To a stirred mixture of 8-bromo-2-chloroquinazolin-4-amine (12.93 g, 50 mmol) in THF (500 mL) was added isoamyl nitrite (23.43 g, 200 mmol) over 3 hours and 40 mins at 6OCompound 19-d (1.5 g, 5.84 mmol) was dissolved in tetrahydrofuran (20 mL) and tertamyl nitrite (2.7 g, 23.36mmol) was added. The reaction mixture was heated at 70°C for 18 hours and the reaction mixture was concentratedunder reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: dichloromethane= 3: 1) to deliver a pale yellow solid 19-c (0.79 g, yield: 56percent). LC-MS (ESI): m/z = 243 [M+H]+.To a solution of 8-bromo-2-chloroquinazolin-4-amine (7.1 g, 27 mmol, 1 eq.) in THF (80 mL) at 70 °C was added isopentyl nitrite (14 mL, 108 mmol, 4 eq.) dropwise. The resulting mixture was stirred at 70 °C for 12 h, then cooled to r.t. and concentrated. The resulting residue was purified via column chromatography (PE/EA=5: 1, v/v) to afford 8-bromo-2-chloroquinazolineCompound 44-d (1.5 g, 5.84 mmol) was dissolved in tetrahydrofuran (20 mL) and tert-amyl nitrite (2.7 g, 23.36 mmol) was added. The reaction mixture was heated at 70° C. for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether: dichloromethane=3:1) to give 44-c as a light yellow solid (0.79 g, yield 56percent). LC-MS (ESI): m/z=243[M+H]Compound 44-c (1.2 g, 5 mmol), compound 2-b (1.25 g, 5 mmol), [1, 1?-bis (diphenylphosphino)ferrocene]dichloropalladium (36 mg, 0.05 mmol) and sodium carbonate (1.06 g, 10 mmol) were dissolved in 1, 4-dioxane (8 mL) and water (2 mL). The reaction mixture was purged with nitrogen gas for three times to remove the oxygen contained in the system, and then heated at 90 C. for 8 hours. The reaction was cooled to room temperature, diluted with ice water (10 mL) and extracted with dichloromethane (50 mL×3). The combined organic phase was washed with water (20 mL×3) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel TLC preparative plate (petroleum ether: ethyl acetate=10:1) to give 44-b as a yellow solid (790 mg, yield 56%). LC-MS (ESI): m/z=283[M+H]+.Compound 44-c (600 mg, 2.48 mmol), pinacol 2-methoxyphenylboronate (415 mg, 2.73 mmol), [1, 1'-bis(diphenylphosphino)ferrocene]dichloropalladium (204 mg, 0.25 mmol) and sodium carbonate (804 mg, 7.44 mmol) were dissolved in 1, 4-dioxane (5 mL) and water (3 mL). The reaction solution was purged with nitrogen gas for three times to remove the oxygen contained in the system and then heated at 80 C. for 16 hours. The reaction was cooled to room temperature, diluted with ice water (10 mL) and extracted with dichloromethane (50 mL*3). The combined organic phase was washed with water (20 mL*3) and brine (20 mL) sequentially, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: dichloromethane=3:1) to give 45-b as a white solid (450 mg, yield 67%). LC-MS (ESI): m/z=271[M+H]+.Compound 19-c (1.02 g, 4.20 mmol), 2-methoxy-5-fluorobenzeneboronic acid (1.0 g, 5.88 mmol), [1, 1?-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (343 mg, 0.42 mmol) and sodium carbonate (1.34 g, 12.6 mmol)were dissolved in 1, 4-dioxane (10 mL) and water (10 mL). The reaction mixture was replaced with nitrogen three timesto remove the oxygen inside the system and then heated at 80C for 16 hours. The reaction mixture was cooled to roomtemperature, diluted with water (50 mL) and extracted with dichloromethane (50 mL 3 3). The combined organic phaseswere washed successively with water (20 mL 3 3) and brine (20 mL), dried over sodium sulfate, filtered, and the filtratewas concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 100: 1) to deliver a white solid 29-b (137 mg, yield: 12%). LC-MS (ESI): m/z = 289 [M+H]+.
skype
-111YR 
