[2-(trifluoromethoxy)phenyl]methanamine

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

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

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a methylene chloride solution of commercially available 2-(trifluoromethoxy)benzyl amine (2.81 mmol) at 0° C. was added solid Proton sponge (2.81 mmol) then a 20% solution of phosgene in toluene (2.81 mmol). The solution was stirred at 25° C. for 1 hour and then washed with 1N HCl (40 mL). The methylene chloride was then dried with sodium sulfate and evaporated. 1H-NMR (CDCl3): 7.5 ppm (d, 1H); 7.4 ppm (m, 2H); 7.3 ppm (d, 1H); 4.6 ppm (s, 2H). washed with 1N HCl (40 mL) The methylene chloride was then dried with sodium sulfate evaporated

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a methylene chloride solution of commercially available 2-(trifluoromethoxy)benzyl amine (2.81 mmol) at 0° C. was added solid Proton sponge (2.81 mmol) then a 20% solution of phosgene in toluene (2.81 mmol). The solution was stirred at 25° C. for 1 hour and then washed with 1N HCl (40 mL). The methylene chloride was then dried with sodium sulfate and evaporated. 1H-NMR (CDCl3): 7.5 ppm (d, 1H); 7.4 ppm (m, 2H); 7.3 ppm (d, 1H); 4.6 ppm (s, 2H). washed with 1N HCl (40 mL) The methylene chloride was then dried with sodium sulfate evaporated

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a methylene chloride solution of commercially available 2-(trifluoromethoxy)benzyl amine (2.81 mmol) at 0° C. was added solid Proton sponge (2.81 mmol) then a 20% solution of phosgene in toluene (2.81 mmol). The solution was stirred at 25° C. for 1 hour and then washed with 1N HCl (40 mL). The methylene chloride was then dried with sodium sulfate and evaporated. 1H-NMR (CDCl3): 7.5 ppm (d, 1H); 7.4 ppm (m, 2H); 7.3 ppm (d, 1H); 4.6 ppm (s, 2H). washed with 1N HCl (40 mL) The methylene chloride was then dried with sodium sulfate evaporated

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a methylene chloride solution of commercially available 2-(trifluoromethoxy)benzyl amine (2.81 mmol) at 0° C. was added solid Proton sponge (2.81 mmol) then a 20% solution of phosgene in toluene (2.81 mmol). The solution was stirred at 25° C. for 1 hour and then washed with 1N HCl (40 mL). The methylene chloride was then dried with sodium sulfate and evaporated. 1H-NMR (CDCl3): 7.5 ppm (d, 1H); 7.4 ppm (m, 2H); 7.3 ppm (d, 1H); 4.6 ppm (s, 2H). washed with 1N HCl (40 mL) The methylene chloride was then dried with sodium sulfate evaporated

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The 4-[(2-chloro-5-nitro-pyridin-4-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.27 mmol) was dissolved in DMA (5.0 mL). 2-Trifluoromethoxybenzyl amine (153 mg, 0.80 mmol) was added followed by diisopropylethylamine (0. 14 mL, 0.80 mmol). The reaction was heated to 100° C. and stirred for 18 h, then cooled to 25° C. The volatiles were removed in vacuo and the crude product was purified by flash column chromatography (SiO2, 15-50% EtOAc-hexanes) to afford 4-{[5-nitro-2-(2-trifluoromethoxy-benzylamino)-pyridin-4-ylamino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester as a yellow foam (91 mg, 64%). cooled to 25° C The volatiles were removed in vacuo the crude product was purified by flash column chromatography (SiO2, 15-50% EtOAc-hexanes)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 2-(Trifluoromethoxy)benzylamine (58.6 mg, 0.307 mmol) in toluene (1.239 mL) at 0° C. was added trimethylaluminium (2M in toluene, 0.557 mL, 1.115 mmol) dropwise. The mixture was stirred for 5 min at 0° C., then a solution of 95 (125 mg, 0.279 mmol) in toluene (0.620 mL) was added dropwise. The mixture was stirred at room temperature for 1 h, then at 55° C. for 1 h, and at 95° C. for 1.5 h till the reaction was complete. Saturated NaHCO3 was added to the reaction mixture followed by extraction with EtOAc. The organic extracts were dried over MgSO4, filtrated and concentrated and the residue was purified via Biotage (5% to 20% MeOH/CH2Cl2; 12M column) to give 99 as yellow oil. LRMS (ESI): calc.593.6; found 594.3 (MH)+. The mixture was stirred at room temperature for 1 h at 55° C. for 1 h at 95° C. for 1.5 h till the reaction was complete followed by extraction with EtOAc The organic extracts were dried over MgSO4 filtrated concentrated the residue was purified via Biotage (5% to 20% MeOH/CH2Cl2; 12M column)

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

Procedure: The title compound, MS: m/e=428.1 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 5-methyl-2-furanmethanamine and 2-(trifluoromethoxy)benzylamine.

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

Procedure: The title compound, MS: m/e=454.0 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-methoxybenzylamine and 2-(trifluoromethoxy)benzylamine.

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: {4-[(2-Chloro-5-fluoro-pyrimidin-4-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester (127 mg, 0.35 mmol) was dissolved in 2-trifluoromethoxybenzylamine (2.5 mL) and heated at 180° C. for 20 min. The reaction mixture was diluted with EtOAc and poured into 1N HCl. The aqueous layer was separated and extracted with EtOAc (×2). The combined organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was dissolved in CH2Cl2 (2.5 mL) and TFA (2.5 mL) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and the resulting residue was diluted with EtOAc. The solution was poured into 10% NaHCO3 and the aqueous layer was re-extracted with EtOAc. The combined organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel preparative TLC using 9:1:0.1 CH2Cl2:MeOH:NH4OH as an eluent to afford 22 mg (15%) of the title compound, m/z 414.6 (M+1)+. The aqueous layer was separated extracted with EtOAc (×2) The combined organic phase was dried over anhydrous Na2SO4 concentrated in vacuo The resulting residue was dissolved in CH2Cl2 (2.5 mL) TFA (2.5 mL) was added The reaction mixture was concentrated in vacuo the resulting residue was diluted with EtOAc The solution was poured into 10% NaHCO3 the aqueous layer was re-extracted with EtOAc The combined organic phase was dried over anhydrous Na2SO4 concentrated in vacuo The resulting residue was purified by silica gel preparative TLC

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The above {4-[(2,5-dichloro-pyrimidin-4-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester (97 mg, 0.26 mmol) was dissolved in 2-trifluoromethoxy-benzylamine (2.5 mL) and the mixture was heated to 180° C. for 20 min. The reaction mixture was diluted with EtOAc and poured into 1N HCl solution. The aqueous layer was separated and extracted with EtOAc (×2). The combined organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was dissolved in CH2Cl2 (2.5 mL) and TFA (2.5 mL) was added. The reaction mixture was stirred at room temperature for 1 h. The mixture was then poured into 10% NaHCO3 and the aqueous layer was extracted with EtOAc (×2). The combined organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel preparative TLC using 9:1:0.1 CH2Cl2:MeOH:NH4OH as an eluent to afford 97 mg (87%) of the title compound, m/z 430.5 (M+1)+. The aqueous layer was separated extracted with EtOAc (×2) The combined organic phase was dried over anhydrous Na2SO4 concentrated in vacuo The resulting residue was dissolved in CH2Cl2 (2.5 mL) TFA (2.5 mL) was added The mixture was then poured into 10% NaHCO3 the aqueous layer was extracted with EtOAc (×2) The combined organic phase was dried over anhydrous Na2SO4 concentrated in vacuo The resulting residue was purified by silica gel preparative TLC