4-Methylmorpholine → 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy)-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide

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To a cooled (0° C.) solution of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (from Step 3) (0.25 g, 0.61 mmol) in DMA (2 mL) was added isobutyl chloroformate (0.96 mL stock solution prepared 0.1 mL in 0.9 mL DCM, 0.74 mmol) and 4-methylmorpholine (0.88 mL stock solution prepared 0.1 mL in 0.9 mL DMA, 0.80 mmol). Stirred at 0° C. for 5 min, ambient temperature for 30 min. Added NMM (0.1 mL, 0.92 mmol), glycineamide HCl (0.10 g, 0.92 mmol), and DMAP (0.01 g, 0.06 mmol) and stirred at ambient temperature for 1.5 h. Removed DMA under reduced pressure. Purified crude product by preparatory HPLC using a 10-90% CH3CN/H2O (30 min) gradient containing 0.5% TFA at a flow rate of 80 mL/min. Appropriate fractions (M+H m/z=463) were combined and concentrated to approximately 20 mL under reduced pressure. Added 5% NaHCO3 (20 mL) and extracted with DCM (3×15 mL). The organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure, and dried in vacuo to give the desired product as an off-white solid (77 mg, 27%). 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.96 (m, 1H), 7.80 (s, 1H), 7.61 (m, 1H), 7.54 (m, 1H), 7.01 (m, 2H), 5.60 (m, 2H), 4.01 (s, 2H), 2.20 (s, 3H). ESHRMS m/z 463.0990 (M+H calculated for C21H18ClF2N4O4 requires 463.0979).

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