EA045036B1 - METHOD FOR PRODUCING CARBAMOYLOXYMETHYLTRIAZOLECYCLOHEXYLIC ACID COMPOUNDS - Google Patents

Description

Cross reference to related application

This application claims priority under U.S. Provisional Patent Application No.

62/834,538, filed April 16, 2019, the contents of which are incorporated herein by reference in their entirety.

Field of technology

The present invention relates to improved methods for preparing carbamoyloxymethyltriazolecyclohexylic acid compounds and new intermediates thereof.

State of the art

Carbamoyloxymethyltriazolecyclohexylic acid compounds have been described as LPA (mainly LPAi) antagonists that are useful in the treatment of fibrosis. See, for example, WO 2017/223016 (US 2017/0360759). Improved methods for the preparation of carbamoyloxymethyltriazolecyclohexylic acid compounds are needed that provide practical large-scale synthesis and improved product quality, efficacy and safety.

The essence of the invention

The present invention relates to new methods and corresponding new intermediates for the preparation of carbamoyloxymethyltriazolecyclohexylic acid compounds.

Methods for preparing the corresponding intermediates, stereoisomers and salts are also described.

Detailed description

The features and advantages of the invention may be better understood by those skilled in the art upon reading the following detailed description. It should be appreciated that certain features of the invention, which are described above and below in the context of individual embodiments for clarity, may also be combined to form a single embodiment. Conversely, various features of the invention, which for brevity are described in the context of a single embodiment, may also be combined to form subcombinations thereof.

One skilled in the art will appreciate that some of the chemical structures described herein may be represented on paper by one or more other resonance modes; or may exist in one or more other tautomeric forms, even kinetically, those skilled in the art will recognize that such tautomeric forms represent only a very small portion of a sample of such compound(s). Such compounds are clearly contemplated within the scope of this disclosure, although such resonance forms or tautomers are not explicitly presented here.

In aspect 1A, the invention relates to a process for preparing a compound having the structure of formula (I):

where R ¹ represents C _1-6 alkyl; and R ² and R ^2a are halogen; comprising contacting a compound of formula (III):

where R ¹ represents C _1-6 alkyl; R ² represents halogen; and R ³ is halogen;

with reagent 2, which is organolithium, in solvent 2, which is a polar aprotic or non-polar aprotic solvent or a mixture of the above solvents;

for a period of time and at a temperature sufficient for the halogen-lithium exchange reaction; followed by an alkylating agent in solvent 3, which is a polar, polar aprotic or non-polar aprotic solvent or a mixture of the above solvents;

for a time and at a temperature sufficient for the alkylation reaction; followed by a strong acid to obtain the compound of formula (I).

In aspect 1B, the invention relates to a process for preparing a compound having the structure of formula (I):

- 1 045036

where R ² and R ³ independently represent halogen;

with a mixture of reagent 1 selected from R5-OM (metal alkoxide), M-OH (metal hydroxide), M ₂ CO ₃ (metal carbonate), MHCO ₃ (metal bicarbonate) (R ⁶ ) ₃ N (tertiary amine) and mixtures thereof, in solvent 1, which is R4-OH, a polar protic, polar aprotic or non-polar aprotic solvent or a mixture of the above solvents; and subsequent addition of an alkylating agent;

where M represents a metal selected from Li, Na, K and Cs; and R ⁴ , R ⁵ and R ⁶ independently represent C _1-6 alkyl;

for a time and at a temperature sufficient for the alkylation reaction to obtain the compound of formula (III):

R ²

Ν-Ν _χ

R ¹ (III), where R1 represents C _1-6 alkyl; R ² represents halogen; and R ³ is halogen;

and (2) contacting the compound of formula (III) with reagent 2, which is organolithium, in solvent 2, which is a polar aprotic or non-polar aprotic solvent or a mixture of the above solvents;

for a time and at a temperature sufficient for the halogen-lithium exchange reaction, followed by an alkylating agent in solvent 3, which is a polar, polar aprotic or non-polar aprotic solvent or a mixture of the above solvents;

for a time and at a temperature sufficient to cause an alkylation reaction, followed by a strong acid, to give the compound of formula (I).

In aspect 2A, within aspect 1A, the invention relates to a process for preparing a compound having the structure of formula (I);

comprising contacting a compound of formula (III) with a reagent 2 selected from p-BuLi, nHexLi and PhLi, in a solvent 2 selected from hexanes, THF, MeTHF and a mixture of the above solvents;

for a time and at a temperature from -30 to -10°C sufficient for the lithium halide exchange reaction; followed by an alkylating agent selected from benzyl chloromethyl ether for a time and at a temperature of -30 to -10° C. sufficient for alkylation, and a strong acid selected from HBr in acetic acid or a mixture of acetyl bromide and 2-propanol in a solvent 3 selected from THF, CH ₃ CN, IPAc, MeTHF and a mixture of the above solvents to obtain a compound of formula (I).

In aspect 2B, within aspect 1B, the invention relates to a process for preparing a compound having the structure of formula (I);

comprising (1) contacting a compound of formula (II) with a mixture of a metal alkoxide selected from LiOtBu, K ₂ CO ₃ , KHCO ₃ , Et ₃ N, NaOtBu, KOtBu, LiOH, LiOH-H ₂ O, LiOMe and mixtures thereof, in a solvent 1, selected from CH3CH2C(CH3 _{) 2OH} , C(CH3)3OH, CH(CH3OH) _2OH , CH3CH2OH, CH3OH, THF, EtOAc, IPAc, MeTHF, acetone, MIBK, _CH3CN , NMP, DMF, DCM, H ₂ O and mixtures of the above solvents; and followed by an alkylating agent selected from methyl iodide, dimethyl sulfate, dimethyl carbonate, methyl tosylate and mixtures thereof;

for 24 to 72 hours and at a temperature sufficient to cause alkylation to give the compound of formula (III);

and (2) contacting the compound of formula (III) with reagent 2 selected from n-BuLi, n-HexLi and PhLi, in solvent 2 selected from hexanes, THF, MeTHF and a mixture of the above solvents;

- 2 045036 for a time and at a temperature from -30 to -10°C sufficient for the lithium halide exchange reaction, and followed by an alkylating agent selected from benzyl chloromethyl ether, for a time and at a temperature from -30 to -10°C , sufficient for alkylation, and a strong acid selected from HBr in acetic acid, or a mixture of acetyl bromide and 2-propanol in solvent 3 selected from THF, CH3CN, IPAc, MeTHF and a mixture of the above solvents, to obtain a compound of formula (I).

In aspect 3A, the invention relates to a process for preparing a compound having the structure of formula (Ia):

*НВг ^N o /(ЭВп NN^

CH3(la); comprising contacting a compound of formula (IIIa):

with n-BuLi in hexanes;

for <1 hour and at a temperature of -30 to -10°C sufficient for the halogen-lithium exchange reaction, followed by benzyl chloromethyl ether;

for 5 to 24 hours and at a temperature of -30 to -10°C sufficient for alkylation, and 33 wt.% HBr in acetic acid in CH3CN, to obtain the compound of formula (Ia).

In aspect 3B, the invention relates to a process for preparing a compound having the structure of formula (Ia):

*НВг ^N w /ΌΒη Ν-Ν _χ ^СН з (1а);

comprising (1) contacting a compound of formula (IIa):

with a mixture of CH ₃ CH2C(CH ₃ )2OH and LiOtBu in THF at a temperature <40°C for 1 to 2 hours; followed by the addition of CH3I and continuing to stand for 24 to 48 hours to give the compound of formula (IIIa):

and (2) contacting the compound of formula (IIIa) with n-BuLi in hexanes;

for <1 hour and at a temperature of -30 to -10°C sufficient for the halogen-lithium exchange reaction, followed by benzyl chloromethyl ether for 5 to 24 hours and at a temperature of -30 to -10°C sufficient for alkylation, and 33 wt.% HBr in acetic acid in CH ₃ CN, to obtain the compound of formula (I).

In aspect 4A, the invention relates to a method for preparing a compound having the structure of formula (IV), or a salt thereof:

- 3 045036

where R ^a represents -N(C _1-4 alkyl)2;

comprising contacting a compound of formula (V):

C^alkyl-O-C^d alkyl R ⁶ (V), where R ⁶ is halogen;

with a compound of formula (VI) or a salt thereof:

where R ^a represents -N(C _1-4 alkyl) ₂ ;

in the presence of an inorganic base and a phase transfer catalyst in solvent 4, which is a polar aprotic solvent or a mixture of the above solvents;

for a time and at a temperature sufficient to complete the reaction to obtain a compound of formula (IV) or a salt thereof.

In aspect 5A within aspect 4A the invention relates to a process for preparing a compound having the structure of formula (IVa) or a salt thereof:

comprising contacting a compound of formula (V) with a compound of formula (VIa) or a salt thereof:

in the presence of KHCO ₃ and (C _1-4 αlkyl) ₄ NBr in solvent 4 selected from DMF, CH ₃ CN, NMP, DMAc, HMPA, DMPU, DME, THF and a mixture of the above solvents;

for a time and at a temperature of from 25 to 35°C sufficient to complete the reaction to obtain a compound of formula (IVa) or a salt thereof.

In aspect 6A, the invention relates to a process for preparing a compound having the structure of formula (IVb):

- 4 045036

_H3CO

N(CH ₃ ) ₂ ( _IVb ). involving contacting a compound of formula (Va):

with a compound of formula (VIa):

in the presence of KHCO ₃ and (Et) ₄ NBr in DMF;

for 4 to 72 hours and at a temperature of 25 to 35° C. sufficient to complete the reaction to give the compound of formula (IVb).

In aspect 7A, the invention relates to a process for preparing a compound of formula (VII) or a stereoisomer or salt thereof:

CO ₂ (C-|^ alkyl)

002(0^4 apkip) (VII), (R ^a )o-1 where Ra represents -N(C _1-4 alkyl) ₂ ;

comprising contacting a compound of formula (VIII) or a salt thereof:

and 4-DMAP, water-based presence

with or without it, in solvent 5, which is a non-polar solvent or a mixture of the above solvents;

for a time and at a temperature sufficient to complete the reaction to obtain a compound of formula (VII) or a stereoisomer or salt thereof.

In aspect 8A within aspect 7A the invention relates to a process for preparing a compound having the structure of formula (VIIa) or a salt thereof:

- 5 045036

CO ₂ (Ci_4 alkyl)

002(0^4 alkyl)

N(Ci-4 alkyl)g (Vila);

comprising contacting a compound of formula (VIII) or a salt thereof;

in the presence

with or without aqueous KOH in solvent 5 selected from toluene, CH ₂ Cl ₂ , trifluorotoluene, 1,2-dichlorobenzene and a mixture of the above solvents;

for a time and at a temperature of from 25 to 35°C sufficient to complete the reaction to obtain a compound of formula (VIIa) or a salt thereof.

In aspect 9A, the invention relates to a process for preparing a compound having the structure of formula (VIIb):

N(CH ₃ ) ₂

CO ₂ CH ₃

CO ₂ CH ₃ (Vllb);

comprising contacting a compound of formula (VIII) or a salt thereof;

in the presence

with or without aqueous KOH in toluene;

for 24 to 48 hours and at a temperature of 25 to 35° C. sufficient to complete the reaction to give the compound of formula (VIIb).

In aspect 10A, the invention relates to a process for preparing a compound of formula (IX) or a stereoisomer or salt thereof:

BUT

CO^C^ alkyl)

CO ₂ (C _1.4 alkyl) (R ^a )o-1 (IX), where R ^a represents -N( _C1.4 alkyl) ₂ ;

comprising contacting a compound of formula (VII) or a salt thereof:

CO ₂ (C-|_4alkyl)

CO ₂ (Ci- ₄ alkyl) (R ^a )oi (VII), where R ^a represents -N(C1. ₄ alkyl) ₂ ;

with a transition metal catalyst in the presence of a diacid in solvent 6, which is a protic or polar aprotic solvent or a mixture of the above solvents;

- 6 045036 for a time and at a temperature sufficient to reduce the ketones to obtain a compound of formula (IX) or a stereoisomer or salt thereof.

In aspect IIA within aspect 10A, the invention relates to a process for preparing a compound of formula (IXa) or a salt thereof:

CO ₂ (Ci- ₄ alkyl)

002(^.4 alkyl)

N(C ₁ _ ₄ alkyl) ₂ (IXa);

comprising contacting a compound of formula (Vila) or a salt thereof:

CO ₂ (C ₁ _ ₄ alkyl) 002 (0-1.4 alkyl)

N(C-|_ ₄ alkyl)g (Vila) with a transition metal catalyst selected from IrCl ₄ , IrCl ₄ hydrate or [Ir(COD)Cl] ₂ in the presence of phosphorous acid in solvent 6 selected from IPA , MeOH, EtOH, tAmOH, H2O, NMP, DMF, DMAc, sulfolane and mixtures of the above solvents;

for a time and at a temperature of 65 to 100° C. sufficient to reduce the ketones to obtain a compound of formula (IXa) or a salt thereof.

In aspect 12A, the invention relates to a process for preparing a compound of formula (IXb):

involving contacting a compound of formula (Viib):

with 1rCl ₄ -hydrate or [Ir(COD)Cl] ₂ in the presence of phosphorous acid in IPA/H2O or a mixture of the above solvents;

for 24 to 96 hours and at a temperature of 80 to 85° C. sufficient to reduce the ketones to give the compound of formula (IXb).

In aspect 13A, the invention relates to a process for preparing a compound of formula (Xa) or a salt thereof:

comprising (1) contacting a compound of formula (IXa) or a salt thereof:

- 7 045036

with reagent 3 selected from NaOH, KOH, LiOH, tetraalkylammonium hydroxide and mixtures thereof, in an aqueous solution of R7-OH, where ^R7 independently represents _C1-6 alkyl; for up to 48 hours at a temperature of 80 to 85° C. sufficient to hydrolyze all three ester moieties to obtain the compound of formula (XI);

HO',CO ₂ M

1xo?m HO (XI) where M represents a metal selected from Li, Na, K, and tetraalkylammonium;

(2) contact with an acid in a protic solvent; and (3) contacting with periodic acid in a protic solvent;

for up to 48 hours at a temperature of 20 to 25°C sufficient for oxidation to obtain a compound of formula (Xa) or a salt thereof.

In aspect 13B, the invention relates to a process for preparing a compound of formula (Xa) or a salt thereof:

But

' ^C °2 ^N (Ha);

comprising (1) contacting a compound of formula (XIX) or a salt thereof:

^C °2 ^H (XIX) with an enreductase biocatalyst in the presence of aqueous phosphate buffer, GDH, NADPH and glucose with or without an organic co-solvent selected from DMSO, IPA, dioxane, acetone and mixtures thereof; for a time and at a temperature sufficient to obtain a compound of formula (XX);

C° ₂ H (XX) followed by (2) adding a ketoreductase biocatalyst with or without an organic solvent selected from DMSO, IPA, dioxane, acetone and mixtures thereof;

for additional time and at a temperature sufficient to obtain the compound of formula (Xa) or a salt thereof.

In another aspect, the invention relates to a process for preparing a compound of formula (Xa) or a salt thereof:

BUT

''CO ₂ H ( _Ha ).

comprising (1) contacting a compound of formula (XIX) or a salt thereof:

CO ₂ H (XIX) with an enreductase biocatalyst selected from ERED-302, ERED-303 and ERED-211, in the presence of aqueous phosphate buffer, GDH, NADPH and glucose with or without an organic co-solvent selected from DMSO, IPA, dioxane, acetone and mixtures thereof; for a period of time at a temperature of from 25 to 35°C sufficient to obtain the compound of formula (XX);

CO ₂ H (xx) followed by (2) adding a ketoreductase biocatalyst with or without an organic solvent selected from DMSO, IPA, dioxane, acetone and mixtures thereof;

for an additional time at a temperature of 25 to 35°C sufficient to obtain the compound of formula (Xa) or a salt thereof.

In another aspect, the invention relates to a process for preparing a compound of formula (Xa) or a salt thereof:

(Ha);

comprising (1) contacting a compound of formula (XIX) or a salt thereof:

with an enreductase biocatalyst selected from ERED-302, ERED-303, and ERED-211, in the presence of aqueous phosphate buffer, GDH, NADPH and glucose with or without an organic co-solvent selected from DMSO, IPA, dioxane, acetone and a mixture thereof;

for at least 14 hours at a temperature of from 25 to 35°C sufficient to obtain the compound of formula (XX);

followed by (2) adding KRED-P2-G03 with or without an organic solvent selected from DMSO, IPA, dioxane, acetone, and mixtures thereof;

for at least 2 additional hours at a temperature of 25 to 35°C sufficient to obtain the compound of formula (Xa) or a salt thereof.

In aspect 13C, the invention relates to a method for preparing a compound of formula (Xa) or a salt thereof: Ηθ^θ·οο ₂ Η _(Xa) .

comprising contacting a compound of formula (XIX) or a salt thereof:

₀ XX _2H ( _X1X ) with a combination of an enreductase biocatalyst with a ketoreductase biocatalyst in the presence of aqueous phosphate buffer, GDH, NADPH and glucose with or without an organic solvent selected from DMSO, IPA, dioxane, acetone and a mixture thereof;

for a time and at a temperature sufficient to obtain the compound of formula (Xa) or a salt thereof.

In another aspect, the invention relates to a process for preparing a compound of formula (Xa) or a salt thereof:

BUT

''CO ₂ H (Ha);

comprising contacting a compound of formula (XIX) or a salt thereof:

С° ₂ Н ( _Х1Х ) with a combination of enreductase biocatalyst selected from ERED-302, ERED-303, and ERED-211; with a ketoreductase biocatalyst in the presence of aqueous phosphate buffer, GDH, NADPH and glucose with or without an organic solvent selected from DMSO, IPA, dioxane, acetone and mixtures thereof;

for a time at a temperature of from 20 to 35°C sufficient to obtain the compound of formula (Xa) or a salt thereof.

In another aspect, the invention relates to a process for preparing a compound of formula (Xa) or a salt thereof:

But

CO ₂ H ( _Xa ) including contacting a compound of formula (XIX) or its salt:

С°2 ^Н (χΐχ)

- 9 045036 with a combination of enreductase biocatalyst selected from ERED-302, ERED-303, and ERED-211; With

KRED-P2-G03 in the presence of aqueous phosphate buffer, GDH, NADPH and glucose with or without an organic solvent selected from DMSO, IPA, dioxane, acetone and mixtures thereof;

for at least 14 hours at a temperature of 20 to 35°C sufficient to obtain the compound of formula (Xa) or a salt thereof.

