Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:3]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16].[C:29]([OH:35])(=[O:34])[CH2:30][CH2:31][CH:32]=[CH2:33].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(#N)C>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][N:8]1[C:9](=[O:11])[C:10]2=[C:2]([CH2:33]/[CH:32]=[CH:31]/[CH2:30][C:29]([OH:35])=[O:34])[N:3]([CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)[CH:4]=[C:5]2[N:6]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:7]1=[O:13]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(I)n(Cc3cccc4ccccc34)cc21
Reactant: C=CCCC(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C/C=C/CC(=O)O)n(Cc3cccc4ccccc34)cc21
Temperature: 25 °C

Procedure:
5-Iodo-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1 H-pyrrolo-[3,4-d]pyrimidine-2,4(3 H,6 H)-dione (100 mg), 4-pentenoic acid (0.042 ml), palladium acetate (5 mg) and tri(o-tolyl)phosphine (13 mg) were dissolved in triethylamine (1 ml) and acetonitrile (5 ml) and heated to 95° C. in a sealed pressure tube for 3 hours. The reaction mixture was allowed to cool to room temperature and was then evaporated to leave a residue which was chromatographed using ethyl acetate containing 1% acetic acid to give an oil (160 mg). Recrystallisation from diethyl ether/isohexane gave the title compound as a pale brown solid (48 mg).
Reaction SMILES: [CH3:1][C:2]1[S:11][C:10]2[NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5](=S)[C:4]=2[CH:3]=1.[O:17]([CH2:24][CH2:25][C@H:26]1[CH2:31][NH:30][CH2:29][CH2:28][NH:27]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1>[O:17]([CH2:24][CH2:25][C@@H:26]1[NH:27][CH2:28][CH2:29][N:30]([C:5]2[C:4]3[CH:3]=[C:2]([CH3:1])[S:11][C:10]=3[NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]=2)[CH2:31]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(OCC[C@H]2CNCCN2)cc1
Reactant: Cc1cc2c(s1)Nc1ccccc1NC2=S
Solvent: c1ccncc1
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCOc2ccccc2)C1

Procedure:
Combine 2-methyl-4,9-dihydro-3-thia-4,9-diazabenzo[f]azulene-10-thione (0.382 g 1.55 mmol), (S)-2-(2-phenoxyethyl)piperazine (0.320 g, 1.55 mmol) and pyridine (5 mL) and reflux for 36 hours. Evaporate the mixture and apply the material to 10 g of SCX, then elute with methanol followed by 5% 2N ammonia-methanol in dichloromethane and then 2N ammonia-methanol. Purification by flash chromatography, eluting with a step gradient starting with dichloromethane going to 7% 2N ammonia-methanol in dichloromethane gives the title compound: mass spectrum (APCI): m/z=419.1 (M+1).
Reaction SMILES: C(C1CC2C(=CC(F)=C(OC)C=2Cl)C1=O)CCC.C(C(C)=O)=C.C[O-].[Na+].CO.[CH2:29]([C:33]1([CH2:47][CH2:48][C:49](=[O:51])[CH3:50])[CH2:41][C:40]2[C:35](=[CH:36][C:37]([F:45])=[C:38]([O:43][CH3:44])[C:39]=2[Cl:42])[C:34]1=O)[CH2:30][CH2:31][CH3:32].N1CCCC1.C(O)(=O)C>O1CCCC1.C1(C)C=CC=CC=1>[CH2:29]([C:33]12[CH2:47][CH2:48][C:49](=[O:51])[CH:50]=[C:34]1[C:35]1[C:40](=[C:39]([Cl:42])[C:38]([O:43][CH3:44])=[C:37]([F:45])[CH:36]=1)[CH2:41]2)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCC1(CCC(C)=O)Cc2c(cc(F)c(OC)c2Cl)C1=O
Agent: C=CC(C)=O
Agent: CCCCC1Cc2c(cc(F)c(OC)c2Cl)C1=O
Agent: C[O-]
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCCCC12CCC(=O)C=C1c1cc(F)c(OC)c(Cl)c1C2
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
A solution of crude 2-butyl-4-chloro-6-fluoro-5-methoxy-1-indanone (386 mg, 1.4 mmol) in tetrahydrofuran (2.8 mL) was treated with methyl vinyl ketone (0.150 mL, 1.78 mmol) and 0.5N sodium methoxide in methanol (1.1 mL, 0.56 mmol). The mixture was stirred at room temperature for 5.5 hours to effect conversion to 2-butyl-4-chloro-6-fluoro-5-methoxy-2-(3-oxobutyl)-1-indanone. The reaction mixture was diluted with toluene (10 mL), treated with pyrrolidine (0.117 mL, 1.4 mmol) and acetic acid (0.112 mmol, 1.46 mmol), and then stirred and heated in an oil bath at 80° C. for 3 hours. After storing overnight at room temperature, the mixture was partitioned between EtOAc (50 mL) and water (50 mL). The organic phase was washed with 0.1N HCl (50 mL), saturated aqueous NaHCO3 (50 mL) and brine (20 mL), dried over MgSO4, filtered, and evaporated under vacuum. The oily residue was purified by preparative layer chromatography on four 0.1×20×20 cm silica gel GF plates, developing with 5% EtOAc in CH2Cl2. The product bands were combined, eluted with EtOAc, and the eluent evaporated under vacuum to provide 9a-butyl-8-chloro-6-fluoro-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (160 mg) as a solid. 1H NMR spectroscopy revealed that the product contained a minor amount of the isomeric product 9a-butyl-6-chloro-8-fluoro-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one which is derived from a minor amount of 2-butyl-6-chloro-4-fluoro-5-methoxy-1-indanone in the starting material.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:23]C(=O)N(C)C)=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:30][CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:23][CH2:30][CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])=[C:16]([C:19]([F:20])([F:22])[F:21])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CN(C)C(=O)Sc1c(C(F)(F)F)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Product: CC(C)(C)OC(=O)N1CCc2ccc(C(F)(F)F)c(SCCO[Si](C)(C)C(C)(C)C)c2CC1

