Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([C@H:7]([OH:10])[CH:8]=[CH2:9])[O:5][C:4](=[O:11])[C@@H:3]1[O:12][CH3:13].[Br:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1C=C.C1COCC1>Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl.C(Cl)Cl>[Br:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1/[CH:9]=[CH:8]/[C@H:7]([C@@H:6]1[O:5][C:4](=[O:11])[C@H:3]([O:12][CH3:13])[C@@H:2]1[OH:1])[OH:10]
Reactant: C=Cc1ccccc1Br
Reactant: C=C[C@@H](O)[C@@H]1OC(=O)[C@H](OC)[C@@H]1O
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CO[C@H]1C(=O)O[C@@H]([C@H](O)/C=C/c2ccccc2Br)[C@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 26 %

Procedure:
400 mg of 31 (2.13 mmol), 1.56 g of 2-bromostyrene (8.5 mmol), 1 mL of THF, 16 mL of CH2Cl2 and 54 mg of 2nd generation Grubb's catalyst (C46H65Cl2N2PRu, MW 848.98, 0.06 mmol) are added to a 100 mL round-bottomed flask. The medium is stirred for 24 h at RT. The solvent is evaporated, the crude product (1.9 g) is chromatographed on a silica cartridge (90 g), eluting with a CH2Cl2/MeOH (95/5) mixture. 190 mg of expected product 45 are obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[N:7]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][CH:18]=[C:17]2[S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30])(=[O:23])=[O:22])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:34]I>CN(C)C=O>[C:1]([O:5][C:6](=[O:31])[N:7]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[N:19]([CH3:34])[CH:18]=[C:17]2[S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30])(=[O:23])=[O:22])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CCOc1cccc2c(S(=O)(=O)c3ccccc3F)c[nH]c12)C(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCOc1cccc2c(S(=O)(=O)c3ccccc3F)cn(C)c12)C(=O)OC(C)(C)C
Reaction time: 0.17 h

Procedure:
A dry 25 mL flask equipped with a magnetic stirrer was charged with {2-[3-(2-fluoro-benzenesulfonyl)-1H-indol-7-yloxy]-ethyl}-methyl-carbamic acid tert-butyl ester (0.116 g., 0.258 mmol) and dimethylformamide (5 mL.) This solution was treated with sodium hydride (0.011 g. of 60% suspension in mineral oil, 0.284 mmol) and allowed to stir for 10 minutes under N2. Methyl iodide was then added via syringe in one portion. After 18 hours stirring at ambient temperature, the reaction mixture was extracted into 45 mL ethyl acetate and washed with water (2×45 mL). The organic fraction was dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (85:15 hexanes:EtOAc to 70:30 hexanes:EtOAc) to give 45 mg of {2-[3-(2-fluoro-benzenesulfonyl)-1-methyl-1H-indol-7-yloxy]-ethyl}-methyl -carbamic acid tert-butyl ester as a clear oil: 1H NMR (CDCl3, 300 MHz) δ: 1.45 (s, 9H), 2.94 (s, 3H), 3.71 (m, 2H), 4.09 (s, 3H), 4.19 (m, 2H), 6.67 (d, 1H, J=7.7), 7.04 (m, 1H), 7.08 (t, 1H, J=8.0), 7.27 (td, 1H, J=7.6, J′=1.13), 7.44 (d, 1H, J=7.6), 7.49 (m, 1H), 7.74 (d, 1H, J=1.3), 8.15 (td, 1H, J=7.6, J′=1.8).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[C:22](=[O:23])[C:14]3[CH:15]=[C:16]4[N:21]([C:13]=3[CH:12]=[N:11]2)[CH2:20][CH2:19][CH2:18][CH2:17]4)[N:5]=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:56][O:55][CH2:54]4)[CH2:49][C@@H:48]3[CH3:57])=[CH:43][N:42]=2)[C:26]1=[O:58].C([O-])(=O)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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].O.C(#N)C>[CH3:24][N:25]1[C:26](=[O:58])[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:54][O:55][CH2:56]4)[CH2:49][C@@H:48]3[CH3:57])=[CH:43][N:42]=2)=[CH:28][C:29]([C:2]2[C:7]([CH:8]=[O:9])=[C:6]([N:10]3[C:22](=[O:23])[C:14]4[CH:15]=[C:16]5[N:21]([C:13]=4[CH:12]=[N:11]3)[CH2:20][CH2:19][CH2:18][CH2:17]5)[N:5]=[CH:4][CH:3]=2)=[CH:30]1
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Reactant: O=Cc1c(Cl)ccnc1-n1ncc2c(cc3n2CCCC3)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ncc5c(cc6n5CCCC6)c4=O)c3C=O)cn(C)c2=O)nc1
Temperature: 100 °C
Yield: 53 %

