Reaction SMILES: [C:1]([O:5][C:6](=[O:48])[N:7]([C:15]1[C:20]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([CH2:32][N:33]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[CH:28][CH:27]=3)[CH:22]=2)=[N:19][C:18](Br)=[CH:17][N:16]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH:55]([S:58]([C:61]1[CH:66]=[CH:65][C:64](B(O)O)=[CH:63][CH:62]=1)(=[O:60])=[O:59])([CH3:57])[CH3:56]>C1(C)C=CC=CC=1.O>[C:1]([O:5][C:6]([N:7]([C:15]1[C:20]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([CH2:32][N:33]([C:40]([O:42][C:43]([CH3:45])([CH3:46])[CH3:44])=[O:41])[CH:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[CH:28][CH:27]=3)[CH:22]=2)=[N:19][C:18]([C:64]2[CH:63]=[CH:62][C:61]([S:58]([CH:55]([CH3:57])[CH3:56])(=[O:60])=[O:59])=[CH:66][CH:65]=2)=[CH:17][N:16]=1)[C:8](=[O:9])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:48])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)S(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1cc(-c2ccc(CN(C(=O)OC(C)(C)C)C3CCOCC3)cc2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3cc(-c4ccc(CN(C(=O)OC(C)(C)C)C5CCOCC5)cc4)no3)n2)cc1
Temperature: 70 °C

Procedure:
A mixture of tert-butyl(5-bromo-3-(3-(4-(((tert-butoxycarbonyl)(tetrahydro-2H-pyran-4-yl)amino)methyl)phenyl)isoxazol-5-yl)pyrazin-2-yl)(tert-butoxycarbonyl)carbamate (A-5) (425 g, 582 mmol), K2CO3 (161 g, 1.16 mol; 2.0 equiv.), and (4-(isopropylsulfonyl)phenyl)boronic acid (133 g, 582 mmol) in toluene (2.98 L) and water (850 mL) is stirred and degassed with N2 at ambient temperature. The catalyst [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), (Pd(dtbpf)Cl2; 1.90 g, 2.91 mmol) is added and the mixture is degassed for an additional 10 min. The mixture is heated at 70° C. until the reaction is complete. The mixture is cooled to 50° C., diluted with water (850 mL) and filtered through a bed of Celite. The phases are separated. The organic phase is concentrated then the residue is diluted with EtOH (1.70 L) and re-concentrated. With mixing at 40° C., the concentrate is diluted with EtOH (1.70 L) to induce crystallization. The suspension is cooled to 20° C. and stirred for 4 h. The solid is collected by filtration. The filter-cake is washed with EtOH (2×425 mL) and air-dried to afford tert-butyl tert-butoxycarbonyl(3-(3-(4-(((tert-butoxycarbonyl)(tetrahydro-2H-pyran-4-yl)amino)methyl)phenyl)isoxazol-5-yl)-5-(4-(isopropylsulfonyl)phenyl)pyrazin-2-yl)carbamate (A-6) as a beige powder. The solid is dissolved in THF (2.13 L) and slurried with Biotage MP-TMT resin (48 g) at ambient temperature. The resin is removed by filtration and the filtrate concentrated to remove most of the THF. The concentrate is diluted with EtOH (970 mL) and re-concentrated to about half the original volume. The concentrate is diluted again with EtOH (970 mL) and mixed for 1 h at 40° C. The suspension is cooled to ambient temperature and the solid is collected by filtration then dried to afford tert-butyl tert-butoxycarbonyl(3-(3-(4-(((tert-butoxycarbonyl)(tetrahydro-2H-pyran-4-yl)amino)methyl)phenyl)isoxazol-5-yl)-5-(4-(isopropylsulfonyl)phenyl)pyrazin-2-yl)carbamate (A-6) (416 g 86% yield, 99.3 area % purity by HPLC) as a white powder. 1H NMR (400 MHz, CDCl3) δ 9.04 (s, 1H), 8.38-8.28 (m, 2H), 8.10-8.01 (m, 2H), 7.82 (d, J=8.2 Hz, 2H), 7.34 (m, 3H), 4.44 (br s, 2H), 3.94 (dd, J=10.5, 3.5 Hz, 2H), 3.40 (br s, 2H), 3.25 (hept, J=6.8 Hz, 1H), 1.65 (m, 4H), 1.38 (br s, 27H), 1.33 (d, J=6.9 Hz, 6H).