Procedure:
Use a method similar to the Preparation 177, using 3-tert-butoxycarbonyl-6-dimethylcarbamoylthio-7-trifluoromethyl-2,3,4,5-tetrahydro-benzo[d]azepine and (2-bromoethoxy)-tert-butyldimethylsilane to give the desired intermediate.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].C(N1CCN(C2C=C(N[C:31]([C:33]3[C:34]4[N:35]=[CH:36][CH:37]=[N:38][C:39]=4[C:40]([C:43]4[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[CH:45][C:44]=4[Cl:51])=[CH:41][CH:42]=3)=[O:32])C=CC=2)CC1)C>>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:15]=[CH:14][C:12]([NH:13][C:31]([C:33]3[C:34]4[N:35]=[CH:36][CH:37]=[N:38][C:39]=4[C:40]([C:43]4[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[CH:45][C:44]=4[Cl:51])=[CH:41][CH:42]=3)=[O:32])=[CH:11][CH:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2ccc(N)cc2)CC1
Reactant: CCN1CCN(c2cccc(NC(=O)c3ccc(-c4cc(OC)ccc4Cl)c4nccnc34)c2)CC1
Product: CCN1CCN(c2ccc(NC(=O)c3ccc(-c4cc(OC)ccc4Cl)c4nccnc34)cc2)CC1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 4-(4-ethylpiperazin-1-yl)-aniline (Step 1.9) and 8-(2-chloro-5-methoxy-phenyl)-quinoxaline-5-carboxylic acid (Example 63). Title compound: ESI-MS: 502.1 [M]+; tR=3.50 min (System 3).
Reaction SMILES: [CH2:1]([C@H:3]1[C@:7]([OH:9])([CH3:8])[CH2:6][CH2:5][N:4]1C(OCC1C=CC=CC=1)=O)[CH3:2]>[Pd].O>[CH2:1]([C@H:3]1[C@@:7]([CH3:8])([OH:9])[CH2:6][CH2:5][NH:4]1)[CH3:2]
Reactant: CC[C@@H]1N(C(=O)OCc2ccccc2)CC[C@]1(C)O
Agent: [Pd]
Solvent: O
Product: CC[C@@H]1NCC[C@]1(C)O

