[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[N:9])[CH2:3][CH2:2]1.[OH-].[K+].[NH2:12][C:13]1[CH:20]=[C:19]([F:21])[C:18]([Br:22])=[CH:17][C:14]=1[CH:15]=O>CS(C)=O.O.[NH4+].[Cl-]>[Br:22][C:18]1[CH:17]=[C:14]2[C:13](=[CH:20][C:19]=1[F:21])[N:12]=[C:8]([NH2:9])[C:7]([N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[CH:15]2
To a solution of 2-morpholinoacetonitrile (1.29 g, 10.26 mmol) in DMSO (13 mL) was added aqueous KOH (11.7 M, 0.276 mL, 3.23 mmol). The reaction was heated at 80° C., and a solution of 2-amino-5-bromo-4-fluorobenzaldehyde (1.41 g, 6.45 mmol) in DMSO (13 mL) was added dropwise over 2.5 h. The reaction mixture was stirred at 80° C. for 14 h. It was then cooled to RT and diluted with water (200 mL) and saturated NH4Cl (5 mL). The aqueous phase was extracted with DCM (2×200 mL). The organic fractions were combined, washed with half-saturated brine (4×300 mL), dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (150 mL) which had been deactivated with TEA (15 mL) eluting with 75:25:1:0.5 EtOAc/hexane/MeOH/Et3N to afford 6-bromo-7-fluoro-3-morpholinoquinolin-2-amine.
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