1,3-difluoro-5-isocyanatobenzene

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

Procedure: 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.032 g, 0.11 mmol) was treated with 3,5-difluorophenyl isocyanate (0.018 g, 14 μL, 0.11 mmol, 1.0 equiv.) in CH2Cl2 (2 mL), in a similar manner as described in Example 1.2 to afford Compound 7 (0.038 g, 0.09 mmol, 77%) as a white solid. LCMS m/z (%)=437 (M+H79Br, 100), 439 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.47 (s, 1H), 8.23 (s, 1H), 7.68 (dd, J=2.7, 9.0 Hz, 1H), 7.50 (s, 1H), 7.42 (d, J=2.7 Hz, 1H), 7.18-7.27 (m, 2H), 7.15 (d, J=9.0 Hz, 1H), 6.59 (ttt, J=2.3, 9.1, 9.1 Hz, 1H), 3.82 (s, 3H), 3.68 (s, 3H).

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

Procedure: The compound of example 29 was prepared analogous to compound of example 7 by reaction of compound of example 6 with 3,5-difluorophenyl isocyanate. The compound of example 29 was used directly without isolation for the preparation of compound of example 30.

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

Procedure: In 100 ml of dry toluene was 5 g of 3-(4-amino-4′-trifluoromethyl-biphenyl-3-yl)-4H-[1,2,4]oxadiazol-5-one suspended and 2.5 g of 3,5-difluorophenyl isocyanate was added, the reaction mixture was stirred at room temperature overnight, 1.3 g of 3,5-difluorophenyl isocyanate was added and stirring was continued overnight. 3,5-Difluorophenyl isocyanate (1.3 g) and 100 ml of acetonitrile was added, the reaction mixture was stirred at room temperature for 90 min. and evaporated to dryness. The residue was dissolved in 100 ml of boiling acetone, then cooled to 0° C. and filtrated. The precipitate was recrystallized from 200 ml of ethanol, after filtration while hot, the solution was added 400 ml of water. The product was isolated by filtration. Yield 4 g (54%) mp.>150° C. decomp. stirring was continued overnight the reaction mixture was stirred at room temperature for 90 min. evaporated to dryness The residue was dissolved in 100 ml of boiling acetone cooled to 0° C. filtrated The precipitate was recrystallized from 200 ml of ethanol after filtration while hot, the solution was added 400 ml of water The product was isolated by filtration

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

Procedure: In 100 ml of dry toluene was 5 g of 3-(4-amino-4′-trifluoromethyl-biphenyl-3-yl)-4H-[1,2,4]oxadiazol-5-one suspended and 2.5 g of 3,5-difluorophenyl isocyanate was added, the reaction mixture was stirred at room temperature overnight, 1.3 g of 3,5-difluorophenyl isocyanate was added and stirring was continued overnight. 3,5-Difluorophenyl isocyanate (1.3 g) and 100 ml of acetonitrile was added, the reaction mixture was stirred at room temperature for 90 min. and evaporated to dryness. The residue was dissolved in 100 ml of boiling acetone, then cooled to 0° C. and filtrated. The precipitate was recrystallized from 200 ml of ethanol, after filtration while hot, the solution was added 400 ml of water. The product was isolated by filtration. Yield 4 g (54%) mp.>150° C. decomp. stirring was continued overnight the reaction mixture was stirred at room temperature for 90 min. evaporated to dryness The residue was dissolved in 100 ml of boiling acetone cooled to 0° C. filtrated The precipitate was recrystallized from 200 ml of ethanol after filtration while hot, the solution was added 400 ml of water The product was isolated by filtration

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

Procedure: 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.032 g, 0.11 mmol) was treated with 3,5-difluorophenyl isocyanate (0.018 g, 14 μL, 0.11 mmol, 1.0 equiv.) in CH2Cl2 (2 mL), in a similar manner as described in Example 1.2 to afford Compound 7 (0.038 g, 0.09 mmol, 77%) as a white solid. LCMS m/z (%)=437 (M+H79Br, 100), 439 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.47 (s, 1H), 8.23 (s, 1H), 7.68 (dd, J=2.7, 9.0 Hz, 1H), 7.50 (s, 1H), 7.42 (d, J=2.7 Hz, 1H), 7.18-7.27 (m, 2H), 7.15 (d, J=9.0 Hz, 1H), 6.59 (ttt, J=2.3, 9.1, 9.1 Hz, 1H), 3.82 (s, 3H), 3.68 (s, 3H).

