1-(3-chloropropyl)-3H-indol-2-one

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

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

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

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

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

Procedure: Add potassium hydroxide (899 mg, 16.64 mmol) in one portion to a solution of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 0.52 mmol) in methanol (10 mL). Heat the reaction to 50° C. under nitrogen for 24 h, then cool to room temperature and add 1-(3-chloro-propyl)-1,3-dihydro-indol-2-one (217 mg, 1.04 mmol). Stir the reaction at room temperature for 4 days. Remove solvents in vacuo, add dichloromethane (20 mL) and water (20 mL). Remove the organic layer and dry using an ISCO® phase separator then concentrate in vacuo to give 3-tert-butoxycarbonyl-7-chloro-6-[3-(2-oxo-2,3-dihydro-indol-1-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as orange powder. MS (ES+) m/z: 509 (M+Na)+. Heat the reaction to 50° C. under nitrogen for 24 h the reaction at room temperature for 4 days Remove the organic layer dry then concentrate in vacuo

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

Procedure: Reflux together oxindole (2.66 g, 20.0 mmol), 1-bromo-3-chloropropane (2.56 mL, 26.0 mmol) and potassium carbonate (5.52 g, 40.0 mmol) in acetonitrile (300 mL) under nitrogen for 16 h. Cool the suspension to room temperature and filter off the precipitate. Concentrate the filtrate in vacuo and purify the crude mixture by chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 3:2 gradient over 40 min) to give the title compound as an orange oil (1.65 g, 39%). MS (ES+) m/z: 210 (M+H)+. filter off the precipitate Concentrate the filtrate in vacuo purify the crude mixture by chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 3:2 gradient over 40 min)

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

Procedure: Reflux together oxindole (2.66 g, 20.0 mmol), 1-bromo-3-chloropropane (2.56 mL, 26.0 mmol) and potassium carbonate (5.52 g, 40.0 mmol) in acetonitrile (300 mL) under nitrogen for 16 h. Cool the suspension to room temperature and filter off the precipitate. Concentrate the filtrate in vacuo and purify the crude mixture by chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 3:2 gradient over 40 min) to give the title compound as an orange oil (1.65 g, 39%). MS (ES+) m/z: 210 (M+H)+. filter off the precipitate Concentrate the filtrate in vacuo purify the crude mixture by chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 3:2 gradient over 40 min)

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

Conditions: temp:78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of N-(3((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)phenyl)methanesulfonamide (0.22 g, 0.53 mmol), sodium iodide (0.032 g, 0.21 mmol) and potassium carbonate (0.146 g, 1.06 mmol) in 2-butanone (5 mL), was added 1-(3-chloropropyl)indolin-2-one (0.11 g, 0.53 mmol). After stirring at 78° C. for 3 hours, the reaction mixture was filtered and isolated by preparatory TLC (10% methanol/dichloromethane) to obtain the title compound (0.041 g, 13%); 1H NMR (DMSO-d6): δ 1.66 (d, 2H, J=13.6 Hz), 1.78 (t, 2H, J=6.8 Hz), 2.33-2.47 (m, 2H), 2.50-2.56 (m, 2H), 2.76 (br, 4H), 2.96 (s, 3H), 3.54 (s, 2H), 3.73 (t, 2H, J=6.8 Hz), 4.52 (s, 2H), 4.58 (s, 2H), 6.77 (t, 1H, J=7.2 Hz), 6.85 (d, 2H, J=8.4 Hz), 6.97-7.02 (m, 2H), 7.08-7.13 (m, 3H), 7.20-7.26 (m, 4H), 7.32 (t, 1H, J=8 Hz), 9.80 (s, 1H); MS for C32H37N5O4S m/z 588.3 (M+H)+. the reaction mixture was filtered isolated by preparatory TLC (10% methanol/dichloromethane)

Conditions: temp:78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of N-(3((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)phenyl)methanesulfonamide (0.22 g, 0.53 mmol), sodium iodide (0.032 g, 0.21 mmol) and potassium carbonate (0.146 g, 1.06 mmol) in 2-butanone (5 mL), was added 1-(3-chloropropyl)indolin-2-one (0.11 g, 0.53 mmol). After stirring at 78° C. for 3 hours, the reaction mixture was filtered and isolated by preparatory TLC (10% methanol/dichloromethane) to obtain the title compound (0.041 g, 13%); 1H NMR (DMSO-d6): δ 1.66 (d, 2H, J=13.6 Hz), 1.78 (t, 2H, J=6.8 Hz), 2.33-2.47 (m, 2H), 2.50-2.56 (m, 2H), 2.76 (br, 4H), 2.96 (s, 3H), 3.54 (s, 2H), 3.73 (t, 2H, J=6.8 Hz), 4.52 (s, 2H), 4.58 (s, 2H), 6.77 (t, 1H, J=7.2 Hz), 6.85 (d, 2H, J=8.4 Hz), 6.97-7.02 (m, 2H), 7.08-7.13 (m, 3H), 7.20-7.26 (m, 4H), 7.32 (t, 1H, J=8 Hz), 9.80 (s, 1H); MS for C32H37N5O4S m/z 588.3 (M+H)+. the reaction mixture was filtered isolated by preparatory TLC (10% methanol/dichloromethane)

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

Procedure: tert-Butyl 4-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.25 g, 0.593 mmol), 1-(3-chloropropyl)indolin-2-one (0.12 g, 0.593 mmol), sodium iodide (0.026 g, 0.18 mmol), and potassium carbonate (0.12 g, 0.890 mmol) in 2-butanone (8 mL) were heated at 78° C. for 4 hours. The reaction was diluted with 10% methanol/dichloromethane, filtered, and evaporated. The residue was purified by PTLC (5% methanol/dichloromethane) to give product as an oil (0.088 g, 25%); MS for C36H42N4O4 m/z 595 (M+H)+. filtered evaporated The residue was purified by PTLC (5% methanol/dichloromethane)

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

Procedure: tert-Butyl 4-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.25 g, 0.593 mmol), 1-(3-chloropropyl)indolin-2-one (0.12 g, 0.593 mmol), sodium iodide (0.026 g, 0.18 mmol), and potassium carbonate (0.12 g, 0.890 mmol) in 2-butanone (8 mL) were heated at 78° C. for 4 hours. The reaction was diluted with 10% methanol/dichloromethane, filtered, and evaporated. The residue was purified by PTLC (5% methanol/dichloromethane) to give product as an oil (0.088 g, 25%); MS for C36H42N4O4 m/z 595 (M+H)+. filtered evaporated The residue was purified by PTLC (5% methanol/dichloromethane)