N-(2-fluorophenyl)prop-2-enamide

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

Procedure: To a solution of compound 44 (0.080 g, 0.204 mmol) and cesium carbonate (0.133 g, 0.408 mmol) in anhydrous acetonitrile (1.0 mL) at room temperature was added N-(2-fluorophenyl)acrylamide (C-4) (0.101 g, 0.612 mmol) in one portion. The reaction mixture was stirred at room temperature for 30 h, then additional N-(2-fluorophenyl)acrylamide (C-4) (0.168 g, 1.02 mmol) was added, and the reaction mixture was heated at 50° C. for 24 h. The reaction mixture was filtered over a celite pad, washed with methylene chloride (50 mL) and concentrated. Purification of the crude residue by silica gel chromatography (eluant gradient: 100% methylene chloride to 100% EtOAc) followed by C18 reverse phase chromatography (H2O:CH3CN eluant gradient) gave 8.7 mg (6.8% yield) of N-[1-(3-(2-fluorophenylamino)-3-oxopropyl)-1H-indol-5-yl]-2-(3-methylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (71) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 10.05 (br s, 1H), 10.05 (br s, 1H), 9.82 (br s, 1H), 7.88 (m, 1H), 7.85 (m, 1H), 7.53 (d, 1H, J=9.1 Hz), 7.37 (m, 1H), 7.24 (m, 1H), 7.15 (m, 2H), 6.42 (m, 1H), 4.49 (br t, 2H, J=6.6 Hz), 4.12 (m, 2H), 3.05 (t, 1H, J=11.5 Hz), 2.92 (t, 2H, J=6.6 Hz), 2.74 (t, 1H, J=11.9 Hz), 1.78 (m, 3H), 1.54 (m, 1H), 1.16 (m, 1H), 0.94 (d, 3H, J=6.3 Hz). MS (M+1): 558. the reaction mixture was heated at 50° C. for 24 h The reaction mixture was filtered over a celite pad washed with methylene chloride (50 mL) concentrated Purification of the crude residue by silica gel chromatography (eluant gradient: 100% methylene chloride to 100% EtOAc)

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

Procedure: To a solution of acryloyl chloride (0.70 mL, 8.63 mmol) and sodium phosphate dibasic (2.45 g, 17.26 mmol) in anhydrous methylene chloride (18.0 mL) at 0° C. was added dropwise 2-fluoroaniline (0.834 mL, 8.63 mmol). The reaction mixture was stirred at room temperature for 12 h. It was then filtered over a celite pad, washed with methylene chloride (50 mL) and concentrated to afford N-(2-fluorophenyl)acrylamide (C-4) as a white solid (0.959 g, 68% yield). MS (M+1): m/e 166. This material was used for the next step with no additional purification. It was then filtered over a celite pad washed with methylene chloride (50 mL) concentrated

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

Procedure: To a solution of acryloyl chloride (0.70 mL, 8.63 mmol) and sodium phosphate dibasic (2.45 g, 17.26 mmol) in anhydrous methylene chloride (18.0 mL) at 0° C. was added dropwise 2-fluoroaniline (0.834 mL, 8.63 mmol). The reaction mixture was stirred at room temperature for 12 h. It was then filtered over a celite pad, washed with methylene chloride (50 mL) and concentrated to afford N-(2-fluorophenyl)acrylamide (C-4) as a white solid (0.959 g, 68% yield). MS (M+1): m/e 166. This material was used for the next step with no additional purification. It was then filtered over a celite pad washed with methylene chloride (50 mL) concentrated

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

Procedure: To a solution of compound 44 (0.080 g, 0.204 mmol) and cesium carbonate (0.133 g, 0.408 mmol) in anhydrous acetonitrile (1.0 mL) at room temperature was added N-(2-fluorophenyl)acrylamide (C-4) (0.101 g, 0.612 mmol) in one portion. The reaction mixture was stirred at room temperature for 30 h, then additional N-(2-fluorophenyl)acrylamide (C-4) (0.168 g, 1.02 mmol) was added, and the reaction mixture was heated at 50° C. for 24 h. The reaction mixture was filtered over a celite pad, washed with methylene chloride (50 mL) and concentrated. Purification of the crude residue by silica gel chromatography (eluant gradient: 100% methylene chloride to 100% EtOAc) followed by C18 reverse phase chromatography (H2O:CH3CN eluant gradient) gave 8.7 mg (6.8% yield) of N-[1-(3-(2-fluorophenylamino)-3-oxopropyl)-1H-indol-5-yl]-2-(3-methylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (71) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 10.05 (br s, 1H), 10.05 (br s, 1H), 9.82 (br s, 1H), 7.88 (m, 1H), 7.85 (m, 1H), 7.53 (d, 1H, J=9.1 Hz), 7.37 (m, 1H), 7.24 (m, 1H), 7.15 (m, 2H), 6.42 (m, 1H), 4.49 (br t, 2H, J=6.6 Hz), 4.12 (m, 2H), 3.05 (t, 1H, J=11.5 Hz), 2.92 (t, 2H, J=6.6 Hz), 2.74 (t, 1H, J=11.9 Hz), 1.78 (m, 3H), 1.54 (m, 1H), 1.16 (m, 1H), 0.94 (d, 3H, J=6.3 Hz). MS (M+1): 558. the reaction mixture was heated at 50° C. for 24 h The reaction mixture was filtered over a celite pad washed with methylene chloride (50 mL) concentrated Purification of the crude residue by silica gel chromatography (eluant gradient: 100% methylene chloride to 100% EtOAc)

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

Procedure: To a solution of acryloyl chloride (0.70 mL, 8.63 mmol) and sodium phosphate dibasic (2.45 g, 17.26 mmol) in anhydrous methylene chloride (18.0 mL) at 0° C. was added dropwise 2-fluoroaniline (0.834 mL, 8.63 mmol). The reaction mixture was stirred at room temperature for 12 h. It was then filtered over a celite pad, washed with methylene chloride (50 mL) and concentrated to afford N-(2-fluorophenyl)acrylamide (C-4) as a white solid (0.959 g, 68% yield). MS (M+1): m/e 166. This material was used for the next step with no additional purification. It was then filtered over a celite pad washed with methylene chloride (50 mL) concentrated