Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.[CH:87]([N:90]1[CH2:95][CH2:94][N:93]([CH2:96][C:97]([OH:99])=O)[CH2:92][CH2:91]1)([CH3:89])[CH3:88]>>[CH:87]([N:90]1[CH2:91][CH2:92][N:93]([CH2:96][C:97]([NH:1][C@:2]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5]2)=[O:99])[CH2:94][CH2:95]1)([CH3:88])[CH3:89]
Reactant: CC(C)N1CCN(CC(=O)O)CC1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)CN3CCN(C(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 22 %

Procedure:
The title compound was prepared in 22% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except (4-isopropyl-piperazin-1-yl)-acetic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 698.6 (M+H)+, 2.64 min (method 6). 1H NMR (500 MHz, 1:1 CDCl3:MeOD) δ=7.92 (d, J=8.2 Hz, 2H), 7.37 (br. s., 1H), 7.20 (d, J=8.2 Hz, 2H), 6.34-6.03 (m, 1H), 5.29 (d, J=4.6 Hz, 1H), 4.76 (br. s., 1H), 4.70 (br. s., 1H), 3.95 (br. s., 1H), 3.84-3.55 (m, 8H), 3.17 (q, J=7.2 Hz, 2H), 2.64 (d, J=13.1 Hz, 2H), 2.39 (dd, J=8.1, 11.4 Hz, 1H), 2.12 (dd, J=6.3, 17.2 Hz, 1H), 1.96-1.84 (m, 2H), 1.79 (d, J=12.5 Hz, 1H), 1.76-1.65 (m, 5H), 1.59-1.40 (m, 14H), 1.35 (t, J=7.2 Hz, 4H), 1.29-1.21 (m, 1H), 1.15 (d, J=6.1 Hz, 1H), 1.10 (br. s., 3H), 1.02 (s, 3H), 1.01 (br. s., 2H), 0.94 (br. s., 3H), 0.93 (br. s., 3H).
Reaction SMILES: [I:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[Cl:11]Cl.O>C(O)(=O)C>[Cl:11][C:4]1[C:5]([OH:10])=[C:6]([CH:9]=[C:2]([I:1])[CH:3]=1)[CH:7]=[O:8]
Reactant: ClCl
Reactant: O=Cc1cc(I)ccc1O
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1cc(I)cc(Cl)c1O
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To 24 g (96.8 mmole) of 5-iodosalicylaldehyde in 320 mL of acetic acid was added an excess of gaseous chlorine. After addition of about 10 g of Cl2, a white solid appeared in the solution. The mixture was heated to 70° C. and allowed to stir for 3 h. The heated solution was homogeneous and remained so after cooling to rt. The mixture was added to 1200 mL of water and allowed to stir for 1 h. The resultant solid was collected by filtration, washed with water, filtered and allowed to air dry to afford 27.3 g of a yellow solid. The solid was recrystallized by dissolving the material in 250 mL of hot methanol and adding 80 mL of H2O. After standing overnight, the crystalline solid was collected and air-dried to afford 20.3 g (74.2%) of a yellow solid. The product contained a minor impurity (approx. 9% by 1H NMR) and was used in the next step without further purification: 1H NMR (CDCl3/400 MHz) 7.78 (d, 1H, J=2.1 Hz), 7.88 (d, 1H, J=1.8 Hz), 9.83 (s, 1H), 11.40 (s, 1H); 13C NMR (CDCl3/100 MHz) 79.5, 122.8, 123.7, 140.3, 144.4, 156.9, 194.8; MS (ESI+) 283 (M+1, 100); HRMS (El) m/z calcd for (C7H4O2ICl) 281.8945, found 281.8899.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:12]=[CH:13][C:14]([OH:16])=O.[NH2:22][C:23]1[CH:35]=[C:34]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=[CH:32][C:24]=1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl.CN(C)C=O>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:13]/[C:14]([NH:22][C:23]2[CH:35]=[C:34]([O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:33]=[CH:32][C:24]=2[C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])=[O:16])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1N
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(/C=C/C(=O)Nc2cc(Oc3ccccc3)ccc2C(=O)OC(C)(C)C)cc1OC
Reaction time: 1 h