In aspect 13D, the invention relates to a method for preparing a compound of formula (Xa) or a salt thereof: ΗΟ^θ·''ΟΟ ₂ Η _(Xa); comprising (1) contacting a compound of formula (XXI) or a salt thereof:

(XX) (XXI) with a reagent with a sulfonyl chloride group in an aprotic polar solvent and an inorganic or organic base;

for a time and at a temperature sufficient to cause O-sulfonylation to give a compound of formula (XXII);

(2) either (a) contacting a compound of formula (XXII) with a transition metal catalyst, a phosphine ligand and an organic or inorganic base in the presence of (C _1-4 alkyl)-OH and purging with carbon monoxide; for a period of time at a temperature and pressure sufficient for carbonylation to obtain a compound of formula (XXIII);

_o <X^^ _CO 2 _{Cl 4alkyl} ( _XX q) then followed by contacting a compound of formula (XXIII) with an aqueous base to obtain a compound of formula (XIX) or a salt thereof:

oXXCO ₂ H (XIX) or (b) contacting a compound of formula (XXII) with a transition metal catalyst, a phosphine ligand, in the presence of an inorganic or organic base, in water or another polar aprotic solvent; with carbon monoxide purge;

for a period of time at a temperature and pressure sufficient to carbonylate to obtain a compound of formula (XIX) or a salt thereof;

(3) contacting the compound of formula (XIX) or a salt thereof with an enreductase biocatalyst in the presence of aqueous phosphate buffer, GDH, NADPH and glucose with or without an organic co-solvent selected from DMSO, IPA, dioxane, acetone and a mixture thereof;

for a time and at a temperature sufficient to obtain a compound of formula (XX);

''C°2 ^H ( _XX ) followed by (4) adding a ketoreductase biocatalyst with or without an organic solvent selected from DMSO, IPA, dioxane, acetone and mixtures thereof;

for additional time and at a temperature sufficient to obtain the compound of formula (Xa) or a salt thereof.

In aspect 13E, the invention relates to a method for preparing a compound of formula (Xa) or a salt thereof: hoXXO ₂ n _(Xa) .

comprising (1) contacting a compound of formula (XXI) or its salt: _O XX _O with p-toluenesulfonyl chloride in ethyl acetate and triethylamine;

for at least 12 hours at a temperature of from 0 to 10° C., sufficient for Osulfonylation, to obtain a compound of formula (XXII);

- 10 045036

OTs (χχπ) (2) or (a) contacting a compound of formula (XXII) with palladium (II) acetate, 1,3bis(diphenylphosphino)propane and N,N-diisopropylethylamine in the presence of (C _1-4 alkyl)-OH with the product by carbon monoxide;

for at least 12 hours at a temperature of from 20 to 60°C and a carbon monoxide pressure sufficient for carbonylation to obtain a compound of formula (XXIII);

COgC^d alkyl (χχπη then followed by contacting a compound of formula (XXIII) with an aqueous base to obtain a compound of formula (XIX) or a salt thereof:

or (b) contacting a compound of formula (XXII) with a transition metal catalyst selected from Pd(OAc) ₂ , PdCl ₂ (CH ₃ CN) ₂ , and Pd(DPPP)Cl ₂ , a phosphine ligand selected from 1,3bis (diphenylphosphino)propane, rac-BINAP, Xantphos, Josiphos SL-J001-1, Josiphos SL-J009-1-G3 palladacycle and BIPHEP, and an inorganic or organic base selected from K ₂ CO ₃ , N,Ndiisopropylethylamine, triethylamine, tert -butyltetramethylguanidine, tetramethylguanidine, KHCO3, DBU, Na ₂ CO ₃ , and KOAc, in water and a polar aprotic solvent selected from EtOAc, 2-MeTHF, CH3CN, DMAc, THF, and mixtures thereof; with carbon monoxide purge; for at least 12 hours at a temperature of from 20 to 60°C and a carbon monoxide pressure sufficient for carbonylation to obtain a compound of formula (XIX) or a salt thereof;

(3) contacting a compound of formula (XIX) or a salt thereof with an enreductase biocatalyst selected from ERED-302, ERED-303, and ERED-211, in the presence of aqueous phosphate buffer, GDH, NADPH and glucose with or without an organic co-solvent such as DMSO, IPA, dioxane or acetone;

for a period of time at a temperature of from 20 to 35°C sufficient to obtain the compound of formula (XX);

with ₂ n (χχ) followed by (4) adding a ketoreductase biocatalyst with or without an organic solvent selected from DMSO, IPA, dioxane, acetone and mixtures thereof;

for an additional time at a temperature of 25 to 35°C sufficient to obtain the compound of formula (Xa) or a salt thereof.

In aspect 13F, the invention relates to a method for preparing a compound of formula (Xa) or a salt thereof: ho'G^ -co ₂ h comprising (1) contacting a compound of formula (XXI):

with a reagent with a sulfonyl chloride group in an aprotic polar solvent and an inorganic or organic base;

for a time and at a temperature sufficient to cause O-sulfonylation to give a compound of formula (XXII);

OTs (χχπ) (2) either (a) contacting a compound of formula (XXII) with a catalyst based on a transition metal, a phosphine ligand and an organic amine base in the presence of (C _1-4 alkyl)-OH with a purge of carbon monoxide;

for a period of time at a temperature and pressure sufficient for carbonylation to obtain a compound of formula (XXIII);

- 11 045036 then followed by contacting a compound of formula (XXIII) with an aqueous base to obtain a compound of formula (XIX) or a salt thereof:

O^^CO ₂ H ( _XD q) or (b) contacting a compound of formula (XXII) with a transition metal catalyst, a phosphine ligand in the presence of an inorganic or organic base in water and another polar aprotic solvent with a purge of carbon monoxide;

for a time and at a temperature and pressure of carbon monoxide sufficient to carbonylate to obtain a compound of formula (XIX) or a salt thereof;

(3) contacting the compound of formula (XIX) or a salt thereof with a combination of an enreductase biocatalyst with a ketoreductase biocatalyst in the presence of aqueous phosphate buffer, GDH, NADPH and glucose with or without an organic solvent selected from DMSO, IPA, dioxane, acetone and a mixture thereof;

for a time and at a temperature sufficient to obtain the compound of formula (Xa) or a salt thereof.

In aspect 13G, the invention relates to a method for preparing a compound of formula (Xa) or a salt thereof: Ηθ^θ·%ο ₂ Η _(Xa); comprising (1) contacting a compound of formula (XXI):

₀ ^3Χ ₀ with p-toluenesulfonyl chloride in ethyl acetate and triethylamine;

for at least 12 hours at a temperature of from 0 to 10° C., sufficient for Osulfonylation, to obtain a compound of formula (XXII);

_O <XC^ _OTS ( _ХХП ) (2) or (a) contacting a compound of formula (XXII) with palladium (II) acetate, 1,3bis(diphenylphosphino)propane and N,N-diisopropylethylamine in the presence of (C _1-4 alkyl) -OH with carbon monoxide purge;

for at least 12 hours at a temperature of from 20 to 60°C and a carbon monoxide pressure sufficient for carbonylation to obtain a compound of formula (XXIII);

then followed by contacting a compound of formula (XXIII) with an aqueous base to obtain a compound of formula (XIX) or a salt thereof:

or (b) contacting a compound of formula (XXII) with a transition metal catalyst selected from Pd(OAc) ₂ , PdCl ₂ (CH ₃ CN) ₂ , and Pd(DPPP)Cl ₂ , a phosphine ligand selected from 1,3bis (diphenylphosphino)propane, rac-BINAP, Xantphos, Josiphos SL-J001-1, Josiphos SL-J009-1-G3 palladacyclic, and BIPHEP, and an inorganic or organic base selected from K2CO3, diisopropylethylamine, triethylamine, tert-butyltetramethylguanidine, tetramethylguanidine , KHCO3, DBU, Na ₂ CO ₃ , and COAc, in water and a polar aprotic solvent selected from EtOAc, 2-MeTHF, CH3CN, DMAc, THF, and mixtures thereof; with carbon monoxide purge;

for at least hours and at a temperature of from 20 to 60°C and a carbon monoxide pressure sufficient to carbonylate to obtain a compound of formula (XIX) or a salt thereof;

(3) contacting the compound of formula (XIX) or a salt thereof with a combination of enreductase biocatalyst selected from ERED-302, ERED-303, and ERED-211; with KRED-P2-G03 in the presence of aqueous phosphate buffer, GDH, NADPH and glucose with or without an organic solvent selected from DMSO, IPA, dioxane, acetone and mixtures thereof; for at least 14 hours at a temperature of 20 to 35°C sufficient to obtain the compound of formula (Xa) or a salt thereof.

In aspect 14A, the invention relates to a process for preparing a compound of formula (Xa):

- 12 045036

BUT

''CO ₂ H ( _Ha ).

comprising (1) contacting a compound of formula (IXb) or a salt thereof:

BUT

N(CH ₃ ) ₂

CO ₂ CH ₃

CO ₂ CH ₃ (IXb) with NaOH in an aqueous solution of IPA for at least 12 hours at a temperature of 80 to 85°C sufficient to obtain the compound of formula (XIa);

but' ,CO ₂ N and I^COoNa HO ² (Xia) (2) contact with aqueous HCl; and (3) contacting with periodic acid in an aqueous solution of IPA;

for up to 48 hours at a temperature of 20 to 25°C sufficient for oxidation to give the compound of formula (Xa).

In aspect 15A, the invention relates to a process for preparing a compound of formula (XII) or a stereoisomer or salt thereof:

where: R ⁸ and R ⁹ independently represent N, CH or C(C _1-6 alkyl);

R ¹⁰ independently represents C _1-4 alkyl or halogen; And

R ¹¹ independently represents Br, Cl or I;

comprising contacting a compound of formula (XIII) or a salt thereof:

where: R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are the same as above in formula (XII), and R ^11a represents halogen;

with a compound of formula (X) or a stereoisomer or salt thereof:

in the presence of a metal alkoxide in solvent 7, which is a polar aprotic or non-polar solvent, or a mixture of the above solvents;

for a time and at a temperature sufficient to complete the reaction to obtain a compound of formula (XII) or a stereoisomer or salt thereof.

In aspect 16A within aspect 15A the invention relates to a process for preparing a compound of formula (XIIa) or a salt thereof:

- 13 045036

comprising contacting a compound of formula (XIIIa) or a salt thereof:

with a compound of formula (Xa) or its salt:

in the presence of a metal alkoxide selected from KOtBu, KHMDS, NaHMDS, and potassium amylate; in solvent 7 selected from DMF, MTBE, DMAc, NMP, DMPU, THF, 2-MeTHF, CPME, diisopropyl ether, toluene and a mixture of the above solvents;

for a time and at a temperature of from 20 to 35°C sufficient to complete the reaction to obtain a compound of formula (XIIa) or a salt thereof.

In aspect 17A, the invention relates to a process for preparing a compound of formula (XIIb) or a salt thereof:

comprising contacting a compound of formula (XIIIb) or a salt thereof:

with a compound of formula (Xa) or its salt:

in the presence of KOtBu in a DMF/MTBE mixture;

for 18 to >48 hours and at a temperature of 20 to 35° C. sufficient to displace the fluoride to give a compound of formula (XIIb) or a salt thereof.

In aspect 18A, the invention relates to a process for preparing a compound of formula (XIVc) or a stereoisomer or salt thereof:

R ¹² (XIVc);

where: R ⁸ and R ⁹ independently represent N, CH or C(C1-6 alkyl); R ¹⁰ independently represents C1-4 alkyl or halogen; And

- 14 045036

R ¹² represents C _1-4 alkyl;

comprising (1) contacting a compound of formula (I):

where R ¹ represents C _1-6 alkyl; And

R ² and R ^2a are halogen;

with an organometallic reagent and with or without an inorganic reagent in a solvent 8, which is a polar aprotic or non-polar solvent, or a mixture of the above solvents;

for a period of time and at a temperature sufficient for the halogen-metal exchange reaction;

then (2) contacting a compound of formula (XII) or a stereoisomer or salt thereof:

where: R ⁸ and R ⁹ independently represent N, CH or C(C _1-6 alkyl);

R ¹⁰ independently represents C _1-4 alkyl or halogen; And

R ¹¹ represents Br or Cl;

with the product of the halogen-metal exchange reaction and a palladium catalyst in solvent 8;

for a time and at a temperature sufficient for C-C combination; and (3) contacting with a metal binding agent in solvent 8;

for a time and at a temperature sufficient to stop the reaction to obtain a compound of formula (XIVc) or a stereoisomer or salt thereof.

In aspect 19A within aspect 18A the invention relates to a process for preparing a compound of formula (XIVd) or a salt thereof:

where: R ⁸ and R ⁹ independently represent N, CH or C(C _1-4 alkyl);

R ¹⁰ independently represents C _1-4 alkyl or halogen; And

R ¹² represents C _1-4 alkyl;

comprising (1) contacting a compound of formula (I) with an organometallic reagent which is a Grignard reagent selected from i-PrMgCl, i-PrMgCl-LiCl and i-PrMgBr, or an organolithium reagent selected from methyllithium, n-butyllithium, isopropyllithium, sec-butyllithium, tert-butyllithium, and phenyllithium; with or without an inorganic reagent selected from ZnCl ₂ , ZnBr ₂ , and ZnI ₂ , in a solvent 8 selected from THF, 2-MeTHF, DMF, DMA, DMPU, NMP, 1,4-dioxane, and a mixture of the above solvents;

for a time and at a temperature from -5 to 25°C sufficient for the metal halide exchange reaction and the formation of an organozinc compound;

(2) contacting a compound of formula (XIIa) or a salt thereof:

- 15 045036 with a halogen-metal exchange reaction product, which is an organometallic reagent, and a palladium catalyst selected from PdCl2(Xantphos), Pd(dppf)Cl ₂ or

Pd(OAc)2+Brettphos, BINAP, dppf, DPEPhos and Xantphos in solvent 8; for a period of time and at a temperature from -5 to 40 ° C, sufficient for the C-C combination; and (3) contacting with a metal binding agent selected from trisodium ethylenediaminetetraacetic acid or disodium ethylenediaminetetraacetic acid in solvent 8;

for a time and at a temperature of -5 to 25° C. sufficient to stop the reaction to obtain a compound of formula (XIVd) or a salt thereof.

In another aspect, within the scope of aspect 18A, the invention relates to a method for preparing a compound of formula (XIVd) or a salt thereof, comprising (1) contacting a compound of formula (I) with an organometallic reagent, which is a Grignard reagent selected from i-PrMgCl (2, 15 M in THF), i-PrMgCl-LiCl (1.3 M in THF), and i-PrMgBr (2.9 M in 2-MeTHF), or an organolithium reagent selected from methyllithium, n-butyllithium, isopropyllithium, sec -butyllithium, tert-butyllithium, and phenyllithium; with or without an inorganic reagent selected from ZnCl ₂ , ZnBr ₂ , and ZnI ₂ , in a solvent 8 selected from THF, 2-MeTHF, DMF, DMA, DMPU, NMP, 1,4-dioxane, and a mixture of the above solvents;

for a time and at a temperature from -5 to 25°C sufficient for the metal halide exchange reaction and the formation of an organozinc compound;

(2) contacting a compound of formula (XIIa) or a salt thereof:

'''COgH f^R ⁸ R ⁹ ^;^ ^- ^ ¹⁰ ) ⁰ - ¹ R ¹¹ (XIIa);

with a halogen-metal exchange reaction product, which is an organometallic reagent, and a palladium catalyst selected from PdCl ₂ (Xantphos), Pd(dppf)Cl ₂ or Pd(OAc) 2 + Brettphos, BINAP, dppf, DPEPhos and Xantphos, in solvent 8;

for a period of time and at a temperature from -5 to 40 ° C, sufficient for the C-C combination; and (3) contacting with a metal binding agent selected from trisodium ethylenediaminetetraacetic acid or disodium ethylenediaminetetraacetic acid in solvent 8;

for a time and at a temperature of -5 to 25° C. sufficient to stop the reaction to obtain a compound of formula (XIVd) or a salt thereof.

In aspect 20A, the invention relates to a process for preparing a compound of formula (XIVe) isolated as the free acid or a salt thereof selected from potassium salt, tetramethylammonium salt, tert-butylamine, dicyclohexylamine and tromethamine:

o* ^< '^^' ^, ' ^/ с ₂ n

N^V^OBn

Ν-Ν

SI ₃ (XlVe);

comprising (1) contacting a compound of formula (Ia):

with i-PrMgCl (2.15 M in THF), with or without ZnCl ₂ , in THF;

for a time and at a temperature from -5 to 25°C sufficient for the metal halide exchange reaction and the formation of an organozinc compound (if ZnCl ₂ is present);

(2) contacting a compound of formula (XIIb) or a salt thereof:

- 16 045036

with i-PrMgCl (2.15 M in THF), with or without ZnCl ₂ , organomagnesium (or organozinc) reagent and PdCl2 (Xantphos) in THF;

for >12 hours and at temperatures from -5 to 40°C, sufficient for C-C combination; and (3) sequentially contacting with trisodium ethylenediaminetetraacetic acid or disodium ethylenediaminetetraacetic acid in a solvent mixture of THF, with or without sodium percarbonate and sodium bisulfite (or sodium metabisulfite);

for >1 hour and at a temperature of -5 to 25° C. sufficient to stop the reaction, yielding a compound of formula (XIVe), then isolated as either the free acid or a salt thereof selected from potassium salt, tetramethylammonium salt, tert- butylamine, dicyclohexylamine and tromethamine.

In aspect 20B, the invention relates to a process for preparing a compound of formula (XIVe) isolated as either the free acid or a salt thereof selected from potassium salt, tetramethylammonium salt, tert-butylamine, dicyclohexylamine and tromethamine:

''COGN

CH ₃ (XlVe);

comprising (1) contacting a compound of formula (Ia):

*НВг ^N w /ΌΒη Ν-Ν _χ ^СН з (1а);

with i-PrMgCl (2.15 M in THF) in THF;

for a time and at a temperature from -5 to 25°C sufficient for the halogen-metal exchange reaction;

(2) contacting a compound of formula (XIIb) or a salt thereof:

with i-PrMgCl (2.15 M in THF), ZnCl ₂ , organomagnesium reagent and PdCl ₂ (Xantphos) in THF; for >12 hours and at temperatures from -5 to 40°C, sufficient for C-C combination; and (3) sequentially contacting with trisodium ethylenediaminetetraacetic acid or disodium ethylenediaminetetraacetic acid in a solvent mixture of THF, sodium percarbonate and sodium bisulfite (or sodium metabisulfite);

for >1 hour and at a temperature of -5 to 25° C. sufficient to stop the reaction, yielding a compound of formula (XIVe), then isolated as either the free acid or a salt thereof selected from potassium salt, tetramethylammonium salt, tert- butylamine, dicyclohexylamine and tromethamine.

In another aspect, the invention relates to a process for preparing a compound of formula (XIVe) isolated as either the free acid or a salt thereof selected from potassium salt, tetramethylammonium salt, tert-butylamine, dicyclohexylamine and tromethamine:

- 17 045036

CH ₃ '''CO ₂ H (XIYe);

comprising (1) contacting a compound of formula (Ia):

*НВг ^N o /О В η Ν-Ν _χ ^СН з (la);

with i-PrMgCl (2.15 M in THF) and ZnCl ₂ in THF;

for a time and at a temperature from -5 to 25°C sufficient for the metal halide exchange reaction and the formation of an organozinc compound;

(2) contacting a compound of formula (XIIb) or a salt thereof:

H ₃ C

''CO ₂ H

Br (ХПЪ);

with i-PrMgCl (2.15 M in THF), organozinc reagent and PdCl ₂ (Xantphos) in THF;

for >12 hours and at temperatures from -5 to 40°C, sufficient for C-C combination; and (3) contacting with trisodium ethylenediaminetetraacetic acid in a THF solvent mixture;

for 1 hour and at a temperature of -5 to 25°C sufficient to stop the reaction to obtain the compound of formula (XIVe), then isolated as either the free acid or a salt thereof selected from potassium salt, tetramethylammonium salt, tert-butylamine , dicyclohexylamine and tromethamine.

