Methanol → 4-(2-cyano-4-(trifluoromethyl)phenyl)-8-fluoro-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide

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To a vial charged with N-(4-methoxybenzyl)thiazol-2-amine (0.036 g, 0.162 mmol) was added THF (0.482 ml) and the mixture cooled in an ice water bath prior to the addition of lithium bis(trimethylsilyl)amide, 1.0M solution in tetrahydrofuran (0.177 ml, 0.177 mmol), faster than dropwise. After 15 mins of stirring a solution of 4-(2-cyano-4-(trifluoromethyl)phenyl)-8-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (0.062 g, 0.147 mmol) in THF (0.5 ml) was added dropwise, then washed with 0.2 ml THF and added. The mixture was allowed to warm to rt over 1 hr providing a turbid brown mixture with product as the primary species according to LC-MS (m/z=605). To the turbid brown solution was added MeOH and the mixture concentrated under reduced pressure. To the crude residue was added DCM (2 ml) and TFA (0.2 ml). After 2 hr, the mixture was concentrated under reduced pressure and purified with a 25 g SNAP column ramping EtOAc in heptane (0-75%, 10% DCM throughout) to yield product as a sticky white solid, which was lyophilized from MeOH/H2O affording product as a fluffy white solid, 4-(2-cyano-4-(trifluoromethyl)phenyl)-8-fluoro-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.04 g, 0.083 mmol, 56.0% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.83-3.95 (m, 2 H) 4.34-4.46 (m, 2 H) 6.56 (dd, J=8.90, 1.27 Hz, 1 H) 6.84 (d, J=4.60 Hz, 1 H) 7.17 (dd, J=8.85, 7.29 Hz, 1 H) 7.27 (d, J=4.60 Hz, 1 H) 7.76 (d, J=8.61 Hz, 1 H) 8.11 (dd, J=8.80, 2.05 Hz, 1 H) 8.42 (d, J=1.76 Hz, 1 H) 12.80 (br. s., 1 H). m/z (ESI) 485.2 (M+H)+.

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