4-[(dimethylamino)methyl]-3-(trifluoromethyl)aniline

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

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-amino-N,N-dimethyl-2-(trifluoromethyl)benzamide (8.3 g, 23.59 mmol) in THF (100 mL) stirred under a N2 atmosphere at 20° C. was added BH3.DMS (11.20 mL, 118 mmol) dropwise. The reaction mixture was stirred at 80° C. for 2 h. To the solution was added MeOH, then concentrated in vacuo to give the crude product. The crude material was purified by silica column chromatography (DCM/MeOH=30:1). All fractions found to contain product by TLC (DCM/MeOH=10:1, Rf=0.4) were combined and concentrated to yield light yellow oil of 4-((dimethylamino)methyl)-3-(trifluoromethyl)aniline (4 g, 18.33 mmol, 78.0% yield): 1H NMR (400 MHz, CD3OD) δ 7.99 (d, J=8.0 Hz, 1H), 7.73 (s, 1H), 7.67 (d, 8.0 Hz, 1H), 4.57 (s, 2H), 2.96 (s, 6H); ES-LCMS m/z 219.2 (M+H). was added BH3 concentrated in vacuo to give the crude product The crude material was purified by silica column chromatography (DCM/MeOH=30:1) concentrated

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

Procedure: N-(4-Dimethylaminomethyl-3-trifluoromethyl-phenyl)-pyrimidine-4,6-diamine (359 mg, 1.2 mmol) is dissolved in MeOH (12 mL) and treated with K2CO3 (6 mL of a 1N aqueous solution) at RT. The reaction is heated to reflux for 1.5 h until completion, cooled back to RT and concentrated. The residual oil is taken up in EtOAc and washed with brine. The organic layers are dried over Na2SO4, filtered and concentrated under reduced pressure. Drying under high vacuum gives the title compound as a yellow oil. ESI-MS: 219 [MH]+. The reaction is heated to reflux for 1.5 h until completion concentrated washed with brine The organic layers are dried over Na2SO4 filtered concentrated under reduced pressure Drying under high vacuum

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound is prepared as described in Example 152A but using 4-dimethylaminomethyl-3-trifluoromethyl-phenylamine (218 mg, 1.46 mmol, 1 eq.), 6-chloro-pyrimidin-4-ylamine, and stirring the reaction mixture for 5 h at 150° C. The crude product is purified by silica gel column chromatography (DCM/MeOH+1% NH3aq, 92:8) to afford the title compound as a white solid. ESI-MS: 312.1 [MH]+; tR=1.20 min (purity: 100%, gradient J); TLC: Rf=0.16 (DCM/MeOH+1% NH3aq, 92:8). The title compound is prepared The crude product is purified by silica gel column chromatography (DCM/MeOH+1% NH3aq, 92:8)

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound is prepared as described in Example 152A but using 4-dimethylaminomethyl-3-trifluoromethyl-phenylamine (218 mg, 1.46 mmol, 1 eq.), 6-chloro-pyrimidin-4-ylamine, and stirring the reaction mixture for 5 h at 150° C. The crude product is purified by silica gel column chromatography (DCM/MeOH+1% NH3aq, 92:8) to afford the title compound as a white solid. ESI-MS: 312.1 [MH]+; tR=1.20 min (purity: 100%, gradient J); TLC: Rf=0.16 (DCM/MeOH+1% NH3aq, 92:8). The title compound is prepared The crude product is purified by silica gel column chromatography (DCM/MeOH+1% NH3aq, 92:8)

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-((dimethylamino)methyl)-3-(trifluoromethyl)aniline, 2 hydrochloride (4 g, 13.74 mmol), 2-(4-bromo-2-fluorophenyl)acetic acid (3.20 g, 13.74 mmol) and Et3N (9.57 mL, 68.7 mmol) in DCM (100 mL) stirred under a N2 atmosphere at 20° C. were added EDC (2.63 g, 13.74 mmol) and HOBt (2.104 g, 13.74 mmol) in one charge. The reaction mixture was stirred at 20° C. for 2 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=3:1). All fractions found to contain product by TLC (PE/EA=2:1, Rf 0.6) were combined and concentrated to yield a light yellow solid of 2-(4-bromo-2-fluorophenyl)-N-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)acetamide (5.5 g, 9.14 mmol, 66.5% yield): 1H NMR (400 MHz, CDCl3) δ 7.79 (br. s., 2H), 7.70 (d, J=5.02 Hz, 2H), 7.30 (br. s., 2H), 3.73 (s, 2H), 3.53 (s, 2H), 2.47 (s, 6H); ES-LCMS m/z 435.0 (M+H). charge Then the solution was concentrated The combined organic extract was washed with brine dried over MgSO4 filtered concentrated The crude material was purified by silica column chromatography (PE/EA=3:1) concentrated

