A vial was charged with neopentyl alcohol (0.579 g, 6.57 mmol) and DMF (6.57 mL). Sodium hydride (60% in mineral oil; 0.263 g, 6.57 mmol) was added and the reaction was stirred for 10 minutes at room temperature. The vial was heated to 100° C. for 5 min. The vial was cooled to rt. (S)-7-bromo-3-chloro-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.500 g, 1.314 mmol) was added in one portion. The vial was sealed and heated to 100° C. three hours. The mixture was diluted with ethyl acetate and water. A small amount of brine was added and the layers were separated. The aq. layer was extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (0-100% EtOAc/Hexanes) to give 175 mg of (S)—N-(7-bromo-3-(neopentyloxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazine]-5′-yl)formamide as a light yellow solid. Step 2: A microwave vial was charged with (S)—N-(7-bromo-3-(neopentyloxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazine]-5′-yl)formamide (0.075 g, 0.163 mmol), 2-fluoropyridin-3-ylboronic acid (0.046 g, 0.326 mmol), potassium phosphate (0.104 g, 0.489 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (5.77 mg, 8.15 μmol). The vial was flushed with Ar (g), then dioxane (0.611 mL) and water (0.204 mL) were added in sequence. The vial was sealed and heated in a Biotage Initiator microwave reactor for 30 min at 100° C. The reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (0-10% MeOH:DCM w/1% NH4OH) to afford 32 mg of (S)—N-(7-(2-fluoropyridin-3-yl)-3-(neopentyloxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazine]-5′-yl)formamide as an off-white solid.