Procedure:
A 100-mL round-bottomed flask equipped with a reflux condenser was charged with 193f (200 mg, 0.61 mmol), 191j (293 mg, 0.60 mmol), sodium acetate (98 mg, 1.2 mmol), K3PO4 (254 mg, 1.2 mmol), PdCl2(dppf) (50 mg, 0.060 mmol), acetonitrile (25 mL), and water (1 mL). After bubbling nitrogen through the mixture for 30 minutes, it was heated at 100° C. for 3 hours. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 25:1 methylene chloride/methanol to afford 193g (206 mg, 53%) as a brown solid. MS-ESI: [M+H]+ 648.3.
Reaction SMILES: [C:1]([N:5]([CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)(=[O:4])[CH:2]=[CH2:3].Cl.[CH3:17][NH:18][CH3:19]>>[CH3:17][N:18]([CH3:19])[CH2:3][CH2:2][C:1]([N:5]([CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:4]
Reactant: C=CC(=O)N(C)c1ccc([N+](=O)[O-])cc1
Reactant: CNC
Agent: Cl
Product: CN(C)CCC(=O)N(C)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from N-acryloyl-N-methyl-4-nitro-aniline and dimethylamine hydrochloride
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1.C1(N)CCCCC1>C(O)(C)C>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(Cl)cc2F)cc1
Solvent: NC1CCCCC1
Solvent: CC(C)O
Product: O=C(O)CCCc1ccc(-c2ccc(Cl)cc2F)cc1
Yield: 60 %

Procedure:
Prepared analogous to Example 1 from 4-(2'-fluoro-4'-chloro-4-biphenylyl)-4-oxo-butyric acid. yield: 60% of theory. Melting point of the cyclohexylamine salt: 134°-136° C. (from isopropanol).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]=[C:13]=[O:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=O>>[Cl:27][C:25]1[CH:26]=[C:18]2[C:19]([C:20](=[O:22])[N:12]([S:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:16])([F:1])[F:15])=[CH:8][CH:7]=3)(=[O:10])=[O:11])[C:13](=[O:14])[NH:17]2)=[CH:23][CH:24]=1
Reactant: O=C=NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)n1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Yield: 32.9 %

Procedure:
1.67 g (6.67 mmol) of 4-trifluoromethylbenzenesulfonylisocyanate and 1.14 g (6.67 mmol) of 2-amino-4-chlorobenzoic acid were treated in the same way as in Example 1 to obtain 888 mg of the above-identified compound (yield 32.9%). Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δppm, DMSO-d6):7.13 (1H,s), 7.23 (1H,d), 7.87 (1H,d), 8.06 (2H,d), 8.39 (2H,d), 11.78 (1H,br).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][S:24][C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41]([N:43]2[CH2:50][CH2:49][CH2:48][C@H:44]2[C:45](O)=[O:46])=[O:42])=[CH:36][CH:35]=1>ClCCl>[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][S:24][C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH:27][C:45]([C@@H:44]1[CH2:48][CH2:49][CH2:50][N:43]1[C:41](=[O:42])[CH2:40][C:37]1[CH:36]=[CH:35][C:34]([O:33][CH3:32])=[CH:39][CH:38]=1)=[O:46]
Reactant: Nc1ccccc1SCc1ccccc1Br
Reactant: COc1ccc(CC(=O)N2CCC[C@H]2C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(CC(=O)N2CCC[C@H]2C(=O)Nc2ccccc2SCc2ccccc2Br)cc1
Reaction time: 1 h

