Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)[CH2:9][NH:10][C:11](=O)[CH2:12][CH2:13][C:14](O)=O)=[CH:4][CH:3]=1.[C:26]1(=O)OC(=O)C[CH2:27]1.BrC1C=CC([CH:40]([C:43]2[CH:48]=[CH:47]C=C(OC)C=2)[CH2:41][NH2:42])=CC=1.C(Cl)(=O)C>C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C:18]3[C:23](=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][CH2:27][N:42]4[CH2:41][CH2:40][CH2:43][CH2:48][CH2:47]4)[CH:19]=3)[C@H:14]3[CH2:13][CH2:12][CH2:11][N:10]3[CH2:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc(C(CN)c2ccc(Br)cc2)c1
Reactant: COc1cccc(C(CNC(=O)CCC(=O)O)c2ccc(Br)cc2)c1
Reactant: O=C1CCC(=O)O1
Solvent: CC(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Brc1ccc([C@@H]2CN3CCC[C@@H]3c3ccc(OCCCN4CCCCC4)cc32)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 75 %

Procedure:
2-[(4-Bromo-phenyl)-(3-methoxy-phenyl)-methyl]-malonic acid diethyl ester. A 0° C. solution of 3-methoxyphenyl magnesium bromide (1 M in THF; 414 mL, 0.414 mol) was treated with a solution of 2-(4-bromo-benzylidene)-malonic acid dimethyl ester (114.7 g, 0.3506 mol) in diethyl ether (250 mL), via cannula, over the course of 18 min. The mixture was stirred at 0° C. for 1 h and then was allowed to warm to rt. After 2 h, the reaction was quenched with satd. aq. NH4Cl, and extracted with diethyl ether. The organic layer was washed with satd. aq. NH4Cl and brine, dried (MgSO4), and concentrated to give the crude product as a yellow oil (163.5 g, >100%). The bulk of the crude product was taken on to the next step without purification, but a small portion was purified by normal phase column chromatography (EtOAc/hexanes) for characterization. MS: exact mass calcd for C21H23BrO5, 434.1; m/z found, 457.0 [M+Na]+, 459.0 [M+Na]+. 1H NMR (acetone-d6): 7.42 (m, 4H), 7.17 (d, J=7.9, 1H), 6.98 (m, 2H), 6.35 (m, 1H), 4.67 (d, J=12.3, 1H), 4.47 (d, J=12.2, 1H), 3.98 (m, 4H), 3.95 (s, 3H), 1.00 (m, 6H). Step 3. 2-[(4-Bromo-phenyl)-(3-methoxy-phenyl)-methyl]-malonic acid. A mixture of crude 2-[(4-bromo-phenyl)-(3-methoxy-phenyl)-methyl]-malonic acid diethyl ester (131.3 g, est. 0.3016 mol) in 150 mL hot ethanol was treated with a solution of KOH (85%; 99.6 g, 1.51 mol) in water (301 mL). The mixture was heated overnight at 105° C. and then was allowed to cool to rt. The mixture was diluted with water and extracted with diethyl ether (500 mL, ×3). The aqueous phase was acidified with 12 N HCl until the pH=1 and was extracted with diethyl ether (500 mL, ×3). The latter organic extracts were combined, dried (Na2CO3), and concentrated to give 107.97 g of a white-grey solid. The crude product was divided into two equal portions and each was suspended in 700 mL toluene. The toluene suspensions were heated at 105° C. for 3 h and then allowed to slowly cool to rt. The white solid was filtered off, rinsed with toluene, the portions combined and dried under high vacuum to give 68.8 g (60%) of the desired product as a white solid. MS (ESI, negative ionization): exact mass calcd for C17H15BrO5, 378.0; m/z found, 377.9 [M−H]−, 379.9 [M−H]−. 1H NMR (DMSO-d6): 12.68 (br s, 2H), 7.41 (m, 4H), 7.15 (m, 1H), 6.97 (m, 2H), 6.70 (m, 1H), 4.52 (d, J=12.4, 1H), 4.42 (d, J=12.3, 1H), 3.69 (s, 3H). Step 4. 