[F:1][C:2]1([F:23])[C:11]2[CH:10]=[N:9][C:8](S(C)(=O)=O)=[N:7][C:6]=2[CH2:5][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1.CCN(C(C)C)C(C)C.[O:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1>CC(O)C.CCOC(C)=O>[F:1][C:2]1([F:23])[C:11]2[CH:10]=[N:9][C:8]([NH:39][CH:36]3[CH2:37][CH2:38][O:33][CH2:34][CH2:35]3)=[N:7][C:6]=2[CH2:5][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1To a stirred suspension of 204 (349 mg, 1 mmol) in IPA (3 mL) at RT under nitrogen was added sequentially via syringe neat DIPEA (174 μL, 1 mmol) and neat tetrahydro-2H-pyran-4-amine (101 mg, 1 mmol). The mixture was heated to 90° C. and became homogeneous. Heating was continued for 60 min them cooled to RT, diluted to 30 mL with EtOAc and was washed sequentially with 10% citric acid solution (2×30 mL) and satd. aq. NaHCO3 (2×30 mL). The organic phase was isolated, dried (MgSO4), filtered and concentrated to a clear oil. The oil was triturated with hexane/EtOAc (4/1) with sonication to produce a precipitate that was filtered and rinsed with hexane/EtOAc (4/1). The mother liquor was recovered and re-precipitated. Both precipitated batches were combined to afford 215 mg (58%) of tert-butyl 5,5-difluoro-2-(tetrahydro-2H-pyran-4-ylamino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (206) as a white solid.
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