In aspect 21A, the invention relates to a process for preparing a compound of formula (XV) or a stereoisomer or salt thereof:

where: R ⁸ and R ⁹ independently represent N, CH or C(C ₁ . ₆ alkyl);

R ¹⁰ independently represents C _1-4 alkyl or halogen; And

R ¹² represents C _1-4 alkyl;

comprising contacting a compound of formula (XIVc) or a stereoisomer or salt thereof:

with a transition metal catalyst and with or without an inorganic or organic acid in the solvent 9, which is a polar protic or polar aprotic solvent or a mixture of the above solvents;

for a time and at a temperature sufficient to cause hydrogenolysis to yield a compound of formula (XV) or a stereoisomer or salt thereof.

In aspect 22A within aspect 21A the invention relates to a process for preparing a compound of formula (XVa) or a salt thereof:

R ¹² (XVa);

where: R ⁸ and R ⁹ independently represent N, CH or C(C ₁ - ₄ alkyl);

R ¹⁰ independently represents C _1-4 alkyl or halogen; And

R ¹² represents C _1-4 alkyl;

comprising contacting a compound of formula (XIVd) or a salt thereof:

R ¹² (XIVd);

with a transition metal catalyst selected from 5-20 wt.% Pd/C, with or without an inorganic or organic acid selected from citric acid, oxalic acid, H2SO4, in a solvent 9 selected from EtOH, MeOH, water, THF , DMAc, NMP, IPA, t-AmOH, MeTHF, DMF, CH3CN, EtOAc, IPOAc and mixtures of the above solvents; for a time and at a temperature of from 20 to 60° C. sufficient for hydrogenolysis to obtain a compound of formula (XVa) or a salt thereof.

In another aspect, within aspect 21A, the invention relates to a process for preparing a compound of formula (XVa) or a salt thereof:

where: R ⁸ and R ⁹ independently represent N, CH or C(C _1-4 alkyl);

R ¹⁰ independently represents C _1-4 alkyl or halogen; And

R ¹² represents C _1-4 alkyl;

comprising contacting a compound of formula (XIVd) or a salt thereof:

with a transition metal catalyst selected from 5-20 wt.% Pd/C, with or without an inorganic or organic acid selected from citric acid, oxalic acid, H ₂ SO ₄ , in

- 19 045036 solvent 9 selected from EtOH, MeOH, THF, DMAc, NMP, IP A, t-AmOH, MeTHF, MeTHF, DMF,

CH3CN, EtOAc, IPOAc and mixtures of the above solvents;

for a time and at a temperature of from 20 to 60° C. sufficient for hydrogenolysis to obtain a compound of formula (XVa) or a salt thereof.

In aspect 23A the invention relates to a process for preparing a compound of formula (XVb):

(XVb);

comprising contacting a compound of formula (XI Ve) or a salt thereof:

^sn z (XlVe);

with 10 wt.% Pd/C and with or without citric acid in a solvent 9 selected from EtOH, MeOH, water, THF, DMAc, NMP and a mixture of the above solvents;

for >12 hours and at a temperature of 20 to 60° C. sufficient for hydrogenolysis to give the compound of formula (XVb).

In another aspect, the invention relates to a process for preparing a compound of formula (XVb):

^sn z (XVb);

involving contacting a compound of formula (XIVI):

^sn z (XlVf);

with 10 wt.% Pd/C and citric acid in solvent 9 selected from EtOH, MeOH, THF, DMAc, NMP and a mixture of the above solvents;

for >12 hours and at a temperature of 20 to 60° C. sufficient for hydrogenolysis to give the compound of formula (XVb).

In aspect 24A, the invention relates to a process for preparing a compound of formula (XVI) or a stereoisomer or salt thereof:

-20045036

where: R ⁸ and R ⁹ independently represent N, CH or C(C _1-6 alkyl);

R ¹⁰ independently represents C _1-4 alkyl or halogen;

R ¹² represents C _1-4 alkyl; And

R ¹⁴ and R ^14a independently represent C _1-6 alkyl;

comprising contacting a compound of formula (XV) or a stereoisomer or salt thereof:

with a compound of formula (XVII) or a salt thereof:

ABOUT

R ^14a I

R ¹⁴ (χνιΐ) where R ¹⁴ and R ^14a independently represent C _1-6 alkyl;

in the presence of a metal alkoxide in solvent 9, which is a polar protic or polar aprotic solvent or a mixture of the above solvents;

for a time and at a temperature sufficient to form the carbamate to obtain a compound of formula (XVI) or a stereoisomer or salt thereof.

In aspect 25A within aspect 24A the invention relates to a process for preparing a compound of formula (XVIa) or a salt thereof:

where: R ⁸ and R ⁹ independently represent N, CH or C(C _1-4 alkyl);

R ¹⁰ independently represents C _1-4 alkyl or halogen;

R ¹² represents C _1-4 alkyl; And

R ¹⁴ and R ^14a independently represent C _1-4 alkyl;

comprising contacting a compound of formula (XVa) or a salt thereof:

- 21 045036 with a compound of formula (XVII) or its salt:

ABOUT

(XVII) in the presence of a metal alkoxide selected from KOtBu (20 wt.% in THF) or KOtBu (1 M in THF), in solvent 9 selected from t-AmOH, DMF, THF, CH ₃ CN, MEK, NMP, DMAc, acetone, MIBK, 2MeTHF and mixtures of the above solvents;

for a time and at a temperature of from 20 to 75° C. sufficient to form the carbamate to obtain a compound of formula (XVIa) or a salt thereof.

In aspect 26A the invention relates to a process for preparing a compound of formula (XVIb) or a salt thereof:

Νγί

T O ^Ν Τ'— ^h pA

NN N^\^CH ₃

СНз Н ₃ С (XVIb);

comprising contacting a compound of formula (XVb) or a salt thereof:

o* ^< '^^' ^, ' ^/ co ₂ n n ₃ s_A

A nA^oh

N-N

SI ₃ (XVb);

with a compound of formula (XVIIa) or a salt thereof:

ABOUT /

^H 3C (XVIIa) in the presence of KOtBu (20 wt.% in THF) in solvent 9 selected from t-AmOH, DMF, THF, CH3CN, MEK and a mixture of the above solvents;

for a time and at a temperature of 20 to 75° C. sufficient to form the carbamate to obtain a compound of formula (XVIb) or a salt thereof.

In aspect 26B, the invention relates to a method for preparing a compound of formula (XVIb) or a salt thereof: O*^^'' ^/ CO ₂ H

H ₃ C^A

THAT

N

NN N-^CH ₃

CH ₃ ^{n s} (XVIb);

comprising contacting a compound of formula (XVb) or a salt thereof:

- 22 045036 with a compound of formula (XVIIa):

' oxalic acid (XVIIa) in the presence of KOtBu (20 wt.% in THF) in solvent 9 selected from t-AmOH, DMF, THF, CH ₃ CN, MEK and a mixture of the above solvents;

for a time and at a temperature of from 20 to 75° C. sufficient to form the carbamate to obtain a compound of formula (XVIb) or a salt thereof.

In aspect 27A the invention relates to a compound of formula (Ib) or a salt thereof:

where R ¹ represents C _1-6 alkyl; and R ² is halogen.

In aspect 28A the invention relates to a compound of formula (Ic) or a salt thereof:

In aspect 29A the invention relates to a compound of formula (IV) or a salt thereof:

Oh Oh

C-1.4 alkyl Ό

OC-1.4 alkyl (R ^a )oi (IV), where R ^a represents -N(C _1-4 alkyl) ₂ .

In aspect 30A the invention relates to a compound of formula (IVa) or a salt thereof:

alkyl

alkyl) ₂ ( _IVa )

In aspect 31A the invention relates to a compound of formula (IVb) or a salt thereof:

- 23 045036

n ₃ co

N(CH ₃ ) ₂ (IVb).

In aspect 32A the invention relates to a compound of formula (VII) or a stereoisomer or salt thereof:

002(0^4 alkyl

002(0^4 alkyl (R ^a )oi where Ra represents -N(C1. ₄ alkyl) ₂ .

(VII), aspect

33A the invention relates to a compound of formula (Vila) or a salt thereof:

aspect aspect

•002(0-1-4 alkyl ^002(0-,.4 alkyl

N(Ci_4 alkyl)g (Vila).

34A the invention relates to a compound of formula (Viib) or a salt thereof:

35A the invention relates to a compound of formula (IX) or a stereoisomer or salt thereof:

where Ra represents -N( _C1.4alkyl ) ₂ .

In aspect 36A the invention relates to a compound of formula (IXa) or a salt thereof:

BUT

CO ₂ (Ci-4 alkyl

ΟΟ ₂ (Ο,-4 alkyl

14(0.4 alkyl)g (IXa).

- 24 045036

In aspect 37A the invention relates to a compound of formula (IXb):

In aspect 38A the invention relates to a compound of formula (XII) or a stereoisomer or salt thereof:

where: R ⁸ and R ⁹ independently represent N, CH or C(C _1-6 alkyl);

R ¹⁰ independently represents C _1-4 alkyl or halogen; And

R ¹¹ is independently Br, Cl or I.

In aspect 39A within aspect 38A the invention relates to a compound of formula (XIIa) or a salt thereof:

where: R ⁸ and R ⁹ independently represent N, CH or C(C _1-4 alkyl);

R ¹⁰ independently represents C _1-4 alkyl or halogen; And

R ¹¹ is independently Br, Cl or I.

In aspect 40A the invention relates to a compound of formula (XIIb) or a salt thereof:

''COGN

Br (ХПь).

In aspect 41A the invention relates to a compound of formula (XIV) or a stereoisomer or salt thereof:

where: R ⁸ and R ⁹ independently represent N, CH or C(C _1-6 alkyl);

R ¹⁰ independently represents C _1-4 alkyl or halogen;

R ¹² represents C _1-4 alkyl; And

R ¹³ independently represents H, C _1-4 alkyl or benzyl.

In aspect 42A within aspect 41A the invention relates to a compound of formula (XIVa) or a salt thereof:

- 25 045036

where: R ⁸ and R ⁹ independently represent N, CH or C(C _1-4 alkyl);

R ¹⁰ independently represents C _1-4 alkyl or halogen;

R ¹² represents C _1-4 alkyl; And

R ¹³ independently represents H, C _1-4 alkyl or benzyl.

In aspect 43A the invention relates to a compound of formula (XIVb) or a salt thereof:

H ₃ C

'CO ₂ H,R ¹³

N-N

CH ₃ (XIVb);

where: R ¹³ independently represents H or benzyl.

In aspect 44A the invention relates to a compound of formula (XVIIa):

O\=/

H ₃ s * oxalic acid (XVIIa)

In aspect 45A, the invention relates to a process for preparing a compound of formula (XVII) or a salt thereof:

where R ¹⁴ and R ^14a independently represent C _1-6 alkyl; involving contacting a compound of formula (XVIII):

o _ν ^ν ^Λ ν^ _ν

1-=/ (XVIII);

with NHR ¹⁴ R ^14a in the presence of solvent 10, which is a polar protic, aprotic or non-polar solvent or a mixture of the above solvents;

for a time and at a temperature of -5 to 25° C. sufficient to form the carboxamide to obtain the compound of formula (XVII).

In aspect 46A, the invention relates to a process for preparing a compound of formula (XVIIa):

O \ / ^N N^\^CH ₃ n ₃ s *oxalic acid (XVIIa)' involving contacting the compound of formula (XVIII): o _ν ^ν ^Λ ν^ _ν

1-=/ (XVIII);

with N-methylpropylamine in the presence of a solvent 10 selected from DCM, t-AmOH, water, MTBE, acetonitrile, THF, MeTHF, acetone, MEK, MIBK, MeOAc, EtOAc, IPAc, DMF, NMP, DMAc and a mixture of the above solvents;

for at least 1 hour and at a temperature of -5 to 25°C sufficient to form the carboxamide;

- 26 045036 followed by the addition of (HO2C)2 to obtain a compound of formula (XVIIa).

In aspect 47A, the invention relates to a process for preparing a compound of formula (XVIIa);

comprising contacting a compound of formula (XVIII);

with N-methylpropylamine in the presence of solvent 10 selected from DCM, t-AmOH, water,

MTBE, acetonitrile and a mixture of the above solvents;

for at least 1 hour and at a temperature of -5 to 25°C sufficient to form the carboxamide;

followed by the addition of (HO ₂ C) ₂ to obtain the compound of formula (XVIIa).

In aspect 48A, the invention relates to a method for preparing a compound of formula (XVI) or a stereoisomer or salt thereof, comprising the step of aspect 21A;

then the aspect step 24A;

wherein all formulas and variables are as defined in aspects 21A and 24A.

In aspect 49A, the invention relates to a method for preparing a compound of formula (XVIa) or a stereoisomer or salt thereof, comprising the step of aspect 22A;

then aspect stage 25 A;

wherein all formulas and variables are as defined in aspects 22A and 25A.

In aspect 50A, the invention relates to a method for preparing a compound of formula (XVIb) or a stereoisomer or salt thereof, comprising the step of aspect 23A;

then the aspect step 26A;

wherein all formulas and variables are as defined in aspects 23A and 26A.

In aspect 51A, the invention relates to a process for preparing a compound of formula (XVI) or a stereoisomer or salt thereof, comprising steps (1), (2) and (3) of aspects 18A;

aspect stage 21A;

then the aspect step 24A;

wherein all formulas and variables are as defined in aspects 18A, 21A and 24A.

In aspect 52A, the invention relates to a process for preparing a compound of formula (XVIa) or a stereoisomer or salt thereof, comprising steps (1), (2) and (3) of aspects 19A;

aspect stage 22A;

then aspect stage 25 A;

where all formulas and variables are as defined in aspects 19A, 22A and 25A

In aspect 53A, the invention relates to a process for preparing a compound of formula (XVIb) or a stereoisomer or salt thereof, comprising steps (1), (2) and (3) of aspects 20A;

aspect stage 23 A;

then the aspect step 26A;

wherein all formulas and variables are as defined in aspects 20A, 23A and 26A.

In aspect 54A, the invention relates to a method for preparing a compound of formula (XVI) or a stereoisomer or salt thereof, comprising the step of aspect 15A;

steps (1), (2) and (3) of aspects 18A;

aspect stage 21A;

then the aspect step 24A;

wherein all formulas and variables are as defined in aspects 15A, 18A, 21A and 24A.

In aspect 55A, the invention relates to a method for preparing a compound of formula (XVIa) or a stereoisomer or salt thereof, comprising the step of aspect 16A;

steps (1), (2) and (3) of aspects 19A;

aspect stage 22A;

then the aspect stage 25A;

wherein all formulas and variables are as defined in aspects 16A, 19A, 22A and 25A.

In aspect 56A, the invention relates to a method for preparing a compound of formula (XVIb) or a stereoisomer or salt thereof, comprising the step of aspect 17A;

steps (1), (2) and (3) of aspects 20A;

aspect stage 23A;

then the stage of aspect 26A or 26B;

wherein all formulas and variables are as defined in aspects 17A, 20A, 23A and 26A or 26B.

In another aspect, the invention relates to a method for preparing a compound of formula (XVIb) or a stereoisomer or salt thereof, comprising the step of aspect 17A;

steps (1), (2) and (3) of aspects 20A;

aspect stage 23 A;

then the aspect step 26A;

wherein all formulas and variables are as defined in aspects 17A, 20A, 23A and 26A.

In another aspect, the invention relates to a method for preparing a compound of formula (XVIb) or a stereoisomer or salt thereof, comprising the step of aspect 17A;

- 27 045036 stages (1), (2) and (3) aspects of 20A;

aspect stage 23A;

then the aspect stage 26B;

wherein all formulas and variables are as defined in aspects 17A, 20A, 23A and 26B.

Definitions.

The presence of reaction impurities and/or process impurities can be determined using analytical techniques known in the art, such as, for example, chromatography, nuclear magnetic resonance spectroscopy, mass spectrometry and/or infrared spectroscopy.

Other embodiments include those described in the detailed description and/or claims.

To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. In general, the nomenclature used here and the organic chemistry, medicinal chemistry and pharmacology laboratory techniques described herein are well known and commonly used in the art. Unless otherwise specified, all technical and scientific terms used herein generally have the same meaning as commonly understood by one skilled in the art to which this disclosure pertains.

The term acceptable in relation to a formulation, composition or ingredient as used herein means no persistent adverse effect on the general health of the subject being treated.

API refers to an active pharmaceutical ingredient.

The term halogen refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

The term alkyl refers to a hydrocarbon chain, which may be straight or branched, containing a specified number of carbon atoms.

For example, C1_ ₁₀ indicates that the group can contain from 1 to 10 (inclusive) carbon atoms. Non-limiting examples include methyl, ethyl, isopropyl, t-butyl, n-hexyl.

The term haloalkyl refers to an alkyl in which one or more hydrogen atoms are/are replaced by an independently selected halogen.

The term alkoxy refers to the -O-alkyl radical (eg -OCH3).

The term haloalkoxy refers to the -O-haloalkyl radical (eg -OCF3).

The term alkylene refers to a branched or straight-chain divalent alkyl (for example, -CH2-).

The term aryl refers to a 6-carbon monocyclic, 10-carbon bicyclic or 14-carbon tricyclic aromatic ring system, where 0, 1, 2, 3 or 4 atoms of each ring may be substituted by a substituent, and where the ring containing the monocyclic radical is aromatic and where at least one of the fused rings containing a bicyclic or tricyclic radical is aromatic, for example tetrahydronaphthyl. Examples of aryl groups also include phenyl, naphthyl and the like.

As used herein, the term cycloalkyl includes saturated cyclic hydrocarbon groups containing from 3 to 10 carbon atoms, preferably from 3 to 8 carbon atoms, and more preferably from 3 to 6 carbon atoms, where the cycloalkyl group may be optionally substituted. Preferred cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl and cyclooctyl. As used herein, the term cycloalkylene refers to divalent cycloalkyl.

The term heteroaryl refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic or 11-14 membered tricyclic ring system containing 1-3 heteroatoms in the case of monocyclic, 1-6 heteroatoms in the case of bicyclic or 1-9 heteroatoms, in the case of a tricyclic system, wherein said heteroatoms are selected from O, N or S (for example, carbon atoms and 1-3, 1-6 or 1-9 N, O or S heteroatoms in the case of a monocyclic, bicyclic or tricyclic system, respectively), where 0, 1, 2, 3 or 4 atoms of each ring may be replaced by a substituent, and where the ring containing a monocyclic radical is aromatic, and where at least one of the fused rings containing a bicyclic or tricyclic radical, is aromatic (but does not necessarily have a ring that contains a heteroatom, such as tetrahydroisoquinolinyl.

Examples of heteroaryl groups also include pyridyl, furyl or furanyl, imidazolyl, benzimidazolyl, pyrimidinyl, thiophenyl or thienyl, quinolinyl, indolyl, thiazolyl and the like.

The term heterocyclyl refers to a non-aromatic 5-8 membered monocyclic, 8-12 membered bicyclic or 11-14 membered tricyclic ring system containing 1-3 heteroatoms in the case of monocyclic, 1-6 heteroatoms in the case of bicyclic or 1-9 heteroatoms in the case of in the case of a tricyclic system, wherein said heteroatoms are selected from O, N or S (for example, carbon atoms and 1-3, 1-6 or 1-9 N, O or S heteroatoms in the case of a monocyclic, bicyclic or tricyclic system, respectively), where 0, 1, 2 or 3 atoms of each ring may be replaced by a substituent. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpho-linyl, tetrahydrofuranyl and the like.

