Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[CH3:45][S:46][CH2:47][CH2:48][O:49][C:50]1[CH:51]=[C:52]2[C:56](=[CH:57][CH:58]=1)[NH:55][C:54]([C:59](O)=[O:60])=[CH:53]2.CCN(C(C)C)C(C)C>CN(C=O)C.O.CCOC(C)=O>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:59]([C:54]2[NH:55][C:56]3[C:52]([CH:53]=2)=[CH:51][C:50]([O:49][CH2:48][CH2:47][S:46][CH3:45])=[CH:58][CH:57]=3)=[O:60])=[C:28]([F:44])[C:29]=1[O:34][C:35]1[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=1
Reactant: CSCCOc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
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: CN(C)C=O
Solvent: O
Product: CSCCOc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)cc2c1
Yield: 51.9 %

Procedure:
HATU (0.055 g, 0.145 mmol) was added as a solid to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.045 g, 0.145 mmol), 5-{[2-(methylthio)ethyl]oxy}-1H-indole-2-carboxylic acid (0.036 g, 0.145 mmol) and DIPEA (0.025 mL, 0.145 mmol) in DMF (1 mL). After 2 hours the reaction mixture was poured into EtOAc and water and the layers were separated. The organic layer was dried over MgSO4, filtered and the solvent evaporated. The residue was dissolved in MeOH and purification was accomplished by reverse-phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.041 g, 52%) as a white solid. 1H NMR (400 MHz, Acetone-d6) δ ppm 10.64 (br. s., 1H), 8.28 (br. s., 1H), 7.61 (s, 1H), 7.33-7.51 (m, 5H), 7.00-7.13 (m, 2H), 6.89 (dd, 1H), 4.66 (d, 2 H), 4.15 (t, 2H), 2.85 (t, 2H), 2.17 (s, 3H). LC-MS (ES+) m/z 544.4 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([CH3:23])([CH3:22])[CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1.[C:24]([CH:27]=[C:28]=[O:29])(=[O:26])[CH3:25]>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:28](=[O:29])[CH2:27][C:24](=[O:26])[CH3:25])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([CH3:23])([CH3:22])[CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1
Reactant: CC(=O)C=C=O
Reactant: CC(C)(Cc1ccc2ccccc2c1)Nc1ccc(N)cc1Cl
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)Nc1ccc(NC(C)(C)Cc2ccc3ccccc3c2)c(Cl)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 265.8 %

Procedure:
To a solution of 2-chloro-N1-(2-methyl-1-(naphthalen-2-yl)propan-2-yl)benzene-1,4-diamine (2.0 g, 6.16 mmol) in EtOAc (30 mL) was added acetyl ketene (1.55 g, 1.84 mmol) and the mixture was stirred at 90° C. overnight. The mixture was cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a white solid (2.00 g, 79%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:20]=[CH:19][C:6]([CH:7]=[CH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[CH:5][CH:4]=1.NC(N)=[S:23].[OH-].[Na+].S(=O)(=O)(O)O>CCOCC.ClCCl.C(O)C>[SH:23][CH2:2][C:3]1[CH:20]=[CH:19][C:6]([CH:7]=[CH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[CH:5][CH:4]=1
Reactant: NC(N)=S
Reactant: COc1ccc(OC)c(C=Cc2ccc(CCl)cc2)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Solvent: CCOCC
Product: COc1ccc(OC)c(C=Cc2ccc(CS)cc2)c1
Yield: 38.7 %

