1-(1-bromoethyl)-2-(trifluoromethyl)benzene

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 4-[4-(6-Amino-5-hydroxy-pyridin-3-yl)-benzoyl]-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (50 mg, 0.12 mmol) and 1-(1-bromo-ethyl)-2-trifluoromethyl-benzene (32 mg, 0.12 mmol) in DMF (2 ml) was added 2 M Cs2CO3 (0.18 mL, 0.35 mmol), followed by water (0.5 mL), the mixture was stirred overnight then heated at 70° C. for 8 hr, LCMS showed that the reaction was completed. The DMF and water were removed. TFA (2 mL was added to the residue and stirred at room temperature for 3 hr. The TFA was removed, followed by addition of methanol. The residue was purified by prep-HPLC to afford (4-{6-amino-5-[1-(2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(3,5-dimethyl-piperazin-1-yl)-methanone (20 mg, yield 34.2%). The DMF and water were removed TFA (2 mL was added to the residue stirred at room temperature for 3 hr The TFA was removed followed by addition of methanol The residue was purified by prep-HPLC

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 4-[4-(6-Amino-5-hydroxy-pyridin-3-yl)-benzoyl]-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (50 mg, 0.12 mmol) and 1-(1-bromo-ethyl)-2-trifluoromethyl-benzene (32 mg, 0.12 mmol) in DMF (2 ml) was added 2 M Cs2CO3 (0.18 mL, 0.35 mmol), followed by water (0.5 mL), the mixture was stirred overnight then heated at 70° C. for 8 hr, LCMS showed that the reaction was completed. The DMF and water were removed. TFA (2 mL was added to the residue and stirred at room temperature for 3 hr. The TFA was removed, followed by addition of methanol. The residue was purified by prep-HPLC to afford (4-{6-amino-5-[1-(2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(3,5-dimethyl-piperazin-1-yl)-methanone (20 mg, yield 34.2%). The DMF and water were removed TFA (2 mL was added to the residue stirred at room temperature for 3 hr The TFA was removed followed by addition of methanol The residue was purified by prep-HPLC

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a similar manner as described for example B3, 8.0 g of an isomeric mixture of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3H-imidazo[4,5-c]pyridin-3-yl]-3-hydroxythiophene-2-carboxylate and methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-hydroxythiophene-2-carboxylate (example C3) and 3.15 g of K2CO3 and 5.95 g of 1-(1-bromoethyl)-2-(trifluoromethyl)benzene in 240 ml anhydrous N,N-dimethylformamide yield compound B25a and compound B25b. yield compound B25a

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a similar manner as described for example B3, 8.0 g of an isomeric mixture of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3H-imidazo[4,5-c]pyridin-3-yl]-3-hydroxythiophene-2-carboxylate and methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-hydroxythiophene-2-carboxylate (example C3) and 3.15 g of K2CO3 and 5.95 g of 1-(1-bromoethyl)-2-(trifluoromethyl)benzene in 240 ml anhydrous N,N-dimethylformamide yield compound B25a and compound B25b. yield compound B25a

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a similar manner as described for example B3, 300 mg of an isomeric mixture of methyl 3-hydroxy-5-(1H-imidazo[4,5-c]pyridin-1-yl)thiophene-2-carboxylate and methyl 3-hydroxy-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate (example C1) and 181 mg K2CO3 and 332 mg 1-(1-bromoethyl)-2-(trifluoromethyl)benzene in 5 ml N,N-dimethylformamide yield methyl 5-(1H-imidazo[4,5-c]pyridin-1-yl)-3-{1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxylate and methyl 5-(3H-imidazo[4,5-c]pyridin-3-yl)-3-{1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxylate.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a similar manner as described for example B3, 300 mg of an isomeric mixture of methyl 3-hydroxy-5-(1H-imidazo[4,5-c]pyridin-1-yl)thiophene-2-carboxylate and methyl 3-hydroxy-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate (example C1) and 181 mg K2CO3 and 332 mg 1-(1-bromoethyl)-2-(trifluoromethyl)benzene in ml N,N-dimethylformamide yield methyl 5-(1H-imidazo[4,5-c]pyridin-1-yl)-3-{1-[2-(trifluoro-methyl)phenyl]ethoxy}thiophene-2-carboxylate and methyl 5-(3H-imidazo[4,5-c]pyridin-3-yl)-3-{1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxylate.

