2-(trifluoromethoxy)aniline

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

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

Procedure: A solution of o-trifluoromethoxyaniline (1.77 g, 10 mmol) in cold, concentrated HCl (11.6 mL) was diazotized at -5° C. (internal temperature) with a solution of NaNO2 (0.69 g, 10 mmol) in water (11 mL). After 15-20 minutes the mixture was treated portionwise with a cold (0° C.) solution of tin (II)chloride dihydrate (4.5 g, 20 mmol) in concentrated HCl (4 mL). Stirring was continued for another 3 hours with the ice bath warming to room temperature after one hour. The suspension was recooled, basified with 50% NaOH (to pH 14) and extracted with ether. The extracts were washed with 1N NaOH, water and brine, dried (MgSO4) and acidified with an excess of ethereal HCl. Removal of the solvent in vacuo yielded the title compound as an off-white solid (2 g, 88%). It was used without further purification. was diazotized at -5° C. extracted with ether The extracts were washed with 1N NaOH, water and brine dried (MgSO4) Removal of the solvent in vacuo

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-(Trifluoromethoxy)aniline (50 g, 0.282 mol) was dissolved in DME (1000 mL) and cooled to −5° C. Sodium hydride (12.3 g, 55%, 0.282 mol) was added in portions and the suspension was allowed to warm to room temperature. Ethyl chloroformate (23.5 mL, 0.245 mol) was added drop by drop and the mixture was stirred for 2 h at room temperature and for 1.5 h at reflux after addition was complete. Hydrolysis was with water (110 mL). The phases were separated and the water phase was extracted with ethyl acetate. The organic phases were washed with brine, pooled and dried with MgSO4. Evaporation of the solvent yielded 70.6 g of a brown oil, which was purified by chromatography on silica gel with hexane/ethyl acetate (6:1). This yielded the title compound, (44.2 g, 62%) as a beige yellow oil. (EI-MS: m/e=249.1 (M+)) to warm to room temperature at reflux after addition Hydrolysis The phases were separated the water phase was extracted with ethyl acetate The organic phases were washed with brine dried with MgSO4 Evaporation of the solvent

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

Procedure: The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-trifluoromethoxyaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.

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

Procedure: Ethyl chloroformate (4.4 mL, 0.046 mol) was added to a mixture of 2-(trifluoromethoxy)aniline (8.25 g, 0.0466 mol), sodium carbonate (15 g, 0.14 mol), 1,4-dioxane (70 mL) and water (70 mL) at 0° C. and the the reaction mixture stirred at room temperature overnight. The reaction mixture was then washed with ether, acidified (pH 3) and the product extracted into EtOAc (3×40 mL). The combined extracts were washed with water (40 mL) and brine (40 mL), dried over Na2SO4 and the solvent removed in vacuo to give the desired product in a 84% yield. 1H NMR (400 MHz, CDCl3): δ 1.33 (t, J=5.2 Hz, 3H), 4.25 (q, J=6.8 Hz, 2H), 6.91 (br, 1H), 7.04 (m, 1H), 7.23 (m, 1H), 7.28 (m, 1H) and 8.2 (m, 1H). MS (ES+): m/z 250.12 [MH+]. The reaction mixture was then washed with ether the product extracted into EtOAc (3×40 mL) The combined extracts were washed with water (40 mL) and brine (40 mL) dried over Na2SO4 the solvent removed in vacuo

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-(Trifluoromethoxy)aniline (50 g, 0.282 mol) was dissolved in DME (1000 mL) and cooled to −5° C. Sodium hydride (12.3 g, 55%, 0.282 mol) was added in portions and the suspension was allowed to warm to room temperature. Ethyl chloroformate (23.5 mL, 0.245 mol) was added drop by drop and the mixture was stirred for 2 h at room temperature and for 1.5 h at reflux after addition was complete. Hydrolysis was with water (110 mL). The phases were separated and the water phase was extracted with ethyl acetate. The organic phases were washed with brine, pooled and dried with MgSO4. Evaporation of the solvent yielded 70.6 g of a brown oil, which was purified by chromatography on silica gel with hexane/ethyl acetate (6:1). This yielded the title compound, (44.2 g, 62%) as a beige yellow oil. (EI-MS: m/e=249.1 (M+)) to warm to room temperature at reflux after addition Hydrolysis The phases were separated the water phase was extracted with ethyl acetate The organic phases were washed with brine dried with MgSO4 Evaporation of the solvent

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

Procedure: The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-trifluoromethoxyaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.