Procedure:
A solution of 4'-chloromethyl-2,5-dimethoxystilbene (856 mg, 2.96 mmol), thiourea (0.29 g, 3.8 mmol), and ethanol (16 ml) was heated to reflux for 3.5 h. Aqueous sodium hydroxide (2.5 M, 2.8 ml) was added and the mixture refluxed for further 2 h. The reaction mixture was allowed to cool and dichloromethane (50 ml), ether (200 ml) and sulfuric acid (10%, 10 ml) were added. The organic layer was separated, washed with water (2×200 ml), brine (100 ml), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography over silica (dichloromethane/hexane; 4:1) to give (32b) (328 mg, 39%); νmax /cm-1 2950s, 1490m, 1470s, 1430m, 1390s, 1215s, 1180s, 1050s.
Reaction SMILES: [NH2:1][C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[CH:11]1[C:20]2[C:15](=[C:16]([CH2:21][C:22](O)=[O:23])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1>>[CH:11]1[C:20]2[C:15](=[C:16]([CH2:21][C:22]([NH:1][C:2]3[S:6][CH:5]=[N:4][C:3]=3[C:7]([O:9][CH3:10])=[O:8])=[O:23])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1
Reactant: COC(=O)c1ncsc1N
Reactant: O=C(O)Cc1cccc2cnccc12
Product: COC(=O)c1ncsc1NC(=O)Cc1cccc2cnccc12

Procedure:
Methyl 5-(2-(isoquinolin-5-yl)acetamido)thiazole-4-carboxylate was prepared from methyl 5-aminothiazole-4-carboxylate (0.132 g, 0.834 mmol) and 2-(isoquinolin-5-yl)acetic acid (0.163 g, 0.834 mmol) according to protocol A. Retention time (min)=2.400, method [3], MS (ESI) 328.0 (M+H).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C:22]#[N:23])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH4+].[OH-]>CO.[Ni]>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH2:23])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C#N)ccc3c2)CC1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CN)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Compound 6-((trans)-4-tert-butylcyclohexyloxy)-2-naphthonitrile (1.7 g, 5.53 mmol, 1.0 eq.) and NH4OH (0.3 mL, 6.65 mmol, 1.2 eq.) was dissolved in MeOH (5 mL). Then Raney Ni (64 mg, 1.11 mmol, 0.2 eq.) was added to the mixture and the suspension solution was stirred at r.t. under hydrogen atmosphere for 15 h. The mixture was filtrated and purified by silica gel column chromatography using DCM/MeOH (10/1) as eluent to give product as a pale solid (1.76 g, 63%). ESI-MS (M-NH2)+: 295.1. 1H NMR (400 MHz, CDCl3) δ 7.71-7.65 (m, 3H), 7.38 (dd, 1H), 7.15-7.11 (m, 2H), 4.28-4.24 (m, 1H), 3.98 (s, 2H), 2.30-2.26 (m, 2H), 1.91-1.87 (m, 2H), 1.76 (s, 2H), 1.46-1.40 (m, 2H), 1.21-1.12 (m, 3H), 0.90 (s, 9H).
Reaction SMILES: [F:1][C:2]1[C:25]([O:26][CH3:27])=[CH:24][C:5]2[NH:6][C:7]([C:9]3[C:21]4[C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14](=[N:22]O)[C:13]=4[CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.O.C(O)(=O)C>C(O)C.[Zn]>[F:1][C:2]1[C:25]([O:26][CH3:27])=[CH:24][C:5]2[NH:6][C:7]([C:9]3[C:21]4[C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[CH:14]([NH2:22])[C:13]=4[CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: COc1cc2[nH]c(-c3cccc4c3-c3ccccc3C4=NO)nc2cc1F
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2[nH]c(-c3cccc4c3-c3ccccc3C4N)nc2cc1F