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 4-[4-(6-Amino-5-hydroxy-pyridin-3-yl)-benzoyl]-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (50 mg, 0.12 mmol) and 1-(1-bromo-ethyl)-2-trifluoromethyl-benzene (32 mg, 0.12 mmol) in DMF (2 ml) was added 2 M Cs2CO3 (0.18 mL, 0.35 mmol), followed by water (0.5 mL), the mixture was stirred overnight then heated at 70° C. for 8 hr, LCMS showed that the reaction was completed. The DMF and water were removed. TFA (2 mL was added to the residue and stirred at room temperature for 3 hr. The TFA was removed, followed by addition of methanol. The residue was purified by prep-HPLC to afford (4-{6-amino-5-[1-(2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(3,5-dimethyl-piperazin-1-yl)-methanone (20 mg, yield 34.2%). The DMF and water were removed TFA (2 mL was added to the residue stirred at room temperature for 3 hr The TFA was removed followed by addition of methanol The residue was purified by prep-HPLC

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 4-[4-(6-Amino-5-hydroxy-pyridin-3-yl)-benzoyl]-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (50 mg, 0.12 mmol) and 1-(1-bromo-ethyl)-2-trifluoromethyl-benzene (32 mg, 0.12 mmol) in DMF (2 ml) was added 2 M Cs2CO3 (0.18 mL, 0.35 mmol), followed by water (0.5 mL), the mixture was stirred overnight then heated at 70° C. for 8 hr, LCMS showed that the reaction was completed. The DMF and water were removed. TFA (2 mL was added to the residue and stirred at room temperature for 3 hr. The TFA was removed, followed by addition of methanol. The residue was purified by prep-HPLC to afford (4-{6-amino-5-[1-(2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl)-phenyl)-(3,5-dimethyl-piperazin-1-yl)-methanone (20 mg, yield 34.2%). The DMF and water were removed TFA (2 mL was added to the residue stirred at room temperature for 3 hr The TFA was removed followed by addition of methanol The residue was purified by prep-HPLC

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 4-[4-(6-Amino-5-hydroxy-pyridin-3-yl)-benzoyl]-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (50 mg, 0.12 mmol) and 1-(1-bromo-ethyl)-2-trifluoromethyl-benzene (32 mg, 0.12 mmol) in DMF (2 ml) was added 2 M Cs2CO3 (0.18 mL, 0.35 mmol), followed by water (0.5 mL), the mixture was stirred overnight then heated at 70° C. for 8 hr, LCMS showed that the reaction was completed. The DMF and water were removed. TFA (2 mL was added to the residue and stirred at room temperature for 3 hr. The TFA was removed, followed by addition of methanol. The residue was purified by prep-HPLC to afford (4-{6-amino-5-[1-(2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(3,5-dimethyl-piperazin-1-yl)-methanone (20 mg, yield 34.2%). The DMF and water were removed TFA (2 mL was added to the residue stirred at room temperature for 3 hr The TFA was removed followed by addition of methanol The residue was purified by prep-HPLC

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 4-[4-(6-Amino-5-hydroxy-pyridin-3-yl)-benzoyl]-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (50 mg, 0.12 mmol) and 1-(1-bromo-ethyl)-2-trifluoromethyl-benzene (32 mg, 0.12 mmol) in DMF (2 ml) was added 2 M Cs2CO3 (0.18 mL, 0.35 mmol), followed by water (0.5 mL), the mixture was stirred overnight then heated at 70° C. for 8 hr, LCMS showed that the reaction was completed. The DMF and water were removed. TFA (2 mL was added to the residue and stirred at room temperature for 3 hr. The TFA was removed, followed by addition of methanol. The residue was purified by prep-HPLC to afford (4-{6-amino-5-[1-(2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(3,5-dimethyl-piperazin-1-yl)-methanone (20 mg, yield 34.2%). The DMF and water were removed TFA (2 mL was added to the residue stirred at room temperature for 3 hr The TFA was removed followed by addition of methanol The residue was purified by prep-HPLC