Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]([N:10]1[CH2:14][C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:12][C:11]1=[O:23])[CH2:5][C:6]([F:9])([F:8])[F:7].O1CCCC1.O.[OH-].[Li+]>O>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][C:13]1[CH2:14][N:10]([CH:4]([CH2:5][C:6]([F:9])([F:8])[F:7])[C:3]([OH:24])=[O:2])[C:11](=[O:23])[CH:12]=1
Reactant: COC(=O)C(CC(F)(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(CC(F)(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.5 %

Procedure:
A mixture of 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4,4,4-trifluoro-butyric acid methyl ester (212 mg, 0.58 mmol) in a 1:1 solution of tetrahydrofuran:water (8 mL) was treated with lithium hydroxide monohydrate (55 mg, 1.16 mmol) and stirred for 1.5 h at 25° C. After such time, the mixture was concentrated in vacuo to remove the tetrahydrofuran and then diluted with water (10 mL) and the pH adjusted to pH=4 with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layers were then dried over sodium sulfate and concentrated in vacuo to afford 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4,4,4-trifluoro-butyric acid (149 mg, 73%) as a white solid: HR-ES-MS m/z calculated for C14H11NO4ClF3 [M+Na]+ 372.0221, observed 372.0224.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N+:21]([O-])=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(OCC)C>[C:1]1([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[NH2:21])[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccccc1CCN1CCN(c2ccccc2)CC1
Solvent: CCOCC
Product: Nc1ccccc1CCN1CCN(c2ccccc2)CC1

Procedure:
The 2-(4-phenylpiperazinylethyl)aniline was isolated by crystallization of the evaporation residue dissolved in a mixture of ethyl ether and petroleum ether. Melting point was 103° C.
Reaction SMILES: O([C:8]([NH:10][C:11]1[S:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[N:19]=1)=[O:9])C1C=CC=CC=1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>CN(C=O)C>[N:20]1([C:8]([NH:10][C:11]2[S:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[N:19]=2)=[O:9])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(Nc1nc2cnccc2s1)Oc1ccccc1
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: O=C(Nc1nc2cnccc2s1)N1CCCC1
Temperature: 70 °C
Yield: 98 %

Procedure:
A mixture of 2-phenoxycarbonylaminothiazolo[4,5-c]-pyridine (200 mg, 0.73 mmole) and pyrrolidine (0.3 ml) in DMF (2 ml) was heated at 70° C. for 30 minutes and evaporated in vacuo. The residue was triturated with ether to give 180 mg (98%) of the desired product. Mp. 218°~220° C.
Reaction SMILES: [Cl:1][C:2]1[CH:40]=[CH:39][CH:38]=[CH:37][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[CH:17]=[N:16][N:15]=[C:14]1[CH2:18][NH:19][C:20]([C:22]1[N:23]([CH2:31][C:32]([O:34]CC)=[O:33])[C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[O:5].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:40]=[CH:39][CH:38]=[CH:37][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[CH:17]=[N:16][N:15]=[C:14]1[CH2:18][NH:19][C:20]([C:22]1[N:23]([CH2:31][C:32]([OH:34])=[O:33])[C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[O:5]
Reactant: CCOC(=O)Cn1c(C(=O)NCc2nncn2-c2sc(CC)cc2C(=O)c2ccccc2Cl)cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2cnnc2CNC(=O)c2cc3ccccc3n2CC(=O)O)s1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 23.7 %

Procedure:
Ethyl 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) [1,2,4]triazol-3-ylmethylcarbamoyl)indole-1-acetate (2.0 g) and a solution of sodium hydroxide (0.39 g) in ethanol were added to ethanol (20 ml), and the mixture was stirred at 50° C. for 20 minutes. The solvent was evaporated, and the residue was dissolved in water. Toluene was added to the solution for washing. The aqueous layer was taken out, and 2M hydrochloric acid was added to adjust the solution to pH 2. The solution was extracted with chloroform. The extract was dried over magnesium sulfate, and the solvent was evaporated. The residue was recrystallized from ethyl acetate to give 0.45 g of 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) [1,2,4]triazol-3-ylmethylcarbamoyl)indole-1-acetic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][C:7]=1[CH3:25])=[O:5])[CH3:2].[Br:26]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[N:8][C:7]=1[CH2:25][Br:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(N(C(=O)OC(C)(C)C)c2ccccc2)nc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1sc(N(C(=O)OC(C)(C)C)c2ccccc2)nc1CBr
Temperature: 25 °C
Yield: 82 %

