[NH2:1][C:2]1[C:3]([Cl:22])=[C:4]([N:10]2[CH2:15][CH2:14][C@@H:13]([NH:16][C:17](=[O:20])[CH2:18]Cl)[C@H:12]([OH:21])[CH2:11]2)[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[H-].[Na+]>C1COCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[NH2:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([N:10]2[CH2:15][CH2:14][C@@H:13]3[C@H:12]([O:21][CH2:18][C:17](=[O:20])[NH:16]3)[CH2:11]2)[C:3]=1[Cl:22])[C:8]#[N:9](+/−)-N-((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-hydroxypiperidin-4-yl)-2-chloroacetamide (549 mg, 1.600 mmol) was dissolved in anhydrous THF. The solution was cooled to 0° C. sodium hydride (96 mg, 2.399 mmol) and tetrabutylammonium bromide (77 mg, 0.240 mmol) were added (briefly opening the reaction flask to air). The reaction mixture was stirred at 0° C. for 5 minutes, then the ice bath was removed and the mixture stirred at room temperature for 1.5 hours. The reaction was quenched with aq. NH4Cl solution. The reaction mixture was partitioned between water and EtOAc. The organic layer was washed with brine (+small amount of NaHCO3 solution), then dried over MgSO4. The organic layer was filtered and evaporated to dryness to give 0.85 g crude colorless solid, which was purified via silica gel chromatography: gradient from 100% DCM to 100% EtOAc, then isocratic at 100% EtOAc to afford (+/−)-3-amino-4-chloro-5-((4aR,8aR)-2-oxohexahydro-1H-pyrido[3,4-b][1,4]oxazin-6(7H)-yl)benzonitrile (197 mg).
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