Procedure:
The procedure used in stage 4 of Example 216 is followed. In a 30 ml round-bottomed flask under an argon atmosphere, dissolve 140 mg of equimolecular mixture of 4-(5-fluoro-6-methoxy-1H-benzimidazol-2-yl)-9H-fluoren-9-one oxime (Z,E), obtained in the previous stage, in a mixture of 0.7 ml of ethanol, 0.7 ml of water and 0.7 ml of acetic acid. At room temperature, add 100 mg of zinc, in three stages, and, between each addition, stir for approximately one hour to two hours. After purification by flash chromatography on silica gel (40-63 μm), eluting with a mixture of dichloromethane and ammonia as a 7N solution in methanol (95/5 by volume), in this way we obtain 127 mg of 4-(5-fluoro-6-methoxy-1H -benzimidazol-2-yl)-9H-fluorene-9(R,S)-amine, in the form of a beige resin which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[Cl:13]N1C(=O)CCC1=O>O1CCCC1>[Cl:13][C:9]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1ccc(-n2cccc2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: Cc1ccc(-n2cccc2Cl)cc1
Temperature: 10 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
To a solution of 1-(4-methylphenyl)pyrrole (1 g) in tetrahydrofuran (50 ml) was added N-chlorosuccinimide (850 mg) in one portion at -78° C. under nitrogen atmosphere. The mixture was warmed to 10° C., stirred for one hour, and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to yield 2-chloro-1-(4-methylphenyl)pyrrole (1.2 g) as an oil. (This product was a mixture of the starting material and the desired product and used to the next reaction furthermore without purification.)
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6](=O)[C:7]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)=[CH:8][O:9][C:4]=2[C:3]=1[CH3:20].O1CCCC1.C(O)(=O)C.S(=O)(=O)(O)O>O1CCOCC1.C(O)C>[OH:1][C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][CH:7]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[CH2:8][O:9][C:4]=2[C:3]=1[CH3:20]
Reactant: Cc1c(O)ccc2c(=O)c(-c3ccc(Cl)cc3)coc12
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1c(O)ccc2c1OCC(c1ccc(Cl)cc1)C2

Procedure:
As example 39, but using 7-hydroxy-8-methyl-3-(4-chlorophenyl)-4H-1-benzopyran-4-one (1.2 g) instead of 6,7-dihydroxy-3(3-methylphenyl)-4H-1-benzopyran-4-one. Tetrahydrofuran and acetic acid are used instead of dioxan/ethanol and sulphuric acid. The resulting oil is finally purified by elution on a silica gel column (CHCl3) to yield 3,4-dihydro-7-hydroxy-8-methyl-3-(4-chlorophenyl)-2H-1-benzopyran, m.p. 98°-100°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:19]([OH:21])=[O:20])[CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:19]([OH:21])=[O:20])[CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCOCCOCC(NC(=O)OC(C)(C)C)C(=O)O
Solvent: ClC(Cl)Cl
Product: COCCOCCOC[C@H](NC(=O)OC(C)(C)C)C(=O)O

Procedure:
Nα-tert-butyloxycarbonyl-L-serine (4.59 g, 22.3 mmol) was dissolved in N,N-dimethylformamide (100 mL), the solution was then cooled to 0° C. and treated with sodium hydride (1.97 g, 49.2 mmol). 1-Bromo-2-(2-methoxyethoxy)ethane (10.0 g, 49.2 mmol) was added to the solution and the reaction mixture was stirred at ambient temperature for 3 h. The solvent was then removed under a reduced pressure at 40° C. bath temperature. The residue was dissolved in water (75 mL) and washed twice with diethyl ether (30 mL each time). The aqueous layer was then acidified to pH 3 with 1 M HCl and then extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4 and the solvent was removed in vacuo to yield the compound as a yellow oil (4.1 g, 63%). The compound has the following characteristics: FTIR (CHCl3): 1735 (vCO, s), 1712 (νCO, s). 1H NMR (CDCl3): δ 5.63 (d, (CH3)3COC(O)NHCH(CH2OCH2CH2OCH2CH2OCH3)C(O)OH, 1H), 4.38 (s, (CH3)3COC(O)NHCH(CH2OCH2CH2O—CH2CH2OCH3)C(O)OH, 1H), 4.14-3.53 (m, (CH3)3COC(O)NHCH(CH2OCH2CH2O—CH2CH2OCH3)C(O)OH,10H), 3.47 (s, (CH3)3COC(O)NHCH(CH2OCH2CH2OCH2—CH2OCH3)C(O)OH, 3H), 1.52 (s, (CH3)3COC(O)NHCH(CH2O—CH2CH2OCH2CH2—OCH3)C(O)OH, 9H). MALDITOF-MS: MH30 : 307.34 calcd, 309.19 found.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1.C(N(CC)CC)C>C(O)CCC>[F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)[N:3]=1
Reactant: COc1cccc(N)c1
Reactant: Fc1nc(Cl)c2[nH]cnc2n1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: COc1cccc(Nc2nc(F)nc3nc[nH]c23)c1
Temperature: 25 °C

