METHOD FOR PREPARING TERT-BUTYL N-((1R,2S,5S)-2-((2-((5-CHLOROPYRIDIN-2-YL)AMINO)-2-OXOACETYL)AMINO)-5-(DIMETHYLCARBAMOYL)CYCLOHEXYL)CARBAMATE

1 . A method of preparing a compound of Formula VI, wherein

each of R 5 -R 10 is independently selected from hydrogen and halogen; and

R 13 is an organic acid, the method comprising

I) forming a mixture comprising

A) a compound of Formula V, wherein

each of R 5 -R 10 is independently selected from hydrogen and halogen;

R 12 is nitrile; and

wherein the compound of Formula V is prepared according to a method comprising

i) forming a mixture comprising

 a) a compound of Formula III, wherein

 each of R 4 -R 10 is independently selected from hydrogen and halogen; wherein at least one of R 4 , R 5 , and R 6 is halogen, and wherein the compound of Formula III is prepared according to a method comprising

 IA) forming a mixture comprising

 AA) a compound of Formula II, wherein

 each of R 4 , R 5 , and R 6 is independently selected from hydrogen and halogen; and

 wherein at least one of R 4 , R 5 , and R 6 is halogen;

 BB) a compound of Formula IV, wherein

 each of R 7 -R 11 is independently selected from hydrogen and halogen and at least one of R 7 -R 11 is fluoride, wherein the compound of Formula IV is prepared according to a method comprising

 ia) forming a mixture comprising

 aa) a compound of Formula VII, wherein

 each of R 14 -R 18 is independently selected from hydrogen and halogen, wherein at least one of R 14 -R 18 is halogen; and

 none of R 14 -R 18 are fluoride;

 bb) a fluoride source;

 cc) a solvent; and

 dd) optionally a phase transfer catalyst; and

 iia) reacting the mixture;

 CC) a solvent; and

 DD) a base; and

 IIA) reacting the mixture;

 b) a cyanide reagent;

 c) a solvent;

 d) a compound comprising a metal; and

 e) optionally an additive; and

ii) reacting the mixture; and

B) an acid, base or enzyme; and

II) reacting the mixture.

2 . The method of claim 1 , wherein the acid is selected from H 2 SO 4 , hydrochloric acid (HCl), hydrobromic acid (HBr), formic acid (HCOOH), acetic acid (AcOH) and methylsulfonic acid (MSA), and combinations thereof; the base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium phosphate, potassium bicarbonate, combinations thereof; and the enzyme is selected from nitrilase, amidohydrolase, and combinations thereof.

3 . The method of claim 1 , wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 50° C. to about 120° C.

4 . The method of claim 1 , wherein the compound comprising a metal is a transition metal catalyst.

5 . The method of claim 1 , wherein the transition metal catalyst is selected from cuprous iodide, cuprous bromide and cuprous chloride, Copper(I)oxide, cuprous triflate (CuOTf), Copper(I) acetate and combinations thereof.

6 . The method of claim 1 , wherein the additive e) is selected from ethylene glycol, propylene glycol, water, glycerin, glucose, cyclodextrin, potassium iodide, sodium iodide, iodine and combinations thereof.

7 . The method of claim 1 , wherein the compound comprising metal d) is cuprous chloride, and the additive e) is ethylene glycol.

8 . The method of claim 1 , wherein the cyanide reagent is selected from sodium cyanide, potassium cyanide, copper(I) cyanide, zinc cyanide, potassium hexacyanoferrate (II) and combinations thereof.

9 . The method of claim 1 , wherein the solvent c) is selected from sulfolane, diglyme, triglyme, acetonitrile, toluene, N,N-Dimethylformamide (DMF), N,N-Dimethylacetamide (DMAc), N-methyl-2-pyrrolidone (NMP), and combinations thereof.