Procedure:
A solution of 1,3-dicyclohexylcarbodiimide (DCC) (705 g) in dichloromethane (1400 ml) was added over 30 minutes to a stirred solution of 2-(2-bromophenylmethylthio)aniline (see Bull. Chem. Soc. Japan, 48, 2323 (1975)) (957 g) and (S)-1-(4-methoxyphenylacetyl)proline (see Preparation 24) (900 g) in dichloromethane (5.5 L). The mixture was stirred at 25°-35° C. for one hour and filtered. The filtrate was evaporated under reduced pressure to give the desired product as a brown gum which was used directly in Preparation 22.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]([O:16][CH3:17])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][CH2:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].CC1C=CC(S(O)(=O)=O)=CC=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.O.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][NH:18][C:10](=[O:12])[C@@H:9]1[CH2:13][C@@H:14]([O:16][CH3:17])[CH2:15][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CO[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NCC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@@H]1C[C@@H](C(=O)NCC(=O)OCc2ccccc2)N(C(=O)OC(C)(C)C)C1
Yield: 82 %

Procedure:
A solution of Boc-Mop-OH (0.42 g, 1.71 mmol), H-Gly-OBn.TsOH (0.64 g, 1.88 mmol), DCC (0.35 g, 1.71 mmol), HOBt.H2O (0.26 g, 1.71 mmol) and DIEA (0.89 mL, 5.13 mmol) in DMF (30 mL) was stirred at room temperature under Ar(g) for 20 h. The mixture was filtered to remove insoluble DCU and concentrated by rotary evaporation under high vacuum. The product was isolated by flash chromatography (two columns were needed; the first was run in 8:2 EtOAc/hexanes and the second in 7:3 EtOAc/hexanes) affording Boc-Mop-Gly-OBn (0.55 g, 82%) as a clear oil. 1H NMR (500 MHz, CDCl3, ˜3:2 ratio of 2 rotamers): δ7.41-7.32 (m, 5 H), 6.53 (app bs, 0.4 H), 5.22-5.15 (m, 2 H), 4.44 (dd, J=7.9, 5.6 Hz, 0.6 H); 4.31 (t, J=7.8 Hz, 0.4 H), 4.16-3.97 (m, 2.6 H), 3.93 (app bs, 0.4 H), 3.81-3.72 (m, 0.6 H), 3.53-3.43 (m, 1.4 H), 3.32 and 3.31 (overlapping s, 3 H), 2.49-2.42 (m, 0.6 H), 2.41-2.33 (m, 0.4 H), 2.16-2.05 (m, 1 H), 1.89 (bs, 0.6 H), 1.47 (s, 5 H), 1.42 (s, 4 H);
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10](Cl)[C:5]=2[S:4][CH:3]=1.[NH3:12]>C(O)(C)C>[Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([NH2:12])[C:5]=2[S:4][CH:3]=1
Reactant: Clc1ncnc2c(Br)csc12
Reactant: N
Solvent: CC(C)O
Product: Nc1ncnc2c(Br)csc12
Temperature: 100 °C
Reaction time: 12 h
Yield: 83 %

Procedure:
7-Bromo-4-chlorothieno[3,2-d]pyrimidine (5 g, 20.17 mmol) obtained in Step 3 of Preparation Example 1 and 2.0M NH3 dissolved in isopropanol solution (50 mL) were added to a sealed reaction vessel and stirred at 100° C. for 12 hours. The reaction mixture was cooled to room temperature and filtered to obtain a solid. The solid was washed with water and dried with N2 gas to obtain the title compound (3.8 g, 83%) without further purification.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([F:16])[C:10]=1[F:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:18]([C@H:22]1[CH2:27][CH2:26][C@H:25]([C:28](O)=[O:29])[CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:18]([C@H:22]1[CH2:23][CH2:24][C@H:25]([C:28]([O:15][C:12]2[CH:13]=[CH:14][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[C:10]([F:17])[C:11]=2[F:16])=[O:29])[CH2:26][CH2:27]1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCc1ccc(O)c(F)c1F
Reactant: CCCC[C@H]1CC[C@H](C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCc1ccc(OC(=O)[C@H]2CC[C@H](CCCC)CC2)c(F)c1F