Procedure:
This compound was prepared by the reaction of 2-fluoro-6-chloropurine (1.7 g; 0.01 mol), m-anisidine (1.23 g; 0.01 mol) and triethylamine (3.5 ml; 0.025 mol) in n-butanol (20 ml) at 90° C. for 4 hours. The reaction mixture was then cooled to the room temperature. The white precipitate was filtered off, rinsed with n-butanol (3×10 ml) and water (3×10 ml) and dried in the drying oven into constant weight. Yield: 5.55 g (61%) of yellowish crystalline powder. TLC (chloroform-methanol; 85:15): one single spot. HPLC purity: 99+%.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])=[O:24]
Reactant: O=[N+]([O-])c1ccccc1CO
Reactant: O=C(O)CCCCCCCCCCBr
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(CCCCCCCCCCBr)OCc1ccccc1[N+](=O)[O-]

Procedure:
One equivalent of 2-nitrobenzyl alcohol (1.91 g, 12.49 mmol) was combined with one equivalent of 11-bromoundecanoic acid (3.31 g, 12.49 mmol), 0.1 equivalents DMAP (0.153 g, 1.25 mmol) and dissolved in 100 mL CH2Cl2. To this mixture a solution of DCC (2.58 g, 12.49 mmol) in 50 mL CH2Cl2 was slowly added while stirring. Upon addition a yellow-brown precipitate formed after a few minutes. The mixture was stirred at room temperature overnight. The precipitate was removed by vacuum filtration and the solvent was removed by rotovap. The product was purified using silica gel column chromatography with CH2Cl2/MeOH (v/v 50:1) as eluent. The product was dried over Na2SO4, the solvent removed by rotovap, and dried under vacuum, producing a white solid. Yield: 4.37 g (87.4%). 1H-NMR (CDCl3) δ (ppm): 8.1 (d, 1H, Ar), 7.6 (t, 1H, Ar), 7.5 (d, 1H, Ar), 7.4 (t, 1H, Ar), 5.5 (s, 2H, O—CH2), 3.4 (t, 2H, CH2—Br), 2.4 (t, 2H, CH2—C═O), 1.8 (m, 2H, CH2), 1.6 (m, 2H, CH2), 1.4 (m, 2H, CH2), 1.3 (m, 10H, CH2). 13C-NMR (CDCl3) δ (ppm): 173.5, 147.9, 134.1, 132.7, 129.5, 129.2, 125.5, 63.2, 34.6, 34.5, 33.2, 29.7, 29.6, 29.5, 29.4, 29.1, 28.5, 25.3.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])=[O:13])[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.CN1CCOCC1.C1CN([P+](O[N:47]2N=[N:54][C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][C:48]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1(N)C=CC=CC=1N>CN(C=O)C>[NH2:54][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[N:47]1[C:16](=[O:17])[C:15]2[C:14](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]1([C:9]1[CH:10]=[CH:11][C:5]2[O:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=2[CH:8]=1)[OH:13]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: O=C1COc2ccc(C(=O)c3ccccc3C(=O)O)cc2N1
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccccc1N
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Nc1ccccc1N1C(=O)c2ccccc2C1(O)c1ccc2c(c1)NC(=O)CO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 3 %

