To a solution of 6-fluoro-2-[(1S,5S)-6-(4-methoxyphenyl)-3,6-diazabicyclo[3.2.2]non-3-yl]quinazoline (E-5, 0.020 g, 0.053 mmol, 1.0 equiv) in acetonitrile/water (0.3 mL total; 2:1) at 0° C. was added ceric ammonium nitrate (0.043 g, 0.079 mmol, 1.5 equiv) and the reaction was stirred 1 h. At 1 h, added more ceric ammonium nitrate (0.0 43 g, 0.079 mmol, 1.5 equiv) and the reaction was complete after 2 h. The reaction mixture was quenched with 10% aqueous sodium thiosulfate and concentrated directly. The resulting residue was azeotroped with methanol (2×10 mL) and toluene (2×20 mL). The oily residue was dissolved in DMF (0.3 mL) and to this solution was added EDC (0.030 g, 0.16 mmol, 3.0 equiv), HOBt (0.024 g, 0.16 mmol, 3.0 equiv), triethylamine (0.037 mL, 0.26 mmol, 5.0 equiv), and 2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid (0.032 g, 0.16 mmol, 3.0 equiv). The reaction mixture was heated to 70° C. for 1 h and cooled to ambient temperature. The reaction was partitioned between ethyl acetate (20 mL) and saturated NaHCO3 (20 mL) and the organic phase was washed with water (4×10 mL). The combined organic phase was dried over MgSO4, concentrated and purified by column chromatography on silica gel (0 to 100% ethyl acetate in hexanes). The resulting product was further purified by reverse phase column chromatography (15 to 85% acetonitrile in water, 0.1% TFA buffer) to afford, after free-basing with saturated NaHCO3, E-6 as a yellow foam. HRMS [M+H] C25H24FN7O calc'd 458.2104, found 458.2115.