Procedure:
1.3 mL of methylene chloride, 1.3 μL of N,N-dimethylformamide and 0.031 mL of oxalyl chloride were added to 69 mg of 3,4-dimethoxycinnamic acid at room temperature sequentially and stirred at the same temperature for 1 hour. The reaction mixture was added to a mixed solution of 57 mg of tert-butyl 2-amino-4-phenoxybenzoate, 3.7 mL of methylene chloride and 0.22 mL of triethylamine and stirred at room temperature for 2 hours. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane; ethyl acetate=4:1] to obtain tert-butyl 2-((E)-3-(3,4-dimethoxyphenyl)acrylamido)-4-phenoxybenzoate.
Reaction SMILES: C=O.[CH3:3][C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=[C:7]([N:18]3[CH2:23][CH2:22][NH:21][C@@H:20]([CH2:24][CH2:25][C:26]4[CH:30]=[CH:29][S:28][CH:27]=4)[CH2:19]3)[C:6]=2[CH:5]=1.[C:31](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)[Cl:46]>C(=O)(O)[O-].[Na+]>[ClH:46].[ClH:46].[CH3:3][C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=[C:7]([N:18]3[CH2:23][CH2:22][N:21]([CH3:31])[C@@H:20]([CH2:24][CH2:25][C:26]4[CH:30]=[CH:29][S:28][CH:27]=4)[CH2:19]3)[C:6]=2[CH:5]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccsc2)C1
Reactant: ClCCl
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CCc2ccsc2)C1
Product: Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59 %

Procedure:
Add formaldehyde (45 μL, 0.56 mmol, 37% in water) to a solution of (S)-2-methyl-10-[3-(2-thiophen-3-yl-ethyl)-piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulene (210 mg, 0.51 mmol) in methylene chloride (6 mL). Stir 15 min at ambient temperature. Add sodium triacetoxyborohydride (163 mg, 0.77 mmol) and stir 2h at ambient temperature. Dilute with saturated sodium bicarbonate solution and extract with methylene chloride. Dry the extracts with sodium sulfate, filter and concentrate the filtrate. Purify by radial silica gel chromatography using a 2 mm plate and 2N ammonia in methanol-methylene chloride (2%) as the eluent to give 127 mg (59%) of the free base of the title compound. Crystallize the dihydrochloride salt from ethyl acetate and ethanol to give the title compound: mass spectrum (ion spray): m/z=423 (M+1), 421 (M−1). Analysis calculated for C23H28Cl2N4S2.0.2HCl.0.3H2O: C, 54.35; H, 5.71; N, 11.01; Cl, 15.35. Found: C, 54.10; H, 5.34; N, 10.99; Cl, 15.00. HR-MS calculated for C23H27N4S2423.1677. Found 423.1656.
Reaction SMILES: [Br:1][C:2]1C=CC(C=C)=CC=1.[CH:10]([CH:12]=[CH2:13])=O.[C:14]([O-:19])(=[O:18])[C:15]([CH3:17])=[CH2:16].CC(N=NC(C#N)(C)C)(C#N)C.[CH3:32][CH:33](OC(C)=O)[CH2:34][O:35]C>>[Br:1][CH:2]=[CH:14][C:15]1[CH:17]=[CH:13][CH:12]=[CH:10][CH:16]=1.[CH:34]([CH:33]=[CH2:32])=[O:35].[C:14]([O-:19])(=[O:18])[C:15]([CH3:17])=[CH2:16]
Reactant: C=Cc1ccc(Br)cc1
Reactant: COCC(C)OC(C)=O
Agent: C=C(C)C(=O)[O-]
Agent: C=CC=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: BrC=Cc1ccccc1
Temperature: 67 °C