Procedure:
0.1 mol of this phenol, 0.1 mol of trans-4-butylcyclohexanecarboxylic acid and 0.01 mol of 4-dimethylaminopyridine are initially introduced into 150 ml of methylene chloride, a solution of 0.1 mol of dicyclohexylcarbodiimide in 30 ml of methylene chloride is added dropwise at 10°, while stirring, and the mixture is then subsequently stirred at room temperature for 15 hours. The mixture is filtered over silica gel with suction and the solvent is evaporated off to give 2,3-difluoro-4-octylphenyl trans-4-butylcyclohexanoate as the residue.
Reaction SMILES: [C:1]([N:5]1[CH2:31][CH2:30][CH2:29][C:8]2[C:9](Br)=[C:10]3[C:19]4[CH:18]=[C:17]([C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)[C:16]([O:26][CH3:27])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:32])([CH3:4])([CH3:3])[CH3:2].[N:33]1[CH:38]=[CH:37][CH:36]=[C:35](B(O)O)[CH:34]=1.C([O-])([O-])=O.[K+].[K+]>C(COC)OC.O.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>[C:1]([N:5]1[CH2:31][CH2:30][CH2:29][C:8]2[C:9]([C:35]3[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)[C:16]([O:26][CH3:27])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccnc1
Reactant: COc1cc2c(cc1-c1cccnc1)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCC3
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: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1cc2c(cc1-c1cccnc1)-c1c(-c3cccnc3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCC3
Temperature: 90 °C
Yield: 69.1 %

Procedure:
A mixture of 45 mg of 13d, 20 mg of pyridine-3-boronic acid, 30 mg of K2CO3 and 10 mg of Pd(PPh3)4 in 2 ml of degassed dimethoxyethane was heated at 90° C., for 16 hr. The reaction mixture was cooled, diluted with water and the product was extracted with ethyl acetate. The extract was washed once with 2N KOH and once with water, dried and concentrated. The residue was purified by chromatography over silica gel, using a gradient of toluene/acetone as eluent. The isolated product was triturated with diethyl ether, to provide 31 mg of 13e as white, crystalline material; Mp 310-312° C.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[C:13]([CH3:14])=[N:12][N:11]=[C:10]([C:15]2[CH:16]=[CH:17][C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=2)[C:9]2[CH:8]=[C:7]([O:25][CH3:26])[C:6]([O:27][CH3:28])=[CH:5][C:4]1=2>CCCCCC.CC(O)C>[CH3:1][CH2:2][CH:3]1[C:13]([CH3:14])=[N:12][N:11]=[C:10]([C:15]2[CH:16]=[CH:17][C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=2)[C:9]2[CH:8]=[C:7]([O:25][CH3:26])[C:6]([O:27][CH3:28])=[CH:5][C:4]1=2
Reactant: CC[C@H]1C(C)=NN=C(c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc21
Solvent: CCCCCC
Solvent: CC(C)O
Product: CCC1C(C)=NN=C(c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc21

Procedure:
Analytical evaluations of the starting material, and final preparations of R- and S-tofisopam were performed by using Chiral Tech OD GH060 columns (Daicel) (Hexane/IPA 90/10, 25° C., detection at 310 nm). See FIG. 3a and 3b. The final preparation of R-tofisopam was 98%+ pure by analytical chromatography. The final preparation of S-tofisopam was 95%+ pure by analytical chromotography.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.O(Cl)[Cl:15]>CN(C)C1C=CC=CC=1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:15])=[N:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1nc2cc(Br)ccc2c(=O)[nH]1
Reactant: ClOCl
Solvent: CN(C)c1ccccc1
Product: Cc1nc(Cl)c2ccc(Br)cc2n1
Temperature: 60 °C
Yield: 59 %

