FC(F)(F)C(O)=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17][NH:18]C(=O)OC(C)(C)C)=[C:11]([C:26](=O)[C:27]2[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=2[F:35])[CH:10]=1.C(N(CC)C(C)C)(C)C.CO[CH:48](OC)[N:49]([CH3:51])[CH3:50]>ClCCl.O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]2[C:15](=[O:4])[C:16](=[CH:48][N:49]([CH3:50])[CH3:51])[CH2:17][N:18]=[C:26]([C:27]3[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=3[F:35])[C:11]=2[CH:10]=1
Trifluoroacetic acid (158 L) and water (8.3 L) were added to a reactor. A solution of 8 (37.8 kg, 90.5 mol) in dichloromethane (63 L) was added via a second reactor to the trifluoroacetic acid solution over a minimum of 60 min while maintaining the temperature between 20 and 30° C. The reactor containing the solution of 8 was rinsed with dichloromethane (19 L) and transferred to the reaction mixture while maintaining the temperature between 20 and 30° C. The mixture was heated to 30 to 35° C. and stirred for at least 19 h until ≧98.0% conversion was obtained by HPLC analysis. The mixture was concentrated under vacuum at 35 to 45° C. until 76 to 79 kg remained in the reactor. Dichloromethane (424 L) was added while maintaining the internal temperature between 20 and 30° C. N,N-Diisopropylethylamine (64 kg, 495 mol) was added over a minimum of 30 min while maintaining the temperature between 20 and 30° C. If the pH was <8.0 then 5 L portions of N,N-diisopropylethylamine were added until the pH was ≧8.0. The mixture was stirred at 20 to 30° C. for a minimum of 2 h until ≧99.0% conversion was obtained by HPLC analysis. Water (378 L) was added while maintaining the temperature between 20 and 25° C. and stirred for 30 min. The phases were separated and the organic phase was washed with a 10% w/w brine solution (38 kg NaCl in 340 kg of water). The phases were separated and the organic phase was dried with sodium sulfate (5.4 kg) for a minimum of 30 min at 20 to 25° C. The mixture was filtered and the reactor that contained the sodium sulfate mixture was rinsed with additional dichloromethane (27 L) and filtered. Dimethylformamide dimethylacetal (152 kg, 1276 mol) was added to the combined filtrate over a minimum of 30 min while maintaining the temperature between 20 and 30° C. The mixture was warmed to 37 to 42° C. and stirred for a minimum of 20 h until ≧99.0% conversion was obtained by HPLC analysis. The reaction mixture was concentrated under vacuum using a jacket temperature of 40 to 45° C. until 234 to 252 kg remained in the reactor. MTBE (355 L) was added at 35 to 40° C. and the resulting mixture was concentrated under vacuum using a jacket temperature of 40 to 45° C. until 414 to 432 kg remained in the reactor. The suspension was cooled to 20 to 25° C. over a minimum of 3 h and stirred for an additional 2 h. The suspension was filtered and washed at 20 to 25° C. while stirring with MTBE (2×50 L) followed by acetone (2×101 L). The wet cake was dried under vacuum at 35 to 45° C. to provide 28.0 kg (83% yield) of 9. 1H NMR (300 MHz, DMSO-d6) δ 7.87 (d, J=8.2 Hz, 1H), 7.63 (s, 1H), 7.58 (d, J=9.4 Hz, 1H), 7.42 (dd, J=6.96, 8.2 Hz, 1H), 6.94 (m, 2H), 4.83 (d, J=12.9 Hz, 1H), 3.44 (d, J=12.9 Hz, 2H), 3.31 (s, 3H), 3.22 (s, 6H); MS (ESI) m/z 373.2 (M+H+, 100%).
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