oligonucleotide O-n, and each individual coupling cycle comprising the following steps (b-x) to (h-x) is identified by a serial number x, which runs in steps of 1 from 3 to n: (b-x) incubating the (x−1)-th cycle oligonucleotide O-(x−1) obtained in the previous coupling cycle with a deprotection mixture M-(b-x), thereby cleaving the protecting group PG-(x−1) from the (x−1)-th cycle oligonucleotide O-(x−1), so as to obtain a (x−1)-th cycle oligonucleotide (O-(x−1))^# having a free backbone hydroxyl group; (c-x) subjecting a solution comprising the (x−1)-th cycle oligonucleotide (O-(x−1))^# to one or more aqueous extractions, wherein the organic phase comprises the (x−1)-th cycle oligonucleotide (O-(x−1))^#; (d-x) optionally, reducing the water content of the organic phase comprising the (x−1)-th cycle oligonucleotide (O-(x−1))^#; (e-x) reacting the (x−1)-th cycle oligonucleotide (O-(x−1))^# with a building block B-x, wherein said building block B-x is selected from the group consisting of a nucleoside and an oligonucleotide and comprises - a backbone hydroxyl moiety protected by a protecting group PG-x removable under acidic conditions, and - a phosphorus moiety covalently bonded via its phosphorus atom to an oxygen atom of the backbone of the building block B-x, under conditions suitable to form a covalent bond between said free backbone hydroxyl group of the (x−1)-th cycle oligonucleotide (O-(x−1))^# and the phosphorus atom of said phosphorus moiety of the building block B-x, thereby obtaining a x-th cycle oligonucleotide O-x; (f-x) optionally, incubating the x-th cycle oligonucleotide O-x with an oxidizing or sulfurizing agent, thereby converting any P (III) atoms within said x-th cycle oligonucleotide O-x to P (V) atoms; (g-x) optionally, subjecting a solution comprising the x-th cycle oligonucleotide O-x to one or more aqueous extractions, wherein the organic phase comprises the x-th cycle oligonucleotide O-x; (h-x) if step (g-x) has been carried out, optionally reducing the water content of the organic phase comprising the x-th cycle oligonucleotide O-x; wherein during and in between steps (b-1) to (h-n), no solid-liquid separation is performed, and steps (c-1), (g-1), (c-2), and (g-2), as well as each iteration of steps (c-x) and (g-x) are carried out in the presence of one or more organic solvents S^O as defined in claim 1, and in each of the one or more aqueous extractions of each step (c-x), the aqueous phase has a pH-value in the range of 4−7. 5. The method according to any one of claims 2 to 4, wherein - the phosphorus moiety of the building blocks B-1, B-2, and each building block B-x is independently selected from the group consisting of a phosphoramidite moiety and a H-phosphonate monoester moiety; - in each coupling cycle, in which said phosphorus moiety of the building block B-1, B-2 or B-x is a phosphoramidite moiety, step (f-1) or (f-2) or (f-x) is carried out; and - at least in the final coupling cycle, step (f-1) or (f-2) or (f-x) is carried out. 6. The method according to any one of claims 2 to 5, wherein each of the building blocks B-1, B-2, and B-x is a compound of the following Formula II-1: (Formula II-1), wherein in Formula II-1: each oxygen atom O depicted within each nucleoside subunit y-0 to y-q represents the oxygen atom of a hydroxyl moiety of the respective nucleoside subunit; each nucleoside subunit y-0 to y-q may be the same or different; PG is the protecting group PG-1 or PG-2 or PG-x and is a protecting group removable under acidic conditions; q is an integer equal to or larger than 0; Y² is selected independently for each repetitive unit q from the group consisting of O and S; Z² is selected independently for each repetitive unit q from the group consisting of O-R^z-2 and S-R^z-2; R^z-2 is a protecting group, which may be the same or different for each repetitive unit q; Z³ is selected from the group consisting of O and S; and R^z-3 is a protecting group; each of R^a and R^b is a C1−C6-alkyl group, wherein R^a and R^b may be the same or different and may also bond to each other to form a 5-membered or 6-membered aliphatic cyclic amine moiety together with the nitrogen atom to which R^a and R^b are bonded; and wherein step (f-1) or (f-2) or (f-x) is carried out in each coupling cycle. 7. The method according to any one of claims 2 to 6, wherein - the first coupling cycle further comprises a step (i-1) of reacting free hydroxyl groups with a blocking agent, wherein step (i-1) is carried out after step (e-1) or after step (f-1); and/or - the second coupling cycle further comprises a step (i-2) of reacting free hydroxyl groups with a blocking agent, wherein step (i-2) is carried out after step (e-2) or after step (f-2); and/or - at least one coupling cycle comprising steps (b-x) to (h-x) further comprises a step (i-x) of reacting free hydroxyl groups with a blocking agent, wherein step (i-x) is carried out after step (e-x) or after step (f-x). 