Procedure:
A suspension of 0.45 g 7-bromo-2-methyl-3H-quinazolin-4-one in 0.48 ml N,N-dimethylaniline is treated with 1.41 ml phosphourous oxychloride and heated at 60° C. for 2 h. The reaction mixture is evaporated in vacuo and the residue is taken up with 20 ml water, neutralized with 10 ml saturated aqueous sodium bicarbonate and extracted with 25 ml dichloromethane twice. The organic layer is washed with 25 ml water, 25 ml brine, dried over magnesium sulfate and evaporated in vacuo. The residue is purified by chromatography on silica gel with Heptane/ethylacetate 2:1. 0.288 g (59%) of 7-bromo-4-chloro-2-methyl-quinazoline are obtained as an orange solid. Mp. >82° C. (dec). MS (EI): peaks at m/e: 258(M+, 37%), 221 (100%), 179(9%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[CH2:13][C:12]([CH3:16])=[N:11]2)=[CH:6][CH:5]=1)([OH:3])=[O:2].O=[CH:18][C:19]1[CH:27]=[CH:26][C:24]([OH:25])=[C:21]([O:22][CH3:23])[CH:20]=1>CN(C)C=O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14](=[O:15])[C:13](=[CH:18][C:19]3[CH:27]=[CH:26][C:24]([OH:25])=[C:21]([O:22][CH3:23])[CH:20]=3)[C:12]([CH3:16])=[N:11]2)=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1
Reactant: COc1cc(C=O)ccc1O
Solvent: CN(C)C=O
Product: COc1cc(C=C2C(=O)N(c3ccc(C(=O)O)cc3)N=C2C)ccc1O
Temperature: 100 °C

Procedure:
218 g (1 mole) of 1-p-carboxyphenyl-3-methyl-2-pyrazolin-5-one and 152 g (1 mole) of vanillin were dissolved in 500 ml of dimethylformamide. The reaction mixture was heated for 3 h at 100° C. After cooling down to room temperature the crystallized dye was filtered with suction and rinsed with methanol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5](Cl)[CH2:6][CH2:7][Cl:8])[CH3:2].[NH2:11][C:12]1[C:13]([F:20])=[CH:14][C:15]([Cl:19])=[C:16]([SH:18])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([S:18][C:16]1[CH:17]=[C:12]([NH2:11])[C:13]([F:20])=[CH:14][C:15]=1[Cl:19])[CH2:6][CH2:7][Cl:8])[CH3:2]
Reactant: Nc1cc(S)c(Cl)cc1F
Reactant: CCOC(=O)C(Cl)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(CCCl)Sc1cc(N)c(F)cc1Cl

Procedure:
At room temperature, 16.2 g of 2,4-dichlorobutyric acid ethyl ester are added dropwise to a mixture of 14 g of 5-amino-2-chloro-4-fluoro-thiophenol and 12.7 g of potassium carbonate in 280 ml of methyl ethyl ketone (exothermic reaction). The reaction mixture is then heated under reflux for 18 hours. After cooling of the reaction mixture, the inorganic portion of the mixture is filtered off and washed with methyl ethyl ketone. Concentration of the organic solution by evaporation and chromatographic purification of the residue by silica gel chromatography yield 14.2 g of 2-(5-amino-2-chloro-4-fluorophenylthio)-4-chlorobutyric acid ethyl ester having a melting point of from +97° to +99° C.
Reaction SMILES: C([BH3-])#N.[Na+].O=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.[CH2:19]1[NH:24][CH2:23][CH2:22][N:21]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:20]1.C(O)(=O)C>CO>[C:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][CH:6]([N:24]2[CH2:19][CH2:20][N:21]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH2:22][CH2:23]2)[CH2:7][CH2:8]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CCN(C(=O)OCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.89 g (30.1 mmol) of sodium cyanoborohydride were added to a stirred solution of 3.00 g (15.1 mmol) of tert-butyl 4-oxo-1-piperidinecarboxylate and 3.48 g (15.8 mmol) of 1-Z-piperazine in methanol (60 ml) at room temperature. The pH of the solution was adjusted to about pH 7 by dropwise addition of acetic acid and was monitored during the course of the reaction. The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was mixed with water (60 ml) and extracted with dichloromethane (4×60 ml). The combined organic phases were washed with saturated NaCl solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (mobile phase gradient 3-10% methanol in dichloromethane). Yield: 3.41 g (56%) of colorless oil
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]1COCC1.[Cl-].[NH4+].CO>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[C:2]1([C:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH2:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: C1CCOC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CO
Product: C=C(c1ccccc1)c1ccccc1
Reaction time: 13 h