10 . A method of preparing a compound of Formula V, wherein

each of R 5 -R 10 is independently selected from hydrogen and halogen; and

R 12 is nitrile, the method comprising

i) forming a mixture comprising

a) a compound of Formula III, wherein

each of R 4 -R 10 is independently selected from hydrogen and halogen; wherein at least one of R 4 , R 5 , and R 6 is halogen, and wherein the compound of Formula III is prepared according to a method comprising

IA) forming a mixture comprising

 AA) a compound of Formula II, wherein

 each of R 4 , R 5 , and R 6 is independently selected from hydrogen and halogen; and

 wherein at least one of R 4 , R 5 , and R 6 is halogen;

 BB) a compound of Formula IV, wherein

 each of R 7 -R 11 is independently selected from hydrogen and halogen and at least one of R 7 -R 11 is fluoride, wherein the compound of Formula IV is prepared according to a method comprising

 ia) forming a mixture comprising

 aa) a compound of Formula VII, wherein

 each of R 14 -R 18 is independently selected from hydrogen and halogen; and

 wherein at least one of R 14 -R 18 is halogen, none of R 14 -R 18 are fluoride;

 bb) a fluoride source;

 cc) a solvent; and

 dd) optionally a phase transfer catalyst; and

 iia) reacting the mixture;

 CC) a solvent; and

 DD) a base; and

IIA) reacting the mixture;

b) a cyanide reagent;

c) a solvent;

d) a compound comprising a metal; and

e) optionally an additive; and

ii) reacting the mixture.

11 . The method of claim 10 , wherein the compound comprising a metal is a transition metal catalyst.

12 . The method of claim 10 , wherein the transition metal catalyst is selected from cuprous iodide, cuprous bromide and cuprous chloride, Copper(I)oxide, cuprous triflate (CuOTf), Copper(I) acetate and combinations thereof.

13 . The method of claim 10 , wherein the additive e) is selected from ethylene glycol, propylene glycol, water, glycerin, glucose, cyclodextrin, potassium iodide, sodium iodide, iodine and combinations thereof.

14 . The method of claim 10 , wherein the compound comprising metal d) is cuprous chloride, and the additive e) is ethylene glycol.

15 . The method of claim 10 , wherein the cyanide reagent is selected from sodium cyanide, copper(I) cyanide, zinc cyanide, potassium cyanide, potassium hexacyanoferrate(II) and combinations thereof.

16 . The method of claim 10 , wherein the solvent c) is selected from sulfolane, diglyme, triglyme, acetonitrile, toluene, N,N-Dimethylformamide (DMF), N,N-Dimethylacetamide (DMAc), N-methyl-2-pyrrolidone (NMP), and combinations thereof.

17 . A method of preparing a compound of Formula III, wherein

each of R 4 -R 18 is independently selected from hydrogen and halogen; wherein at least one of R 4 , R 5 , and R 6 is halogen, the method comprising

IA) forming a mixture comprising

AA) a compound of Formula II, wherein

each of R 4 , R 5 , and R 6 is independently selected from hydrogen and halogen; and

wherein at least one of R 4 , R 5 , and R 6 is halogen;

BB) a compound of Formula IV, wherein

each of R 7 -R 11 is independently selected from hydrogen and halogen and at least one of R 7 -R 11 is fluoride, wherein the compound of Formula IV is prepared according to a method comprising

ia) forming a mixture comprising

 aa) a compound of Formula VII, wherein

 each of R 14 -R 18 is independently selected from hydrogen and halogen; and

 wherein at least one of R 14 -R 18 is halogen,

 none of R 14 -R 18 are fluoride;

 bb) a fluoride source;

 cc) a solvent; and

 dd) optionally a phase transfer catalyst; and

iia) reacting the mixture;

CC) a solvent; and

DD) a base; and

IIA) reacting the mixture.

18 . The method of claim 17 , wherein R 5 -R 6 of Formula III are each independently hydrogen.

19 . The method of claim 17 , wherein the inorganic base is selected from sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium phosphate, lithium hydroxide, lithium carbonate, and organic base is selected from triethylamine, DBU, 1,4-Diazabicyclo[2.2.2]octane(DABCO), sodium methoxide, potassium t-butoxide, potassium methoxide, sodium t-butoxideand combinations thereof.

20 . The method of claim 17 , wherein the solvent CC) is selected from sulfolane, diglyme, triglyme, toluene, N,N-Dimethylformamide (DMF), N,N-Dimethylacetamide (DMAc), N-methyl-2-pyrrolidone (NMP), and combinations thereof.