1-chloro-3-ethynylbenzene

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The titled compound was prepared according to Method CB using the product of Example 95B (79 mg, 0.5 mmol) and 1-chloro-3-ethynylbenzene (Apollo, 68 mg, 0.5 mmol). 1H NMR (300 MHz, CDCl3) δ6.88 (s, 1H), 7.43-7.52 (m, 3H), 7.69-7.78 (m, 1H), 7.81-7.89 (m, 1H), 8.18 (dd, J=8.3, 2.4 Hz, 1H), 8.84 (d, J=2.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 291 (M+H)+, 293 (M+H)+.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The titled compound was prepared according to Method CB using the product of Example 83D (79 mg, 0.5 mmol) and 1-chloro-3-ethynylbenzene (Apollo, 68 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ7.49 (s, 1H), 7.51-7.59 (m, 2 H), 7.85-7.91 (m, 1H), 7.94-8.04 (m, 1H), 8.70 (d, J=2.4 Hz, 1H), 8.76 (dd, J=2.5, 1.5 Hz, 1H), 9.30 (d, J=1.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 258 (M+H)+, 260 (M+H)+.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The titled compound was prepared according to Method CB using the product of Example 69B (57 mg, 0.3 mmol) and 1-chloro-3-ethynylbenzene (Apollo, 41 mg, 0.3 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.61-7.68 (m, 2H), 7.85-7.89 (m, 1H), 7.90 (s, 1H), 7.96-8.00 (m, 1H), 8.43 (t, J=2.1 Hz, 1H), 8.81 (d, J=2.4 Hz, 1H), 9.08 (d, J=1.6 Hz, 1H) ppm; MS (DCI/NH3) m/z 291 (M+H)+, 293 (M+H)+.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The titled compound was prepared according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 1-chloro-3-ethynylbenzene (Apollo, 68 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.46 (s, 1H), 7.49-7.55 (m, 2 H), 7.60 (ddd, J=8.0, 4.9, 1.0 Hz, 1H), 7.82-7.90 (m, 1H), 7.93-8.00 (m, 1H), 8.37 (dt, J=7.9, 2.0 Hz, 1H), 8.67 (dd, J=5.1, 1.7 Hz, 1H), 9.09 (d, J=1.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 259 (M+H)+, 257 (M+H)+.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A dried pressure tube was charged with (R)-5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepan-3-one (intermediate B6.1) (250 mg, 622 μmol) and dimethylformamide (2 ml). The solution was flushed with argon, thereafter, successively bis(triphenylphosphin)palladium(II)chloride (31.2 mg, 43.5 μmol), triphenylphoshine (3.26 mg, 12.4 μmol), triethylamine (126 mg, 1.24 mmol), 1-chloro-3-ethynylbenzene (175 mg, 1.24 mmol), and copper(i) iodide (3.6 mg, 18.7 μmol) were added. The tube was sealed and the reaction mixture stirred at room temperature for 10 minutes, then it was heated at 60° C. for 16 hours. For the workup, the reaction mixture was cooled and evaporated at reduced pressure. The residue was directly purified by chromatography on an amine-silica phase using a gradient of heptane/ethyl acetate=100:0 to 60:10 as the eluent. The (R)-5-[5-(3-chloro-phenylethynyl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-one (235 mg, 90% yield) was obtained as a green foam. MS (ISP): m/z=422.1 [M+2+H]+ and 424.2 [M+H]+. The solution was flushed with argon The tube was sealed it was heated at 60° C. for 16 hours For the workup, the reaction mixture was cooled evaporated at reduced pressure The residue was directly purified by chromatography on an amine-silica phase

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-Chloro-3-ethynyl-benzene (0.018 g, 0.132 mmol), copper iodide (0.0012 g, 0.006 mmol) and PdCl2(PPh3)2 (0.0023 g, 0.003 mmol) were added under argon to a solution of 2-(2-iodo-pyrimidin-4-yl)-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (0.030 g, 0.066 mmol) and triethylamine (0.170 ml) in dry ACN (0.500 ml). The reaction mixture was stirred at 80° C. for 3 h in argon atmosphere. The solvent was removed under vacuum and the crude residue was purified by flash chromatography, over silica gel, using DCM/MeOH (9.8:0.2) as eluent, to afford 2-[2-(3-chloro-phenylethynyl)-pyrimidin-4-yl]-1-methyl-4-oxo-1,4,6,7-tetra-hydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (0.018 g, 0.04 mmol, 60%). The solvent was removed under vacuum the crude residue was purified by flash chromatography, over silica gel

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The title compound was synthesized according to the procedure described for the preparation of Example 160 using Compound 83 (100 mg, 0.43 mmol) and 1-ethynyl-3-chloro-benzene (88 mg, 0.65 mmol) to provide 165 (103 mg, 72% yield) as a white solid. LC-MS (M+H=331, obsd.=331). The title compound was synthesized

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-Chloro-3-ethynyl-benzene (0.018 g, 0.132 mmol), copper iodide (0.0012 g, 0.006 mmol) and PdCl2(PPh3)2 (0.0023 g, 0.003 mmol) were added under argon to a solution of 2-(2-iodo-pyrimidin-4-yl)-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (0.030 g, 0.066 mmol) and triethylamine (0.170 ml) in dry ACN (0.500 ml). The reaction mixture was stirred at 80° C. for 3 h in argon atmosphere. The solvent was removed under vacuum and the crude residue was purified by flash chromatography, over silica gel, using DCM/MeOH (9.8:0.2) as eluent, to afford 2-[2-(3-chloro-phenylethynyl)-pyrimidin-4-yl]-1-methyl-4-oxo-1,4,6,7-tetra-hydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (0.018 g, 0.04 mmol, 60%). The solvent was removed under vacuum the crude residue was purified by flash chromatography, over silica gel

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Add triethylamine (2.38 mL, 16.88 mmol), copper (I) iodide (80.4 mg, 0.422 mmol) and bis(triphenylphosphine)palladium (II) dichloride (148 mg, 0.211 mmol) to a solution of 3,5-dibromopyridine (1 g, 4.22 mmol) and 1-chloro-3-ethynylbenzene, (prepared as described in PREPARATION 12), (574 mg, 4.22 mmol) in ethyl acetate (4.22 mL). Stir under nitrogen at 50° C. for 18 h. Concentrate and purify the residue by silica gel chromatography, eluting with 100:0 to 0:100 hexanes:ethyl acetate, to give the title compound (571 mg, 46%). Concentrate purify the residue by silica gel chromatography eluting with 100:0 to 0:100 hexanes