The term heterocycloalkylene refers to divalent heterocyclyl.

The term Brønsted acid refers to a proton donor (H ⁺ ).

The term Lewis acid refers to a chemical compound that can accept an electron pair from an electron donor compound.

The term Brønsted base refers to a proton acceptor (H ⁺ ).

The term Lewis base refers to a chemical compound that can donate an electron pair to an electron acceptor compound.

The term transition metal catalyst refers to a coordination complex that contains any of various metal elements, such as palladium and nickel, that have valence electrons in two shells instead of one, and when added to a chemical reaction increases the rate of the reaction.

A protic solvent refers to a solvent that contains a hydrogen atom bonded to an oxygen (as in a hydroxyl group) or nitrogen (as in an amine group).

An aprotic solvent refers to a solvent that is not a hydrogen bond donor.

A polar solvent refers to a solvent with large dipole moments or partial charges; they contain bonds between atoms with very different electronegativity, such as oxygen and hydrogen.

A solvent mixture refers to a combination of two or more solvents.

In addition, the atoms constituting the compounds of the present embodiments are intended to include all isotopic forms of such atoms. As used herein, isotopes include atoms having the same atomic number but different mass numbers. By general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include ¹³ C and ¹⁴ C.

Examples

The following Examples are presented to provide those skilled in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors believe to be their invention, nor are they intended to demonstrate that the experiments listed below have been performed, or that they are all experiments that can be performed. It should be understood that the exemplary descriptions written in the present tense were not necessarily executed, but rather, the descriptions may be executed to obtain the data and the like described therein. Efforts have been made to ensure the accuracy of the numbers used (e.g. quantity, temperature, etc.), but some experimental errors and deviations should be taken into account.

The starting materials used in the synthesis sequence of the invention are known, prepared by known methods or commercially available. One skilled in the art will also appreciate that the conditions and reagents described herein may be interchanged with alternative art-recognized equivalents. For example, in some reactions, hydrochloric acid may be replaced by other acids such as hydrobromic acid, sulfuric acid, etc.

The skilled artisan will appreciate the variety of analytical techniques that may be used to characterize the compounds described herein, including, for example, 1H nuclear magnetic resonance (NMR) spectroscopy, heteronuclear NMR, mass spectrometry (MS), liquid chromatography (LC), and infrared spectroscopy ( IR). The above list represents a subset of characterization techniques available to the qualified individual and is not intended to be limiting.

To further illustrate the foregoing, the following non-limiting example synthesis schemes are included. Variations of these examples within the scope of the claims are within the scope of one skilled in the art and are considered to fall within the scope of the invention as described and claimed herein. The reader will appreciate that one skilled in the art and skilled in the art can prepare and practice the invention without detailed examples.

The following abbreviations have the meanings indicated:

AcOH=acetic acid, t-AmOH=tert-amyl alcohol, aq=aqueous,

BINAP=(2,2'-bis(diphenylphosphino)-1,1'-binaphthyl),

BOMCl=benzyl chloromethyl ether,

Brettphos=2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl, n-BuBr=butyl bromide, n-BuLi=butyllithium,

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CDCl ₃ =deuterated chloroform,

CH ₃ CN=acetonitrile,

CH ₃ 1=methyl iodide,

CDI=carbonyldiimidazole,

CO2=carbon dioxide,

CPME=cyclopentyl methyl ether, d=doublet,

DCM=dichloromethane,

DMAc=dimethylacetamide, 4-DMAP=4-dimethylaminopyridine, DME=1,2-dimethoxyethane, DMF=dimethylformamide,

DMPU=N,N'-dimethylpropylene urea, DMSO=dimethyl sulfoxide,

DMSO-d ₆ =deuterated dimethyl sulfoxide, DPEPhos=bis[(2-diphenylphosphino)phenyl]ether, Dppf=1,1'-ferrocenediyl-bis(diphenylphosphine), DPPP=1,3-bis(diphenylphosphino)propane, equiv=equivalent (s),

ERED=ene reductase

ESI=electrospray ionization,

Et ₃ N=trimethylamine, (Et) ₄ NBr or Et ₄ NBr=tetraethylammonium bromide,

EtOAc=ethyl acetate,

EtOH=ethanol, g=gram(s), GDH=glucose dehydrogenase,

b=hour(s),

H2=hydrogen,

HC1=hydrogen chloride (usually in solution),

HBr = 6hydrogen oxide (usually in the form of a solution), n-HexLi = hexyllithium, _H13 = iodic acid, _H14 = periodic acid, HMPA = hexamethylphosphoramide,

H2O=water,

H ₃ PO ₄ = phosphoric acid,

H ₂ SO ₄ = sulfuric acid,

12=IOD,

1PA=isopropyl alcohol,

IPAc=isopropyl acetate,

IrCl ₄ = iridium tetrachloride,

IrCl ₄ hydrate=iridium tetrachloride hydrate, [Ir(COD)Cl] ₂ =bis(1,5-cyclooctadiene)diiridium(I) dichloride, iPrMgCl=isopropylmagnesium chloride, iPrMgCPLiCl=isopropylmagnesium chloride-lithium chloride complex, iPrMgBr=isopropylmagnesium bromide,

KC1=potassium chloride,

K ₂ CO ₃ = potassium carbonate,

KHCO ₃ = potassium bicarbonate,

KHMDS=potassium bis(trimethylsilyl)amide,

KOtBu=potassium tert-butoxide,

KOH=potassium hydroxide, kg=kilogram(s), KRED=ketoreductase, L=liter(s),

LCAP=liquid chromatography peak area, LC/MS=liquid chromatography/mass spectrometry,

LiCl=lithium chloride,

LiOtBu=lithium tert-butoxide,

LiOH=lithium hydroxide,

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LiOHH ₂ O=lithium hydroxide hydrate, LiOMe=MemoKCug lithium, LRMS=low resolution mass spectrometry, m=multiplet, M=molarity, md=milligram(s), MEK=methyl ethyl ketone, MeOH or CH ₃ OH=methanol, MeTHF= 2-methyltetrahydrofuran, 2-MeTHF or CH ₃ THF=2-methyltetrahydrofuran, MgCl ₂ =magnesium chloride, MgClBr=magnesium chloride bromide, MHz=megahertz, MIB K=m ethyl isobutyl ketone, min=minute(s), mL=milliliter (s), mmol = millimole(s), MTBE = methyl tert-butyl ether, NaCl = sodium chloride, Na ₂ CO ₃ = sodium carbonate, NADPH = reduced nicotinamide adenine dinucleotide phosphate, Na ₃ EDTAxH ₂ O = trisodium ethylenediaminetetraacetic acid hydrate, Na ₂ EDTA2H ₂ O=ethylenediaminetetraacetic acid disodium dihydrate, NaHMDS=sodium bis(trimethylsilyl)amide, NaOtBu=sodium tert-butoxide, NaOH=sodium hydroxide, NaOMe=sodium methoxide, NH ₂ C(CH ₃ ) ₃ =tert-butylamine ,

NH4OH or NH ₃ H ₂ O=ammonium hydroxide, NH ₄ OAC=ammonium acetate

NMP=N-methyl-2-pyrrolidone,

Pd/C=palladium on carbon support,

PdCl ₂ (Xantphos)=dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)-xanthene]palladium(I), Pd(dppf)Cl ₂ =[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (P),

Pd(OAc) ₂ = palladium(P) acetate, PhLi = phenyllithium,

P(OH) ₃ =phosphorous acid, ppm=parts per million, PTFE=polytetrafluoroethylene, RT=retention time, s=singlet, t=triplet, t-BuOH=tert-butanol, THF=tetrahydrofuran, TFA=trifluoroacetic acid, ° C=degrees Celsius,

UPLC/MS=ultra-high performance liquid chromatography-mass spectrometry, vol=volumes, wt=mass,

Xantphos=[5-(diphenylphosphino)-9,9-dimethyl-9H-xanthen-4-yl](diphenyl)-phosphine, ZnBr ₂ =zinc bromide, ZnClBr=zinc chloride-bromide, ZnCl ₂ =zinc chloride, ZnI ₂ =zinc iodide.

A number of embodiments of the invention have been described. However, it should be appreciated that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.

Experimental methods.

Example 1: Preparation of 4,5-dibromo-1-methyl-1H-1,2,3-triazole.

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Br

m ^{Br N} N N l/kg t-AmOH

1.1 eq. THF °C

Br

1.1 eq. LiOtBu

1.5 eq. Mel IPA/water for highlighting

m ^{Br N} 'N

CH ₃

A 10 L reactor was charged with t-AmOH (2.0 L, 4.0 ml/g) under a protective nitrogen atmosphere and the temperature was adjusted to 20°C. The reaction mixture was sequentially charged with 4,5-dibromo-1H-1,2,3-triazole (500 g, 1.0 eq., limiting reagent) and THF (175 g, 1.1 eq.) followed by LiOtBu (195 g, 1.1 eq.) in portions into the reactor, maintaining the internal temperature <40°C. The reaction mixture was heated to 40°C and stirred for 1 hour; and then CH3I (470 g, 1.5 eq.) was charged and continued at 40°C for 24 hours. The reaction mixture was heated to 50°C and concentrated to 3.0 ml/g under vacuum (80 torr) at maintaining internal temperature <60°C; and then IPA (1.0 L, 2.0 ml/g) and water (4.0 L, 8.0 ml/g) were loaded. The reaction mixture was heated to 60°C and kept for 2 hours. The resulting homogeneous solution was then cooled to 0°C over 5 hours and kept overnight. The resulting suspension was filtered, washed successively with a mixture of 1PA:H ₂ O (35:65), pre-cooled to 0-5°C (1.0 l, 2 ml/g), followed by water (1.5 l, 3 ml/g) at ambient temperature and dried under vacuum at 50°C to obtain 430 g (82-81% yield) 4,5-dibromo-1-methyl-1H-1,2,3-triazole as a white solid substances. 1H NMR (400 MHz, CDCl ₃ ) δ 4.10 (s, 3H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 122.70, 112.98, 36.89. LC-MS (ESI), calculated for [C ₃ H ₃ Br ₂ N ₃ +H] ⁺ =239.88, found 239.88. UHPLC method conditions: column: Phenomenex Kinetex C8, 1.7 µm, 2.1x50 mm; mobile phase A: 0.05% TFA in acetonitrile:water (5:95); mobile phase B: 0.05% TFA in acetonitrile:water (95:5); temperature: 40°C; gradient: 0 min (0% B), 2.0 min (100% B), 2.5 min (100% B); flow rate: 1.0 ml/min; 220 nm; UHPLC RT 1.02 min.

Example 2: Preparation of 5-((benzyloxy)methyl)-4-bromo-1-methyl-7H-1,2,3-triazole bromide salt.

Br l-BuLi (1.1 eq.)

THF (4 vol.), -25 oC

Br

BOMCI (1.15 eq.)

Br

'3 + 0.1 l-BuLi + 1.0 eq. n-BuBr + 1.0 eq. ' LiCI + 0.1 eq. BOMCI HBr/AcOH (0.1 eq.) solvent change to CH ₃ CN solids washing IPAc

HBr/AcOH (1.05 eq.)

Br

CH ₃ (solid

LiCI substances) + 0.05 equiv. HBr

A 10 L reactor under a protective nitrogen atmosphere was charged with THF (4.0 L, 4.0 ml/g) and 4,5-dibromo-1methyl-7H-1,2,3-triazole (1.00 kg, 1. 0 equivalent, limiting reagent) at 20°C. The solution was cooled to 25°C and n-BuLi (2.5 M in n-hexane solution, 1.26 kg, 1.1 eq.) was added dropwise while maintaining the internal temperature <-20°C. After an additional 20 min, BOMCI (0.75 kg, 1.15 eq) was loaded into the thick suspension, maintaining the internal temperature <-20°C. After 2 hours, the reaction mixture was charged with 33% HBr in AcOH solution (0.10 kg, 0.10 eq.) and stirred for 30 minutes at -20°C. The reaction mixture was then heated to 15°C and concentrated to 2.0-2.5 ml/g under vacuum (50 Torr), maintaining the internal temperature <40°C; and then CH=CN (5.0 L, 5 ml/g) was charged into the concentrated solution and the sample was continued to distill to 2.0-2.5 ml/g, maintaining the internal temperature <40°C. CH3CN (3.0 L, 3.0 ml/g) was charged into the reaction mixture, the suspension was heated to 20°C and kept for 1 hour. The reaction suspension was filtered and solid contaminants were washed with IPAc (2x2.0 L, 2x2.0 ml/g). The combined filtrate was then heated to 20°C and charged with 33% HBr in AcOH solution (1.07 kg, 1.05 eq.) dropwise over at least 1 hour. After an additional 1 hour, the resulting suspension was filtered, washed successively with a mixture of IPAc:CH ₃ CN (1:1) (3.0 L, 3 ml/g) followed by IPAc (3.0 L, 3 ml/g) and dried under vacuum at 40°C to obtain 1, 27 g (83% yield) 5-((benzyloxy)methyl)-4-bromo-1-methyl-7H-1,2,3-triazole bromide salt as a white solid.

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1H NMR: (500 MHz, DMSO- _d6 ) δ 7.29-7.37 (m, 5H), 6.35 (br s, 1H), 4.61 (s, 2H), 4.51 (s , 2H), 4.04 (s,

3H). ¹³ C NMR: (100 MHz, DMSO-de) δ 137.48, 132.61, 128.42, 127.86 (2 C's), 121.01, 71.86, 58.62, 36.02.

LC-MS (ESI) calculated for [C _p H12BrK3O+H] ⁺ =282.02, found 282.02.

UHPLC method conditions: column: Phenomenex Kinetex C8, 1.7 µm, 2.1x20 mm; mobile phase A: 0.05% TFA in acetonitrile:water (5:95); mobile phase B: 0.05% TFA in acetonitrile:water (95:5); temperature: 40°C; gradient: 0 min (0% B), 2.0 min (100% B), 2.5 min (100% B); flow rate: 1.0 ml/min; 220 nm; UHPLC RT 1.32 min.

Example 3: Preparation of dimethyl 2-((4-(dimethylamino)benzoyl)oxy)malonate.

Oh Oh

HO^O OMG(6l/kg) H ₃ CO^\^OSH ₃ 1.2 eq. KNSO ₃ ^ό I ³ o

0.10 eq. Et ₄ NBr base ₃ ⁺ G N water (9 l/kg) G I I for isolation JJ N(CH ₃ ) ₂ y

1.05 eq. N(CH ₃ ) ₂

DMF (900 ml, 3.0 ml/g) was charged into a 5 L reactor under a protective nitrogen atmosphere and the temperature was adjusted to 20°C. 4-Dimethylaminobenzoic acid (299.4 g, 1.05 eq., limiting reagent), potassium bicarbonate (203.5 g, 1.20 eq.) and Et ₄ NBr (35.6 g, 0.10 eq.) were charged sequentially .) followed by additional DMF (900 ml, 3.0 L/kg) as a rinse. The reaction mixture was then heated to 30°C and charged with dimethyl chloromalonate (300.0 g, 94.0 wt%, 1.69 mol, limiting reagent) and continued at 30°C overnight. The reaction mixture was cooled to 15-20°C, and water (2.7 L, 9.0 ml/g) was slowly charged over 2 hours. After an additional 4 hours, the resulting suspension was filtered, washed successively with a mixture of DMF:H ₂ O (1:1.5) (750 ml, 2.5 ml/g) followed by 2-propanol (2x750 ml, 2x2.5 ml/g) and dried under vacuum at 45-50°C to give 473 g (95 % yield) of dimethyl 2-((4-(dimethylamino)benzoyl)oxy)malonate as a white solid. 1H NMR (400 MHz, DMSO): δ 7.81 (d, J=9.1 Hz, 2H), 6.76 (d, J=9.1 Hz, 2H), 5.80 (s, 1H) , 3.78 (s, 6H), 3.02 (s, 6H). ¹³ C NMR (100 MHz, DMSO): δ 165.17, 164.36, 153.82, 131.29, 113.48, 110.88, 71.50, 53.04, 39.53. Found: 295.11 g/mol. LC-MS (ESI) calculated for [C _u Hi7NO6+H] ⁺ =296.11, found 296.11.

UHPLC method conditions: column: Supelco Ascentis Express C18, 2.7 µm, 2.1x20 mm; mobile phase A: 0.05% TFA in MeOH:water (20:80); mobile phase B: 0.05% TFA in MeOH:acetonitrile (20:80); temperature: 40°C; gradient: 0 min (0% B), 2.0 min (100% B), 2.5 min (100% B); flow rate: 1.0 ml/min; 229 nm; UHPLC RT 1.25 min.

Example 4: Preparation of dimethyl (S)-2-((4-(dimethylamino)benzoyl)oxy)-2-(3-oxocyclohexyl)malonα.

(5 mol%) toluene, aq. KOH "KCI + H ₂ O

Toluene (100 ml, 1.0 ml/g) and 1-((1S,2S)-2-aminocyclohexyl)-3-(3,5-bis(trifluoromethyl)phenyl) were charged into a 2 L reactor under a protective nitrogen atmosphere. thiourea hydrochloride (7.07 g,

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0.05 equiv.) at 20°C. Loaded 1 n. aqueous KOH (50 ml, 0.5 ml/g) and left to stir for 1 hour. The lower aqueous layer was then removed and dimethyl 2-((4-(dimethylamino)benzoyl)oxy)malonate was sequentially charged into the remaining upper layer of toluene (100.0 g, 335.3 mmol, 1.0 eq., limiting reagent), 4-pyrrolidinopyridine (2.54 g, 0.05 eq.) and additional toluene (300 mL, 3.0 mL/g) . The reaction mixture was heated to 33°C to obtain a homogeneous solution and then charged with 2cyclohexen-1-one (39.42 g, 1.2 eq.) in one portion. After 48 hours, the resulting suspension was slowly charged with 2-propanol (63 ml, 0.63 ml/g) in one portion, followed by the addition of heptane (800 ml, 8.0 ml/g) over 3 hours. The suspension was cooled to 20 °C and after standing overnight, filtered, washed successively with 5% IPA in a 2:1 heptane:toluene mixture (300 ml, 3.0 ml/g) followed by the addition of heptane (300 ml, 3.0 ml/g) and dried under vacuum at 45-50°C to obtain 114.7 g (87-88% yield) dimethyl (S)-2-((4-(dimethylamino)benzoyl)oxy)-2-(3-oxocyclohexyl)malonate in as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 7.81 (d, J=8.8 Hz, 2H), 6.75 (d, J=9.1 Hz, 2H), 3.72 ( s, 3H), 3.72 (s, 3H) 3.02 (s, 6H), 2.72-2.58 (m, 1H), 2.54-2.34 (m, 3H), 2.28-2.16 (m, 2H), 2.08-1.95 (m, 1H), 1.93-1.80 (m, 1H), 1.69-1.52 (m, 1H ). Note: The singlets at 3.72 correspond to the methyl ester peaks. Although theoretically they should not be diastereotopic and therefore should be magnetically equivalent and form a 6 H singlet, due to the slow rotation they actually appear as two overlapping 3 H singlets and therefore the repetition of the 3.72 peak is not a typo.

