Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([OH:9])=[C:4]([S:10]([N:13]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]2=3)(=[O:12])=[O:11])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:31][CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>CN(C=O)C>[C:37]([O:36][C:34](=[O:35])[CH2:33][CH2:32][CH2:31][O:9][C:5]1[CH:6]=[C:7]([Cl:8])[C:2]([Br:1])=[CH:3][C:4]=1[S:10]([N:13]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]2[CH:20]=[CH:21][CH:22]=[CH:23][C:14]1=2)(=[O:12])=[O:11])([CH3:40])([CH3:39])[CH3:38]
Reactant: O=S(=O)(c1cc(Br)c(Cl)cc1O)N1CCCCc2ccccc21
Reactant: CC(C)(C)OC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCCOc1cc(Cl)c(Br)cc1S(=O)(=O)N1CCCCc2ccccc21
Temperature: 62 °C
Yield: 93.9 %

Procedure:
To 4-bromo-5-chloro-2-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenol (0.83 g, 2 mmol) in dry DMF (8 mL), was added K2CO3 (0.69 g, 5 mmol), followed by the addition of t-butyl 4-bromobutyrate (0.58 g, 2.6 mmol). The mixture was heated at 62° C. for 15 hrs and partitioned between ethyl acetate (50 mL) and water (25 mL). The organic layer was separated, washed with brine (2×25 mL), and dried over MgSO4. After filtration, the solution was concentrated and purified by silica gel column chromatography eluting with ethyl acetate in hexanes (1/8) yielding 4-[4-bromo-5-chloro-2-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenoxy]-butyric acid tert-butyl ester as a pale yellow foam (1.05 g). MS: 501.8 (M+H-tBu)+; tR=11.2 min (method 2). NMR (CDCl3), δ, 8.060 (1H, s), 7.133-7.205 (3H, m), 7.011-7.067 (1H, m), 6.789 (1H, d, J=8.1 Hz), 4.086 (2H, t), 3.742 (2H, t), 2.826 (2H, m), 2.346 (2H, t), 1.827-1.959 (4H, m), 1.617-1.641 (2H, m), 1.431 (9H, s).
Reaction SMILES: [OH:1][NH:2]/[C:3](=[N:14]\[H])/[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1.[O:16]=[C:17]1[C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][CH2:19][N:18]1[CH2:34][CH2:35][CH2:36][C:37](O)=O.Cl.C(N=C=NCCCN(C)C)C>ClC(Cl)C>[C:28]1([C:21]2([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:19][N:18]([CH2:34][CH2:35][CH2:36][C:37]3[O:1][N:2]=[C:3]([C:4]4[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=4)[N:14]=3)[C:17]2=[O:16])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: [H]/N=C(\NO)c1ccc(C(F)(F)F)cc1
Reactant: O=C(O)CCCN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(Cl)Cl
Product: O=C1N(CCCc2nc(-c3ccc(C(F)(F)F)cc3)no2)CCC1(c1ccccc1)c1ccccc1
Temperature: 85 °C

Procedure:
A suspension of (Z)—N-hydroxy-4-(trifluoromethyl)benzimidamide (0.233 g, 1.143 mmol), 4-(2-oxo-3,3-diphenylpyrrolidin-1-yl)butanoic acid (0.336 g, 1.039 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.299 g, 1.559 mmol) were stirred together in dichloroethane (5 mL) for 3 hours then heated to 85° C. for 18 hours. The reaction was cooled and concentrated. The reaction was loaded onto a GraceResolv™ 40 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 4% ethyl acetate/hexanes (Flow=40 mL/minute) over 40 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 8.17 (d, J=8.0, 2H), 7.73 (d, J=8.2, 2H), 7.38-7.20 (m, 10H), 3.56 (t, J=7.0, 2H), 3.41 (t, J=6.4, 2H), 2.92 (t, J=7.6, 2H), 2.77 (t, J=6.4, 2H), 2.22-2.09 (m, 2H); MS (ESI+) m/z 492.1 (M+H)+.
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-])=[O:2].[O:6]1[CH2:10][CH:9]=[CH:8][CH2:7]1>>[CH3:5][C:4]1[C@H:8]2[CH2:7][O:6][CH2:10][C@H:9]2[O:2][N:1]=1
Reactant: CC[N+](=O)[O-]
Reactant: C1=CCOC1
Product: CC1=NO[C@@H]2COC[C@H]12