Procedure:
A mixture of 2-(tert-butoxycarbonyl-phenyl-amino)-4-methyl-thiazole-5-carboxylic acid ethyl ester (1.61 g, 4.45 mmol), N-bromosuccinimide (833 mg, 4.68 mol) and benzoyl peroxide (54 mg, 0.22 mmol) in carbon tetrachloride (30 mL) was refluxed for 16 h before it was cooled to room temperature and partitioned between dichloromethane and water. The organic layer was washed with saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (1.61 g); MS: (+) m/z 341.0, 343.0 (M+1-Boc, 79Br/81Br).
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].Br[C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[C:32]#[N:33].[OH:37][CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[OH:37][CH:38]1[CH2:43][CH2:42][N:41]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[C:32]#[N:33])[CH2:40][CH2:39]1
Reactant: OC1CCNCC1
Reactant: N#Cc1cccc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: N#Cc1cccc(N2CCC(O)CC2)c1
Temperature: 80 °C

Procedure:
To a toluene (140 mL) suspension of tris(dibenzylideneacetone)dipalladium (2.06 g, 2.25 mmol), 2-(di-tert-butylphosphino)biphenyl (0.839 g, 2.81 mmol), sodium tert-butoxide (4.05 g, 42.2 mmol) was added 3-bromobenzonitrile (5.11 g, 28.1 mmol), followed by 4-hydroxypiperidine (2.84 g, 28.1 mmol). The reaction mixture was heated to 80° C. for 5 hours while stirring under nitrogen. It was allowed to cool to room temperature, filtered, and concentrated in vacuo. Chromatography over silica gel, eluting with hexanes/ethyl acetate, afforded the title compound. 1H NMR (500 MHz, CDCl3) δ 7.33-7.24 (m, 1H), 7.15-7.10 (m, 2H), 7.06 (d, J=7.5 Hz, 1H), 3.95-3.87 (m, 1H), 3.57 (dt, J=12.7, 4.8 Hz, 2H), 3.00 (ddd, J=12.8, 9.5, 3.2 Hz, 2H), 2.05-1.95 (m, 2H), 1.73-1.59 (m, 2H); LC-MS: m/z 203.2 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH:10]([O:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])=[CH:17][CH:16]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([OH:11])[CH:12]([N:26]2[CH2:25][CH2:24][N:23]([C:21](=[O:22])[C:18]3[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=3)[CH2:28][CH2:27]2)[CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(c1ccc(Cl)cc1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Product: CC(C)(C)OC(=O)N1CC(O)C(N2CCN(C(=O)c3ccc(Cl)cc3)CC2)C1
Temperature: 130 °C
Yield: 84.2 %

Procedure:
This is an example of Procedure A in Scheme 1 above. 6-Oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (1.85 g 1 eq) and (4-Chloro-phenyl)-piperazin-1-yl-methanone (2.2 g 1 eq) were added into a sealed tube. The mixture was heated to 130° C. for 5 h. The resulting oil was purified by column chromatography (EtOAc:MeOH:Et3N 10:1:0.01) to give 3.38 g of desired product as a sticky oil (84% yield). 1H-NMR (300 MHz, DMSO): δ 1.43 (s, 9H), 2.40-2.80 (m, 4H), 3.15-3.85 (m, 9H), 4.26-4.30 (m, 1H), 7.35 (d, 2H), 7.38 (d, 2H) Retention Time (LC, method: Formic acid polar): 1.19 min. MS (M+H+): 410
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)/[CH:5]=[CH:6]/[C:7]1[S:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.Cl[C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].C(=O)([O-])[O-].[K+].[K+]>[Cu].II.C(O)CC(C)C>[C:22]([C:21]1[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=1[NH:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)/[CH:5]=[CH:6]/[C:7]1[S:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)([OH:24])=[O:23]
Reactant: Nc1cccc(/C=C/c2nc3ccccc3s2)c1
Reactant: O=C(O)c1ccccc1Cl
Agent: [Cu]
Agent: II
Agent: O=C([O-])[O-]
Solvent: CC(C)CCO
Product: O=C(O)c1ccccc1Nc1cccc(/C=C/c2nc3ccccc3s2)c1
Yield: 11.2 %