Procedure:
By an operation in the same manner as in Reference Example 4 and using benzyl (2S,3S)-2-ethyl-3-hydroxy-3-methylpyrrolidine-1-carboxylate (2.84 g) and 50% water containing-10% Pd/C (0.31 g), the title compound was obtained as a colorless solid (yield: 1.77 g, yield: 88%).
Reaction SMILES: C(N=C=NC(C)C)(C)C.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[N:18]2[CH2:21][CH:20]([NH2:22])[CH2:19]2)=[CH:13][CH:12]=1.[C:30]1([S:36]([CH2:39][C:40](O)=[O:41])(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.OC1C2N=NNC=2C=CC=1>ClCCl.CN(C)C=O.CO>[C:30]1([S:36]([CH2:39][C:40]([NH:22][CH:20]2[CH2:19][N:18]([CH:17]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C:14]3[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=3)[CH2:21]2)=[O:41])(=[O:37])=[O:38])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reactant: O=C(O)CS(=O)(=O)c1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(CS(=O)(=O)c1ccccc1)NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reaction time: 17 h

Procedure:
0.031 cm3 of diisopropylcarbodiimide, a solution of 30 mg of 1-[bis(4-chlorophenyl)methyl]azetidin-3-ylamine in 0.5 cm3 of anhydrous dichloromethane, and 3 cm3 of anhydrous dichloromethane are added to a solution of 80.1 mg of benzenesulfonylacetic acid, 27 mg of hydroxybenzotriazole in solution in 0.5 cm3 of dimethylformamide under an inert argon atmosphere, at a temperature in the region of 23° C. After 17 hours at a temperature in the region of 23° C., the reaction mixture is loaded onto a 3-cm3 SPE cartridge containing 1 g of SCX phase preconditioned with methanol. After washing with twice 5 cm3 of methanol and then 4 cm3 of 0.1 N ammoniacal methanol, the expected product is eluted with 4 cm3 of 1 N ammoniacal methanol. The fraction containing the expected product is evaporated under an air stream at a temperature in the region of 45° C. and then dried under reduced pressure (1 mbar) at a temperature in the region of 40° C. 2-Benzenesulfonyl-N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}acetamide is thus obtained in the form of a white solid [1H NMR spectrum (500 MHz, CDCl3, δ in ppm): 2.96 (mt: 2H); 3.51 (mt: 2H); 4.00 (s: 2H); 4.34 (unresolved complex: 1H); 4.48 (mt: 1H); 7.10 (unresolved complex.: 1H); from 7.20 to 7.45 (mt: 8H); 7.57 (t, J=8 Hz: 2H); 7.70 (t, J=8 Hz: 1H); 7.90 (d, J=8 Hz: 2H)].
Reaction SMILES: C[O:2][C:3](=[O:51])[CH2:4][N:5]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:14]=[C:13]([O:36][CH2:37][CH2:38][CH2:39][O:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:43][CH:42]=2)[CH:12]=1)[CH2:6][C:7]([O:9]C)=[O:8].[OH-].[Na+].O1CCOCC1>CO>[C:3]([CH2:4][N:5]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:14]=[C:13]([O:36][CH2:37][CH2:38][CH2:39][O:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([CH3:48])([CH3:50])[CH3:49])=[CH:43][CH:42]=2)[CH:12]=1)[CH2:6][C:7]([OH:9])=[O:8])([OH:51])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccc(C(C)(C)C)cc2)cc(N(CC(=O)OC)CC(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccc(C(C)(C)C)cc2)cc(N(CC(=O)O)CC(=O)O)c1
Yield: 92.3 %

Procedure:
A solution of 0.815 g (1.14 mmol) of N-[3-[3-[4-(1,1-dimethylethyl)phenoxy]propoxy]-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester and 0.76 mL of 6N NaOH in 20 mL of methanol-10 mL of dioxane was stirred at reflux under argon for 5 hours. The solvents were removed at reduced pressure, the residue was acidified with dilute HCl and the product was extracted with ethyl acetate. The dried extract was concentrated at reduced pressure and the residue was crystallized from methanol-water to give 0.72 g (92% yield, mp99°-101°) of N-(carboxymethyl)-N-[3-[3-[4-(1,1-dimethylethyl)phenoxy]propoxy]-5-(octadecyloxy) phenyl]glycine.
Reaction SMILES: Cl[C:2]1[C:3]([CH2:15][O:16][CH3:17])=[N:4][CH:5]=[C:6]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[N:9]2)[N:7]=1.[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:2]2[C:3]([CH2:15][O:16][CH3:17])=[N:4][CH:5]=[C:6]([N:8]3[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[N:9]3)[N:7]=2)=[CH:21][CH:20]=1
Reactant: COCc1ncc(-n2nc(C)cc2C)nc1Cl
Reactant: Nc1ccc(Cl)cc1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COCc1ncc(-n2nc(C)cc2C)nc1Nc1ccc(Cl)cc1
Temperature: 120 °C
Yield: 80 %