Procedure:
Intermediate IV-1: Starting from nitroethane and 2,5-dihydro-furan, the product (3aS,6aS)-rel-3-methyl-3a,4,6,6a-tetrahydro-furo[3,4-d]isoxazole was obtained as a pale yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.[C:14]1([CH3:24])[C:15]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=1>ClCCl>[C:14]1([CH3:24])[C:15]([S:20]([O:1][CH2:2][C:3]([O:5][CH3:6])=[O:4])(=[O:22])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)CO
Reactant: Cc1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)COS(=O)(=O)c1ccccc1C
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
18 g (0.2 mol) of methyl hydroxyacetate and 20.2 g (0.2 mol) of triethylamine are first introduced into 300 ml of dichloromethane at 0° C. 41.9 g (0.22 mol) of toluenesulfonyl chloride are then added at this temperature in small portions. Stirring of the batch at 0° C. is continued overnight. Ice water is added, the phases are separated, and the aqueous phase is extracted three times with dichloromethane. The combined organic phases are washed once with water, dried, and the solvent is removed on a rotary evaporator. 48 g (98% of theory) of methyl toluenesulfonyloxyacetate having a GC content of 96% are isolated as a colorless solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=1)(=[O:25])=[O:24].[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][NH2:41])[CH:35]=1>>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:41][CH2:40][C:36]3[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=3)=[O:19])=[CH:20][CH:21]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=1)(=[O:24])=[O:25]
Reactant: NCc1cccnc1
Reactant: COc1cccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)c1
Agent: O=C(Cl)C(=O)Cl
Product: COc1cccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)NCc4cccnc4)cc3)oc2C)c1
Yield: 25.9 %

Procedure:
Reaction of oxalyl chloride (50 λL, 0.57 mmol) and benzoic acid 38 (146 mg, 0.38 mmol) with subsequent coupling to 3-pyridinylmethylamine (43 λL, 0.42 mmol) gave benzamide 39 (47 mg, 26%) as a white powder: mp (EtOAc) 143-145° C.; 1H NMR δ 9.23 (t, J=5.8 Hz, 1H, CONH), 8.56 (d, J=1.6 Hz, 1H, H-2′), 8.46 (dd, J=4.7, 1.4 Hz, 1H, H-6′), 8.00 (br d, J=8.5 Hz, 2H, H-2, H-6), 7.91 (br d, J=8.5 Hz, 2H, H-3, H-5), 7.74 (br d, J=7.9 Hz, 1H, H-4′), 7.53 (br dd, J=8.9, 7.6 Hz, 1H, H-5″), 7.34-7.39 (m, 2H, H-5′, H-2″), 7.25-7.29 (m, 2H, H-4″, H-6″), 4.70 (s, 2H, CH2SO2), 4.51 (d, J=5.8 Hz, 2H, CH2N), 3.79 (s, 3H, OCH3), 2.17 (s, 3H, CH3); 13C NMR δ 165.5, 159.4, 158.0, 150.1, 148.9, 148.1, 139.7, 135.4, 135.2, 134.9, 130.4, 128.8, 128.1 (2), 125.9, 125.4 (2), 123.5, 120.3, 120.1, 112.8, 55.6, 52.7, 40.5, 9.7; MS m/z 478.6 (MH+, 100%). Anal. calcd for C25H23N3O5S.½CH3OH: C, 62.06, 5.11; N, 8.51. Found: C, 62.23; H, 4.90; N, 8.66%.
Reaction SMILES: [K].[C:2]1(=[O:12])[NH:6][C:5](=[O:7])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]12.CN(C)C=O.[Cl:18][C:19]1[C:20]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)=[C:21]2[C:29]3[CH2:30][CH2:31][S:32][CH2:33][C:28]=3[S:27][C:22]2=[N:23][C:24]=1[CH2:25]Cl>O>[Cl:18][C:19]1[C:20]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)=[C:21]2[C:29]3[CH2:30][CH2:31][S:32][CH2:33][C:28]=3[S:27][C:22]2=[N:23][C:24]=1[CH2:25][N:6]1[C:2](=[O:12])[C:3]2[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5]1=[O:7]
Reactant: COc1ccc(-c2c(Cl)c(CCl)nc3sc4c(c23)CCSC4)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(Cl)c(CN3C(=O)c4ccccc4C3=O)nc3sc4c(c23)CCSC4)cc1
Temperature: 62.5 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a mixture of phthalimide potassium (6.2 kg) and dimethylformamide (110.74 L) was added 3-chloro-2-chloromethyl-5,8-dihydro-4-(4-methoxyphenyl)-6H-thiopyrano-[4′,3′:4,5]thieno[2,3-b]pyridine (11.055 kg) obtained in Reference Example 27 and the mixture was stirred at 60 to 65° C. for 1 hour. After cooling to 25° C., water (36.91 L) was added dropwise thereto and the mixture was stirred at the same temperature for 1 hour. The crystals deposited was filtered off and washed with water (29.14 L) to obtain the titled compound (14.057 kg, 99.4%). 1H-NMR (CDCl3) δ: 2.14 (2H, t, J=5.7 Hz), 2.64 (2H, t, J=5.7 Hz), 3.80 (2H, s), 3.89 (3H, s), 5.20 (2H, s), 6.98–7.13 (2H, s), 6.98–7.13 (3H, m), 7.75–7.78 (2H, m), 7.79–7.794 (2H, m).
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].O.[NH2:18][C@@H:19]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>ClCCl.O>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([NH:18][C@@H:19]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.8 %