Procedure:
To 10 ml of isoamyl alcohol were added 504 mg of 2-(trans-3-aminostyryl)benzothiazole, 311 mg of 2-chlorobenzoic acid, 290 mg of potassium carbonate, 1 mg of iodine and 15 mg of copper powder, and the mixture was refluxed for 6 hours. The solvent was evaporated under reduced pressure and the residue was extracted with ethyl acetate. The crude product after evaporation of the solvent was purified through silica gel column chromatography by use of ethyl acetate-toluene to obtain 83 mg (yield 11%) of the title compound.
Reaction SMILES: [C:1]([O:4][CH:5]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([CH:21]2[O:25][N:24]=[C:23]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH2:22]2)=[O:20])=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2]>CO>[C:1]([O:4][C@H:5]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([CH:21]2[O:25][N:24]=[C:23]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH2:22]2)=[O:20])=[CH:16][CH:17]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(c1ccccc1)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Solvent: CO
Product: CC(=O)O[C@@H](c1ccccc1)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Yield: 3.8 %

Procedure:
) (±)-[4-[[[4,5-dihydro-3-(3-pyridinyl)-5-isoxazolyl]carbonyl]amino]phenyl]phenylmethyl acetate (0.019 mol) was separated into its enantiomers by chiral column chromatography over Chiralcel OJ (eluent: 100% methanol). The desired fraction group was collected and the solvent was evaporated, yielding 0.3 g of (S)-[4-[[[4,5-dihydro-3-(3-pyridinyl)-5-isoxazolyl]carbonyl]amino]phenyl]phenylmethyl acetate (compound 498).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[CH2:16][CH2:15][CH:14]([NH:18][S:19]([CH:22]4CC4)(=[O:21])=[O:20])[C:13]=3[CH:12]=[N:11][CH:10]=2)=[CH:5][CH:4]=1.CS(Cl)(=O)=O>>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[CH2:16][CH2:15][CH:14]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:13]=3[CH:12]=[N:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(NC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21)C1CC1
Agent: CS(=O)(=O)Cl
Product: CS(=O)(=O)NC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Yield: 15 %