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

Procedure: 1,3-Difluoro-5-isocyanatobenzene (119 mg, 0.769 mmol) was added to a solution of 5-fluoro-4-imino-3-methyl-3,4-dihydropyrimidin-2(1H)-one (100 mg, 0.699 mmol) in DMF (1.8 mL) and stirred overnight at room temperature. The solution was then concentrated under vacuum and the resulting residue stirred in dichloromethane (2 mL) for 30 min. The solids were filtered and washed with dichloromethane (2×3 mL) and dried under vacuum to afford the title compound; mp 203.0-204.5° C.; 1H NMR (400 MHz, CDCl3) δ 11.03 (s, 1H), 9.87 (s, 1H), 7.68 (d, J=6.2 Hz, 1H), 7.25 (d, J=7.4 Hz, 2H), 6.80 (s, 1H), 3.25 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 163.77, 163.62, 161.36, 161.21, 158.57, 149.14, 146.14, 145.90, 142.72, 142.58, 142.44, 138.68, 136.41, 122.85, 122.52, 101.05, 100.76, 97.32, 97.06, 96.79, 29.43; ESIMS m/z 299.0 ([M+H]+). The solution was then concentrated under vacuum the resulting residue stirred in dichloromethane (2 mL) for 30 min The solids were filtered washed with dichloromethane (2×3 mL) dried under vacuum

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

Procedure: 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.032 g, 0.11 mmol) was treated with 3,5-difluorophenyl isocyanate (0.018 g, 14 μL, 0.11 mmol, 1.0 equiv.) in CH2Cl2 (2 mL), in a similar manner as described in Example 1.2 to afford Compound 7 (0.038 g, 0.09 mmol, 77%) as a white solid. LCMS m/z (%)=437 (M+H79Br, 100), 439 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.47 (s, 1H), 8.23 (s, 1H), 7.68 (dd, J=2.7, 9.0 Hz, 1H), 7.50 (s, 1H), 7.42 (d, J=2.7 Hz, 1H), 7.18-7.27 (m, 2H), 7.15 (d, J=9.0 Hz, 1H), 6.59 (ttt, J=2.3, 9.1, 9.1 Hz, 1H), 3.82 (s, 3H), 3.68 (s, 3H).

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

Procedure: 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.032 g, 0.11 mmol) was treated with 3,5-difluorophenyl isocyanate (0.018 g, 14 μL, 0.11 mmol, 1.0 equiv.) in CH2Cl2 (2 mL), in a similar manner as described in Example 1.2 to afford Compound 7 (0.038 g, 0.09 mmol, 77%) as a white solid. LCMS m/z (%)=437 (M+H79Br, 100), 439 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.47 (s, 1H), 8.23 (s, 1H), 7.68 (dd, J=2.7, 9.0 Hz, 1H), 7.50 (s, 1H), 7.42 (d, J=2.7 Hz, 1H), 7.18-7.27 (m, 2H), 7.15 (d, J=9.0 Hz, 1H), 6.59 (ttt, J=2.3, 9.1, 9.1 Hz, 1H), 3.82 (s, 3H), 3.68 (s, 3H).

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

Procedure: The compound of example 29 was prepared analogous to compound of example 7 by reaction of compound of example 6 with 3,5-difluorophenyl isocyanate. The compound of example 29 was used directly without isolation for the preparation of compound of example 30.

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

Procedure: The compound of example 29 was prepared analogous to compound of example 7 by reaction of compound of example 6 with 3,5-difluorophenyl isocyanate. The compound of example 29 was used directly without isolation for the preparation of compound of example 30.

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

Procedure: A solution of Example A7 (0.12 g, 0.266 mmol) in dioxane (5 mL) was treated with 3,5-difluorophenyl isocyanate (0.038 mL, 0.320 mmol) and stirred at RT overnight. Additional 3,5-difluorophenyl isocyanate (0.038 mL, 0.320 mmol) was added and the mixture stirred for 4 h. The resulting precipitate was collected via filtration and dried to yield 1-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2,4a,8a-tetrahydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-(3,5-difluorophenyl)urea (112 mg, 69% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.38 (s, 1H), 8.67 (s, 1H), 8.52 (s, 1H), 8.05 (t, 1H), 7.86 (s, 1H), 7.38 (t, 1H), 7.19-7.14 (m, 4H), 6.86 (d, 2H), 6.80-6.77 (m, 1H), 6.32 (s, 1H), 4.85 (s, 2H), 4.19 (q, 2H), 3.70 (s, 3H), 3.12 (s, 3H), 1.13 (t, 3H); MS (ESI) m/z: 606.3 [M+H]+. the mixture stirred for 4 h The resulting precipitate was collected via filtration dried

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

Procedure: 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.032 g, 0.11 mmol) was treated with 3,5-difluorophenyl isocyanate (0.018 g, 14 μL, 0.11 mmol, 1.0 equiv.) in CH2Cl2 (2 mL), in a similar manner as described in Example 1.2 to afford Compound 7 (0.038 g, 0.09 mmol, 77%) as a white solid. LCMS m/z (%)=437 (M+H79Br, 100), 439 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.47 (s, 1H), 8.23 (s, 1H), 7.68 (dd, J=2.7, 9.0 Hz, 1H), 7.50 (s, 1H), 7.42 (d, J=2.7 Hz, 1H), 7.18-7.27 (m, 2H), 7.15 (d, J=9.0 Hz, 1H), 6.59 (ttt, J=2.3, 9.1, 9.1 Hz, 1H), 3.82 (s, 3H), 3.68 (s, 3H).