Procedure:
A mixture of 3-chloro-5-(3,5-dimethyl-pyrazol-1-yl)-2-methoxymethyl-pyrazine (34 mg, 0.12 mmol), 4-chloroaniline (22 mg, 0.17 mmol) and cesium carbonate (80 mg, 0.24 mmol) in dry dioxane (2 mL) was degassed with argon for 15 minutes. Tris(dibenzylideneacetone)dipalladium (0) (3 mg, 0.003 mmol) and 1,1′-bis(diphenyl-phosphino) ferrocene (6 mg, 0.01 mmol) were added followed by degassing for 5 minutes and the reaction mixture was stirred at 120° C. over night. Dichloromethane was added and the solution was filtrated. The filtrate was concentrated in vacuo. Flash chromatography (ethyl acetate/heptane as eluent) gave (4-chloro-phenyl)-[6-(3,5-dimethyl-pyrazol-1-yl)-3-methoxymethyl-pyrazin-2-yl]-amine (33 mg, 80%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[CH3:12])[CH:7]=O)([O-:3])=[O:2].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:25][C:26]#[N:27])[CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22].[OH-].[Na+]>[Cl-].C([N+](CCCCCCCC)(CCCCCCCC)C)CCCCCCC.O.ClCCl>[N+:1]([C:4]1[CH:5]=[C:6](/[CH:7]=[C:25](/[C:17]2[CH:18]=[C:19]([O:23][CH3:24])[C:20]([O:21][CH3:22])=[C:15]([O:14][CH3:13])[CH:16]=2)\[C:26]#[N:27])[CH:9]=[CH:10][C:11]=1[CH3:12])([O-:3])=[O:2]
Reactant: COc1cc(CC#N)cc(OC)c1OC
Reactant: Cc1ccc(C=O)cc1[N+](=O)[O-]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1cc(/C(C#N)=C/c2ccc(C)c([N+](=O)[O-])c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 14 %

Procedure:
5.0 g of 3-nitro-4-methylbenzaldehyde, 6.27 g of 3,4,5-trimethoxyphenylacetonitrile, 1.44 g of sodium hydroxide and 500 mg of trioctylmethylammonium chloride were dissolved in 25 ml of water and 500 ml of dichloromethane. The mixture was stirred vigorously for 3 hours at room temperature. The ice water was added to the mixture and the mixture was extracted with dichloromethane three times and dried over anhydrous sodium sulfate. The organic layer was concentrated and the residue was purified by silica gel column chromatography (dichloromethane) to give 1.5 g of the intended compound. The yield was 14.1%.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=2[C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].Cl[S:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[C:28]([OH:35])[CH:27]=1)(=[O:25])=[O:24]>>[CH2:1]([C:5]1[O:6][C:7]2[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=2[C:9]=1[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][S:23]([C:26]2[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[C:28]([OH:35])[CH:27]=2)(=[O:25])=[O:24])=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1Cc1ccc(O)cc1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Product: CCCCc1oc2ccccc2c1Cc1ccc(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)cc1
Yield: 85.1 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using 4-(2-butyl-benzofuran-3-ylmethyl)-phenol (0.500 g, 1.78 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.844 g, 3.56 mmol). Purification on 2% H3PO4/MeOH treated silica gel, eluting with EtOAc/hexane gave 0.728 g (86%) of the title compound as an orange solid, mp 135-138° C. 1H NMR (DMSO-d6) δ0.84 (t, 3H), 1.27 (sextet, 2H), 1.58 (quintet, 2H), 2.76 (t, 2H), 3.97 (s, 2H), 6.96 (d, 2H), 7.10 (dt, 1H), 7.17 (dt, 1H), 7.22-7.31 (m, 5H), 7.43 (d, 1H), 7.95 (d, 1H). IR (KBr) 3300, 2950, 1675, 1390 and 1175 cm−1. mass spectrum (−ESI) m/z 479 (M−H). Anal. Calcd. for C26H24O7S.0.2H2O: C, 64.50; H, 5.08; N, 0.00. Found: C, 64.50; H, 5.07; N, 0.06.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH:14](O)[C:13]3[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:12]=3[C:11]2=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>Cl.CCO>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:14][C:13]3[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:12]=3[C:11]2=[O:22])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc2c(c1)C(O)N(CCCc1ccccc1)C2=O
Agent: Cl
Solvent: CCO
Product: COc1ccc2c(c1)CN(CCCc1ccccc1)C2=O
Reaction time: 3 h

