A mixture of ethyl 10-(((benzyloxy)carbonyl)amino)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate (0.08 g, 0.187 mmol), (2,5-dibromo-4-fluorophenyl)methanamine hydrochloride (0.080 g, 0.250 mmol) and Et3N (0.139 mL, 1 mmol) in EtOH (3 mL) was heated at 90° C. for 22 h. Then, cooled, diluted with Ethyl acetate (50 mL), washed with 1N aq. HCl (2×5 mL), water (10 mL) followed by brine (10 mL), dried (Na2SO4), filtered and concentrated to give light purple foam which was used in the next without purification. To CH2Cl2 (5 mL) solution of this crude material was added HBr/AcOH (1.5 mL, 45% w/v) and the mixture stirred at room temperature for 4 h. The reaction mixture was concentrated and resulting light brown solid was used in the next step without purification. A 10 mL flask was charged with this intermediate and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (0.190 g, 0.5 mmol). To this was added diisopropyl-ethylamine (0.3 mL, 1.718 mmol), N,N-dimethyloxamic acid (0.117 g, 1 mmol) and DMF (3 mL). After 4 h at room temperature, 2M Me2NH/methanol (2 mL) was added and this was stirred at room temperature overnight (15 h). The solution was diluted with Et2O (50 mL), washed with 1N HCl (10 ml), water (2×5 mL) followed by brine (5 mL), then dried (Na2SO4), filtered, concentrated and purified by preparative-HPLC to afford the title compound (0.0136 g, 0.020 mmol, 11% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ: 11.84 (1H, s), 8.69 (1H, t, J=5.8 Hz), 7.98 (1H, s), 7.56 (1H, d, J=7.3 Hz), 7.35 (1H, d, J=7.9 Hz), 4.63 (2H, d, J=6.1 Hz), 4.17 (2H, d, J=3.7 Hz), 3.28 (3H, s), 2.89 (3H, s), 2.55-2.49 (3H, m), 2.16-2.10 (2H, m), 2.00-1.93 (2H, m), 1.76-1.69 (2H, m). LCMS (M+H) calcd for C23H25Br2FN5O5: 628.02; found: 629.88.