Procedure:
In analogy to the procedure described for the preparation of (rac)-cyclopropanesulfonic acid [4-(4-trifluoromethyl-phenyl)-6,7-dihydro-5H-[2]pyrindin-7-yl]-amide (example 94), replacing cyclopropanesulfonyl chloride with methanesulfonyl chloride. The title compound was obtained as a light brown oil in 15% yield. MS: 357.4 (M+H)+.
Reaction SMILES: CC1C=CC(S(Cl)(=O)=[O:9])=CC=1.[F:12][C:13]([F:46])([F:45])[C:14]1[CH:15]=[C:16]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:17][N:18]([CH3:37])[C:19]([N:21]1[CH2:26][CH2:25]/[C:24](=[N:27]/O)/[CH2:23][C@@H:22]1[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[CH3:36])=[O:20]>CC(C)=O.C(=O)([O-])[O-].[Na+].[Na+]>[F:42][C:41]([F:44])([F:43])[C:39]1[CH:38]=[C:16]([CH:15]=[C:14]([C:13]([F:46])([F:12])[F:45])[CH:40]=1)[CH2:17][N:18]([CH3:37])[C:19]([N:21]1[C@@H:22]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[CH3:36])[CH2:23][C:24](=[O:9])[NH:27][CH2:25][CH2:26]1)=[O:20]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(F)ccc1[C@H]1C/C(=N\O)CCN1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1cc(F)ccc1[C@H]1CC(=O)NCCN1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of p-tosyl chloride (91.17 mg) in acetone (1.6 mL) was added drop-wise to a mixture of intermediate 11b (161 mg) in acetone (3.2 mL) and 5% sodium carbonate solution (3.2 mL) under a Nitrogen atmosphere. The mixture was stirred for 15 minutes at room temperature then it was heated to reflux for 45 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[S:18](=[O:20])(=[O:19])[CH2:17][CH2:16][C:15]([C:21]([O:23]C)=[O:22])=[CH:14][C:13]=3[CH:25]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>COCCOC>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[S:18](=[O:19])(=[O:20])[CH2:17][CH2:16][C:15]([C:21]([OH:23])=[O:22])=[CH:14][C:13]=3[CH:25]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)C1=Cc2cc(-c3ccc(Cl)c(Cl)c3)ccc2S(=O)(=O)CC1
Agent: Cl
Solvent: COCCOC
Product: O=C(O)C1=Cc2cc(-c3ccc(Cl)c(Cl)c3)ccc2S(=O)(=O)CC1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
To a solution of methyl 7-(3,4-dichlorophenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (450 mg) in 1,2-dimethoxyethane (10 ml) was added 6N hydrochloric acid (10 ml), and the mixture was refluxed for 64 hours, cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give crystals, which were collected by filtration to give colorless crystals of 7-(3,4-dichlorophenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (395.5 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].ClCCl.C(Cl)(=O)C(Cl)=O.C[N:24](C)C=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH2:24])=[O:5]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-chloro-5-nitrobenzoic acid (15.0 g, 74.0 mmol) and 200 mL of dichloromethane was reacted with oxalyl chloride (16.2 mL, 186.0 mmol) and a catalytic amount of dimethylformamide. The mixture was stirred at 25° C. for 3 hours. The solvent was removed in vacuo, and the residue was redissolved in 200 mL of dichloromethane. The solution was cooled to 0° C., and ammonia was bubbled through the cold solution for 5 minutes, whereupon the product precipitated to form solution. The product was collected by filtration to yield 6.8 g, mp 174-175° C.
Reaction SMILES: [CH3:1][C:2]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[C:5]([CH3:12])[C:3]=1[NH2:4].[C:13]([C:18]1[CH:19]=[N:20][C:21]2[C:26]([C:27]=1Cl)=[CH:25][CH:24]=[CH:23][C:22]=2[O:29][CH3:30])(=[O:17])[CH2:14][CH2:15][CH3:16]>O1CCOCC1>[C:13]([C:18]1[CH:19]=[N:20][C:21]2[C:26]([C:27]=1[NH:4][C:3]1[C:5]([CH3:12])=[CH:6][C:7]3[O:11][CH2:10][O:9][C:8]=3[C:2]=1[CH3:1])=[CH:25][CH:24]=[CH:23][C:22]=2[O:29][CH3:30])(=[O:17])[CH2:14][CH2:15][CH3:16]
Reactant: Cc1cc2c(c(C)c1N)OCO2
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1c(C)cc2c(c1C)OCO2
Yield: 433.2 %

Procedure:
2,6-Dimethyl-3,4-(methylenedioxy)aniline (1.67 g, 20 mmol) and 3-butyryl-4-chloro-8-methoxyquinoline (2.3 g, 10 mmol) were heated together under reflux in 1,4-dioxan (50 ml) for 2 hours. The solvent was evaporated and the residue was dissolved in dichloromethane, washed with 2M HCl, sodium hydrogen carbonate solution (×2) and brine. The organic solution was dried, filtered and evaporated to a solid which was recrystallized from ethanol to give 3-butyryl-4-(3,4-methylenedioxy-2,6-dimethylphenylamino)-8-methoxyquinoline (17 g, 43%), m.p. 150°-2° C.
Reaction SMILES: [CH:1](/[N:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:2]\[CH3:3].CO>ClCCl>[CH:1]([N:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:2][CH3:3]
Reactant: C/C=C/n1c2ccccc2c2ccccc21
Solvent: CO
Solvent: ClCCl
Product: CC=Cn1c2ccccc2c2ccccc21