Procedure:
2-[(3-Oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]benzoic acid (100 mg, 0.34 mmol.) was taken into DMF (1 mL) followed by addition of 4-methylmorpholine (75 uL, 0.7 mmol.) and PyBOP (177 mg, 0.34 mmol.) and the resulting solution was stirred for 15 minutes at room temperature. o-Phenylenediamine (37 mg, 0.34 mmol.) was added to the solution thus obtained and the mixture was allowed to stir an additional hour then partitioned with ethyl acetate and water. The organic layer was washed with water (3×), 10% aqueous citric acid (2×), saturated aqueous sodium bicarbonate (1×) and brine then dried over anhydrous sodium sulfate. A portion of the residue obtained on filtration and concentration of the organic solution was purified by silica gel flash chromatography (2:1 ethyl acetate:hexanes to 100% ethyl acetate) gave 6-[2-(2-aminophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one (4.0 mg, 3% yield). The remainder of the crude residue was taken into acetic acid (5 mL) and heated to reflux for one hour. The solvent was removed in vacuo and the residue partitioned with ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and the residue was purified by silica gel flash chromatography (2.5:1 ethyl acetate:hexanes) to give 6-{[2-(1H-benzimidazol-2-yl)phenyl]carbonyl}-2H-1,4-benzoxazin-3(4H)-one (28 mg, 22% yield). 6-[2-(2-Aminophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one: MS (EI) for C22H17N3O4: 388 (MH+). 6-{[2-(1H-Benzimidazol-2-yl)phenyl]carbonyl}-2H-1,4-benzoxazin-3(4H)-one: 1H NMR (400 MHz, d6-DMSO): 12.84 (br s, 1H), 10.75 (br s, 1H), 8.00 (d, 1H), 7.73 (tr, 1H), 7.59 (tr, 1H), 7.44-7.37 (m, 3H), 7.32 (s, 1H), 7.15-7.06 (m, 3H), 6.87 (d, 1H), 4.58 (s, 2H). MS (EI) for C22H15N3O3: 370 (MH+).
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][CH2:5][NH:6][C:7]([C:9]([S:12]([CH2:15][CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:17]([OH:19])=[O:18])(=[O:14])=[O:13])([CH3:11])[CH3:10])=[O:8].O.[CH2:28](O)[CH3:29]>>[OH:3][CH2:4][CH2:5][NH:6][C:7]([C:9]([S:12]([CH2:15][C@H:16]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:17]([O:19][CH2:28][CH3:29])=[O:18])(=[O:14])=[O:13])([CH3:10])[CH3:11])=[O:8]
Reactant: CCO
Reactant: CC(C)(C(=O)NCCO)S(=O)(=O)CC(Cc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)[C@@H](Cc1ccccc1)CS(=O)(=O)C(C)(C)C(=O)NCCO

Procedure:
0.1N sodium hydroxide solution was added dropwise while stirring to a mixture of 0.86 g (2.23 mmol) of rac-α-[[[1-[(2 -hydroxyethyl)carbamoyl]-1-methylethyl]sulfonyl]methyl]hydrocinnamic acid and 200 mg of α-chymotrypsin in 5 ml of ethanol and 100 ml of water in such a manner that the pH value was held at 7.5. After sodium hydroxide solution was no longer consumed the working-up of the reaction mixture was effected by adjusting to pH 8 and extracting twice with 40 ml of ether each time. The combined organic extracts were washed with 15 ml of saturated sodium hydrogen carbonate solution, dried over sodium sulphate and evaporated under reduced pressure. There was obtained ethyl (R)-α-[[[1-[(2-hydroxyethyl)carbamoyl]-1-methylethyl]sulfonyl]methyl]hydrocinnamate as a yellowish oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[CH:25]([NH:28][C:21]([C:17]1[S:16][C:15](/[CH:14]=[CH:13]/[C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]=[N:10][C:11]=2[CH3:24])=[N:19][C:18]=1[CH3:20])=[O:23])([CH3:27])[CH3:26]
Reactant: CC(C)N
Reactant: Cc1nc(/C=C/c2c(C)nnn2-c2ccc(F)cc2)sc1C(=O)O
Product: Cc1nc(/C=C/c2c(C)nnn2-c2ccc(F)cc2)sc1C(=O)NC(C)C
Yield: 71 %

