[F:1][C:2]([F:10])=[CH:3][CH:4]1[CH2:8][NH:7][C:6](=[O:9])[CH2:5]1.[H-].[Na+].[Br:13][C:14]1[CH:15]=[C:16]2[C:22]([CH2:23]Br)=[N:21][N:20](C(OC(C)(C)C)=O)[C:17]2=[N:18][CH:19]=1>CN(C=O)C.O>[Br:13][C:14]1[CH:15]=[C:16]2[C:22]([CH2:23][N:7]3[CH2:8][CH:4]([CH:3]=[C:2]([F:10])[F:1])[CH2:5][C:6]3=[O:9])=[N:21][NH:20][C:17]2=[N:18][CH:19]=1To a solution of 4-(2,2-difluorovinyl)pyrrolidin-2-one x98 (2.86 mmol, 2 eq, 0.42 g) in dry DMF (5 ml) maintained at 0° C. is added natrium hydride (60% dispersion in oil; 2.86 mmol, 2 eq, 0.114 g). The resulting mixture is stirred at room temperature for 0.5 hour and tert-butyl 5-bromo-3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate x155 (1.43 mmol, 1 eq, 0.56 g) dissolved in DMF (2 ml) is added. The resulting mixture is stirred overnight at room temperature. The mixture is poured in water and extracted with AcOEt. The cumulated organic layers are dried over MgSO4, filtered and evaporated under reduced pressure. The crude mixture is purified twice by chromatography on silicagel (CH2Cl2/MeOH/NH4OH 98/2/0.2) to afford pure 1-[(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one 221 (0.025 g).
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