3-(4-Bromo-phenyl)-3-(3-methoxy-phenyl)-propionic acid. To a 1-L round bottomed flask was added 79.9 g (0.211 mol) 2-[(4-bromo-phenyl)-(3-methoxy-phenyl)-methyl]-malonic acid, the flask fitted with a septum, and the system subjected to a continuous stream of nitrogen (nitrogen line into septum and a needle as a bleed). The flask was then heated slowly in an oil bath to 160° C. for 2 h. Gas evolution was evident beginning at 140° C. The mixture was allowed to cool to rt to give 70.1 g (99%) of the desired product as a white solid. MS (ESI, negative ionization): exact mass calcd for C16H15BrO3, 334.0; m/z found, 333.0 [M−H]−, 335.0 [M−H]−. 1H NMR (DMSO-d6): 12.14 (br s, 1H), 7.42 (dd, J=1.8, 6.6, 2H), 7.28 (m, 2H), 7.17 (m, 1H), 6.88 (m, 2H), 6.73 (m, 1H), 4.38 (t, J=7.9, 1H), 3.70 (s, 3H), 3.00 (dd, J=3.6, 8.0, 2H). Step 5. [2-(4-Bromo-phenyl)-2-(3-methoxy-phenyl)-ethyl]-carbamic acid tert-butyl ester. A mixture of 3-(4-bromo-phenyl)-3-(3-methoxy-phenyl)-propionic acid (24.99 g, 74.55 mmol), triethylamine (12.5 mL, 89.5 mmol) and diphenylphosphoryl azide (17.0 mL, 78.3 mmol) in tert-butanol (250 mL) was heated at 85° C. overnight. The reaction mixture was then concentrated and the residue was purified by normal phase column chromatography (EtOAc/hexanes) to give 24.19 g (80%) of the desired product as a viscous colorless oil. MS: exact mass calcd for C20H24BrNO3, 405.1; m/z found, 428.1 [M+Na]+, 430.1 [M+Na]+. 1H NMR (acetone-d6): 7.45 (d, J=8.4, 2H), 7.27 (d, J=8.4, 2H), 7.20 (m, 1H), 6.86 (m, 2H), 6.76 (dd, J=1.9, 7.8, 1H), 5.96 (br s, 1H), 4.25 (t, J=7.9, 1H), 3.76 (s, 3H), 3.70 (m, 1H), 1.34 (s, 9H). Step 6. 2-(4-Bromo-phenyl)-2-(3-methoxy-phenyl)-ethylamine. Prepared as described in Example 29, Step 2, on a 59.5 mmol scale, to give 16.8 g (92%) product as the free base. MS: exact mass calcd for C15H16BrNO, 305.0; m/z found, 306.1 [M+H]+, 308.1 [M+H]+. 1H NMR (MeOH-d4): 7.24 (m, 2H), 7.03 (m, 3H), 6.64 (m, 3H), 4.66 (br s, 2H), 3.76 (m, 1H), 3.57 (s, 3H), 3.01 (m, 2H). Step 7. N-[2-(4-Bromo-phenyl)-2-(3-methoxy-phenyl)-ethyl]-succinamic acid. A solution of succinic anhydride (5.77 g, 57.6 mmol) in CH2Cl2 (55 mL) was stirred under nitrogen until homogeneous, cooled to 0° C., and then treated with a solution of 2-(4-bromo-phenyl)-2-(3-methoxy-phenyl)-ethylamine (16.8 g, 54.9 mmol) in CH2Cl2 (55 mL). Once the addition was complete, the ice bath was removed and the mixture was stirred at rt for 2.5 h. The mixture was concentrated to give the crude product. The crude material was immediately taken on to the next step without purification. MS: exact mass calcd for C19H20BrNO4, 405.1; m/z found, 406.0 [M+H]+, 408.0 [M+H]+. Step 8. 1-[2-(4-Bromo-phenyl)-2-(3-methoxy-phenyl)-ethyl]-pyrrolidine-2,5-dione. A solution of the crude product from Step 7 (54.9 mmol) in EtOAc (55 mL) was treated with acetyl chloride (14.0 mL) and then was heated at reflux overnight. The mixture was cooled, and a precipitate formed. The solid was filtered to provide 15.9 g (75%) of the desired product. The filtrate was purified by chromatography (EtOAc/hexanes) to give an additional 3.28 g, for a combined yield of 19.2 g (90%). MS: exact mass calcd for C19H18BrNO3, 387.1; m/z found, 410.0 [M+Na]+, 412.0 [M+Na]+. 1H NMR (CDCl3): 7.38 (m, 2H), 7.19 (m, 3H), 6.81 (d, J=7.6, 1H), 6.73 (m, 2H), 4.60 (t, J=8.4, 1H), 4.06 (m, 2H), 3.74 (s, 3H), 2.51 (s, 4H).