4-(4-Fluorobenzyl)-N-isopropyl-2-{2-[methoxy(methyl)amino]ethyl}-5-oxopiperazine-1-carboxamide (777 mg, 2.04 mmol) was azeotroped with anhydrous toluene (10 μL) and dissolved in anhydrous DMF (10 mL). The solution was cooled to 0° C. under inert atmosphere and treated with 1.0 M lithium bis(trimethylsilyl)amide in THF (2.45 mL, 2.45 mmol). After stirring for 10 min, diethyl oxalate (416 μL, 3.06 mmol) was added. The mixture was stirred at 0° C. for an additional 15 min and then allowed to warm to ambient temperature. Following addition of excess 1.0 M lithium bis(trimethylsilyl)amide in THF (7.30 mL, 7.30 mmol), the reaction was stirred at ambient temperature for 18 h. The mixture was treated with MeOH and concentrated in vacuo to give a dark oil. Purification by reverse phase chromatography [95:5 water (+0.1% TFA)/MeCN (+0.1% TFA) to 5:95 water (+0.1% TFA)/MeCN (+0.1% TFA)] afforded the title compound as tan foam. 1H NMR (400 MHz, d6-DMSO) δ 11.78 (br s, 1H), 7.44-7.41 (m, 2H), 7.24-7.19 (m, 2H), 5.04 (dt, J=6.4, 13.6 Hz, 1H), 4.84 (d, J=14.8 Hz, 1H), 4.72 (br s, 1H), 4.51 (d, J=14.4 Hz, 1H), 3.77 (dd, J=3.6, 13.2 Hz, 1H), 3.43 (d, J=13.6 Hz, 1H), 3.31 (s, 3H), 2.36 (s, 3H), 2.33-2.31 (m, 2H), 1.71-1.62 (m, 1H), 1.51-1.43 (m, 1H), 1.37 (d, J=6.8 Hz, 6H). HRMS (FT/ES) M+H: calcd for (C21H27FN4O5)+ 435.2038. found 435.2038.
