A vial charged with a solution of (S)-3-bromo-7-iodo-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.880 g, 1.864 mmol), 2-fluoropyridin-3-ylboronic acid (0.276 g, 1.957 mmol), PdCl2(dppf)-CH2Cl2-adduct (0.038 g, 0.047 mmol), and potassium carbonate (1.031 g, 7.46 mmol). Dioxane (10 mL) and water (5 mL) were added, and the vial was flushed with argon and heated to 100° C. for 90 minutes. Pd2(dba)3 (0.171 g, 0.186 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethylbiphenyl-2-yl)phosphine (0.224 g, 0.466 mmol), and potassium hydroxide (1.046 g, 18.64 mmol) were added to the reaction mixture. The vial was sealed and heated to 120° C. for an additional 3 hours. The reaction mixture was then neutralized to pH 7 with 1N HCl, and was diluted with 2-MeTHF. The organics were dried over MgSO4 and concentrated. Purification of the crude residue by column chromatography [0-100% (90:10:1 DCM/MeOH/NH4OH)/DCM] gave (S)-5′-amino-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-3-ol (0.133 g, 0.352 mmol). Step 2: A solution of (S)-5′-amino-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-3-ol (0.133 g, 0.352 mmol), potassium carbonate (0.194 g, 1.406 mmol), and neopentyl iodide (0.093 mL, 0.703 mmol) in 1.5 mL DMF was heated to 115° C. overnight. The reaction mixture was then diluted with 2-MeTHF and washed with water. The organics were dried over MgSO4 and concentrated. Purification of the crude residue by column chromatography [0-100% (9:1 EtOAc/MeOH)/DCM] gave (S)-7-(2-fluoropyridin-3-yl)-3-(neopentyloxy)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.025 g, 0.056 mmol, 15.86% yield). MS m/z=449.20 [M+H]+. Calculated for C25H25FN4O3: 448.49.