Procedure:
As described for example 8c, 2-{(E)-2-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-yl]-vinyl}-4-methyl-thiazole-5-carboxylic acid (72 mg, 0.21 mmol), was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (57 mg, 71%) which was obtained as an off white solid. MS: m/e=386.4 [M+H]+.
Reaction SMILES: [C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:23])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([OH:24])[CH:6]=1)(=[O:3])[CH3:2].[CH3:25]C(C)=O>>[C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:23])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:24][CH3:25])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(O)cc2c1[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2
Reactant: CC(C)=O
Product: COc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2

Procedure:
1-Acetoxy-3-hydroxyestra-1,3,5(10)-trien-17-one (7.6 g, 23 mM) is added to 600 ml of anhydrous acetone in a 3-neck, 1 liter round bottom flask equipped with condenser, magnetic stirring bar, drying tube and pressure-compensated addition funnel. Dimethyl sulfate (3.2 g, 25 mM) is added and the resulting suspension is refluxed for 16 hrs, and then filtered while still warm. The filter cake is washed repeatedly with anhydrous acetone, and the combined filtrates are evaporated in vacuo. The residue is recrystallized from acetone-water to obtain 1-acetoxy-3-methoxyestra-1,3,5(10)-trien-17-one, yield 6.2 g (80%), m.p. 144°-145°. Further recrystallization from CH2Cl2 -hexane gives material of m.p. 150°-151°.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([S:10][C:11]1[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][C:12]=1[CH:13]=[CH:14][C:15]1=[N:16][CH2:17][CH2:18][N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]1=2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Sn](Cl)[Cl:35].Cl>O1CCCC1.C(O)C>[ClH:35].[ClH:1].[CH2:3]([S:10][C:11]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][C:12]=1/[CH:13]=[CH:14]/[C:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]([CH3:26])[CH2:18][CH2:17][N:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CN1CCN=C(C=Cc2cc([N+](=O)[O-])ccc2SCc2ccccc2)c2ccccc21
Reactant: Cl[Sn]Cl
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CCN=C(/C=C/c2cc(N)ccc2SCc2ccccc2)c2ccccc21
Temperature: 60 °C
Yield: 19.5 %

Procedure:
To 215 mg (0.50 mmol) of (E)-5-(2-benzylthio-5-nitrostyryl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepine dihydrochloride (prepared as described in Example 15) in 8 ml of tetrahydrofuran and 8 ml of ethanol was added 380 mg (0.90 mmol) of tin (II) chloride and 0.48 ml of concentrated hydrochloric acid. The mixture was heated at 60° C. for 7 hours. The solution was reduced to half volume and partitioned between 50 ml of saturated sodium hydrogen carbonate solution and 100 ml and 50 ml of dichloromethane. The combined organic phases were dried (magnesium sulphate), filtered and evaporated. The residue was purified by column chromatography eluting with 2-5% methanol/dichloromethane and treated with 0.30 ml of 4M hydrogen chloride in dioxan. The solvent was evaporated and the residue was recrystallised from methanol/ether to give 46 mg of (E)-4-benzylthio-3-[2-(2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-5-yl)vinyl]aniline dihydrochloride as dark red crystals; MS: m/e 400 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[Cl:31][C:32]1[N:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>O1CCCC1.C(OCC)(=O)C>[Cl:31][C:32]1[N:37]=[CH:36][C:35]([S:38]([N:11]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:9]([CH:12]=[O:13])=[CH:10]2)(=[O:40])=[O:39])=[CH:34][CH:33]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: O=Cc1c[nH]c(-c2ccccc2)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(Cl)nc2)c1
Yield: 73.2 %

Procedure:
Under an argon atmosphere, 5-phenyl-1H-pyrrole-3-carbaldehyde (514 mg) was dissolved in absolute tetrahydrofuran (15 mL), and sodium hydride (60% in oil, 180 mg) was added at room temperature while stirring. After stirring at the same temperature for 15 min, 15-crown-5 (0.90 mL) was added, and the mixture was further stirred at the same temperature for 15 min. 6-Chloropyridin-3-ylsulfonyl chloride (827 mg) was added, and the mixture was further stirred at the same temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→7:3) to give the title compound as an oil (yield 762 mg, 73%).