1268454-23-4

1404480-15-4

1434089-03-8

1268454-23-4

1. assemble a 5L three-necked, round-bottomed flask equipped with a mechanical stirrer, thermocouple probe, nitrogen/vacuum inlet, and reflux condenser, and place in a heating jacket. 2. add 1,4-dioxane (3.75 L) and water (1.25 L) to the flask at room temperature. 3. (2-Amino-1,3-benzoxazol-5-yl)boronic acid hydrochloride (250 g) and (6-bromo-5H-imidazo[2,1-b][1,3]oxazin-3-yl)(morpholinyl)methanone (210 g) were added sequentially at room temperature. 4. The reaction mixture was stirred at room temperature for 10 minutes. 5. Sodium carbonate (300 g) was added followed by Pd(PPh3)4 (47 g) at room temperature. 6. the reactor was sprayed with nitrogen for about 30 minutes under stirring to deoxygenate the reaction mixture by 5 to 6 vacuum/nitrogen cycles. 7. The reaction mixture was heated to reflux (88 °C to 102 °C) and stirred for 5 to 8 hours under light nitrogen bubbling. 8. The progress of the reaction was monitored by HPLC. 9. Upon completion of the reaction, the reaction mixture was cooled to 75-80°C. 10. 10. Water (3.75 L) and ethyl acetate (1.25 L) were added at 75-80 °C. 11. The mixture was cooled to room temperature and stirred for 2 hours. 12. The mixture was filtered and the collected solid was washed sequentially with water (2 x 1.25 L), methanol (1.25 L) and ethyl acetate (2 x 1.25 L). 13. Suspend the solid in ethyl acetate (1.5L) for 1 hour at room temperature. 14. Filtered the suspension and washed the solid with ethyl acetate (250mL). 15. Repeat steps 13 and 14 twice. 16. The solid obtained was dried under vacuum to obtain the crude product (250 g, 85% yield; HPLC purity 98.1%; Pd content 1831 ppm). 17. Purification of crude product: the crude product (250 g) was suspended in methanol (2.5 L) and HCl (158 mL) at room temperature. 18. The mixture was heated to 40 to 45°C to form a slightly turbid solution. 19. Charcoal (250 g) was added and stirred at 40 to 45°C for 30 minutes. 20. The hot solution was filtered through a polymer pad fitted with a 2-inch bed of diatomaceous earth, and the filter cake was washed with methanol (3 x 500 mL). 21. The filtrate was refilled into a flask (Pd content: 330 ppm). 22. the solution was heated to 40 to 45 °C and charcoal (50 g) and silica thiols (50 g) were added. 23. After stirring at 40 to 45°C for 30 minutes, the hot solution was filtered through a polymer pad and the filter cake was washed with methanol (250 mL). 24. Steps 22 and 23 were repeated once. 25. Concentrate under vacuum at 30 to 35°C to about 2.5L. 26. The solution was cooled to 10 to 15 °C and the pH was adjusted to 8-9 by adding concentrated ammonia solution (200 mL). 27. cool the reaction mixture to 0 to 5°C and stir for 1 to 2 hours. 28. The mixture was filtered and the filter cake was washed sequentially with water (2 x 500 mL) and methanol (2 x 500 mL). 29. Transfer the solid to a round bottom flask and suspend in ethyl acetate (2.5 L) for 2 to 3 hours at room temperature. 30. The solid was collected by filtration and washed with ethyl acetate (750mL). 31. The solid was dried under vacuum at about 50 °C to constant weight to afford the target compound (180 g, 61% yield; HPLC purity 98.5%; 1H NMR (DMSO-d6, 300 MHz) δ 9.1 (s, 1H), 8.1 (s, 1H), 7.8-7.65 (m, 2H), 7.60-7.40 (m, 4H), 7.3- 7.2 (m, 1H), 3.8-3.6 (m, 8H); 1 ppm Pd.