[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[N:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1CCCCC1.[Br:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[C:25]([CH2:30]Br)[N:24]=1.Cl.[Cl-].[NH4+]>O1CCCC1>[Br:22][C:23]1[N:24]=[C:25]([CH2:30][C:11]2([C:14]#[N:15])[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)[CH:26]=[CH:27][C:28]=1[F:29]N-Boc-4-cyanopiperidine (5.35 g, 25.4 mmol) was dissolved in 100 mL of tetrahydrofuran. After cooling the resulting mixture to −78° C., a solution of lithium diisopropylamide/tetrahydrofuran complex in cyclohexane (1.5 M, 16.5 mL, 24.8 mmol) was added while keeping the internal temperature at or below −70° C. The resulting reaction mixture was stirred at −78° C. for 20 minutes. To the reaction mixture thus obtained, 10 mL of a solution of 2-bromo-6-(bromomethyl)-3-fluoropyridine in THF (6.28 g, 23.4 mmol) was added while keeping the internal temperature at or below −70° C., followed by stirring at −78° C. for 20 minutes. To this reaction solution, a mixture of hydrochloric acid (5M, 4.95 mL, 24.8 mmol) and 95 mL of a saturated aqueous solution of ammonium chloride was added, followed by stirring at room temperature and then extraction with ethyl acetate. The extract thus obtained was washed with saturated brine and dried over anhydrous sodium sulfate, and then filtered and concentrated. The tarry residue was dissolved in 6 mL of ethyl acetate, and 50 mL of heptane was added dropwise while stirring. Seed crystals were then added, followed by stirring at room temperature for one hour. To the resulting light yellow suspension, 50 mL of heptane was further added dropwise, followed by stirring overnight. The solid thus obtained was collected by filtration and washed with a solution of ethyl acetate in heptane, and then dried under reduced pressure, whereby the titled product was obtained as an off-white solid (7.10 g, 17.8 mmol) (yield 76%). The physical property values are shown below.
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