Procedure:
3 g of 4-bromostyrene, 4 g of acrolein, 3 g of methacrylate and 0.2 g of AIBN were sufficiently mixed with 50 g of PGMEA. The mixture was polymerized by heating the mixture at 67° C. for 8 hours. After completion of the polymerization, the polymerization product was precipitated in n-hexane, filtered, and dried in vacuo to give a poly(bromostyrene-acrolein-methacrylate) copolymer.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[C:21]([C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1)(=[O:23])[CH3:22]>>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:33]2[CH2:32][CH2:31][N:30]([C:27]3[CH:26]=[CH:25][C:24]([C:21](=[O:23])[CH3:22])=[CH:29][CH:28]=3)[CH2:35][CH2:34]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Product: COc1ccc2nc(NC(=O)N3CCN(c4ccc(C(C)=O)cc4)CC3)c(OC)nc2c1
Yield: 93 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate and 1-(4-acetylphenyl)piperazine were reacted by the same way with the example 148 to obtain the titled compound (yield, 93%). 1H NMR (300 MHz, CDCl3): δ 2.53 (s, 3H), 3.48 (s, 4H), 3.77 (s, 4H), 3.90 (s, 3H), 4.13 (s, 3H), 6.86 (d, J=8.7 Hz, 2H), 7.14-7.28 (m, 3H), 7.72 (d, J=8.4 Hz, 1H), 7.89 (d, J=9.0 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[C:5]#[N:6].[CH2:12](N(CC)CC)C.[C:19](=[O:21])=[O:20]>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:12][O:20][C:19](=[O:21])[C:2]1[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C#N)cc1Br
Reactant: O=C=O
Reactant: CCN(CC)CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(C#N)ccc1OC
Temperature: 25 °C

Procedure:
A mixture of 3-bromo-4-methoxybenzonitrile (Aldrich) (10.0 g, 47.2 mmol), PdCl2(dppf)-CH2Cl2 adduct (Aldrich) (1.00 g, 1.22 mmol) and triethylamine (12.5 mL, 89.7 mmol) in 100 mL of methanol in a high pressure vessel was heated to 100° C. at 60 psi of CO2 for 4 h. The mixture was cooled to room temperature and filtered. The mixture was concentrated under reduced pressure to afford the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 3.91 (s, 3H), 3.98 (s, 3H), 7.06 (d, J=8.5 Hz, 1H), 7.76 (dd, J=8.7, 2.3 Hz, 1H), 8.10 (d, J=2.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:25])([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[OH:10])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:29]Cl.CCOCC>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:19][N:20]3[CH:24]=[N:23][CH:22]=[N:21]3)[CH:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])[O:10][CH2:29][O:25]2)=[CH:4][CH:3]=1
Reactant: ClCBr
Reactant: OC(c1ccc(Cl)cc1Cl)C(O)(Cn1cncn1)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Clc1ccc(C2(Cn3cncn3)OCOC2c2ccc(Cl)cc2Cl)cc1
Temperature: 0 °C
Yield: 54.4 %

Procedure:
To a solution of 500 mg of 2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2-propanediol in 5 ml of dry dimethylformamide is added 180 mg of 50% mineral oil dispersion of sodium hydride under ice cooling. Five minutes later 490 mg of bromochloromethane is added to the mixture, which is allowed to react at a temperature of 50° C. for 1 hour. The reaction mixture is mixed with ice water and shaken with ether. The ethereal layer is washed with water, dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica-gel, which is eluted with 3% methanol-methylene chloride. The eluate is concentrated and the residue is crystallized from ethyl acetate to give 280 mg of 4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-4-(1H-1,2,4-triazol-1-yl)methyl-1,3-dioxolane as crystals melting at 201 ° to 203° C. The yield is 54%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]([CH2:23][C:24]([OH:26])=O)[C:13]2=[O:27])=[O:10])[CH:5]=[C:4]([Cl:28])[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:60][N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>CN1C(=O)CCC1>[Cl:28][C:4]1[CH:5]=[C:6]([NH:8][C:9](=[O:10])[CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]([CH2:23][C:24]([N:64]3[CH2:65][CH2:66][N:61]([CH3:60])[CH2:62][CH2:63]3)=[O:26])[C:13]2=[O:27])[CH:7]=[C:2]([Cl:1])[N:3]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)Cn1c(=O)c2ccccc2n(CC(=O)Nc2cc(Cl)nc(Cl)c2)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)Cn2c(=O)c3ccccc3n(CC(=O)Nc3cc(Cl)nc(Cl)c3)c2=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of {1-[(2,6-dichloro-pyridin-4-ylcarbamoyl)-methyl]-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-acetic acid (13.5 mg, 0.0318 mmol) in dry NMP (1.5 ml), HATU (13.3 mg, 0.035 mmol) is added followed by triethylamine (4.89 μL, 0.035 mmol). The orange solution is stirred at RT for 10 minutes, then treated with 1-methyl piperazine (3.89 μL, 0.035 mmol). The reaction mixture is stirred at RT and monitored by HPLC/LCMS until the starting material is consumed. The reaction mixture is partitioned between EtOAc (5 ml) and water (5 ml). The organic layer is separated and washed with brine (5 ml), dried (MgSO4), filtered and concentrated in vacuo. The crude product is purified by passing down a 5 g Isolute™ SCX2 (solid-supported sulfonic acid resin) cartridge, eluting with DCM (20 ml), MeOH (20 ml), and 7N NH3 in MeOH. The basic ammonia wash is concentrated in vacuo to afford the title compound as a white solid, [M+H]+ 505.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15]/[N:16]=[C:17](\[CH3:25])/[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:26]I.Cl>CN(C)C=O.O>[CH3:26][O:3][CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15]/[N:16]=[C:17](\[CH3:25])/[C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(O)c1ccccc1O/N=C(\C)c1ccc(Cl)cc1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(OC)c1ccccc1O/N=C(\C)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 74.4 %

