METHODS FOR THE PREPARATION OF 5-BROMO-2-(3-CHLORO-PYRIDIN-2-YL)-2H-PYRAZOLE-3-CARBOXYLIC ACID

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;

Rig is selected from ether, ester, and 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

R 4 is hydrogen;

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

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

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

 ia) forming a mixture comprising

 aa) a compound of Formula VIII,

 wherein

 R 14 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocycle, and substituted or unsubstituted heterocycle;

 each of R 15 , R 16 , and R 17 is independently selected from hydrogen and halogen; and

 wherein at least one of R 15 , R 16 , and R 17 is a halogen;

 bb) a solvent; and

 cc) an inorganic base; and

 iia) reacting the mixture;

 BB) a compound of Formula IV, wherein

 each of R 7 -R 11 is independently selected from hydrogen and halogen;

 CC) a solvent;

 DD) an inorganic base; and

 EE) optionally an additive; and

 IIA) reacting the mixture;

b) a solvent;

c) an organic compound;

d) a compound comprising a metal; and

e) optionally an additive; and

ii) reacting the mixture; and

B) a metal hydroxide; and

II) reacting the mixture.

2 . The method of claim 1 , wherein the metal hydroxide is selected from alkali hydroxide, alkaline earth metal hydroxide, and combinations thereof.

3 . The method of claim 2 , wherein the alkali hydroxide is selected from lithium hydroxide, sodium hydroxide, and potassium hydroxide.

4 . The method of claim 2 , wherein the alkaline earth metal hydroxide is selected from calcium hydroxide and barium hydroxide.

5 . The method of claim 1 , wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 0° C. to about 90° C.

6 . The method of claim 1 , wherein the compound comprising a metal is selected from a Grignard reagent and a lithium-containing compound.

7 . The method of claim 6 , wherein the Grignard reagent is selected from MeMgCl, iPrMgCl, iPrMgBr, EtMgCl, iPr 2 NMgCl, iPr 2 NMgBr, Et 2 NMgCl, TMPMgCl, TMPMgCl.LiCl, iPr 2 NMgCl.LiCl, iPr 2 NMgBr.LiCl, and combinations thereof.

8 . The method of claim 7 , wherein the Grignard reagent is iPr 2 NMgCl.

9 . The method of claim 6 , wherein the lithium-containing compound is selected from LDA, nBuLi, and combinations thereof.

10 . The method of claim 1 , wherein the solvent b) is selected from THF, toluene, 1,4-dioxane, Me-THF, and combinations thereof.

11 . The method of claim 10 , wherein the solvent b) is THF.

12 . The method of claim 1 , wherein the organic compound is selected from dimethyl carbonate, N,N-dimethyacetamide, and combinations thereof.

13 . The method of claim 12 , wherein the organic compound is dimethyl carbonate.

14 . The method of claim 1 , wherein the method step ii) of reacting the mixture occurs at a reaction temperature in the range of about 0° C. to about 60° C.

15 . The method of claim 14 , wherein the method step ii) of reacting the mixture occurs at a reaction temperature in the range of about 0° C. to about 30° C.

16 . The method of claim 1 , wherein R 5 and R 6 of Formula III are each independently hydrogen.

17 . The method of claim 1 , wherein the inorganic base DD) is selected from powder sodium hydroxide, powder potassium hydroxide, potassium carbonate, potassium phosphate, powder sodium methoxide, powder potassium t-butoxide, and combinations thereof.

18 . 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 III, wherein

R 4 is hydrogen;

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

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

i) forming a mixture comprising

 a) a compound of Formula II, wherein

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

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

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

 IA) forming a mixture comprising

 AA) a compound of Formula VIII, wherein

 R 14 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocycle, and substituted or unsubstituted heterocycle;

 each of R 15 , R 16 , and R 17 is independently selected from hydrogen and halogen; and

 wherein at least one of R 15 , R 16 , and R 17 is a halogen;

 BB) a solvent; and

 CC) an inorganic base; and

 IIa) reacting the mixture;

 b) a compound of Formula IV, wherein

 each of R 7 -R 11 is independently selected from hydrogen and halogen;

 c) a solvent;

 d) an inorganic base; and

 e) optionally an additive; and

ii) reacting the mixture;

B) a carbonyl-containing compound;

C) a solvent;

D) a compound comprising a metal; and

E) optionally an additive; and

II) reacting the mixture.

19 . A method of preparing 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 hydrogen, the method comprising

I) forming a mixture comprising

A) a compound of Formula VIII, wherein

R 14 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocycle, and substituted or unsubstituted heterocycle;

each of R 15 , R 16 , and R 17 is independently selected from hydrogen and halogen; and

wherein at least one of R 15 , R 16 , and R 17 is a halogen;

B) a solvent; and

C) an inorganic base; and

II) reacting the mixture.

20 . The method of claim 19 , wherein the solvent is selected from THF, toluene, heptanes, Me-THF, and combinations thereof.