1-isocyanato-2-(trifluoromethoxy)benzene

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

Procedure: 3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 2-trifluoromethoxyphenyl isocyanate in a similar manner as described in Example 1.53, providing 1.5 mg (3%) of Compound 34: LCMS m/z (%)=440 (M+H37Cl, 14), 438 (M+H35Cl, 14). 1H NMR (400 MHz, acetone-d6) δ: 8.19 (s, 1H), 7.90 (s, 1H), 7.43 (d, J=4 Hz, 1H), 7.25 (s, 1H), 7.04 (t, J=12 Hz, 2H), 6.99 (dd, J1=8 Hz, J2=2 Hz, 1H), 6.75 (d, J=4 Hz, 1H), 6.72 (d, J=4 Hz, 1H), 6.66 (d, J=2 Hz, 1H), 3.63 (s, 3H), 3.45 (s, 3H).

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

Procedure: N-(2-Hydroxy-4-nitrophenyl)-N′-(2-trifluoromethyloxyphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-trifluoromethoxy phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (0.69 g, 60%). EI-MS m/z 358 (M+H)+ The product was purified by dilution with methylene chloride and precipitation with hexanes Filtering

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

Procedure: 3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 2-trifluoromethoxyphenyl isocyanate in a similar manner as described in Example 1.53, providing 1.5 mg (3%) of Compound 34: LCMS m/z (%)=440 (M+H37Cl, 14), 438 (M+H35Cl, 14). 1H NMR (400 MHz, acetone-d6) δ: 8.19 (s, 1H), 7.90 (s, 1H), 7.43 (d, J=4 Hz, 1H), 7.25 (s, 1H), 7.04 (t, J=12 Hz, 2H), 6.99 (dd, J1=8 Hz, J2=2 Hz, 1H), 6.75 (d, J=4 Hz, 1H), 6.72 (d, J=4 Hz, 1H), 6.66 (d, J=2 Hz, 1H), 3.63 (s, 3H), 3.45 (s, 3H).

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

Procedure: N-(2-Hydroxy-4-nitrophenyl)-N'-(2-trifluoromethyloxyphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-trifluoromethoxy phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (0.69 g, 60%). EI-MS m/z 358(M+H)+ The product was purified by dilution with methylene chloride and precipitation with hexanes Filtering

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

Procedure: N-(2-Hydroxy-4-nitrophenyl)-N'-(2-trifluoromethyloxyphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-trifluoromethoxy phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (0.69 g, 60%). EI-MS m/z 358(M+H)+ The product was purified by dilution with methylene chloride and precipitation with hexanes Filtering

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

Procedure: N-(2-Hydroxy-4-nitrophenyl)-N′-(2-trifluoromethyloxyphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-trifluoromethoxyphenylisocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.69 g, 60%). EI-MS m/z 358(M+H)+. The product was purified by dilution with methylene chloride and precipitation with hexanes Filtering

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

Procedure: 3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 2-trifluoromethoxyphenyl isocyanate in a similar manner as described in Example 1.53, providing 1.5 mg (3%) of Compound 34: LCMS m/z (%)=440 (M+H37Cl, 14), 438 (M+H35Cl, 14). 1H NMR (400 MHz, acetone-d6) δ: 8.19 (s, 1H), 7.90 (s, 1H), 7.43 (d, J=4 Hz, 1H), 7.25 (s, 1H), 7.04 (t, J=12 Hz, 2H), 6.99 (dd, J1=8 Hz, H2=2 Hz, 1H), 6.75 (d, J=4 Hz, 1H), 6.72 (d, J=4 Hz, 1H), 6.66 (d, J=2 Hz, 1H), 3.63 (s, 3H), 3.45 (s, 3H).

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

Procedure: 3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 2-trifluoromethoxyphenyl isocyanate in a similar manner as described in Example 1.53, providing 1.5 mg (3%) of Compound 34: LCMS m/z (%)=440 (M+H37Cl, 14), 438 (M+H35Cl, 14). 1H NMR (400 MHz, acetone-d6) δ: 8.19 (s, 1H), 7.90 (s, 1H), 7.43 (d, J=4 Hz, 1H), 7.25 (s, 1H), 7.04 (t, J=12 Hz, 2H), 6.99 (dd, J1=8 Hz, H2=2 Hz, 1H), 6.75 (d, J=4 Hz, 1H), 6.72 (d, J=4 Hz, 1H), 6.66 (d, J=2 Hz, 1H), 3.63 (s, 3H), 3.45 (s, 3H).