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

Procedure: Ethyl chloroformate (4.4 mL, 0.046 mol) was added to a mixture of 2-(trifluoromethoxy)aniline (8.25 g, 0.0466 mol), sodium carbonate (15 g, 0.14 mol), 1,4-dioxane (70 mL) and water (70 mL) at 0° C. and the the reaction mixture stirred at room temperature overnight. The reaction mixture was then washed with ether, acidified (pH 3) and the product extracted into EtOAc (3×40 mL). The combined extracts were washed with water (40 mL) and brine (40 mL), dried over Na2SO4 and the solvent removed in vacuo to give the desired product in a 84% yield. 1H NMR (400 MHz, CDCl3): δ 1.33 (t, J=5.2 Hz, 3H), 4.25 (q, J=6.8 Hz, 2H), 6.91 (br, 1H), 7.04 (m, 1H), 7.23 (m, 1H), 7.28 (m, 1H) and 8.2 (m, 1H). MS (ES+): m/z 250.12 [MH+]. The reaction mixture was then washed with ether the product extracted into EtOAc (3×40 mL) The combined extracts were washed with water (40 mL) and brine (40 mL) dried over Na2SO4 the solvent removed in vacuo

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

Procedure: The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using [2-(trifluoromethoxy)phenyl]amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a light-yellow solid. 1H NMR (300 MHz, CDCl3) δ ppm 1.09 (s, 3H), 2.35 (s, 3H), 4.74 (d, J=5.5 Hz, 2H), 6.81 (s, 1H), 6.98 (t, J=7.8 Hz, 1H), 7.16 (t, J=7.0 Hz, 2H), 7.23 (d, J=7.3 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.62 (t, J=7.3 Hz, 1H), 8.43 (d, J=7.5 Hz, 1H), 8.59 (d, J=3.8 Hz, 1H); MS (ESI) m/z 390.5 (M+1)+. The titled compound was synthesized The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1) the final product was washed with diethyl ether

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

Procedure: The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using [2-(trifluoromethoxy)phenyl]amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a light-yellow solid. 1H NMR (300 MHz, CDCl3) δ ppm 1.09 (s, 3H), 2.35 (s, 3H), 4.74 (d, J=5.5 Hz, 2H), 6.81 (s, 1H), 6.98 (t, J=7.8 Hz, 1H), 7.16 (t, J=7.0 Hz, 2H), 7.23 (d, J=7.3 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.62 (t, J=7.3 Hz, 1H), 8.43 (d, J=7.5 Hz, 1H), 8.59 (d, J=3.8 Hz, 1H); MS (ESI) m/z 390.5 (M+1)+. The titled compound was synthesized The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1) the final product was washed with diethyl ether

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

Procedure: The coupling of [(S)-4-(5-bromo-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate E8) and o-(trifluoromethoxy)phenylamine according to procedure A followed by deprotection yielded the title compound as a white solid. MS (ESI): m/z=439.3 [M+H]+.

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

Procedure: Ethyl chloroformate (4.4 mL, 0.046 mol) was added to a mixture of 2-(trifluoromethoxy)aniline (8.25 g, 0.0466 mol), sodium carbonate (15 g, 0.14 mol), 1,4-dioxane (70 mL) and water (70 mL) at 0° C. and the reaction mixture stirred at room temperature overnight. The reaction mixture was then washed with ether, acidified (pH 3) and the product extracted into EtOAc (3×40 mL). The combined extracts were washed with water (40 mL) and brine (40 mL), dried over Na2SO4 and the solvent removed in vacuo to give the desired product in a 84% yield. 1H NMR (400 MHz, CDCl3): δ 1.33 (t, J=5.2 Hz, 3H), 4.25 (q, J=6.8 Hz, 2H), 6.91 (br, 1H), 7.04 (m, 1H), 7.23 (m, 1H), 7.28 (m, 1H) and 8.2 (m, 1H). MS (ES+): m/z 250.12 [MH+]. The reaction mixture was then washed with ether the product extracted into EtOAc (3×40 mL) The combined extracts were washed with water (40 mL) and brine (40 mL) dried over Na2SO4 the solvent removed in vacuo