Procedure:
To this reaction mixture was added dropwise a liquid mixture of 182.2 g (1.1 mol) of benzophenone (8a; Ar=R=Ph) and 365 ml of dry THF at 35 to 40° C. over a period of 30 minutes. This mixture was stirred at that temperature for 2 hours and for further 13 hours to complete the reaction. The reaction mixture was poured into 1.4 kg of cooled 10% aqueous ammonium chloride solution with cooling with ice. This mixture was stirred for 30 minutes, allowed to stand, and then subjected to liquid separation, followed by washing with aqueous common salt solution, drying with magnesium sulfate, and concentration to obtain 200.2 g of a crude carbinol (theoretical yield based on the benzophenone, 98.6%). Into a 1-liter reaction flask were introduced 200.2 g of the crude carbinol, 400 ml of toluene, and 1 g of p-toluenesulfonic acid (PTSA). Azeotropic dehydration was conducted for 2 hours with toluene refluxing (94-116° C.). After cooling, this reaction mixture was washed with water, with 2% aqueous soda ash solution, and then with water, dried with magnesium sulfate, and concentrated to obtain 190.1 g of crude 1,1-diphenylethylene. This crude reaction product was distilled with a Claisen flask equipped with a vigreux to obtain 174.1 g of 1,1-diphenylethylene (9a; Ar=R=Ph). b.p., 103° C./1 mmHg.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1/[CH:12]=[CH:13]/N(C)C.C([OH:19])C>>[Cl:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[CH2:12][CH:13]=[O:19]
Reactant: CN(C)/C=C/c1ccc([N+](=O)[O-])cc1Cl
Reactant: CCO
Agent: Cl
Product: O=CCc1ccc([N+](=O)[O-])cc1Cl

Procedure:
50 mL of 1N hydrochloric acid is added dropwise to a solution of 10 g (30.88 mmol) of [(E)-2-(2-chloro-4-nitrophenyl)vinyl]dimethylamine in 200 mL of ethanol and the reaction mixture is then refluxed for 1 hour. Then the reaction mixture is evaporated down, diluted with water, and twice extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (eluant: petroleum ether/ethyl acetate (3:1)). Yield: 4.5 g (73% of theory); C8H6ClNO3 (M=199.59); Rf value: 0.62 (silica gel, petroleum ether/ethyl acetate (1:1)).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[O:19][N:18]=[C:17]([CH2:20][N:21]5C(=O)C6=CC=CC=C6C5=O)[N:16]=4)=[C:10]3[C@@H:9]3[CH2:32][CH2:33][N:8]3[C:7](=[O:34])[C:6]=2[CH:35]=1.CN>C(O)C>[NH2:21][CH2:20][C:17]1[N:16]=[C:15]([C:14]2[N:13]=[CH:12][N:11]3[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:35][C:6]=4[C:7](=[O:34])[N:8]4[CH2:33][CH2:32][C@H:9]4[C:10]=23)[O:19][N:18]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1noc(-c2ncn3c2[C@@H]2CCN2C(=O)c2cc(F)ccc2-3)n1
Agent: CN
Solvent: CCO
Product: NCc1noc(-c2ncn3c2[C@@H]2CCN2C(=O)c2cc(F)ccc2-3)n1
Reaction time: 2 h
Yield: 95.8 %

Procedure:
10.8 g (23 mmol) of crude (S)-7-fluoro-12,12a-dihydro-1-(3-phthalimidomethyl-1,2,4-oxadiazol-5-yl)-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one in 150 ml of ethanol were treated dropwise with 150 ml of methylamine (33% in ethanol) at 60° C. within 30 min. The solution was stirred at 70° for 2 hours and subsequently concentrated. The residue was taken up in methylene chloride and 30 ml of 4N hydrochloric acid and the solution was washed three times with methylene chloride. The aqueous phase was made alkaline with 30 ml of 4N sodium hydroxide solution and extracted five times with methylene chloride. After drying the combined organic solutions and evaporating the solvent there were obtained 7.5 g (96%) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was used without further crystallization as the starting material for the Example described hereinafter.