Procedure:
To a mixture of Boc-Leu-OH.H2O (2.5 g), H-DTrp-OBzl (2.9 g) and HOBT.H2O (1.6 g) in dichloromethane (50 ml) was added EDCI.HCl (2.0 g) under ice cooling. After being stirred at room temperature for 16 h, the mixture was washed with water, 10% aq. citric acid, sat. aq. NaHCO3 and brine successively, dried over MgSO4 and evaporated in vacuo. The residue was triturated with hexane to give Boc-Leu-DTrp-OBzl (4.79 g). To a solution of the dipeptide (753 mg) in dichloromethane (7 ml) were added methyl chloroformate (1 ml), pulverized NaOH (89 mg) and TBAHS (20 mg) under ice cooling. After being stirred of the mixture at room temperature for 30 min, pulverized NaOH (89 mg) was added. This procedure was repeated twice more. The reaction mixture was diluted with dichloromethane, washed with sat. aq. NaHCO3, 10% aq. citric acid, water and brine successively, dried over MgSO4 and evaporated in vacuo. The residue was recrystallized from dichloromethane and petroleum ether to give Boc-Leu-DTrp(COOMe)-OBzl (721 mg) as colorless crystals. The dipeptide (708 mg) was dissolved in methanol (7 ml)--THF (5 ml) and 10% Pd/C (70 mg) was added. The mixture was vigorously stirred at room temperature under an atmospheric pressure of hydrogen for 1 h. The reaction mixture was filtered and the filtrate was evaporated in vacuo to give Boc-Leu-DTrp(COOMe)-OH (580 mg).
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[CH3:17][C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([CH3:32])[C:24]=1[S:25]([CH2:28][N+:29]([O-:31])=[O:30])(=[O:27])=[O:26])[NH2:21].O>O1CCCC1>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:21][C:20]2[CH:19]=[C:18]([CH3:17])[C:24]([S:25]([CH2:28][N+:29]([O-:31])=[O:30])(=[O:27])=[O:26])=[C:23]([CH3:32])[CH:22]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: Cc1cc(N)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(NS(=O)(=O)c2ccc(Br)cc2)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 24.2 %

Procedure:
2.0 g (20.0 mmol) of calcium carbonate and 3.8 g (14.9 mmol) of 4-bromobenzenesulphonyl chloride are successively added to a mixture of 2.4 g (9.83 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulphonyl]aniline in 45 ml of anhydrous tetrahydrofuran. The reaction medium is stirred for 20 h at room temperature and is then refluxed for 48 h. After cooling, it is poured into 400 ml of water and extracted with methylene chloride. The combined organic extracts are dried over sodium sulphate and concentrated to dryness under reduced pressure. The oily residue obtained is purified by chromatography on a column of silica (eluent: methylene chloride) to give 1.1 g (24%) of 4-bromo-N-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]benzenesulphonamide.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH:13]([CH2:36][OH:37])[CH2:14][CH:15]([C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[C:29]([F:35])[CH:28]=1)[C:16]([NH:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17]>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:37][CH2:36][CH:13]([OH:12])[CH2:14][CH:15]([C:27]2[CH:32]=[C:31]([F:33])[C:30]([F:34])=[C:29]([F:35])[CH:28]=2)[C:16]([NH:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)C(CC(O)CO)c1cc(F)c(F)c(F)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(O)CC(C(=O)NNC(=O)OC(C)(C)C)c2cc(F)c(F)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.1 %