Procedure:
60% oily sodium hydride (0.20 g, 5.0 mmol) was added to a solution of methyl (E)-α-hydroxy-2-(α-methyl-4-chlorobenzylideneaminooxy)phenylacetate (1.59 g, 4.6 mmol) and methyl iodide (1.95 g, 13.7 mmol) in N,N-dimethylformamide (15 ml) with stirring at 0° C. After 45 minutes, water was added, and the mixture was adjusted to pH 1 with 1N hydrochloric acid, extracted with ether, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel (n-hexane/methylene chloride=9/1) to give the desired compound methyl (E)-α-methoxy-2-(α-methyl-4-chlorobenzylideneaminooxy)phenylacetate (1.19 g, 72%) as an oil.
Reaction SMILES: FC(F)(F)[C:3](O)=[O:4].[Cl:8][C:9]1[C:10]([F:37])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:17][CH:16]2C(O)=O)[CH:12]=[CH:13][CH:14]=1.[NH2:38][C:39]1[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][CH:40]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:46][O:45][C:43](=[O:44])[C:42]1[CH:41]=[CH:40][C:39]([NH:38][C:3]([C@H:16]2[C@H:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=3[F:37])[C@:19]([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)([C:20]#[N:21])[C@H:18]([CH2:29][C:30]([CH3:31])([CH3:32])[CH3:33])[NH:17]2)=[O:4])=[CH:48][CH:47]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3)[C@H]2c2cccc(Cl)c2F)cc1
Yield: 34.3 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.38 g, 0.55 mmol) was reacted with methyl 4-aminobenzoate (0.33 g, 2.2 mmol), HATU (0.38 g, 1 mmol) and iPr2NEt (0.29 mL, 1.7 mmol) in CH2Cl2 at room temperature to give rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid methyl ester as a white solid (0.11 g, 34%).
Reaction SMILES: F[C:2](F)(F)C([O-])=O.[Na+].[NH2:9][C@@H:10]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:11][O:12][CH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.S(Cl)([Cl:43])=O>CO>[ClH:43].[CH3:2][O:19][C:18](=[O:20])[C:17]1[CH:21]=[CH:22][C:14]([CH2:13][O:12][CH2:11][C@@H:10]([NH2:9])[CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:15][CH:16]=1
Reactant: N[C@H](COCc1ccc(C(=O)O)cc1)Cc1ccccc1
Reactant: O=S(Cl)Cl
Reactant: O=C([O-])C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(COC[C@@H](N)Cc2ccccc2)cc1
Product: Cl
Reaction time: 8 h

