A microwave vial was charged with 4-amino-3-hydroxy-N-(4-methoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide (0.185 g, 0.472 mmol) (INTERMEDIate AD), cesium carbonate (0.384 g, 1.179 mmol), 4-bromo-3-methoxybenzonitrile (0.05 g, 0.236 mmol, Combi Blocks) and copper(i) iodide (0.011 g, 0.059 mmol). The vial was sealed and flushed with argon, and wrapped with aluminum foil to exclude light, then DMF (0.5 mL) was added. The reaction was heated to 110° C. for 2 hr to give intermediate 4-((4-cyano-2-methoxyphenyl)amino)-3-hydroxy-N-(4-methoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide. The reaction was cooled to rt, and chloroacetic acid chloride was added dropwise (0.038 ml, 0.472 mmol). The solution was maintained at rt for 30 min. At this time, 10 mL of saturated ammonium chloride solution was added, and the mixture was further diluted with 10 mL of DCM. The layers were separated and the aqueous layer was extracted with DCM (2×10 mL). To the aqueous layer was added n-(2-hydroxyethyl)ethylenediaminetriacetic acid, trisodium salt hydrate (500 mg, Sigma Aldrich) to aqueous to decomplex Cu from the product. The resulting aqueous solution was extracted with DCM (1×10 mL). The combined organics were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product, 4-(4-cyano-2-methoxyphenyl)-N-(4-methoxybenzyl)-3-oxo-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.133 g, 0.236 mmol, 100% yield) was taken forward without further purification.
