8-fluoro-2,3,4,5-tetrahydropyrido[4,3-b]indol-1-one

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

Procedure: Sodium hydride (60% dispersion in oil; 196 mg) was added to a stirred solution of 8-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one (500 mg) in dry DMF (20 ml) at 21° under nitrogen. After 15 min, the solution was cooled (0°) and a 10% (v/v) solution of methyl iodide in DMF (1.6 ml) was added dropwise. After 10 min, water (150 ml) was added and the mixture was extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with water (3×50 ml), then brine (100 ml) and evaporated to give a solid which was purified by FCC Eluting with dichloromethane:methanol (80:1) to give the title compound (240 mg), m.p. 200°-202°. the solution was cooled (0°) After 10 min the mixture was extracted with ethyl acetate (3×50 ml) The combined organic extracts were washed with water (3×50 ml) brine (100 ml) and evaporated to give a solid which was purified by FCC Eluting with dichloromethane:methanol (80:1)

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

Procedure: Cupric acetate (2.9 g) was added to a stirred solution of 4-[(4-fluorophenyl)amino]-5,6-dihydro-2(1H)-pyridinone (1.5 g) and palladium (II) acetate (200 mg) in dry DMF (40 ml). The mixture was heated at 130° for 1 h, evaporated in vacuo and the residue was extracted with methanol (250 ml). This solution was concentrated in vacuo and the residue was purified by FCC eluting with System A (100:8:1) to give the title compound (840 mg), m.p. 242°-245°. The mixture was heated at 130° for 1 h evaporated in vacuo the residue was extracted with methanol (250 ml) This solution was concentrated in vacuo the residue was purified by FCC eluting with System A (100:8:1)

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

Procedure: 60% NaH (196 mg, 8.16 mmol) was added to a stirred solution of 8-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one (500 mg, 2.44 mmol) in DMF (20 mL) at −10° C. and stirred for 10 minutes at room temperature. This was followed by the addition of benzene sulfonyl chloride (517 mg, 2.92 mmol) at 0° C. and the resulting reaction mass was stirred at room temperature for 5 minutes. The reaction was monitored by TLC (5% methanol in DCM). The reaction mass was quenched with ice and extracted using ethyl acetate. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated to afford the crude product. Purification by column chromatography on silica gel (0.5% methanol in DCM) afforded 450 mg of the product (53.6% yield). the resulting reaction mass was stirred at room temperature for 5 minutes The reaction mass was quenched with ice extracted The organic layer was washed with water, brine solution dried over Na2SO4 concentrated to afford the crude product Purification by column chromatography on silica gel (0.5% methanol in DCM)

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

Procedure: 8-Fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one (I-59f: 500 mg, 2.44 mmol) in DMF (200 mL) was reacted with 60% NaH (196 mg, 8.16 mmol) and ethyl iodide (456 mg, 2.92 mmol) to afford the crude product. The reaction mass was quenched with chilled water and extracted with ethyl acetate. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated to afford the crude product. Purification by column chromatography on silica gel (1% methanol in DCM) afforded 120 mg of the product (21.2% yield). to afford the crude product The reaction mass was quenched with chilled water extracted with ethyl acetate The organic layer was washed with water, brine solution dried over Na2SO4 concentrated to afford the crude product Purification by column chromatography on silica gel (1% methanol in DCM)

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Cu(OAc)2 (9.69 g, 53.39 mmol) was added to a stirred solution of 4-(4-fluorophenylamino)-5,6-dihydropyridin-2(1H)-one (I-59e: 5 g, 24.27 mmol) and Pd(OAc)2 (490 mg, 2.18 mmol) in DMF (96 mL) under argon atmosphere and the resulting reaction mass was heated at 130° C. for 2 hours. The reaction was monitored by TLC (5% methanol in DCM). The reaction mass was cooled to room temperature and filtered through a celite bed. The filtrate was partitioned between water and ethyl acetate. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated to afford the crude product. Purification by column chromatography on silica gel (1% methanol in DCM) afforded 2.2 g of the product (44.7% yield). the resulting reaction mass The reaction mass was cooled to room temperature filtered through a celite bed The filtrate was partitioned between water and ethyl acetate The organic layer was washed with water, brine solution dried over Na2SO4 concentrated to afford the crude product Purification by column chromatography on silica gel (1% methanol in DCM)