¹³ C NMR:(100 MHz, DMSO-d6) δ: 208.29, 165.92, 164.47, 153.74, 131.29, 114.11, 110.85, 82.94, 52.77, 43.19, 41.95, 40.18, 25.37, 23.41. (One carbon signal is not observed). LC-MS (ESI) calculated for [C ₁₀ H ₂₅ NO ₇ +H]+=392.17, found 392.17.

UHPLC method conditions: column: Supelco Ascentis Express C18, 2.7 µm, 2.1x20 mm; mobile phase A: 0.05% TFA in MeOH:water (20:80); mobile phase B: 0.05% TFA in MeOH:acetonitrile (20:80); temperature: 40°C; gradient: 0 min (0% B), 2.0 min (100% B), 2.5 min (100% B); flow rate: 1.0 ml/min; 229 nm; UHPLC RT 1.28 min. Chiral HPLC method conditions: Column: Phenomenex Lux

Cellulose-2, 3 µm, 4.6x150 mm; mobile phase A: 0.05% TFA in MeOH:water (20:80); mobile phase B: 0.05% TFA in MeOH:acetonitrile (20:80); temperature: 30°C; gradient: 0 min (20% B), 2.0 min (20% B), 5.0 min (55% B), 12.0 min (63% B), 18.0 min (100% B), 21.0 min (100% B); flow rate: 1.2 ml/min; 229 nm; HPLC RT of target enantiomer 11.89 min; HPLC RT of undesired enantiomer 9.94 min.

Example 5: Preparation of dimethyl 2-((4-(dimethylamino)benzoyl)oxy)-2-((1S,3S)-3-hydroxycyclohexyl)malonate.

1gCl ₄ (1 mol%) P(OH) ₃ (1.5 eq.)

IPA, water, 80-82 °C

N(CH ₃ ) ₂

A 5 L N(CH ₃ ) ₂ reactor under a protective nitrogen atmosphere was charged with dimethyl (S)-2-((4(dimethylamino)benzoyl)oxy)-2-(3-oxocyclohexyl)malonate (364 g, 930 mmol, 1. 0 eq., limiting reagent), phosphorous acid (114.4 g, 1.50 eq.), 2-propanol (730 ml, 2.0 ml/g), H2O (1100 ml, 3 ml/g) and [ Ir(COD)Cl] ₂ (3.27 g, 0.005 eq.) in this sequence at 20°C. The reaction mixture was then heated to gentle reflux (~80°C internal temperature) and the mixture became homogeneous upon heating. After 24 hours, the reaction mixture was cooled to 20°C to obtain a suspension. The reaction mixture was then sequentially charged with H2O (182 ml, 0.5 ml/g) in one portion, kept for 5 hours, and H ₂ O (1638 ml, 4.5 ml/g) was added over 2 hours. The resulting suspension was then kept overnight, filtered and washed successively with a 1:4 mixture of 2-propanol:H ₂ O (1100 ml, 3.0 ml/g) and then H2O (1100 ml, 3.0 ml). The wet residue was dried under vacuum at 50°C with a stream of nitrogen to obtain 333 g (91% actual adjusted yield) dimethyl 2-((4-(dimethylamino)benzoyl)oxy)-2-((1S,3S)-3 -hydroxycyclohexyl)malonate as a white solid.

Alternatively, 2-propanol (200 mL, 2.0 mL/g), dimethyl (S)-2-((4-(dimethylamino)benzoyl)oxy)-2-(3 -oxocyclohexyl) malonate (100 g, 255.5 mmol, 1.0 eq., limiting reagent), phosphorous acid (33 g, 1.50 eq.), IrCl ₄ -H ₂ O (0.89 g, 0. 01 eq.), 2-propanol (200 ml, 2.0 ml/g) and H2O (50 ml, 0.5 ml/g) in this order at 20°C. The reaction mixture did not become homogeneous at 20°C. The reaction mixture was then heated to gentle reflux (80-82°C internal temperature) and the mixture became homogeneous

- 34 045036 during heating. After 48 h, the reaction mixture was cooled to 20°C. The reactor was charged with H ₂ O (350 ml, 3.5 ml/g) for 2 hours. After this addition, crystallization nuclei of dimethyl 2-((4(dimethylamino)benzoyl)oxy)-2-((1S,3S) were charged -3-hydroxycyclohexyl)malonate (100 mg, 0.01 eq.) at 20°C and leave the mixture overnight. The next day, H2O (1200 ml, 12.0 ml/g) was charged for 6 hours. The resulting suspension was kept overnight. The next day, the suspension was filtered and washed successively with a 1:4 mixture of 2-propanol:H ₂ O (300 ml, 3.0 ml/g) and then H2O (300 ml, 3.0 ml). The wet residue was dried under vacuum at 50°C with a stream of nitrogen to obtain 90 g (82% actual adjusted yield) dimethyl 2-((4-(dimethylamino)benzoyl)oxy)-2-((1S,3S)-3hydroxycyclohexyl )malonate in solid form.

^1H NMR (400 MHz, DMSO-de) δ: 7.79 (d, J=9.1 Hz, 2H), 6.75 (d, J=9.1 Hz, 2H), 4.03-3 .96 (m, 1H), 3.67 (s, 6H), 3.01 (s, 6H), 2.66-2.54 (m, 1H), 1.74-1.56 (m, 4H ), 1.54-1.43 (m, 1H), 1.43-1.11 (m, 3H). ¹³ C NMR (100 MHz, DMSO-de): 166.32, 164.64, 153.63, 131.14, 114.61, 110.82, 84.06, 63.79, 52.40, 52, 39, 38.28, 33.62, 31.75, 26.78, 19.52. LC-MS (ESI) calculated for [C ₂₍₎ H ₂ 7NO7+H] ⁺ =394.19, found 394.19.

UHPLC method conditions: column: Supelco Ascentis Express C18, 2.7 µm, 2.1x20 mm; mobile phase A: 0.05% TFA in MeOH:water (20:80); mobile phase B: 0.05% TFA in MeOH:acetonitrile (20:80); temperature: 40°C; gradient: 0 min (0% B), 2.0 min (100% B), 2.5 min (100% B); flow rate: 1.0 ml/min; 229 nm; UHPLC RT 1.24 min. Chiral HPLC method conditions: column: Phenomenex Lux Cellulose-2, 3 µm, 4.6x150 mm; mobile phase A: 0.05% TFA in MeOH:water (20:80); mobile phase B: 0.05% TFA in MeOH:acetonitrile (20:80); temperature: 30°C; gradient: 0 min (50% B), 2.0 min (50% B), 11.0 min (80% B), 12.0 min (100% B), 15.0 min (100% B); flow rate: 1.2 ml/min; 229 nm; HPLC RT of target trans-enantiomer 10.8 min; HPLC RT of unwanted trans-enantiomer 5.9 min; HPLC RT of undesired major cis-enantiomer 5.0 min; HPLC RT of unwanted minor cis enantiomer 9.8 min.

Example 6: Preparation of (1S,3S)-3-hydroxycyclohexane-1-carboxylic acid.

2-propanol (300 ml, 1 ml/g), water (450 ml, 1.5 l/kg), dimethyl 2-((4-( dimethylamino)benzoyl)oxy)-2-((1S,3S)-3hydroxycyclohexyl)malonate (300 g, 1.00 eq., limiting reagent) and 2-propanol (60 ml, 0.2 L/kg) as a wash . The resulting suspension was then loaded with 10 N. aqueous NaOH (460 mL, 6.0 eq.) and water (300 mL, 1.0 L/kg) as a wash. The reaction mixture was then heated to 80-85°C and held for at least 16 hours. The reaction mixture was then cooled to 515°C and charged with 6 M aqueous hydrochloric acid (620 ml, 4.88 eq.) for, for at least 2 hours, maintaining internal temperature <15°C. After an additional 4 hours, the reaction mixture was filtered and washed with water (2x300 ml, 2x1 ml/g). The combined filtrate was then transferred to a new reactor and washed with MTBE (1500 ml, 5 ml/g). The lower product-enriched aqueous layer was then transferred to a new reactor, rinsed with water (150 ml, 0.5 ml/g) followed by 2-propanol (300 ml, 1 ml/g). A solution of H ₅ IO ₆ (435 g, 2.50 eq.) in water (300 ml, 1 ml/g) was then added to the reaction mixture over at least 2 hours, maintaining the internal temperature <22°C. After an additional 17 hours, potassium chloride (600 g, 2 g/g) was charged and after an additional 1.5 hours the mixture was filtered and the solids were washed with 20 wt% aqueous potassium chloride (2x300 ml, 2x1 ml/g). Unite

- 35 045036 The resulting filtrate was then washed twice successively with 2-methyltetrahydrofuran (2x1200 ml, 2x4 ml/g). The combined organic layers were then charged with 20 wt% aqueous sodium chloride (1200 ml, 4 ml/g) and cysteine hydrochloride (120 g, 0.40 g/g). After stirring for at least 0.5 hour, the layers were separated and the upper organic layer was washed with a solution of 20 wt.% aqueous sodium chloride (1200 ml, 4 ml/g). The product-rich organic layer was then concentrated under vacuum (internal temperature <40°C), 2-methyltetrahydrofuran (900 ml, 3 ml/g) was added, re-concentrated and then 2-methyltetrahydrofuran (900 ml, 3 ml/g) was added. The solution was then concentrated to 1 g/ml followed by distillation with additional 2-methyltetrahydrofuran (3x300 ml, 3x1 ml/g). The resulting ~1 mL/g solution was then filtered and heptane:toluene (3:1, 300 mL, 1 g/mL) was charged. The resulting suspension was then kept for at least 2 hours at 15-25°C followed by the addition of heptane:toluene (3:1,900 ml, 3 g/ml) for at least 1 hour. After standing overnight, the suspension was cooled to 0°C, kept for at least 3 hours, filtered, washed with toluene (300 ml, 1 g/ml) and dried in a vacuum oven overnight at 50°C under a stream of nitrogen to give 72.2 g of (lS,3S)-3-hydroxycyclohexane1-carboxylic acid as an off-white solid (66% yield as is).

Alternatively, a 1 L jacketed reactor was charged with 10 M sodium hydroxide (200 mL, 2 mL/g, ~8 eq) under a nitrogen protective atmosphere at 20°C, followed by the addition of water (300 mL, 3 mL/g). Dimethyl 2-((4-(dimethylamino)benzoyl)oxy)-2-((1S,3S)-3-hydroxycyclohexyl)malonate (91.12 g, 95.13% quantitative NMR spectroscopy activity, 1.00) was then loaded eq., limiting reagent) followed by the addition of 2-propanol (100 ml, 1 ml/g). The suspension was heated to reflux (internal temperature ~82°C) and held for 14.5 hours. The reaction mixture was then cooled to 7-8°C and charged with 3 M aqueous hydrochloric acid (569 ml, ~5.7 ml /g, ~7.75 eq.) for 4 hours. After an additional 26 hours at 7-8°C, the reaction mixture was heated to 20°C, filtered and washed with water (200 ml, 2 ml/g). The combined filtrate was then transferred to a new reactor and water (50 ml, 0.5 ml/g) and 2-propanol (200 ml, 2 ml/g) were added. The reaction mixture was then charged with a solution of periodic acid (232.09 g, 4.00 eq) in water (200 mL, 2 mL/g) for 2.5 h to monitor gas removal, followed by incubation for an additional 27 h. Potassium chloride (199.9 g, 2 g/g) was then added and after a further 18 hours the mixture was filtered and the solids washed with 20 wt% aqueous potassium chloride (200 ml, 2 ml/g). The combined filtrate was then washed twice successively with 2-methyltetrahydrofuran (2x400 ml, 800 ml total, 8 ml/g). The lower aqueous layer was then washed with additional 2-methyltetrahydrofuran (800 ml, 8 ml/g). 20 wt% aqueous potassium chloride (500 ml, 5 ml/g) and cysteine hydrochloride (25 g, 0.25 g/g) were then added to the combined organic layers. The layers were separated and the top organic layer was washed with a solution of 20 wt% aqueous potassium chloride (500 ml, 5 ml/g) and cysteine hydrochloride (25 g, 0.25 g/g). The upper organic layer was then washed with 20 wt% aqueous potassium chloride (500 ml, 5 ml/g). The cloudy product-rich organic layer was then concentrated under vacuum (rotary vacuum evaporator; bath temperature: 50°C) to 2 ml/g, followed by the addition of 2-methyltetrahydrofuran (200 ml, 2 ml/g). Activated carbon (Darco G-60; 2 g; 0.02 g/g) was then added to the mixture and after stirring overnight (~18 h), the mixture was filtered and washed with 2-methyltetrahydrofuran (2x50 ml, 2x0.5 ml/ G). The combined filtrate was then concentrated under vacuum (internal pressure: 200 torr, internal solution temperature at stabilized acceleration: 39-41°C) to ~100 ml (~1 ml/g), cooled to 20°C, and heptane (45) was added sequentially ml, 0.45 ml/g) for 25 min followed by nucleation of (1S,3S)-3-hydroxycyclohexane-1-carboxylic acid (369 mg, 0.0037 g/g). After standing overnight (~16 hours), additional heptane (355 ml, 3.55 ml/g) was added to the suspension over 4-6 hours, filtered and washed with a 1:4 mixture of 2-methyltetrahydrofuran:heptane (100 ml, 1 ml/g) followed by heptane (100 ml, 1 ml/g). The wet residue was then resuspended (with stirring) with toluene (100 ml, 1 ml/g), and after removing the solvent under vacuum, further dried in a vacuum oven overnight at 50°C under a stream of nitrogen to obtain 20.76 g (1S, 3S)-3-Hydroxycyclohexane-1carboxylic acid as an off-white solid (95.01% activity by quantitative 1H NMR spectroscopy, 62.1% actual corrected yield).

^1H NMR (400 MHz, d4-MeOH) δ 3.93-4.00 (m, 1H), 2.67-2.75 (m, 1H), 1.65-1.85 (m, 4H) , 1.45-1.63 (m, 4H). ¹³ C NMR: (100 MHz, d4-MeOH) δ 179.64, 66.88, 39.11, 36.51, 33.75, 29.27, 21.05.

LC-MS (DCI) calculated for [C ₇ H1 ₂ O ₃ +H]+=145.086, found 145.0865.

HPLC method conditions: column: Supelco Ascentis Express C18, 2.7 µm, 4.6x150 mm; mobile phase A: 0.05% MSA in water: CH3CN (98:2); mobile phase B: 0.05% MSA in water: CH ₃ CN (10:90); temperature: 25°C; gradient: 0 min (0% B), 7.0 min (100% B), 9.0 min (100% B); flow rate: 0.8 ml/min; 210 nm; HPLC RT 4.62 min.

Chiral HPLC method conditions: column: Chiralpak AD-3, 3 µm, 4.6x150 mm; mobile phase A: 0.03% MSA in heptane:EtOH (85:15), isocratic elution for 15 min; temperature: 25°C; flow rate: 1.0 ml/min; 210 nm; HPLC RT of target trans-enantiomer 7.67 min; HPLC RT of unwanted trans-enantiomer 9.29 min; HPLC RT of unwanted major/minor cis- 36 045036 diastereomers 6.89 min.

Example 7: Receiving

1-((1S,2S)-2-aminocyclohexyl)-3-(3,5-bis(Ίrifluoromethyl)phenyl)thiourea hydrochloride.

aqueous layer

A 4 L reactor under a protective nitrogen atmosphere was sequentially charged with 2-MeTHF (280 ml, 1.0 ml/g), a solution of (1S,2S)-(+)-1,2-diaminocyclohexane (235.8 g, 2. 0 eq.) in 2-MeTHF (840 ml, 3 ml/g) and 2MeTHF (280 ml, 1.0 ml/g) as a wash. The resulting solution was cooled to -10°C and then a solution of 3,5-bis(trifluoromethyl)phenyl isocyanate (280 g, 1032 mmol, 1.0 eq, limiting reagent) in 2-MeTHF (840 mL, 3 ml/g) for 4.5 hours. The reaction mixture was then slowly loaded with 6 N. aqueous HCl (560 mL, 2.0 mL/g) for 30 min while maintaining internal temperature <20°C. After an additional 10 min, the layers were separated and the lower aqueous layer was removed. The upper organic layer was then concentrated under vacuum (320 mbar) to 4.0 ml/g, maintaining the internal temperature between 40-45°C. Freshly prepared 2-MeTHF (560 mL, 2.0 mL/g) was charged and concentration continued to 3.0 mL/g. The reaction mixture was then placed under N2 at 1 atm and brought to an internal temperature of 40-45°C. Heptane (2520 ml, 9.0 ml/g) was added slowly over 3.5 hours and the resulting suspension was cooled from 40-45°C to 20°C over 2 hours. After standing overnight, the suspension was filtered, washed successively with a mixture of heptane:2-MeTHF (3:1) (840 ml, 3.0 ml/g) followed by the addition of heptane (840 ml, 3.0 ml/g) and dried under vacuum at 45-50°C with obtaining 298 g (74-75% yield) of 1-((1S,2S)-2-aminocyclohexyl)-3-(3,5bis(trifluoromethyl)phenyl)thiourea hydrochloride as a white solid.

^1H NMR (400 MHz, DMSO-d6) δ: 10.75-11.24 (m, 1H), 8.77-8.99 (m, 1H), 8.26-8.45 (m, 2H ), 7.96-8.26 (m, 3H), 7.60-7.76 (m, 1H), 5.70-5.73 (m, 1H), 4.23-4.43 (m , 1H), 2.95-3.17 (m, 1H), 1.94-2.18 (m, 2H), 1.591.80 (m, 2H), 1.39-1.57 (m, 1H), 1.11-1.39 (m, 3H). ¹³ C NMR: (100 MHz, DMSO-d ₆ ) δ: 181.3, 142.7, 130.5 (q, J=33.0 Hz), 122.0, 123.7 (q, J=272 .9 Hz), 116.3, 55.0, 53.5, 30.9, 29.6, 24.3, 23.6. LC-MS (ESI) calculated for [Ci5Hi7F6NsS+H] ⁺ =386.11, found 386.11.

HPLC method conditions: column: Supelco Ascentis Express C18, 2.7 µm, 4.6x50 mm; mobile phase A: 0.05% TFA in acetonitrile:water (5:95); mobile phase B: 0.05% TFA in acetonitrile:water (95:5); temperature: 50°C; gradient: 0 min (0% B), 15.0 min (100% B), 18.0 min (100% B); flow rate: 1.2 ml/min; 229 nm; HPLC RT 6.53 min.

Example 8: Preparation of (1S,3S)-3-((6-bromo-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid.

A 100 mL reactor was charged with MTBE (45 mL, 7.5 mL/g) under a protective nitrogen atmosphere, followed by the addition of KOtBu (11.2 g, 2.4 eq.) at 20°C. A separate dropping funnel was charged with DMF (45 mL, 7.5 mL/g) followed by the addition of (1S,3S)-3-hydroxycyclohexane-1-carboxylic acid (6.0 g, 1.0 eq., limiting reagent) which quickly dissolved, resulting in a clear solution.