Procedure:
2-(3-Phenylpropyl)-5-methoxy-3-hydroxy-1-oxo- 1,3-dihydrobenzo[c]pyrrole (2.49 g, 8.38 mmol) is dissolved in HCl/EtOH (50 ml concentrated HCl, 150 ml EtOH), and N2 is bubbled through the solution for 10 minutes followed by the addition of the catalyst, 10% Pd/C (200 mg). The mixture is hydrogenated on a Parr-Shaker apparatus at 3 atmospheres pressure for 3 hours. After filtering the reaction through a pad of Celite, the filtrate is concentrated in vacuo, and the residue is dissolved in EtOAc (200 ml). The EtOAc is washed with 2N HCl (200 ml), H2O (200 ml), saturated NaHCO3 solution (200 ml) and saturated NaCl solution (200 ml) dried over MgSO4 and evaporated. The product is purified by chromatography (SiO2 ; 1:9 EtOAc/hexanes, 1:4 EtOAc/hexanes) to yield 2-(3-phenylpropyl)-5-methoxy-1-oxo-1,3-dihydrobenzo[c]pyrrole. Treatment with BBr3 yields 2-(3-phenylpropyl)- 5-hydroxy-1-oxo-1,3-dihydrobenzo[c]pyrrole.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH:5]=[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:7])C.[OH-].[K+]>C(O)C>[C:11]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:12]=[CH:13][C:8]([C:6]([CH3:7])=[CH:5][C:4]([OH:20])=[O:3])=[CH:9][CH:10]=1
Reactant: CCOC(=O)C=C(C)c1ccc(-c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(=CC(=O)O)c1ccc(-c2ccccc2)cc1

Procedure:
The product resulting from (a), above, is mixed with 6 g of 85% potassium hydroxide in 100 ml of aqueous ethanol and the resulting mixture heated on a steam bath for 30 minutes. The mixture is then cooled, poured into ice and extracted thrice with 25 ml portions of diethylether. The aqueous phase is filtered over Celite and the filtrate acidified with 2 N hydrochloric acid to pH 4 and cooled. The resulting precipitate is filtered, washed with ether, air dried with suction and then dried under high vacuum at 50° C. to yield the heading compound, substantially in trans form.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([F:8])=[C:6]([CH:9]=[O:10])[C:5]([C:11]([F:14])([F:13])[F:12])=[N:4]1)[CH3:2].[BH4-].[Na+].O.C(OCC)C>CO>[CH2:1]([N:3]1[C:7]([F:8])=[C:6]([CH2:9][OH:10])[C:5]([C:11]([F:13])([F:12])[F:14])=[N:4]1)[CH3:2]
Reactant: CCn1nc(C(F)(F)F)c(C=O)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: CCn1nc(C(F)(F)F)c(CO)c1F
Temperature: 0 °C
Reaction time: 3 h
Yield: 81.2 %

Procedure:
A solution of 11.1 g (52.8 mmoles) of 1-ethyl-5-fluoro-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde dissolved in 50 ml of methanol was cooled to 0° C. Thereto was gradually added 2.1 g (55.5 mmoles) of sodium borohydride. The mixture was stirred at room temperature for 3 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water and extraction with diethyl ether was conducted. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein, to obtain 9.1 g (yield: 81.3%) of (1-ethyl-5-fluoro-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:12](=O)[C:11]=3[C:21](O)=[O:22])=[CH:4][C:3]=2[O:2]1.P(Cl)(Cl)([Cl:26])=O>O1CCCC1>[Cl:26][C:12]1[C:11]2[C:21](=[O:22])[C:6]3[C:5]([C:10]=2[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)=[CH:4][C:3]1[O:2][CH2:1][O:9][C:8]=1[CH:7]=3
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(O)c1c(-c2ccc3c(c2)OCO3)c2ccccc2[nH]c1=O
Solvent: C1CCOC1
Product: O=C1c2cc3c(cc2-c2c1c(Cl)nc1ccccc21)OCO3
Temperature: 90 °C
Yield: 59.9 %

