Reaction SMILES: COC([C@@H]1CC2C=C3OC[C@H](C4C=CC(OCC5C=CC(Cl)=C(Cl)C=5)=CC=4)OC3=CC=2CN1C(OC(C)(C)C)=O)=O.[C:42]([O:46][C:47]([N:49]1[C@H:58]([C:59]([OH:61])=O)[CH2:57][C:56]2[CH:55]=[C:54]3[O:62][CH2:63][C@H:64]([C:66]4[CH:71]=[CH:70][C:69]([O:72][CH2:73][C:74]5[CH:79]=[CH:78][C:77]([Cl:80])=[C:76]([Cl:81])[CH:75]=5)=[CH:68][CH:67]=4)[O:65][C:53]3=[CH:52][C:51]=2[CH2:50]1)=[O:48])([CH3:45])([CH3:44])[CH3:43].Cl.[CH3:83][O:84][C:85](=[O:103])[C@@H:86]([NH2:102])[CH2:87][C:88]1[CH:93]=[CH:92][C:91]([C:94]2[CH:99]=[CH:98][C:97]([C:100]#[N:101])=[CH:96][CH:95]=2)=[CH:90][CH:89]=1>>[C:42]([O:46][C:47]([N:49]1[C@H:58]([C:59](=[O:61])[NH:102][C@H:86]([C:85]([O:84][CH3:83])=[O:103])[CH2:87][C:88]2[CH:89]=[CH:90][C:91]([C:94]3[CH:99]=[CH:98][C:97]([C:100]#[N:101])=[CH:96][CH:95]=3)=[CH:92][CH:93]=2)[CH2:57][C:56]2[CH:55]=[C:54]3[O:62][CH2:63][C@H:64]([C:66]4[CH:71]=[CH:70][C:69]([O:72][CH2:73][C:74]5[CH:79]=[CH:78][C:77]([Cl:80])=[C:76]([Cl:81])[CH:75]=5)=[CH:68][CH:67]=4)[O:65][C:53]3=[CH:52][C:51]=2[CH2:50]1)=[O:48])([CH3:43])([CH3:44])[CH3:45]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: COC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Yield: 77.3 %

Procedure:
(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester 8-methyl ester (708 mg) was hydrolyzed according to General Procedure B and the resulting (3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester (670 mg) was coupled with (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester hydrochloride (363 mg) according to General Procedure L to give (3S,8S)-8-[(S)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (750 mg). This intermediate (720 mg) was deprotected as described in General Procedure C to give (S)-3-(4′-cyano-biphenyl-4-yl)-2-({(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester hydrochloride salt. This product was neutralized with aqueous Na2CO3 and the resulting solid was extracted with ethyl acetate (100 mL). The organic layer was washed with water, brine, dried and concentrated to furnish a white solid. The solid was purified by silica gel flash chromatography (9:1 to 1:1 DCM/EtOAc) to furnish (S)-3-(4′-cyano-biphenyl-4-yl)-2-({(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (550 mg). LCMS (m/z): 748; 1H NMR (400 MHz, DMSO-d6): 8.25 (d, 1H), 7.85 (m, 4H), 7.70 (d, 1H), 7.65 (m, 3H), 7.42 (m, 1H), 7.31 (m, 4H), 7.02 (m, 2H), 6.60 (a, 1H), 6.65 (s, 1H), 5.12 (s, 2H) 5.06-5.08 (m, 1H), 4.6 (m, 1H), 4.27 (dd, 1H), 3.96 (m, 2H), 3.65 (bs, 1H), 3.64 (s, 3H), 3.38 (m, 1H), 3.0-3.16 (m, 2H), 2.5-2.76 (m, 2H).