- 37 045036

The contents of the addition funnel were then added dropwise to the MTBE/KOtBu mixture over 90-120 min, maintaining the internal temperature below 30°C. After an additional 30 minutes, 6-bromo-3-fluoro-2-methylpyridine (7.84 g, 1.00 eq.) was added to the resulting well-dispersed suspension and the reactor contents were heated to 33°C. After 6 hours, KOtBu (2.4 g, 1.00 eq) was added as a solid, followed by 6-bromo-3-fluoro-2-methylpyridine (1.96 g, 0.25 eq). After standing for an additional 24 hours, the contents of the reactor were cooled to 25°C and water (48 ml, 8.0 ml/g) was added dropwise, maintaining the internal temperature below 30°C. After an additional 15 min, MTBE (24 ml, 4.0 ml/g) was charged and the resulting two-phase solution was stirred for 15 min at 25°C. The layers were then separated and the top organic layer was removed. The lower product-rich aqueous layer was then washed with additional MTBE (24 mL, 4.0 mL/g) and the upper organic layer was removed. The product-enriched aqueous layer was then charged with MeTHF (60 mL, 10.0 mL/g) and acidified to pH 5-7 using 6 N. HCl (18 ml, 3.0 ml/g). The layers were then separated and the resulting top product-enriched organic layer was washed twice with water (2x18 ml, 2x3 ml/g), concentrated in vacuo at 45°C to 6.0 ml/g. The resulting solution was solvent replaced with toluene (48 mL, 8.0 mL/g) under constant volume distillation conditions, and the resulting solution was treated with Zeta Plus 55SP Carbon (0.9 g, 0.15 eq.) for 2 hours and filtered. The resulting solution was then concentrated under reduced pressure, seeded for crystallization using 1 wt.% of the target substance, followed by the addition of heptane (108 ml, 18.0 ml/g) over 4-6 hours. After standing overnight, the resulting solution As a result, the suspension was filtered, washed successively with a mixture of toluene/heptane (1:3) (18 ml, 3.0 ml/g), heptane (18 ml, 3.0 ml/g) and dried under vacuum at 45°C to obtain 10.1 g (78% yield) of the desired product as a brown solid. Alternatively,

A 100 mL reactor was charged with MTBE (45 mL, 7.5 mL/g) under a protective nitrogen atmosphere, followed by the addition of KOtBu (14.0 g, 3.0 eq.) at 20°C. A separate dropping funnel was charged with DMF (45 mL, 7.5 mL/g) followed by the addition of (1S,3S)-3-hydroxycyclohexane-1-carboxylic acid (6.0 g, 1.0 eq., limiting reagent). (1S,3S)-3-hydroxycyclohexane-1-carboxylic acid dissolved quickly, resulting in a clear solution. The contents of the addition funnel were then added dropwise to the MTBE/KOtBu mixture over 15-30 min, maintaining the internal temperature below 30°C. After an additional 30 minutes, 6-bromo-3-fluoro-2-methylpyridine (9.8 g, 1.25 eq.) was charged into the resulting well-dispersed suspension and the reactor contents were heated to 33°C. After 24 h, the contents of the reactor were cooled to 25°C and water (48 ml, 8.0 ml/g) was added dropwise, maintaining the internal temperature below 30°C. After an additional 15 min, MTBE (18 mL, 3.0 mL/g) was added and the resulting biphasic solution was stirred for 15 min at 25°C. The layers were then separated and the top organic layer was removed. Toluene (48 mL, 8.0 mL/g) was then added to the product-enriched aqueous layer and acidified to pH 5-7 using 6N. HCl (18 ml, 3.0 ml/g). The layers were then separated and the resulting top product-enriched organic layer was concentrated under vacuum at 45° C. to 6.0 mL/g. Heptane (108 ml, 18.0 ml/g) was then added dropwise to the resulting solution over 2-4 hours and left overnight. The resulting suspension was then filtered and washed successively with toluene/heptane (1:3) (18 ml, 3.0 ml/g) and heptane (18 ml, 3.0 ml/g) and dried under vacuum at 45°C yielding 7.9 g (61% yield) of (1S,3S)-3-((6-bromo-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid as a brown solid.

^1H NMR (400 MHz, CDCl3) δ 11.61 - 10.99 (m, 1H), 7.27 - 7.14 (m, 1H), 7.07 - 6.95 (m, 1H), 4 .68 - 4.50 (m, 1H), 2.91 - 2.77 (m, 1H), 2.56 - 2.39 (m, 3H), 2.15 - 2.04 (m, 1H) , 2.04 - 1.82 (m, 3H), 1.81 - 1.57 (m, 4H). ¹³ C NMR (100 MHz, CDCl3) δ 181.3, 151.2, 150.9, 130.1, 125.5, 121.9, 72.3, 38.2, 31.8, 29.4, 27.9, 20.2, 19.1. LC-MS (ESI) calculated for [C13H ₁₆ BrNO ₃ +H]+=314.04, found 314.04.

Analytical study: column: Phenomex Kinetex C8, 150x4.6 mm, 2.6 µm; mobile phase A: 0.05% TFA in water; mobile phase B: 0.05% TFA in methanol:acetonitrile (80:20); temperature: 27°C; gradient: 0 min (44% B), 1.0 min (44% B), 17.0 min (60% B), 18.0 min (60% B), 25.0 min (90% B), 28.0 min (90% B), 30.0 min (100% B), 30.1 min (44% B), 35 min (44% B); flow rate: 0.8 ml/min; 220 nm; HPLC RT 14.88 min.

- 38 045036

Example 9: Preparation of (1S,3S)-3-((6-(5-((benzyloxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2methylpyridin-3-yl )oxy)cyclohexane-1-carboxylic acid tert-butylamine salt.

Vg

ORP i-PrMgCI (2.55 eq.)

CH ₃ (1.3 eq.)

THF (9 vol.)

R

Ί ORP sn ₃

H ₃ C CH ₃ (1.3 eq.)

R = MgCI:Br (98:2) (1.3 eq.) n T ₊ MgClBr H3C^CH3 (1.3 eq.

(1.28 eq)

R = MgCI:Br (2:98)

(1.0 eq. LR) (0.95 eq.

ZnCI ₂ (0.35 eq.) PdCI ₂ Xantphos (0.025 eq.)

THF (4 vol.)

'z n ₃ s

(0.20 eq.) (0.05 eq.) (0.025 eq.)

MgClBr (1.0eq)

ZnCI ₂ (0.35 eq.) PdXantphos (0.025 eq.)

Na ₃ EDTA xH ₂ O (0.45 eq.) water (12 vol.) HCI to adjust pH

Na ₂ CO ₃ 1.5 H ₂ O ₂ (0.20 eq.) water (3.2 vol.)

Na ₂ S ₂ O ₅ (0.20 eq.)

NaCl _aq (5 wt.%, 3.2 vol.)

Zn ²⁺ (0.35 eq.) Md ²⁺ (3.5 eq.) Na ⁺ (2.15 eq.)

Pd ²⁺ (0.025 eq.; XantphosO ₂ (0.025 eq.;

VG (2.3 eq.) sg (4.2 eq.) EDTA ⁴ ' (0.45 eq.)

Preparation of organomagnesium - 5-((benzyloxy)methyl)-4-bromo-1-methyl-1H-1,2,3-triazole bromide salt (36, 05 g, 1.3 eq.) and tetrahydrofuran (209 ml, 8.5 ml/g). The reactor was sealed, equipped with a nitrogen inlet, and the suspension was degassed using a subsurface nitrogen purge into

- 39 045036 for 30 minutes. The suspension was cooled to an internal temperature of 5°C and kept for min. Isopropylmagnesium chloride (103 mL, 2.55 eq., 1.90 M in THF) was added over 30 min (Caution: gas evolution!). After addition was complete, the reactor was heated to 20°C. After 3 h, a homogeneous solution of organomagnesium was immediately used in the subsequent Negishi combination (see below).

Negishi Combination - A separate 1 L Chemglass jacketed reactor equipped with an overhead stirring paddle was charged with (1S,3S)-3-((6-bromo-2-methylpyridin-3-yl)oxy)cyclohexane-1carboxylic acid (25 .00 g, 1.0 eq., limiting reagent), anhydrous zinc chloride (3.65 g, 0.35 eq.) and tetrahydrofuran (85 ml, 3.4 ml/g). The reactor was sealed and equipped with a nitrogen inlet, and the headspace was purged with nitrogen for 5 minutes. The resulting homogeneous solution was cooled to 0°C and kept for 10 minutes with stirring. Add isopropylmagnesium chloride (37.8 mL, 0.95 eq., 1.90 M in THF) over 15 min (Caution: gas evolution!). After an additional 15 minutes, the reactor was heated to 20° C. and PdCl ₂ (Xantphos) (1.44 g, 0.025 eq.) was added in one portion. The resulting heterogeneous solution was degassed using a subsurface nitrogen purge for 30 min. After degassing, the solution was heated to 40°C and kept for 10 min with stirring. The organomagnesium solution (see above) was loaded over 10-15 minutes in a slow, steady stream. The resulting solution was stirred for 16 hours at 40°C and then cooled to 23°C. The reaction was stopped by adding trisodium ethylenediaminetetraacetic acid (11.67 g, 0.45 eq.) in water (300 ml) over 1 hour. The pH of the solution was adjusted to 4.05.0 with 6 N. HCl (1.1 eq) and the biphasic mixture was stirred for 30 min. The phases were allowed to settle for 30 min and then separated. The organic layer was treated with a freshly prepared solution of sodium percarbonate (2.43 g, 0.20 eq.) in water (80 ml, 3.2 ml/g) [Caution: gas evolution! (CO2)]. The resulting homogeneous mixture was stirred for 4 hours at 20°C. Oxidation was stopped with a solution of sodium metabisulfite (2.87 g, 0.20 eq.) in 15 wt.% aqueous NaCl (80 ml, 3.2 ml/g). Toluene (75 ml, 3.0 ml/g) was added and the resulting two-phase mixture was stirred for 30 minutes. The phases were allowed to settle for 30 min and then separated. The organic layer was concentrated under reduced pressure (100 - 150 torr) to a solution of 4 ml/g. The product-enriched organic layer was diluted with fresh toluene (150 ml, 6.0 ml/g) and then concentrated under reduced pressure (100 - 150 torr) to a 6 ml/g solution. The product-enriched organic layer was diluted with toluene (25 ml, 1.0 ml/g) and tetrahydrofuran (25 ml, 1.0 ml/g). The resulting solution was filtered into a clean 250 ml Chemglass jacketed reactor and heated to 55°C. One third of a solution of tert-butylamine (1.90 mL, 1.2 eq.) in toluene (83 mL, 3.3 mL/g) and tetrahydrofuran (17 mL, 0.7 mL/g) was added in one portion, followed by target substance (0.125 g, 0.5 wt.%). The remaining two-thirds of the amine solution was added dropwise over 60 minutes. After 30 minutes, the suspension was slowly cooled to 0°C over 2 hours. The suspension was kept at 0°C for 14 hours. The solids were filtered and collected. The solids were washed successively with toluene:tetrahydrofuran (5:1) (75 ml, 3.0 ml/g) followed by the addition of toluene (75 ml, 3.0 ml/g) and dried in a vacuum oven at 65°C in a stream nitrogen to obtain 35.96 g (93.4%) of the desired product as a white solid. Alternatively,

- 40 045036

Br

HBr i-PrMgCI (3.0 eq.

THF

ZnCI ₂ (1.5 eq.)

Η ₃ ι ^N 'N OBn

CH ₃ (1.5EQ.)

ι-PrMgCI (0.95 eq.

MgCI ₂ (1.5 eq.) MgClBr (1.5 eq.)

PdCI ₂ Xantphos (0.03 eq.) THF

(1.0 EQ. ) M = Mg or Zn Mg:Zn; 95:5

ZnCI N'V ^N 'N OBn

CH ₃ (0.39 eq.)

ZnCIBr (1.0 eq.) ⁺ ZnCI ₂ (0.06 eq.) PdXantphos (0.03 eq.)

- 41 045036

Na ₃ EDTA xH ₂ O (2.0 eq.) water (11.9 vol.) HCI to adjust pH

O^^^COgN

NH ₂ C(CH ₃ ) ₃ n ₃ s^ . _{NH C((} (1.0 eq.) D J toluene/THF to release N. /^OBp NN

CH ₃ (1.0 eq.)

5-((benzyloxy)methyl)-4-bromo-1-methyl-1H-1,2,3-triazole bromide salt (1.7059 g, 1.5 eq.) was loaded into a 20 mL vial. The vial was hermetically sealed with a lid with a PTFE septum. The vial was equipped with a nitrogen inlet, and the headspace was purged with nitrogen for 5 min. Tetrahydrofuran (8.90 ml, 8.95 ml/g) was loaded into the vial. The resulting suspension was cooled to 0°C and kept for 10 minutes. Isopropylmagnesium chloride (4.11 mL, 3.0 eq., 2.15 M in THF) was added over 15 min (Caution: gas evolution!). After 2 hours, the vial was heated to 23°C and transferred to a glove chamber under a nitrogen atmosphere. Anhydrous zinc chloride (0.601 g, 1.5 eq.) was added in one portion, and the solution was stirred in a glove box under a nitrogen atmosphere at 23°C. After 1 h, the homogeneous organozinc solution was removed from the nitrogen atmosphere of the glove compartment and immediately used in the subsequent Negishi combination (see below). Negishi coupling - (1S,3S)-3((6-bromo-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (1.00 g, 1.0 eq.) was loaded into a separate 40 mL vial. , limiting reagent). The vial was hermetically sealed with a lid with a PTFE septum. The vial was equipped with a nitrogen inlet, and the headspace was purged with nitrogen for 5 min. Tetrahydrofuran (4.03 ml, 4.0 ml/g) was loaded into the vial. The resulting homogeneous solution was cooled to 0°C and kept for 10 minutes. Isopropylmagnesium chloride (1.30 mL, 0.95 eq., 2.15 M in THF) was added over 15 min (Caution: gas evolution!). After 15 minutes, the vial was heated to 23°C, and PdCl ₂ (Xantphos) (0.0665 g, 0.03 eq.) was added in one portion. The resulting heterogeneous solution was degassed by subsurface nitrogen flushing for 5 min.

After degassing the solution, an organozinc solution was added (see above) over 10 minutes. The resulting solution was stirred vigorously at 23°C. After 21 hours, a solution of trisodium ethylenediaminetetraacetic acid (2.16 g, 2.0 eq.) in water (12.0 ml) was added over 1 hour. The phases were separated and the organic layer was concentrated under reduced pressure (100 torr) to a solution volume 4 ml/g. The product-enriched organic layer was diluted with fresh tetrahydrofuran (8.0 mL, 8 mL/g). The solvent was removed under reduced pressure (100 torr) to a solution volume of 4 ml/g. The product-enriched organic layer was diluted with fresh tetrahydrofuran (8.0 mL, 8 mL/g). The solvent was removed under reduced pressure (100 torr) to a solution volume of 4 ml/g. The product-enriched organic layer was diluted with toluene (8.0 mL, 8.0 mL/g). One third of a solution of tert-butylamine (0.33 mL, 1.0 eq.) in toluene (1.0 mL, 1.0 mL/g) was added in one portion, followed by (1 S,3S)-3-(( 6-(5-((benzyloxy)methyl)-1 -methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3 yl)oxy)cyclohexane-1-carboxylic acid tert-butylamine salt (0.010 g, 1.0 wt.%). The remaining two-thirds of the amine solution was added dropwise over 20 minutes. After 15 h, the suspension was filtered and the solids were collected. The solids were washed successively with toluene:tetrahydrofuran (2:1) (6.0 ml, 6.0 ml/g) followed by the addition of toluene (6.0 ml, 6.0 ml/g) and dried in a vacuum oven at 50 °C in a stream of nitrogen to obtain 1.22 g (76%) (1S,3S)-3-((6-(5((benzyloxy)methyl)-1-methyl-1H-1,2,3-triazol- 4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1carboxylic acid tert-butylamine salt as a white solid. Ή NMR (400 MHz, DMSO-d6) δ: 8.54 - 7.37 (br s, 3H), 7.81 (d, J=8.6 Hz, 1H), 7.54 (d, J= 8.6 Hz, 1H), 7.33 - 7.19 (m, 5H), 5.18 (s, 2H), 4.69 (br s, 1H), 4.53 (s, 2H), 4 .06 (s, 3H), 2.33 - 2.35 (m, 1H), 2.32 (s, 3H), 2.00 - 1.42 (m, 8H), 1.19 (s, 9H ). ¹³ CNMR: (100 MHz, DMSO-d ₆ ) δ 178.3, 151.2, 148.1, 144.5, 141.8, 138.4, 131.4, 128.7, 128.1, 128 ,0, 120.4, 119.5, 73.2, 72.0, 59.7, 49.8, 40.4 (overlap with DMSO-d ₆ ) 35.4, 33.4, 30.6, 29.1, 29.0, 21.3, 19.8. LC-MS (ESI) calculated for [C24H28N ₄ O4+H] ⁺ =437.22, found 437.22.

- 42 045036

Analytical study: column: Phenomenex Kinetex C8, 2.6 µm, 4.6x150 mm; mobile phase A: 0.05% TFA in _H2O ; mobile phase B: 0.05% TFA in MeOH:CH ₃ CN (80:20); temperature: 27°C;

gradient: 0 min (44% B), 1.0 min (44% B), 17.0 min (60% B), 18.0 min (60% B), 25.0 min (90% B), 28.0 min (90% B), 30.0 min (100% B), 30.1 min (44% B), 35.0 min (44% B); flow rate: 0.8 ml/min; 220 nm; HPLC RT 17.849 min.

Example 10: Preparation of (1S,3S)-3-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triαzol-4-yl)-2methylpyridin-3-yl)oxy) cyclohexane-1-carboxylic acid.

(1S,3S)-3-((6-(5((benzyloxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-) was loaded into a high-pressure stainless steel reactor methylpyridin-3-yl)oxy)cyclohexane-1 carboxylic acid tert-butylamine salt (1.00 g, 1.0 eq., limiting reagent), citric acid monohydrate (0.411 g, 1.00 eq.), Pd/C (10 wt%, wet) (0.100 g, 0.10 g/g), ethanol (6.0 ml, 6.0 ml/g) and water (2.0 ml, 2.0 ml/g). The reactor was hermetically sealed and mixing began from above. The atmosphere in the reactor was first replaced with nitrogen. The reactor was then pressurized with 30 psi of hydrogen and the reactor was heated to 40°C. After 25 hours, the reactor was cooled to 20-25°C and the reaction mixture was filtered. The reactor and filter cake were then washed with ethanol:water (3:1) (2x2.0 ml, 2x2.0 ml/g). The combined filtrate was then concentrated under reduced pressure (<10 Torr) to a solution of 5.0 mL/g. Water (7.0 mL, 9.0 mL/g) was then added over 2 hours. The resulting suspension was filtered and the solids were washed successively with water:ethanol (3:1) (3.0 mL, 3.0 mL /g) followed by water (3.0 ml, 3.0 ml/g) and then dried in a vacuum oven at 50°C under a stream of nitrogen to obtain 0.622 g (90%) of the desired product as a white solid. Alternatively,

(1S,3S)-3-((6-(5((benzyloxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-) was loaded into a high-pressure stainless steel reactor methylpyridin-3-yl)oxy)cyclohexane-1 carboxylic acid tert-butylamine salt (1.00 g, 1.0 eq., limiting reagent), anhydrous citric acid (0.508 g, 1.34 eq.), Pd/C (10 wt%, wet) (0.100 g, 0.10 g/g) and ethanol (200 proof) (10.0 ml, 10.0 ml/g). The reactor was hermetically sealed and mixing began from above. The atmosphere in the reactor was replaced with nitrogen. The reactor was then pressurized with 30 psi of hydrogen and the reactor was heated to 40°C. After 25 hours, the reactor was cooled to 23°C and the reaction mixture was filtered. The reactor and filter cake were washed twice with ethanol (2x2.0 ml, 2x2.0 ml/g). The combined organic layer was concentrated under reduced pressure (<10 torr) to a solution volume of 3.0 ml/g. Water (9.0 mL, 9.0 mL/g) was added over 2 hours. The solids were filtered and washed successively with water:ethanol (3:1) (3.0 mL, 3.0 mL/g) followed by water (3.0 ml, 3.0 ml/g) and dried in a vacuum oven at 50°C under a stream of nitrogen to obtain 0.491 g (71%) (1S,3S)-3-((6-(5-( hydroxymethyl)-1-methyl-1H-1,2,3triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid as a white solid.

