Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][C:15](/[CH:21]=[CH:22]/[C:23]([CH2:29][F:30])([CH2:27][F:28])[C:24]([OH:26])=[O:25])=[CH:16][CH:17]=2)[N:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.CC1C=CC=C([N+]([O-])=O)C=1C(OC(=O)C1C([N+]([O-])=O)=CC=CC=1C)=O.[Cl:65][C:66]([Cl:90])([Cl:89])[CH2:67][O:68][C:69]([C@@H:71]1[CH2:76][CH2:75][CH2:74][N:73]([C:77](=[O:88])[C@@H:78]([NH:80][C:81](=[O:87])[C@@H:82](O)[CH:83]([CH3:85])[CH3:84])[CH3:79])[NH:72]1)=[O:70]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:89][C:66]([Cl:65])([Cl:90])[CH2:67][O:68][C:69]([C@@H:71]1[CH2:76][CH2:75][CH2:74][N:73]([C:77](=[O:88])[C@@H:78]([NH:80][C:81](=[O:87])[C@@H:82]([O:25][C:24](=[O:26])[C:23]([CH2:27][F:28])([CH2:29][F:30])/[CH:22]=[CH:21]/[C:15]2[CH:14]=[C:13]3[C:18]([CH:19]=[CH:20][C:11]([C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH3:10])=[N:12]3)=[CH:17][CH:16]=2)[CH:83]([CH3:84])[CH3:85])[CH3:79])[NH:72]1)=[O:70]
Reactant: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc2ccc(/C=C/C(CF)(CF)C(=O)O)cc2n1
Agent: CN(C)c1ccncc1
Agent: Cc1cccc([N+](=O)[O-])c1C(=O)OC(=O)c1c(C)cccc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
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)OCC(Cl)(Cl)Cl)N1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-carbamic acid tert-butyl ester (105 mg, 0.3 mmol), 2,2-bis-fluoromethyl-but-3-enoic acid (50 mg, 0.33 mmol), tri(o-tolyl)phosphine (18 mg, 0.06 mmol) and triethylamine (91 mg, 0.13 mL, 0.9 mmol) in 1,4-dioxane (3 mL) was degassed with nitrogen for 15 min. Tris(dibenzylideneacetone)dipalladium(0) (28 mg, 0.03 mmol) was added and the reaction mixture was heated to 60° C. for 1 h. The reaction mixture was cooled to room temperature and the mixture was filtered through a hydrophobic frit and the filtrate was evaporated to afford crude (E)-4-[2-((R)-1-tert-butoxycarbonylamino-ethyl)-quinolin-7-yl]-2,2-bis-fluoromethyl-but-3-enoic acid (0.3 mmol) as a yellow gum. LCMS (m/z) 421.1 [M+H], Tr=2.27 min. A solution of crude (E)-4-[2-((R)-1-tert-butoxycarbonylamino-ethyl)-quinolin-7-yl]-2,2-bis-fluoromethyl-but-3-enoic acid (0.3 mmol), N,N-diisopropylethylamine (96 mg, 0.13 mL, 0.75 mmol), 4-(dimethylamino)-pyridine (73 mg, 0.6 mmol) and 2-methyl-6-nitrobenzoic anhydride (193 mg, 0.56 mmol) in anhydrous dichloromethane (5 mL) was stirred at 0° C. under nitrogen. A solution of (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (142 mg, 0.33 mmol) in dichloromethane (2 mL) was added and the reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 18 h. The reaction mixture was diluted with dichloromethane and the solution was washed with ice-cold saturated sodium hydrogen carbonate solution, water, ice-cold hydrochloric acid (1 M), water and brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 2:1 to 0:1 to afford the partially purified title compound (26 mg, 10%) as a yellow gum. LCMS (m/z) 834.3, 836.2 [M+H], Tr=3.39 min.