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-((dimethylamino)methyl)-3-(trifluoromethyl)aniline, 2 hydrochloride (4 g, 13.74 mmol), 2-(4-bromo-2-fluorophenyl)acetic acid (3.20 g, 13.74 mmol) and Et3N (9.57 mL, 68.7 mmol) in DCM (100 mL) stirred under a N2 atmosphere at 20° C. were added EDC (2.63 g, 13.74 mmol) and HOBt (2.104 g, 13.74 mmol) in one charge. The reaction mixture was stirred at 20° C. for 2 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=3:1). All fractions found to contain product by TLC (PE/EA=2:1, Rf 0.6) were combined and concentrated to yield a light yellow solid of 2-(4-bromo-2-fluorophenyl)-N-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)acetamide (5.5 g, 9.14 mmol, 66.5% yield): 1H NMR (400 MHz, CDCl3) δ 7.79 (br. s., 2H), 7.70 (d, J=5.02 Hz, 2H), 7.30 (br. s., 2H), 3.73 (s, 2H), 3.53 (s, 2H), 2.47 (s, 6H); ES-LCMS m/z 435.0 (M+H). charge Then the solution was concentrated The combined organic extract was washed with brine dried over MgSO4 filtered concentrated The crude material was purified by silica column chromatography (PE/EA=3:1) concentrated

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-amino-N,N-dimethyl-2-(trifluoromethyl)benzamide (8.3 g, 23.59 mmol) in THF (100 mL) stirred under a N2 atmosphere at 20° C. was added BH3.DMS (11.20 mL, 118 mmol) dropwise. The reaction mixture was stirred at 80° C. for 2 h. To the solution was added MeOH, then concentrated in vacuo to give the crude product. The crude material was purified by silica column chromatography (DCM/MeOH=30:1). All fractions found to contain product by TLC (DCM/MeOH=10:1, Rf=0.4) were combined and concentrated to yield light yellow oil of 4-((dimethylamino)methyl)-3-(trifluoromethyl)aniline (4 g, 18.33 mmol, 78.0% yield): 1H NMR (400 MHz, CD3OD) δ 7.99 (d, J=8.0 Hz, 1H), 7.73 (s, 1H), 7.67 (d, 8.0 Hz, 1H), 4.57 (s, 2H), 2.96 (s, 6H); ES-LCMS m/z 219.2 (M+H). was added BH3 concentrated in vacuo to give the crude product The crude material was purified by silica column chromatography (DCM/MeOH=30:1) concentrated

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

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

Procedure: The title compound is prepared as described in Example 7 but using (4-imidazo[4,5-b]pyridin-3-yl-2-methyl-phenyl)-acetic acid (Step 60.1) and 4-dimethylaminomethyl-3-trifluoromethyl-phenylamine (disclosed in WO2005/051366). Title compound: ES-MS: 468.2 [M+H]+; tR=2.97 min (System 1); Rf=0.37 (CH2Cl2/MeOH, 9:1+0.1% NH3aq). The title compound is prepared

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-((dimethylamino)methyl)-3-(trifluoromethyl)aniline, 2 hydrochloride (4 g, 13.74 mmol), 2-(4-bromo-2-fluorophenyl)acetic acid (3.20 g, 13.74 mmol) and Et3N (9.57 mL, 68.7 mmol) in DCM (100 mL) stirred under a N2 atmosphere at 20° C. were added EDC (2.63 g, 13.74 mmol) and HOBt (2.104 g, 13.74 mmol) in one charge. The reaction mixture was stirred at 20° C. for 2 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=3:1). All fractions found to contain product by TLC (PE/EA=2:1, Rf 0.6) were combined and concentrated to yield a light yellow solid of 2-(4-bromo-2-fluorophenyl)-N-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)acetamide (5.5 g, 9.14 mmol, 66.5% yield): 1H NMR (400 MHz, CDCl3) δ 7.79 (br. s., 2H), 7.70 (d, J=5.02 Hz, 2H), 7.30 (br. s., 2H), 3.73 (s, 2H), 3.53 (s, 2H), 2.47 (s, 6H); ES-LCMS m/z 435.0 (M+H). charge Then the solution was concentrated The combined organic extract was washed with brine dried over MgSO4 filtered concentrated The crude material was purified by silica column chromatography (PE/EA=3:1) concentrated

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-amino-N,N-dimethyl-2-(trifluoromethyl)benzamide (8.3 g, 23.59 mmol) in THF (100 mL) stirred under a N2 atmosphere at 20° C. was added BH3.DMS (11.20 mL, 118 mmol) dropwise. The reaction mixture was stirred at 80° C. for 2 h. To the solution was added MeOH, then concentrated in vacuo to give the crude product. The crude material was purified by silica column chromatography (DCM/MeOH=30:1). All fractions found to contain product by TLC (DCM/MeOH=10:1, Rf=0.4) were combined and concentrated to yield light yellow oil of 4-((dimethylamino)methyl)-3-(trifluoromethyl)aniline (4 g, 18.33 mmol, 78.0% yield): 1H NMR (400 MHz, CD3OD) δ 7.99 (d, J=8.0 Hz, 1H), 7.73 (s, 1H), 7.67 (d, 8.0 Hz, 1H), 4.57 (s, 2H), 2.96 (s, 6H); ES-LCMS m/z 219.2 (M+H). was added BH3 concentrated in vacuo to give the crude product The crude material was purified by silica column chromatography (DCM/MeOH=30:1) concentrated