1H NMR (500 MHz, DMSO-d6) δ: 12.09 (br s, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.35 (d, J=8.5 Hz , 1H), 5.69 (br s, 1H), 4.89 (br s, 2H), 4.63 (br s, 1H), 3.94 (s, 3H), 3.28 (br s, 1H), 2.37 (br s, 2H), 2.31 (s, 3H), 1.90-1.80 (m, 1H), 1.75-1.55 (m, 3H), 1, 55-1.31 (m, 4H). ¹³ CNMR: (125 MHz, CDCl ₃ ) δ 176.4, 150.2, 147.7, 143.1, 142.0,

- 43 045036

134.6, 120.6, 119.2, 71.5, 51.8, 37.7, 35.0, 31.7, 28.8, 27.8, 19.9, 19.4. LC-MS (ESI) calculated for [C ₁₇ H ₂₂ N ₄ O ₄ +H] ⁺ =347.17, found 347.17. Analytical study: column: Phenomenex Kinetex C8, 2.6 µm, 4.6x150 mm; mobile phase A: 0.05% TFA in _H2O ; mobile phase B: 0.05% TFA in MeOH:CH ₃ CN (80:20); temperature: 27°C; gradient: 0 min (44% B), 1.0 min (44% B), 17.0 min (60% B), 18.0 min (60% B), 25.0 min (90% B), 28.0 min (90% B), 30.0 min (100% B), 30.1 min (44% B), 35.0 min (44% B); flow rate: 0.8 ml/min; 220 nm; HPLC RT 5.003 min.

Example 11: Preparation of N-methyl-N-propyl-1H-imidazole-1-carboxamide-oxalic acid salt.

О _ν ^ν ^Λ ν% ₊ ην^^ ⁰ ^

CH ₃ -------------------* (1.05 eq.) 2-methyl-2-butanol (7.0 vol.) ^ν ' (1.0 eq., LR) l·o О μ^Ν^Ν^—+ + m^N^N^m

N 7 7 i NH N 'f 7 N

CH ₃

_..n . (1.0 eq. ) (0.05 eq. ) (1.0 eq. ) '''

O^n^n^ ⁰¹⁴³

CH ₃ wt.% aq. NaCl (14.0 vol) (1.0 eq)

HCI (0.97 eq.) To adjust pH -----------------------O _n ^n^n^ ^CH3 sn ₃ (HO ₂ C) ₂

A 4 L reactor was charged with t-AmOH (900 mL, 6.0 mL/g) and 1,1'-carbonyldiimidazole (353 g, 1.05 eq.). The loading port was flushed with additional t-AmOH (150 mL, 1.0 mL/g). The resulting heterogeneous suspension was cooled to 0°C and N-methylpropylamine (150 g, 1.0 eq., limiting reagent) was added over 1 hour. After 17 hours, the solution was warmed to 20°C. The reaction was stopped with water (525 ml, 3.5 ml/g) (Caution: gas evolution!). As soon as gas evolution stopped, aqueous 6N was loaded into the reactor. HCl (228 ml, 0.67 eq.) and sodium chloride (92 g, 0.76 eq.). The phases were separated and the organic layer was left in the reactor. 15 wt.% aqueous NaCl (525 ml, 3.5 ml/g) and aqueous 6 N were added to the reactor. HCl (51 ml, 0.15 eq.). The phases were separated and the organic layer was left in the reactor. 15 wt.% aqueous NaCl (525 ml, 3.5 ml/g) and aqueous 6 N were added to the reactor. HCl (41 ml, 0.12 eq.). The phases were separated and the organic layer was left in the reactor. 15 wt.% aqueous NaCl (525 ml, 3.5 ml/g) and aqueous 6 N were added to the reactor. HCl (10 ml, 0.03 eq.). The phases were separated. The solution was heated to 45°C and concentrated under reduced pressure (75 Torr) to a solution volume of 4 ml/g. Fresh toluene (750 ml, 5.0 ml/g) was added to the reactor and further concentrated under reduced pressure (75 torr) to a solution of 4 ml/g. Fresh toluene (900 ml, 6.0 ml/g) was then added to the reactor. and left to cool to 23°C. The resulting suspension was filtered and the resulting product-enriched organic layer was charged into a clean 4 L reactor. The solution was heated to 65°C and a solution of anhydrous oxalic acid (190 g, 1.0 eq.) in 2-propanol (750 ml, 5.0 ml/g) was added over 3 hours. The resulting suspension was kept for 8 hours at 65°C and then cooled to 0°C over 4 hours. The solids were filtered and washed successively with toluene:2propanol (7:1) (450 ml, 3.0 ml/g) followed by toluene (450 ml, 3.0 ml/g) and dried in a vacuum oven at 50°C under a stream of nitrogen to obtain 406 g (77%) N-methyl-N-propyl-1H-imidazole-1carboxamide-oxalic acid salt as a white solid.

1H NMR (400 MHz, DMSO-d6) 6:14.41 - 13.65 (br s, 2H), 8.31 - 8.04 (m, 1H), 7.62 - 7.50 (m, 1H ), 7.19 7.06 (m, 1H), 3.32 (t, J=7.3 Hz, 2H), 3.00 (s, 3H), 1.60 (sextet, J=7.3 Hz, 2H), 0.84 (t, J=7.5 Hz, 3H). ¹³ CNMR: (100 MHz, CDCl ₃ ) δ 162.02, 151.28, 137.40, 128.01, 119.27, 51.79, 36.48, 20.29, 11.31. LC-MS (ESI) calculated for [C8H ₁₃ N ₃ O+H] ⁺ =168.11, found 168.11.

Analytical study: column: Supelco Ascentis Express C18, 2.7 µm, 4.6x100 mm; mobile phase A: 0.01 M NH ₄ OAc in CH ₃ CN:H ₂ O (5:95); mobile phase B: 0.01 M NH ₄ OAc in CH ₃ CN:H ₂ O (95:5); temperature: 30°C; gradient: 0 min (0% B), 2.0 min (0% B), 15.0 min (25% B), 20.0 min (100% B), 24.0 min (100% B); flow rate: 1.2 ml/min; 210 nm; HPLC RT 8.934 min.

- 44 045036

Example 12: Preparation of (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)1H-1,2,3-triazol- 4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid.

Final product

(1 _S ,3S)-3 -((6-(5 -(hydroxymethyl)-1 -methyl-1H-1,2,3-triazole -4-yl)-2-methylpyridin-3 yl)oxy)cyclohexane-1-carboxylic acid (0.446 g, 1.29 mmol, 1.0 eq., limiting reagent), Nmethyl-N-propyl-1H-imidazol- 1-carboxamide salt of oxalic acid (0.596 g, 2.32 mmol, 1.8 eq.) and 2-methyl-2-butanol (5.4 ml, 12 l/kg). The resulting thick reaction suspension was then heated to 55-60°C and KOtBu (20 wt% in THF, 4.7 mL, 7.8 mmol, 6.0 eq.) was added dropwise over 45 min using a syringe. pump After an additional 2 hours, the resulting liquid reaction mixture was cooled to ambient temperature and water (6.7 mL, 15 L/kg) was added. Then 6 N was added. aqueous HCl (1 ml, 1.2 l/kg) dropwise to bring the pH of the aqueous layer to 4.0 (target pH 3.0-4.5). The layers were separated and the lower aqueous layer was back-extracted with 2-methyl-2butanol (4.0 mL, 9 L/kg). The combined product-enriched aqueous layers were then washed with aqueous NaCl (2 g/L, 4.0 mL, 9.0 L/kg) and the resulting organic layer was concentrated on a rotary vacuum evaporator to near dryness. The residue was then dissolved in DCM (5.5 ml, 12 L/kg) and washed with water (4.0 ml, 9 L/kg). The layers were then separated and the lower product-enriched DCM layer was filtered. The filter was then washed with DCM (2.0 ml, 4.5 L/kg) to obtain a solution of (1S,3S)-3-((2-methyl-6-(1methyl-5-(((methyl(propyl)carbamoyl) oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3yl)oxy)cyclohexane-1-carboxylic acid in DCM. ^1H NMR (500 MHz, CDCl3) δ 7.96 (d, J=8.4 Hz, 1H), 7.22 (d, J=8.5 Hz, 1H), 5.76 (d, J= 9.9 Hz, 2H), 4.71 (br s, 1H), 4.14 (s, 3H), 3.28-3.22 (m, 1H), 3.15-3.07 (m, 1H), 2.99-2.85 (m, 3H), 2.81 (br s, 1H), 2.50 (s, 3H), 2.19-2.11 (m, 1H), 2, 09-1.86 (m, 3H), 1.82-1.72 (m, 1H), 1.71-1.62 (m, 3H), 1.60-1.54 (m, 1H), 1.48-1.38 (m, 1H), 0.90-0.71 (m, 3H)*. Note: The 0.90-0.71 peak is actually observed as two broadened singlets, each combining to 1.5 N, supporting API arrangements as a mixture of rotamers in CDCl3. ¹³ C NMR: (125 MHz, CDCl3) δ 179.7, 155.8, 155.7, 150.7, 148.8, 145.3, 141.2, 129.9, 119.4, 118.9 , 71.4, 55.1, 50.7, 38.0, 35.2, 35.1, 34.5, 33.8, 31.8, 29.2, 27.9, 20.8, 20 ,4, 20.1, 19.5, 10.84, 10.76. 27 carbon atoms (versus 22 theoretical) due to the observed mixture of rotamers. LC-MS (ESI) calculated for [C ₂₂ H ₃₁ N ₅ O ₅ +H] ⁺ =446.24, found 446.24.

HPLC method conditions: column: Waters XBridge C8, 3.5 µm, 4.6x150 mm; mobile phase A: 0.01 M NH ₄ OAc in acetonitrile:water (20:80); mobile phase B: 0.01 M NH ₄ OAc in acetonitrile:water:MeOH (75:5:20); temperature: 40°C; gradient: 0 min (0% B), 9.6 min (25% B), 19.2 min (100% B), 27.0 min (100% B); flow rate: 1.0 ml/min; 233 nm; HPLC RT 14.20 min.

Example 13. Preparation of (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)- 45 045036

1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid

N

1)

2)

f-BuOH

2.4 eq.

'z

Final product

3) rinsing with water. NaCI

Final product in f-AmOH

2.8 eq. imidazole*HC1

2.4 eq. KCI

0.8 eq. 13-V

0.09 eq. 13-A >. KOi-Bu/THF f-AmOH f-BuOH imidazole

ΚΟί-Βυ i-B 3-A

A 40 mL vial equipped with a magnetic stirrer and an N2 inlet was sequentially charged with CDI (0.842 g, 1.8 eq.) and THF (4.0 mL, 4.0 mL/g). The reaction mixture was cooled to 0°C and N-methylpropylamine (0.40 g, 1.89 eq.) was added dropwise over 20-45 minutes. After holding at 0-5°C for an additional 30 min, the reaction mixture was warmed to room temperature and charged with 13-C (1.0 g, 1.0 eq., limiting reagent) and 2-methyl-2-butanol (8, 0 ml, 8 l/kg). The resulting solution was then heated to 45-50°C and KOtBu (20 wt% in THF, 3.8 mL, 2.4 eq.) was added dropwise over 45 min using a syringe pump. After an additional 2 hours, the resulting liquid reaction mixture was cooled to ambient temperature and water (3.0 mL, 3 L/kg) was added. Then 6 N was added. aqueous HCl (2.4 ml, 2.4 L/kg) dropwise to bring the pH of the aqueous layer to 4.0 (target pH 3.0-4.5). The lower aqueous layer was removed and the product-rich organic layer was then washed with aqueous NaCl (3 g/L, 3.0 mL, 3.0 L/kg) to obtain a solution of the final product in t-AmOH. Biocatalytic synthesis of (1S,3S)-3-hydroxycyclohexane-1-carboxylic acid:

- 46 045036

KRED buffer, pH 6

ERED pH 6 buffer, GDH NADPH, glucose

ERED

KRED pH 7 buffer, GDH

NADPH, glucose

Example 14. Preparation of 3-oxocyclohex-1-en-1-yl 4-methylbenzenesulfonate.

A 5 L Chemglass reactor under nitrogen was sequentially charged with 1,3 cyclohexanedione (140.0 g, 1249 mmol, 1.0 eq., limiting reagent), p-toluenesulfonyl chloride (250.0 g, 1311 mmol, 1.05 eq. ) and ethyl acetate (1400 ml, 10 l/kg). The resulting suspension was then cooled to 0-5°C and trimethylamine (151.6 g, 1498 mmol, 1.2 eq.) was added dropwise using an addition funnel over ~35 min while maintaining the internal temperature <10°C. After addition was complete, the addition funnel was washed with ethyl acetate (10 mL, 1 L/kg). After holding at 0-5°C for an additional 1 hour, the reaction mixture was warmed to ambient temperature. After standing overnight, water (700 ml, 5 L/kg) and ethyl acetate (700 ml, 5 L/kg) were added and the resulting layers were separated. The top product-enriched organic layer was then washed with sodium chloride (14 wt%) in water (140 ml, 2 L/kg), and the resulting product-enriched organic layer was dried over MgSO ₄ (140 g, 1 kg/kg), filtered and washed with ethyl acetate (78 ml, 0.6 L/kg) to obtain a crude solution of the target substance in EtOAc. The solution was determined to contain ~15.6 wt.% 3-oxocyclohex-1-en-1-yl 4-methylbenzenesulfonate based on a comparison of the peaks of the target product and ethyl acetate, calculated based on the total mass of the solution 2114.36 g = 329 g of the target product (99% solution yield). 1H NMR (500 MHz, CDCl ₃ ) δ 7.75 (d, J=8.3 Hz, 2H), 7.33 (d, J=8.3 Hz, 2H), 5.70 (s, 1H) , 2.41-2.38 (m, 5H), 2.25-2.22 (m, 2H), 1.93-1.87 (m, 2H).

HPLC method conditions: column: Supelco Ascentis Express C18, 50x2.1 mm, 2.7 µm; mobile phase A: 0.05% TFA in acetonitrile:water (5:95); mobile phase B: 0.05% TFA in acetonitrile:water (95:5); temperature: 40°C; gradient: 0 min (0% B), 2.0 min (100% B), 2.5 min (100% B); flow rate: 1.0 ml/min; 232 nm; UHPLC RT 1.35 min.

Example 15. Preparation of methyl 3-oxocyclohex-1-ene-1-carboxylate.

A mixture of palladium(P) acetate (935.0 mg, 4.165 mmol, 0.05 eq.), 1,3bis(diphenylphosphino)propane (2.06 g, 4.99 mmol, 0.06 eq.) and methanol ( 40 ml, 1.8 l/kg). A 300 ml autoclave reactor was loaded with 3-oxocyclohex-1-en-1-yl 4-methylbenzenesulfonate in EtOAc (solution 141.7 g, ~15.6 wt.%, 22.1 g 3-oxocyclohex-1-en- 1-yl 4-methylbenzenesulfonate, 83.03 mmol, 1.0 eq., limiting reagent). A mixture of Pd(OAc) ₂ /DPPP/MeOH was loaded into the autoclave, followed by the addition of N,N-diisopropylethylamine. The autoclave was sealed and purged with 30 psi nitrogen 3 times followed by carbon monoxide purging 3 times. The autoclave was then pressurized to 30 psi and heated to 60° C. while stirring at 700 rpm. After 15 hours, the autoclave was purged with nitrogen and the contents were transferred to an amber glass bottle. The above process was then repeated an additional 7 times and all 8 reaction streams were combined for purification (theoretical product yield=102.35 g). The combined reaction mixtures were concentrated in vacuo and the resulting residue was first charged with n-heptane (160 ml), EtOAc (80 ml) and water (160 ml). The residue did not dissolve completely, and the supernatants were discarded and stored. The remaining residue was then dissolved by adding EtOAc (240 ml), water (160 ml) and heating to 40°C. The saved n-heptane/EtOAc/water mixture was then added to the biphasic EtOAc/water solution and the layers were separated. The lower aqueous layer was back-extracted with a mixture of n-heptane (160 ml) and EtOAc (160 ml). The combined organic layers were then concentrated on a rotary vacuum evaporator to obtain 110.39 g of an orange residue. The residue was then dissolved in EtOAc (200 ml), silica gel 60 (150 g) was added, filtered and washed with EtOAc (160 ml). The combined filtrates were concentrated on a rotary vacuum evaporator to obtain 98.16 g of an orange liquid, which was then purified by ISCO chromatography using DCM/EtOAc as the mobile phase to obtain 79.16 g

- 47 045036 (77% yield) methyl 3-oxocyclohex-1-ene-1-carboxylate as a yellow oil.

1H NMR (400 MHz, CDCl ₃ ) δ 6.74 (s, 1H), 3.84 (s, 3H), 2.61-2.58 (m, 2H), 2.47-2.44 (m , 2H), 2.10-2.03 (m, 2H).

HPLC method conditions: column: Acquity UPLC HSS C18, 50x2.1 mm, 1.8 µm; mobile phase A: 0.05% TFA in acetonitrile:water (5:95); mobile phase B: 0.05% TFA in acetonitrile:water (95:5); temperature: 40°C; gradient: 0 min (0% B), 2.0 min (100% B), 2.5 min (100% B); flow rate: 1.0 ml/min; 240 nm; UHPLC RT 1.16 min.

Example 16. Preparation of 3-oxocyclohex-1-ene-1-carboxylic acid.