8. The method according to any one of claims 2 and 5 to 7, wherein the method further comprises - a step (k-1) of incubating the first cycle oligonucleotide O-1 with a deprotection mixture M-(k-1), thereby cleaving the protecting group PG-1 from the first cycle oligonucleotide O-1, so as to obtain a first cycle oligonucleotide (O-1)^# having a free backbone hydroxyl group; and/or - a step (m-1) of incubating the first cycle oligonucleotide O-1 or (O-1)^# with a base, thereby cleaving the pseudo solid-phase protecting group PG-s and, optionally, one or more further protecting groups from the first cycle oligonucleotide O-1 or (O-1)^#; and/or - a step (p-1) of modifying the first cycle oligonucleotide O-1 or (O-1)^#; wherein, if more than one of steps (k-1), (m-1), and (p-1) are performed, they may be performed in any order. 9. The method according to any one of claims 3 and 5 to 7, wherein the method further comprises - a step (k-2) of incubating the second cycle oligonucleotide O-2 with a deprotection mixture M-(k-2), thereby cleaving the protecting group PG-2 from the second cycle oligonucleotide O-2, so as to obtain a second cycle oligonucleotide (O-2)^# having a free backbone hydroxyl group; and/or - a step (m-2) of incubating the second cycle oligonucleotide O-2 or (O-2)^# with a base, thereby cleaving the pseudo solid-phase protecting group PG-s and, optionally, one or more further protecting groups from the second cycle oligonucleotide O-2 or (O-2)^#; and/or - a step (p-2) of modifying the second cycle oligonucleotide O-2 or (O-2)^#; wherein, if more than one of steps (k-2), (m-2), and (p-2) are performed, they may be performed in any order. 10. The method according to any one of claims 4 to 7, wherein the method further comprises - a step (k-n) of incubating the n-th cycle oligonucleotide O-n with a deprotection mixture M-(k-n), thereby cleaving the protecting group PG-n from the n-th cycle oligonucleotide O-n, so as to obtain a n-th cycle oligonucleotide (O-n)^# having a free backbone hydroxyl group; and/or - a step (m-n) of incubating the n-th cycle oligonucleotide O-n or (O-n)^# with a base, thereby cleaving the pseudo solid-phase protecting group PG-s and, optionally, one or more further protecting groups from the n-th cycle oligonucleotide O-n or (O-n)^#; and/or - a step (p-n) of modifying the n-th cycle oligonucleotide O-n or (O-n)^#; wherein, if more than one of steps (k-n), (m-n), and (p-n) are performed, they may be performed in any order. 11. The method according to any one of claims 8 to 10, wherein the method comprises exactly one step selected from the group consisting of step (m-1), step (m-2), and step (m-n), and wherein - step (m-1) is carried out by incubating the first cycle oligonucleotide O-1 or (O-1)^# with an aqueous solution of a (C1−C6-alkyl)NH2 monoalkylamine, in particular tert-butylamine, and an aliphatic alcohol comprising 1−6 carbon atoms, in particular methanol; - step (m-2) is carried out by incubating the second cycle oligonucleotide O-2 or (O-2)^# with an aqueous solution of a (C1−C6-alkyl)NH2 monoalkylamine, in particular tert-butylamine, and an aliphatic alcohol comprising 1−6 carbon atoms, in particular methanol; and - step (m-n) is carried out by incubating the n-th cycle oligonucleotide O-n or (O-n)^# with an aqueous solution of a (C₁−C₆-alkyl)NH₂ monoalkylamine, in particular tert-butylamine, and an aliphatic alcohol comprising 1−6 carbon atoms, in particular methanol. 12. The method according to any one of claims 1 to 11, wherein each pseudo solid-phase protecting group is a protecting group of the following Formula P-1: (Formula P-1), wherein in Formula P-1: the asterisk indicates the oxygen atom of a hydroxyl moiety or the nitrogen atom of an amine moiety protected by the respective pseudo solid-phase protecting group; a is an integer of 0 or 1; b is an integer of 0 or 1; L^P is a linker moiety; i is an integer of 1 to 5; and R^P-1 is at each occurrence independently selected from the group consisting of O(C1–C40-alkyl), O(C2–C40-alkenyl), O(C2–C40-alkynyl), a C1–C40-alkyl group, a C2–C40-alkenyl group, a C2–C40-alkynyl group, C(O)(C1–C40-alkyl), C(O)(C₂–C₄₀-alkenyl), and C(O)(C₂–C₄₀-alkynyl); and wherein all present residues R^P-1 together comprise in total 18–200 carbon atoms. 13. The method according to claim 1, wherein said solution comprising the component (C-0)^# further comprises one or more carbocation scavengers or the method according to any one of claims 2 to 12, wherein each of the deprotection mixtures M-(b-1), M-(b-2), and M-(b-x) further comprises one or more carbocation scavengers. 14. The method according to claim 13, wherein the one or more carbocation scavengers are selected from the group consisting of - compounds comprising one or more sulfhydryl groups and one or more carboxyl groups, and - compounds comprising an indole residue and one or more carboxyl groups. 15. The method according to claim 14, wherein the carbocation scavenger is glutathione.