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

Procedure: To a stirred suspension of 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.49 g, 1.5 mmol) and triethylamine (0.28 mL, 2.1 mmol) in THF (12 mL) at 5˜10° C., was added trifluoromethoxy-phenyl isocyanate (0.29 mL, 1.9 mmol), and the mixture was stirred at room temperature overnight. The mixture was quenched with methanol (−1 mL), and the solvent was evaporated. The residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 1-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-3-(4-trifluoromethoxy-phenyl)-urea as an off-white solid (490 mg, 67% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CF3CN/0.1% F3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.47 min (98.6%); mp, 201-203° C.; 1HNMR (DMSO-d6) δ 2.15-2.20 (m, 1H, CHH), 2.56-2.90 (m, 6H, CHCH2, CH3), 4.42 (d, J=5 Hz, 211, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 6.84 (t, J=6 Hz, 1H, CH2NH), 7.21-7.96 (m, 7H, Ar), 8.88 (s, 1H, NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.93, 23.39, 30.61, 42.33, 56.53, 118.81, 120.01, 120.17 (q, JC-F=255 Hz), 121.54, 123.66, 126.54, 133.93, 139.04, 139.69, 142.08, 145.76, 154.52, 155.12, 160.46, 169.48, 172.60. LCMS MH=504; Anal Calcd For C21H20N5O5F3+0.2H2O: C, 54.48; H, 4.06; N, 13.81; F, 11.24. Found: C, 54.25; H, 4.00; N, 13.59; F, 11.24. The mixture was quenched with methanol (−1 mL) the solvent was evaporated The residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%)

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

Procedure: To a stirred suspension of 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.49 g, 1.5 mmol) and triethylamine (0.28 mL, 2.1 mmol) in THF (12 mL) at 5˜10° C., was added trifluoromethoxy-phenyl isocyanate (0.29 mL, 1.9 mmol), and the mixture was stirred at room temperature overnight. The mixture was quenched with methanol (−1 mL), and the solvent was evaporated. The residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 1-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-3-(4-trifluoromethoxy-phenyl)-urea as an off-white solid (490 mg, 67% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CF3CN/0.1% F3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.47 min (98.6%); mp, 201-203° C.; 1HNMR (DMSO-d6) δ 2.15-2.20 (m, 1H, CHH), 2.56-2.90 (m, 6H, CHCH2, CH3), 4.42 (d, J=5 Hz, 211, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 6.84 (t, J=6 Hz, 1H, CH2NH), 7.21-7.96 (m, 7H, Ar), 8.88 (s, 1H, NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.93, 23.39, 30.61, 42.33, 56.53, 118.81, 120.01, 120.17 (q, JC-F=255 Hz), 121.54, 123.66, 126.54, 133.93, 139.04, 139.69, 142.08, 145.76, 154.52, 155.12, 160.46, 169.48, 172.60. LCMS MH=504; Anal Calcd For C21H20N5O5F3+0.2H2O: C, 54.48; H, 4.06; N, 13.81; F, 11.24. Found: C, 54.25; H, 4.00; N, 13.59; F, 11.24. The mixture was quenched with methanol (−1 mL) the solvent was evaporated The residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%)

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

Procedure: To a stirred suspension of 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.49 g, 1.5 mmol) and triethylamine (0.28 mL, 2.1 mmol) in THF (12 mL) at 5˜10° C., was added trifluoromethoxy-phenyl isocyanate (0.29 mL, 1.9 mmol), and the mixture was stirred at room temperature overnight. The mixture was quenched with methanol (˜1 mL), and the solvent was evaporated. The residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 1-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-3-(4-trifluoromethoxy-phenyl)-urea as an off-white solid (490 mg, 67% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.47 min (98.6%); mp, 201-203° C.; 1HNMR (DMSO-d6) 2.15-2.20 (m, 1H, CHH), 2.56-2.90 (m, 6H, CHCH2, CH3), 4.42 (d, J=5 Hz, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 6.84 (t, J=6 Hz, 1H, CH2NH), 7.21-7.96 (m, 7H, Ar), 8.88 (s, 1H, NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.93, 23.39, 30.61, 42.33, 56.53, 118.81, 120.01, 120.17 (q, JC-F=255 Hz), 121.54, 123.66, 126.54, 133.93, 139.04, 139.69, 142.08, 145.76, 154.52, 155.12, 160.46, 169.48, 172.60. LCMS MH=504; Anal Calcd For C23H20N5O5F3+0.2H2O: C, 54.48; H, 4.06; N, 13.81; F, 11.24. Found: C, 54.25; H, 4.00; N, 13.59; F, 11.24. The mixture was quenched with methanol (˜1 mL) the solvent was evaporated The residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%)

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

Procedure: 3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 2-trifluoromethoxyphenyl isocyanate in a similar manner as described in Example 1.53, providing 1.5 mg (3%) of Compound 34: LCMS m/z (%)=440 (M+H37Cl, 14), 438 (M+H35Cl, 14). 1H NMR (400 MHz, acetone-d6) δ: 8.19 (s, 1H), 7.90 (s, 1H), 7.43 (d, J=4 Hz, 1H), 7.25 (s, 1H), 7.04 (t, J=12 Hz, 2H), 6.99 (dd, J1=8 Hz, J2=2 Hz, 1H), 6.75 (d, J=4 Hz, 1H), 6.72 (d, J=4 Hz, 1H), 6.66 (d, J=2 Hz, 1H), 3.63 (s, 3H), 3.45 (s, 3H).