Procedure:
A mixture of 1,2-dihydro-4-(3,4-methylenedioxyphenyl)-2-oxo-3-quinoline carboxylic acid obtained in reference example 1 (10 g, 32.3 mmol) and phosphorous oxychloride (100 ml, 1.07 mol) was refluxed with heat for 4 hours. The reaction mixture was distilled to dryness and washed with n-hexane several times. To the residue obtained was added 50 g of polyphosphoric acid, and the mixture was heated at 90° C. for 2 hours. The reaction mixture was poured into ice water to filtrate a crystal precipitated. The crystal obtained was dissolved in tetrahydrofuran to filter off undissolved substances and purified by silica gel column chromatography (eluent: chloroform) to give 6.0 g (yield 59.9%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:4]=1[NH2:5].CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.Cl[C:31](OC(Cl)(Cl)Cl)=[O:32]>ClCCl>[N:5]([C:4]1[CH:6]=[C:7]([C:10]([F:11])([F:12])[F:13])[CH:8]=[CH:9][C:3]=1[O:2][CH3:1])=[C:31]=[O:32]
Reactant: COc1ccc(C(F)(F)F)cc1N
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClCCl
Product: COc1ccc(C(F)(F)F)cc1N=C=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3 g (15.69 mmol) of 2-methoxy-5-trifluoromethylaniline are dissolved in 100 ml of dichloromethane, and 6.73 g (31.39 mmol) of 1,8-bis(dimethylamino)naphthalene are added. At 0-5° C., 2.24 g (11.3 mmol) of trichloromethyl chloroformate, dissolved in 50 ml of dichloromethane, are added dropwise, and the mixture is stirred at 0° C. for 30 min and then at room temperature for 60 min. At 0° C., the mixture is washed with 1N hydrochloric acid, ice-water and sodium bicarbonate solution. Drying over magnesium sulphate and removal of the solvent by distillation gives the product. The isocyanate is then used for the subsequent reactions without further purification.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1([CH3:22])[O:8][CH:7]([CH2:9][NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:6][O:5]1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[C:26]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:25]=1>CO>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:32])/[CH:31]=[CH:20]/[C:17]2[CH:18]=[CH:19][C:14]([S:11]([NH:10][CH2:9][CH:7]3[CH2:6][O:5][C:4]([CH3:22])([CH3:3])[O:8]3)(=[O:13])=[O:12])=[CH:15][CH:16]=2)=[C:26]([NH:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:25]=1
Reactant: CC1(C)OCC(CNS(=O)(=O)c2ccc(C=O)cc2)O1
Reactant: CC(=O)c1ccc(Cl)cc1Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)OCC(CNS(=O)(=O)c2ccc(/C=C/C(=O)c3ccc(Cl)cc3Nc3ccccc3)cc2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.3 %

Procedure:
NaOH (2 M aq, 0.91 mL, 1.8 mmol) was added to a solution of N-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-4-formyl-benzenesulfonamide (305 mg, 1 mmol) and 1-(4-chloro-2-phenylamino-phenyl)-ethanone (250 mg, 1 mmol) in MeOH (10 mL), and the resulting mixture stirred at RT overnight. A second aliquot of NaOH (2 M aq, 0.1 mL) was added, and the reaction mixture was again stirred at RT overnight. The resulting mixture was evaporated under reduced pressure, and the crude residue partitioned between water and EtOAc. The organic layer was separated, and the aqueous layer was extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to give an oil. The crude residue was purified twice by flash chromatography (EtOAc/hexane) to give 4-[(E)-3-(4-chloro-2-phenylamino-phenyl)-3-oxo-propenyl]-N-(2,2-dimethyl[1,3]dioxolan-4-ylmethyl)-benzenesulfonamide (70 mg).