Procedure:
p-Toluenesulfonyl chloride (605 mg) was added to a solution of tert-butyl N′-[4,5-dihydroxy-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarboxylate (1.09 g) in pyridine (11 mL) at room temperature. The reaction solution was stirred at room temperature for 12 hours and then concentrated under reduced pressure. Ethyl acetate was added to the residue, and the organic layer was washed with brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 1.03 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[N:14][N:15]2[CH:20]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:21]([O:23][CH3:24])=[O:22])=[O:9])([CH3:6])([CH3:5])[CH3:4].FC(F)(F)S(O[CH2:38][C:39]([F:42])([F:41])[F:40])(=O)=O>C1COCC1>[C:3]([O:7][C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[N:14][N:15]2[C:20]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)([CH2:38][C:39]([F:42])([F:41])[F:40])[C:21]([O:23][CH3:24])=[O:22])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COC(=O)C(c1ccc(Cl)cc1)n1ncc2c(NC(=O)OC(C)(C)C)cccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(CC(F)(F)F)(c1ccc(Cl)cc1)n1ncc2c(NC(=O)OC(C)(C)C)cccc21
Reaction time: 0.5 h

Procedure:
A bottle flask was charged with NaH (580 mg, 14.4 mmol, 60% in oil) and then a solution of methyl 2-(4-(tert-butoxycarbonylamino)-1H-indazol-1-yl)-2-(4-chlorophenyl)acetate (3 g, 7.22 mmol), as described in Example 18 Step C, and 2,2,2-trifluoroethyl trifluoromethanesulfonate (3.35 g, 14.4 mmol) in THF (40 mL) at 0° C. The mixture was stirred for 30 min, quenched with saturated NH4Cl solution (10 mL), extracted with ethyl acetate. The organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (PE/EA=3:1) to afford the title compound as colorless oil. LC/MS m/z=498.1[M+H]+.
Reaction SMILES: [CH2:1]([N:8]([CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[C:44]([NH2:56])[CH:43]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:20]([NH2:32])[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:63][S:64](Cl)(=[O:66])=[O:65]>O>[CH2:1]([N:8]([CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)=[C:44]([NH:56][S:64]([CH3:63])(=[O:66])=[O:65])[CH:43]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:20]([NH:32][S:64]([CH3:63])(=[O:66])=[O:65])[CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(CCN(CCCCCCN(CCc2ccc(OCc3ccccc3)c(N)c2)Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Nc1cc(CCN(CCCCCCN(CCc2ccc(OCc3ccccc3)c(NS(C)(=O)=O)c2)Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 7.5 g. (0.01 m.) of N,N'-dibenzyl-N,N'-bis[2-(3-amino-4-benzyloxyphenyl)-ethyl]-hexamethylene-diamine in 30 ml. of pyridine is added 2.5 g. of methanesulfonyl chloride. The reaction mixture is allowed to stand at room temperature overnight and is then added to excess water to yield N,N'-dibenzyl-N,N'-bis[2-(4-benzyloxy-3-methanesulfonamidophenyl)-ethyl]-hexamethylenediamine.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=[O:41])=[O:40])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:49]C1C=CC=CC=1CS(Cl)(=O)=O>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:34][CH:35]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:48]=1[Cl:49])(=[O:41])=[O:40])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1Cl
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3Cl)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 86 %

