Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:53])[C@@H:14]([NH:16][C:17](=[O:52])[C@@H:18]([O:22][C:23](=[O:51])[C:24]([CH2:49][F:50])([CH2:47][F:48])/[CH:25]=[CH:26]/[C:27]2[CH:36]=[C:35]3[C:30]([CH:31]=[CH:32][C:33]([C@H:37]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH3:38])=[N:34]3)=[CH:29][CH:28]=2)[CH:19]([CH3:21])[CH3:20])[CH3:15])[NH:8]1)=[O:6].[OH-].[Na+].Cl>O1CCCC1>[C:43]([O:42][C:40]([NH:39][C@@H:37]([C:33]1[CH:32]=[CH:31][C:30]2[C:35](=[CH:36][C:27](/[CH:26]=[CH:25]/[C:24]([CH2:47][F:48])([CH2:49][F:50])[C:23]([O:22][C@@H:18]([CH:19]([CH3:20])[CH3:21])[C:17]([NH:16][C@@H:14]([CH3:15])[C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@@H:7]([C:5]([OH:6])=[O:4])[NH:8]3)=[O:53])=[O:52])=[O:51])=[CH:28][CH:29]=2)[N:34]=1)[CH3:38])=[O:41])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)[C@H](OC(=O)C(/C=C/c1ccc2ccc([C@@H](C)NC(=O)OC(C)(C)C)nc2c1)(CF)CF)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)[C@H](OC(=O)C(/C=C/c1ccc2ccc([C@@H](C)NC(=O)OC(C)(C)C)nc2c1)(CF)CF)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)O)N1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 90.9 %

Procedure:
A solution of (S)-1-[(S)-2-((S)-2-{(E)-4-[2-((R)-1-tert-butoxycarbonylamino-ethyl)-quinolin-7-yl]-2,2-bis-fluoromethyl-but-3-enoyloxy}-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (100 mg, 0.11 mmol) in tetrahydrofuran (3 mL) was stirred at 0° C. under nitrogen. An ice-cold aqueous solution of sodium hydroxide (0.1 M, 1.1 mL, 0.11 mmol) was added and the reaction mixture was stirred at 0° C. for 20 min. Cold hydrochloric acid (1 M) was added to acidify the mixture to pH 2 and the solvent was evaporated. The residue was co-evaporated with tetrahydrofuran/toluene (1:1, 3×) and the residue was triturated with diethyl ether (2×) and the resulting solid was dried to afford (S)-1-[(S)-2-((S)-2-{(E)-4-[2-((R)-1-tert-butoxycarbonylamino-ethyl)-quinolin-7-yl]-2,2-bis-fluoromethyl-but-3-enoyloxy}-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid (0.1 mmol) as a yellow solid which was used crude in the next reaction. LCMS (m/z) 704.3 [M+H], Tr=2.61 min. A mixture of crude (S)-1-[(S)-2-((S)-2-{(E)-4-[2-((R)-1-tert-butoxycarbonylamino-ethyl)-quinolin-7-yl]-2,2-bis-fluoromethyl-but-3-enoyloxy}-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid (0.1 mmol) in hydrochloric acid (4 M in 1,4-dioxane, 2 mL) was stirred at room temperature for 30 min. The solvent was evaporated and the residue was co-evaporated with diethyl ether (2×) and the resulting solid was dried to afford (S)-1-[(S)-2-((S)-2-{(E)-4-[2-((R)-1-amino-ethyl)-quinolin-7-yl]-2,2-bis-fluoromethyl-but-3-enoyloxy}-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid hydrochloride (0.1 mmol) as an off-white solid which was used crude in the next reaction. LCMS (m/z) 604.3 [M+H], Tr=1.53 min. A suspension of crude (S)-1-[(S)-2-((S)-2-{(E)-4-[2-((R)-1-amino-ethyl)-quinolin-7-yl]-2,2-bis-fluoromethyl-but-3-enoyloxy}-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid hydrochloride (0.1 mmol) in dichloromethane (100 mL) was stirred at 0° C. under nitrogen. A solution of N,N-diisopropylethylamine (52 mg, 0.07 mL, 0.4 mmol) in dichloromethane (5 mL) was added and the resulting solution was stirred at 0° C. 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (76 mg, 0.2 mmol) was added and the reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 18 h. The solvent was partially evaporated to a volume of ˜30 mL. The solution was washed with ice-cold saturated sodium hydrogen carbonate solution, ice-cold hydrochloric acid (1 M) and brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography eluting with a gradient of iso-hexanes/ethyl acetate 1:1 to 0:1 followed silica gel chromatography eluting with iso-hexanes/acetone 3:2. The residue was triturated with diethyl ether and the resulting solid was dried to afford the title compound (4 mg, 7% over 3 steps) as a white solid. 1H NMR (300 MHz, CD3OD) δ 1.01 (d, J=6.5 Hz, 3H), 1.09 (d, J=6.9 Hz, 3H), 1.49-1.55 (m, 2H), 1.61 (d, J=6.9 Hz, 3H), 1.64 (d, J=7.1 Hz, 3H), 1.93-1.98 (m, 1H), 2.15-2.28 (m, 2H), 2.68-2.76 (m, 1H), 3.59-3.63 (m, 1H), 4.41-4.46 (m, 1H), 4.70-5.13 (m, 5H), 5.35 (d, J=8.9 Hz, 1H), 5.84 (q, J=7.1 Hz, 1H), 6.27 (d, J=16.5 Hz, 1H), 6.81 (d, J=16.5 Hz, 1H), 7.49 (d, J=7.9 Hz, 1H), 7.70 (dd, J=8.5, 1.6 Hz, 1H), 7.82 (br s, 1H), 7.88 (d, J=8.5 Hz, 1H), 8.28 (d, J=8.5 Hz, 1H). LCMS (m/z) 586.2 [M+H], Tr=2.48 min.