Procedure:
51.2 mg (128 μmol) of 4-({[(2S)-2-amino-3-phenylpropyl]oxy}methyl)benzoic acid sodium trifluoracetate were added to 5 ml of methanol and mixed with 2.4 mg (13 μmol) of 4-toluenesulfonate acid monohydrate. The batch was stirred overnight under reflux. Then, 18.7 μl (256 μmol) of thionyl chloride were added and the composition heated again under reflux for 6 hours. Then the reaction composition was evaporated in the rotating steam boiler and the residue vacuum dried. Thus, 42.3 mg (80% purity, 88% o. th.) of the title compound were obtained which were used in the consecutive reaction without further purification.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:3]=1.[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:31]=2)[CH:26]=[CH:25]1.C(=O)([O-])O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.O.C(O)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:4]2[CH:3]=[C:2]([C:29]3[CH:28]=[C:27]4[C:32](=[CH:31][CH:30]=3)[N:24]([CH3:23])[CH:25]=[CH:26]4)[CH:14]=[CH:13][C:5]=2[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:17][CH:18]=1
Reactant: Cn1ccc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cn1ccc2cc(-c3ccc(C(=O)OC(C)(C)C)c(Nc4ccc(F)cc4)c3)ccc21
Temperature: 25 °C

Procedure:
To toluene 2.1 mL solution of tert-butyl 4-bromo-2-(4-fluoroanilino)benzoate 0.1 g were added ethanol 0.60 mL, water 0.30 mL, 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole 84 mg, sodium hydrogen carbonate 69 mg and tetrakis(triphenylphosphine)palladium(0) 16 mg at room temperature, and it was heated and refluxed for 4 hours. After the reaction mixture was cooled to room temperature, toluene and saturated sodium hydrogen carbonate aqueous solution were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=10:1] to give tert-butyl 2-(4-fluoroanilino)-4-(1-methyl-1H-indol-5-yl)benzoate.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>C1COCC1.C(OCC)(=O)C>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.8 %

Procedure:
Diisopropylethylamine (0.9 ml, 5.5 mmol) was added in one portion to a stirred solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 5.0 mmol) in THF (10 ml) at room temperature. To this mixture was added benzyl chloroformate (0.78 ml, 5.5 mmol) drop wise and the mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. After this time the mixture was diluted with ethyl acetate (50 ml) and washed with water (100 ml), saturated NaHCO3 (100 ml) and HCl (100 ml, 2M). The organic layer was separated, dried (MgSO4), filtered and concentrated under vacuum. The resulting residue was purified by flash column chromatography (elution: 50% heptane, 50% ethyl acetate) to give the title compound (1.2 g, 73% yield) as a colourless oil. Tr=2.08 min m/z (ES+) (M+Na+) 357.
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)(O)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(C(O)(Cc2ccccc2)c2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc(C(=Cc2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the Grignard reagent prepared from 4-bromoanisole (10 g, 53.5 mmol) and Mg turnings (1.32 g, 54.3 mg-atom) in 25 mL Et2O was added deoxybenzoin (9.81 g, 50 mmol) in 75 mL Et2O dropwise under reflux. After stirring at reflux 3 h, the mixture was carefully poured onto 1N H2SO4 and ice. The layers were allowed to separate and the aqueous layer was extracted with 25 mL Et2O. The ether layers were combined, washed with H2O (2×80 mL), dried (Na2SO4), and concentrated to give a yellow oil which solidified at room temperature (14.2 g, 93.3% crude yield). Recrystallization from 95% EtOH gave 1,2-diphenyl-1-(4-methoxyphenyl)ethanol as a white powder mp: 111°-112° C. (lit. 112°-113° C.); NMR δ 7.2 (m, 14H, ArH), 3.75 (s, 3H, OCH3), 3.63 (s, 2H, CH2), 2.35 (brs, 1H, OH). The tertiary carbinol (14 g, 46 mmol) and p-TsOH.H2O (1 g, 5.31 mmol) were dissolved in 40 mL dry C6H6, heated to reflux, and stirred 2 h. The red mixture was cooled to room temperature and washed with 5% NaHCO3 (2×75 mL). The combined aqueous layers were extracted with 25 mL C6H6. The organic layers were combined, washed with 100 mL H2O, dried (Na2SO4), and concentrated to give a yellow oil. The (E)- and (Z)-olefin mixture was purified on 60 g flash SiO2 (petroleum ether) and 1,2-Diphenyl-1-(4-methoxyphenyl)ethene was obtained as a clear oil (8 g, 61%); NMR δ 7.15 (m, 10H, ArH), 6.9 (s, 1H, C=CH), 6.8 (AA'BB', c, 4H, MeOC6H 4), 3.71 (d, 3H, (E)- & (Z)-OCH3).