Procedure:
To the methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (Step 6, Example 1) was added [(2-chlorophenyl)-methyl]sulfonyl chloride according to the procedure in Example 1 Step 7 to generate the product in 86% yield.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([C:8]([CH3:11])=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH3:25])[CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.ClCCl>O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:4]([C:3]=1[CH3:12])[C:5]([C:16]1[C:17]([CH3:25])=[CH:18][C:19]([O:23][CH3:24])=[C:20]([O:21][CH3:22])[C:15]=1[O:14][CH3:13])=[O:7]
Reactant: Cc1ccc(Br)c(C)c1C(=O)O
Reactant: COc1cc(C)cc(OC)c1OC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: ClCCl
Product: COc1cc(C)c(C(=O)c2c(C)ccc(Br)c2C)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1B (1.3 g, 5.7 mmol), 3,4,5-trimethoxytoluene (1.0 g; 5.7 mmol), P2O5 (3.5 g) and dichloromethane (20 ml) is stirred at room temperature for 16 hours. Subsequently, water (5 ml) and ice are added and dichloromethane is distilled off and the residue is extracted with toluene. The organic phase is washed with water and concentrated. The residue is recrystallized from petrol ethers/toluene. The solid material is collected by vacuum filtration, washed with cold petrol ethers and dried, yielding white crystals, 1.4 g, mp 859° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[C:18]([F:34])=[C:19](/[CH:23]=[C:24](/[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)\[C:25]#[N:26])[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>ClCCCl>[C:1]([O:5][C:6]([CH:7]1[CH:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[C:18]=2[F:34])[C:24]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)([C:25]#[N:26])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1
Yield: 67.6 %

Procedure:
In a manner similar to the method described in Example 1c, [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (2.3 g, 7.9 mmol) prepared in Example 26a, AgF (1.5 g, 12 mmol), and triethylamine (2 g, 20 mmol) in 1,2-dichloroethane (130 mL) at room temperature for 18 h to give 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 tert-butyl ester as a white foam (2.7 g, 68%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-])=O)[C:5]=2[N:4]=[CH:3]1.[H][H]>CCO.[Pd]>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([NH2:11])[C:5]=2[N:4]=[CH:3]1
Reactant: Cn1cnc2c([N+](=O)[O-])cccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cn1cnc2c(N)cccc21
Yield: 93.4 %

Procedure:
A suspension of 1-methyl-4-nitro-1H-benzimidazole [2.1 g, 12 mmol, prepared as described in Viktor Milata et. al., Org. Prep. Proced. Int. 25 (6), 703-704 (1993)] and 5% Pd/C (0.21 g) in EtOH (40 mL) was vigorously stirred under an atmoshphere of hydrogen at rt overnight. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to afford the tiltle compound (1.65 g).
Reaction SMILES: [CH2:1]1[CH2:20][O:19][C:4]2=[CH:5][C:6]3[CH:11]([C:12]([O:14]CC)=[O:13])[S:10][CH2:9][C:8](=[O:17])[C:7]=3[CH:18]=[C:3]2[O:2]1.[OH-].[Na+].O>C(O)C>[CH2:1]1[CH2:20][O:19][C:4]2=[CH:5][C:6]3[CH:11]([C:12]([OH:14])=[O:13])[S:10][CH2:9][C:8](=[O:17])[C:7]=3[CH:18]=[C:3]2[O:2]1
Reactant: CCOC(=O)C1SCC(=O)c2cc3c(cc21)OCCO3
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C1CSC(C(=O)O)c2cc3c(cc21)OCCO3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In ethanol (200 ml) was suspended ethyl 6,7-ethylenedioxy-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylate (55 g) followed by addition of 2N-NaOH (200 ml). The mixture was stirred at room temperature for one hour. The reaction mixture was poured into water, acidified and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and the solvent was distilled off to give 6,7-ethylenedioxy-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylic acid (32.5 g, yield (65%). Recrystallization from ethyl acetate gave colorless prisms.
Reaction SMILES: [CH:1]12[CH2:18][CH:5]([N:6]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:7]1)[CH2:4][CH2:3][NH:2]2.F[C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH2:27]([O:26][C:24]([C:23]1[CH:29]=[CH:30][C:20]([N:2]2[CH2:3][CH2:4][CH:5]3[CH2:18][CH:1]2[CH2:7][N:6]3[C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])=[CH:21][CH:22]=1)=[O:25])[CH3:28]
Reactant: O=C(OCc1ccccc1)N1CC2CC1CCN2
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2CCC3CC2CN3C(=O)OCc2ccccc2)cc1
Temperature: 130 °C

Procedure:
Benzyl 2,6-diazabicyclo[3.2.1]octane-6-carboxylate (300 mg) was dissolved in dimethylsulfoxide (3 mL), then ethyl 4-fluorobenzoate (172 mg) and potassium carbonate (206 mg) were added. The reaction was heated at 130° C. overnight. After cooling, the reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After filtration and concentration of the filtrate, the resultant crude material was purified by column chromatography on silica gel using 7/3 hexanes/ethyl acetate to afford the title compound.