A clean 500 mL reactor was charged with sodium carbonate (54.6 g, 515 mmol, 1.2 eq.) and water (400 mL, ~6 L/kg). Once dissolution was complete, methyl 3-oxocyclohex-1-ene-1-carboxylate (69.58 g, 429 mmol, 1.0 equiv, limiting reagent) was charged and heated to 35°C. After ~24 h, additional water (70 mL, ~1 L/kg) was added and the lower aqueous layer was separated from a small amount of the upper orange oil layer. 3 N was added slowly. aqueous HCl until pH ~1 was reached, and then back-extracted with DCM (5x100 ml). The combined organic layers were then dried over Na ₂ SO ₄ , filtered and concentrated on a rotary evaporator to give 46.72 g of yellow solids. The solids were then added with DCM (125 ml, ~1.8 L/kg), heated to 3035°C and then n-heptane (650 ml, ~9.3 L/kg) was added dropwise over > 1 h. to cause crystallization. The resulting suspension was then filtered, washed with n-heptane (2x50 ml, 2x0.7 L/kg) and dried in a vacuum oven at 50°C to obtain 42.60 g (67% yield) of 3oxocyclohex-1-ene-1- carboxylic acid as a pale yellow solid. Alternatively,

water

A 4 ml high pressure vial in a glove box was loaded with a stock solution of Pd(DPPP)Cl ₂ in DCE (a solution of 337.5 mg, prepared with 1.67 g of DCE and 7.96 mg of Pd(DPPP)Cl ₂ , which corresponds to 1 .60 mg Pd(DPPP)Cl ₂ , 0.0027 mmol, 0.04 eq.) and a solution of 3-oxocyclohex-1-en-1-yl 4methylbenzenesulfonate in EtOAc (solution 150 mg, ~13.4 wt.%, 20.1 mg 3-oxocyclohex-1-en-1-yl 4methylbenzenesulfonate, 0.075 mmol, 1.0 eq., limiting reagent). The mixture was concentrated to dryness (Genevac, full vacuum, ~1 h) and then COAc (18.4 mg, 0.187 mmol, 2.5 eq) and wet CH3CN (0.75 mL, prepared stock solution with 3.7 mL) were added sequentially CH3CN and 67.5 mg of water, which corresponds to ~10 equivalents of water). The vial was then sealed and nitrogen purged/removed 3 times at 30 psi. The vial was then pressurized with carbon monoxide to 55 psi and heated to 60° C. by placing on an orbital shaker at 500 rpm. After >12 h, the vial was vented/placed back under nitrogen to produce an estimated 99 AP of 3-oxocyclohex-1-ene1-carboxylic acid by UHPLC analysis.

1H NMR (500 MHz, CDCl ₃ ) δ 6.86 (t, J=1.9 Hz, 1H), 2.61 (td, J=6.1, 1.9 Hz, 2H), 2.52- 2.47 (m, 2H), 2.142.06 (m, 2H).

HPLC method conditions: column: Acquity UPLC HSS C18, 50x2.1 mm, 1.8 µm; mobile phase A: 0.05% TFA in acetonitrile:water (5:95); mobile phase B: 0.05% TFA in acetonitrile:water (95:5); temperature: 40°C; gradient: 0 min (0% B), 2.0 min (100% B), 2.5 min (100% B); flow rate: 1.0 ml/min; 240 nm; UHPLC RT 0.85 min.

Example 17 (1S,3S)-3-hydroxycyclohexane-1-carboxylic acid. 'CO ₂ H KRED ERED path A ERED, KRED O CO ₂ H path B BUT 'COGN

-

Claims (22)

Step reaction (path A). ERED-302 (450 mg, 45 wt%), GDH-105 (100 mg, 10 wt%) and NADPH (50 mg, 0.05 wt%) were added to a 50 mL reactor. Then 0.5 M sodium phosphate buffer pH 8.0 (17 ml, 17 l/kg) was added and stirring was started at 500 rpm. The reaction was maintained for 30 min until the biocatalysts dissolved. The pH was then checked and adjusted to pH 8.0 with 2.5 M NaOH followed by the addition of D-glucose (3.75 g, 3 eq). At this point, the temperature was set to 32.5°C and pHstat was used to maintain the reaction pH at 8.0. The second vessel was loaded with 3-oxocyclohex-1-ene-1carboxylic acid (1.0 g, limiting reagent), 0.5 M sodium phosphate buffer pH 8.0 (3 ml, 3 l/kg) and stirred for 10 min. The pH of this solution was then adjusted to pH 8.0 by adding 2.5 M NaOH. This solution was then loaded into the biocatalyst solution over 6 h using a syringe pump. After 16 h, the reaction was considered complete (<1 LCAP of 3-oxocyclohex-1-ene-1-carboxylic acid) and 4 M aqueous HCl was charged to adjust the pH to 6.0. A solution of KRED-P2-G03 (200 mg, 20 wt%) in 0.4 M sodium phosphate buffer (1 mL, 1 L/kg) was then added to maintain pH=6.0. After 16 h, the reaction was considered complete (<1 LCAP of 3-oxocyclohex-1-ene-1-carboxylic acid). Cascade reaction (path B). ERED-302 (750 mg, 45 wt%), GDH-105 (100 mg, 10 wt%), NADPH (50 mg, 0.05 wt%) and KRED-P2-G03 ( 100 mg, 10 wt.%). Then 0.5 M sodium phosphate buffer pH 7.0 (57 ml, 57 l/kg) was added and stirred at 500 rpm. The reaction was maintained for 30 min until the biocatalysts dissolved. The pH was then adjusted to pH 7.0 with 2.5 M aqueous NaOH followed by the addition of D-glucose (3.75 g, 2 eq.). At this point, the temperature was set to 32.5°C and a pH stat was used to maintain the reaction pH at 7.0. BMT-203387-01 (1.0 g, limiting reagent), 0.5 M sodium phosphate buffer with pH 8.0 (3 ml, 3 l/kg) was loaded into the second vessel and stirred for 10 min. The pH of this solution was then adjusted to pH 7.0 by adding 2.5 M NaOH. This solution was then loaded into the biocatalyst solution over 6 h using a syringe pump. After 16 h, the reaction was considered complete (>99 LCAP (1S,3S)-3hydroxycyclohexane-1-carboxylic acid). Analytical study: working concentration 1 mg/ml, sample volume: 1 µl. Column: DBFFAP 15 mm x 0.32 mm x 0.50 µm, carrier gas: helium, flow rate: 1.4 ml/min (constant flow); inlet temperature: 250°C, input mode: division, division factor: 10, division rate: 14. Oven temperature: 50°C, 1 min hold, then 10°C/min to 230°C, 3 min hold , then 20°C/min to 250°C, holding for 2 min (analysis time 25 min). Detector type: FID, detector temperature: 250°C, combustible gas flow: 30 ml/min, oxidizer flow: 300 ml/min, auxiliary gas: helium, auxiliary gas flow: 30 ml/min. CLAIM 1. Method for preparing the compound of formula (I): where R ¹ represents C _1-6 alkyl; And R ² and R ^2a represent Br; comprising contacting a compound of formula (III): R ² ✓Dch. rZ N w / NN ₄ ^r1 (ΠΙ), where R ¹ represents C _1-6 alkyl; And R ² and R ³ are Br; with reactant 2, which is organolithium, in solvent 2 selected from THF, MeTHF or a mixture of these solvents; for a period of time and at a temperature sufficient for the halogen-lithium exchange reaction; followed by benzyl chloromethyl ether in solvent 3 selected from THF, CH ₃ CN, IPAc, MeTHF or a mixture of these solvents; for a time and at a temperature sufficient for the alkylation reaction; followed by a strong acid to obtain the compound of formula (I). (2) contacting a compound of formula (XIIb) or a salt thereof: with i-PrMgCl (2.15 M in THF), with or without ZnCl ₂ , organomagnesium (or organozinc) reagent and PdCl ₂ (Xantphos) in THF; for >12 hours and at temperatures from -5 to 40°C, sufficient for C-C combination; and (3) sequentially contacting with trisodium ethylenediaminetetraacetic acid or disodium ethylenediaminetetraacetic acid in a solvent mixture of THF, with or without sodium percarbonate and sodium bisulfite (or sodium metabisulfite); for >1 hour and at a temperature of -5 to 25° C. sufficient to stop the reaction, yielding a compound of formula (XIVe), then isolated as either the free acid or a salt thereof selected from potassium salt, tetramethylammonium salt, tert- butylamine, dicyclohexylamine and tromethamine. (2) contacting a compound of formula (XIIa) or a salt thereof: with a halogen-metal exchange reaction product which is an organometallic reactant and a palladium catalyst selected from PdCl ₂ (Xantphos), Pd(dppf)Cl ₂ or Pd(OAc) ₂ +Brettphos, BINAP, dppf, DPEPhos and Xantphos in a solvent 8; for a period of time and at a temperature from -5 to 40 ° C, sufficient for the C-C combination; and (3) contacting with a metal binding agent selected from trisodium ethylenediaminetetraacetic acid or disodium ethylenediaminetetraacetic acid in solvent 8; for a time and at a temperature of -5 to 25° C. sufficient to stop the reaction to obtain a compound of formula (XIVd) or a salt thereof. 2. Method according to claim 1 for obtaining a compound of formula (Ia): - 49 045036 comprising contacting a compound of formula (IIIa): with n-BuLi in hexanes; for <1 hour and at a temperature of -30 to -10°C sufficient for the halogen-lithium exchange reaction, followed by benzyl chloromethyl ether; for 5 to 24 hours and at a temperature of -30 to -10°C sufficient for alkylation, and 33 wt.% HBr in acetic acid in CH3CN, to obtain the compound of formula (Ia). 3. Method for preparing a compound of formula (XII), or a stereoisomer or salt thereof: where R ⁸ and R ⁹ independently represent N, CH or C(C _1-6 alkyl); R ¹⁰ independently represents C _1-4 alkyl; And R ¹¹ represents Br; comprising contacting a compound of formula (XIII) or a salt thereof: where R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are the same as above in formula (XII), and R ^11a represents F; with a compound of formula (X), or a stereoisomer or salt thereof: in the presence of a metal alkoxide in solvent 7, which is a polar aprotic or non-polar solvent or a mixture of these solvents; for a time and at a temperature sufficient to complete the reaction to obtain a compound of formula (XII), or a stereoisomer or salt thereof. 4. Method according to claim 3 for obtaining a compound of formula (XIIa) or a salt thereof: comprising contacting a compound of formula (XIIIa) or a salt thereof: with a compound of formula (Xa) or its salt: - 50 045036 in the presence of a metal alkoxide selected from KOtBu, KHMDS, NaHMDS, and potassium amylate; in solvent 7 selected from DMF, MTBE, DMAc, NMP, DMPU, THF, 2-MeTHF, CPME, diisopropyl ether, toluene and a mixture of these solvents; for a time and at a temperature of from 20 to 35°C sufficient to complete the reaction to obtain a compound of formula (XIIa) or a salt thereof. 5. Method according to claim 3 or 4 for obtaining a compound of formula (XIIb) or a salt thereof: comprising contacting a compound of formula (XIIIb) or a salt thereof: with a compound of formula (Xa) or its salt: HO^^'CO ₂ H _(Ha) . in the presence of KOtBu in a DMF/MTBE mixture; for 18 to >48 hours and at a temperature of 20 to 35° C. sufficient to displace the fluoride to give a compound of formula (XIIb) or a salt thereof. 6. Method for preparing a compound of formula (XIVc), or a stereoisomer or salt thereof: R ¹² (XIVc); where R ⁸ and R ⁹ independently represent N, CH or C(C _1-6 alkyl); R ¹⁰ independently represents C _1-4 alkyl; And R ¹² represents C _1-4 alkyl; comprising (1) contacting a compound of formula (I): where R ¹ represents C _1-6 alkyl, and R ² and R ^2a represent Br; with or without an organometallic reagent and an inorganic reagent selected from ZnCl ₂ , ZnBr ₂ , and ZnI ₂ in solvent 8, which is a polar aprotic or non-polar solvent or a mixture of these solvents; for a period of time and at a temperature sufficient for the halogen-metal exchange reaction; then (2) contacting a compound of formula (XII) or a stereoisomer or salt thereof: - 51 045036 o with ₂ n r^R ⁸ R^^FiR ¹⁰ ^ R ¹¹ (XII); where R ⁸ and R ⁹ independently represent N, CH or C(C1. ₆ alkyl); R ¹⁰ independently represents C _1-4 alkyl; And R ¹¹ represents Br; with the product of the halogen-metal exchange reaction and a palladium catalyst in solvent 8; for a time and at a temperature sufficient for C-C combination; and (3) contacting with a metal binding agent selected from trisodium ethylenediaminetetraacetic acid or disodium ethylenediaminetetraacetic acid in solvent 8; for a time and at a temperature sufficient to stop the reaction to obtain a compound of formula (XIVc), or a stereoisomer or salt thereof. 7. Method according to claim 6 for preparing a compound of formula (XIVd) or a salt thereof: O*^^''CO ₂ H r^R ⁸ R^tIHR^o-i N-N R ¹² (XIVd); where R ⁸ and R ⁹ independently represent N, CH or C(C _1-4 alkyl); R ¹⁰ independently represents C _1-4 alkyl; And R ¹² represents C _1-4 alkyl; comprising (1) contacting a compound of formula (I) with an organometallic reagent which is a Grignard reagent selected from i-PrMgCl, i-PrMgCl*LiCl and i-PrMgBr, or an organolithium reagent selected from methyllithium, n-butyllithium, isopropyllithium , sec-butyllithium, tert-butyllithium, phenyllithium; with or without an inorganic reagent selected from ZnCl ₂ , ZnBr ₂ , ZnI ₂ , in a solvent 8 selected from THF, 2-MeTHF, DMF, DMA, DMPU, NMP, 1,4-dioxane and a mixture of these solvents; for a time and at a temperature from -5 to 25°C sufficient for the metal halide exchange reaction and the formation of an organozinc compound; 8. The method according to claim 6 or 7 for obtaining a compound of formula (XIVe) isolated as the free acid or its salt selected from potassium salt, tetramethylammonium, tert-butylamine, dicyclohexylamine and tromethamine: - 52 045036 comprising (1) contacting a compound of formula (Ia): with i-PrMgCl (2.15 M in THF), with or without ZnCl ₂ , in THF; for a time and at a temperature from -5 to 25°C sufficient for the metal halide exchange reaction and the formation of an organozinc compound (if ZnCl2 is present); 9. Method for preparing a compound of formula (XV), or a stereoisomer or salt thereof: where R ⁸ and R ⁹ independently represent N, CH or C(C _1-6 alkyl); R ¹⁰ independently represents C _1-4 alkyl; And R ¹² represents C _1-4 alkyl; comprising contacting a compound of formula (XIVc), or a stereoisomer or salt thereof: in an atmosphere of hydrogen with a palladium catalyst on a solid support and with or without an inorganic or organic acid selected from citric acid, oxalic acid and H ₂ SO ₄ , in a solvent 9 which is a polar protic or polar aprotic solvent or a mixture of these solvents; for a period of time and at a temperature sufficient for hydrogenation - 53 045036 lyse, to obtain a compound of formula (XV), or a stereoisomer or salt thereof. 10. Method according to claim 9 for preparing a compound of formula (XVa) or a salt thereof: where: R ⁸ and R ⁹ independently represent N, CH or C(C _1-4 alkyl); R ¹⁰ independently represents C _1-4 alkyl; And R ¹² represents C _1-4 alkyl; comprising contacting a compound of formula (XIVd) or a salt thereof: under a hydrogen atmosphere with a palladium catalyst on a solid support selected from 5-20 wt.% Pd/C, with or without an inorganic or organic acid selected from citric acid, oxalic acid, H ₂ SO ₄ , in a solvent 9 selected from EtOH , MeOH, water, THF, DMAc, NMP, IPA, t-AmOH, MeTHF, DMF, CH ₃ CN, EtOAc, IPOAc and mixtures of these solvents; for a time and at a temperature of from 20 to 60° C. sufficient for hydrogenolysis to obtain a compound of formula (XVa) or a salt thereof. 11. Method according to claim 9 or 10 for obtaining a compound of formula (XVb): under a hydrogen atmosphere with 10 wt.% Pd/C and with or without citric acid in a solvent 9 selected from EtOH, MeOH, water, THF, DMAc, NMP and a mixture of these solvents; for >12 hours and at a temperature of 20 to 60° C. sufficient for hydrogenolysis to give the compound of formula (XVb). 12. Method for preparing a compound of formula (XVI), or a stereoisomer or salt thereof: - 54 045036 where R ⁸ and R ⁹ independently represent N, CH or C(C _1-6 alkyl); R ¹⁰ independently represents C _1-4 alkyl; R ¹² represents C _1-4 alkyl; And R ¹⁴ and R ^14a independently represent C _1-6 alkyl; comprising contacting a compound of formula (XV), or a stereoisomer or salt thereof: with a compound of formula (XVII) or a salt thereof: О □ ^14а ι R ¹⁴ (XVII) where R ¹⁴ and R ^14a independently represent C _1-6 alkyl; in the presence of a metal alkoxide in solvent 9, which is a polar protic or polar aprotic solvent or a mixture of these solvents; for a time and at a temperature sufficient to form the carbamate to obtain a compound of formula (XVI), or a stereoisomer or salt thereof. 13. Method according to claim 12 for obtaining a compound of formula (XVIa) or a salt thereof: where: R ⁸ and R ⁹ independently represent N, CH or C(C _1-4 alkyl); R ¹⁰ independently represents C _1-4 alkyl; R ¹² represents C _1-4 alkyl; And R ¹⁴ and R ^14a independently represent C _1-4 alkyl; comprising contacting a compound of formula (XVa) or a salt thereof: with a compound of formula (XVII) or a salt thereof: - 55 045036 in the presence of a metal alkoxide selected from KOtBu (20 wt.% in THF) or KOtBu (1 M in THF), in solvent 9 selected from t-AmOH, DMF, THF, CH ₃ CN, MEK, NMP, DMAc, acetone , MIBK, 2MeTHF and mixtures of these solvents; for a time and at a temperature of from 20 to 75° C. sufficient to form the carbamate to obtain a compound of formula (XVIa) or a salt thereof. 14. Method according to claim 12 or 13 for obtaining a compound of formula (XVIb) or a salt thereof: with a compound of formula (XVIIa) or a salt thereof: O\ ^zNnYch ₃ YI ^{3 n s} (XVIIa) in the presence of KOtBu (20 wt.% in THF) in solvent 9 selected from t-AmOH, DMF, THF, CH ₃ CN, MEK and a mixture of the above solvents; for a time and at a temperature of 20 to 75° C. sufficient to form the carbamate to obtain a compound of formula (XVIb) or a salt thereof. 15. Compound of formula (Ib) or a salt thereof: R ² R (lb), where R ¹ represents C _1-6 alkyl; And R ² represents Br. 16. A compound according to claim 15, wherein said compound is a compound of formula (Ic) or a salt thereof: 17. Compound of formula (XII), or its stereoisomer, or salt: - 56 045036 where R ⁸ and R ⁹ independently represent N, CH or C(C _1-6 alkyl); R ¹⁰ independently represents C _1-4 alkyl; And R ¹¹ represents Br. 18. A compound according to claim 17, wherein said compound is a compound of formula (XIIa) or a salt thereof: where: R ⁸ and R ⁹ independently represent N, CH or C(C _1-4 alkyl); R ¹⁰ independently represents C _1-4 alkyl; And R ¹¹ represents Br. 19. A compound according to claim 17 or 18, wherein said compound is a compound of formula (XIIb) or a salt thereof: 20. Compound of formula (XIV), or its stereoisomer, or salt: N-N R ¹² (XIV); where R ⁸ and R ⁹ independently represent N, CH or C(C _1-6 alkyl); R ¹⁰ independently represents C _1-4 alkyl; R ¹² represents C _1-4 alkyl; And R ¹³ independently represents H or benzyl. 21. A compound according to claim 20, wherein said compound is a compound of formula (XIVa) or a salt thereof: where R ⁸ and R ⁹ independently represent N, CH or C(C1-4 alkyl); each R ¹⁰ independently represents C1-4 alkyl; R ¹² represents C _1-4 alkyl; And - 57 045036 R ¹³ independently represents benzyl. 22. A compound according to claim 17 or 18, wherein said compound is a compound of formula (XIVb) or a salt thereof: (XlVb); where R ¹³ represents benzyl. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2