[NH2-].[Na+].[C:3]1([C:9]2[N:10]=[C:11]([CH2:14][C:15]#[N:16])[S:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.Cl[CH2:19][CH2:20][N:21]([CH2:23][CH2:24]Cl)[CH3:22].N>C1(C)C=CC=CC=1.O>[CH3:22][N:21]1[CH2:23][CH2:24][C:14]([C:11]2[S:12][CH:13]=[C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:10]=2)([C:15]#[N:16])[CH2:19][CH2:20]1Sodium amide (878 mg, 22.4 mmol) was suspended in toluene (15 mL) and cooled to 0° C. To this suspension was added dropwise a solution of (4-phenyl-thiazol-2-yl)-acetonitrile (1.5 g, 7.4 mmol) in toluene (10 mL) while maintaining the temperature at 0° C. The reaction mixture was stirred for 20 min. Separately the bis-(2-chloroethyl)methylamine hydrochloride (1.45 g, 7.4 mmol) was taken in water (8 mL), cooled to 0° C., and basified with aqueous ammonia solution (adjusted to pH of the solution to ˜8). The oily layer was separated out from the aqueous layer and the organic product was extracted with toluene. The toluene layer was dried over sodium hydroxide pellets. The dry toluene solution of bis-(2-chloroethyl)methylamine was added to the reaction mixture at 0° C. The reaction mixture was allowed to warm up to room temperature and further heated to 110° C. for 3 h. The reaction mixture was then cooled to room temperature, diluted with EtOAc, and extracted with EtOAc. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 5% MeOH in CH2Cl2) to afford 1-methyl-4-(4-phenylthiazol-2-yl)piperidine-4-carbonitrile (350 mg, yield 17%). 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.99-7.97 (m, 2H), 7.49-7.44 (m, 2H), 7.40-7.36 (m, 1H), 2.92-2.90 (m, 2H), 2.40-2.37 (m, 2H), 2.31-2.16 (m, 7H). MS (ESI) m/z: Calculated for C16H17N3S: 283.11. found: 284.2 (M+H)+.
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