Procedure:
In a vial, 0.5 g of trans-9-(1-propenyl)carbazole and 0.013 g of IOC10 (2 mole % based on 9-(1-propenyl)carbazole) were dissolved in 1 mL of dichloromethane. The solution was exposed to UV light using a GE H3T-7 200 W medium pressure mercury arc lamp for 3 minutes and then poured into methanol. After filtering and drying the resulting precipitated oligomer in a vacuum oven, a yield of 0.25 g (50%) was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([NH:10][C:11]2[CH:26]=[CH:25][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18](C(N)=O)[CH:17]=3)=[C:13]([F:27])[CH:12]=2)=[O:9])[C:4](=[O:28])[N:3]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.CCOC(C)=O.CC#[N:58].O>>[NH2:58][C:18]1[CH:17]=[C:16]([O:15][C:14]2[CH:25]=[CH:26][C:11]([NH:10][C:8]([C:5]3[C:4](=[O:28])[N:3]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:2]([CH3:1])[C:6]=3[CH3:7])=[O:9])=[CH:12][C:13]=2[F:27])[CH:21]=[CH:20][N:19]=1
Reactant: CC#N
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: Ic1ccccc1
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a solution of 4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2-fluorophenoxy)picolinamide (2.5 g, 6.0 mmol) in EtOAc/MeCN/H2O (60 mL/60 mL/30 mL) was added iodobenzene diacetate (2.9 g, 9.0 mmol) at 0° C. The reaction was stirred at rt for 2 hours, then concentrated in vacuo. The resulted residue was dissolved with EtOAc (150 mL), washed with saturated aq. NaHCO3 (80 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was washed with DCM/ether (1/10, 22 mL) to give the title compound as a yellow solid (2.09 g, 81% yield).
Reaction SMILES: Cl.C([O:9][CH2:10][CH2:11][CH2:12][C:13]1[N:14]([CH2:30][CH2:31][OH:32])[C:15]([S:21][C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=2)=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=1)C1C=CC=CC=1.C(=O)([O-])O.[Na+]>>[Cl:29][C:24]1[CH:23]=[C:22]([S:21][C:15]2[N:14]([CH2:30][CH2:31][OH:32])[C:13]([CH2:12][CH2:11][CH2:10][OH:9])=[N:17][C:16]=2[CH:18]([CH3:20])[CH3:19])[CH:27]=[C:26]([Cl:28])[CH:25]=1
Reactant: CC(C)c1nc(CCCOCc2ccccc2)n(CCO)c1Sc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)c1nc(CCCO)n(CCO)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 110 °C
Yield: 26.6 %

Procedure:
To 14 ml of concentrated hydrochloric acid, 1.4 g (2.9 mmol)of the alcohol (136e)was added and the mixture was heated at 110° C. for 7 hours. After cooling, the mixture was neutralized with sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% methanol-ethyl acetate)to provide 300 mg (yield 26%)of 3-(5-(3,5-dichlorophenylthio)-1-(2-hydroxyethyl)-4-isopropyl-1H-imidazol-2-yl)-propan-1-ol (137d)as oil.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH:2]1[CH2:7][CH:8]=[C:9]([F:15])[CH2:10][CH2:11][CH2:12][CH:13]=[O:14].[BH4-].[Na+].CC(C)=O.C(O)(=O)C>CO>[S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH:2]1[CH2:7][CH:8]=[C:9]([F:15])[CH2:10][CH2:11][CH2:12][CH2:13][OH:14]
Reactant: O=CCCCC(F)=CCC1SCCCS1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)=O
Solvent: CO
Product: OCCCCC(F)=CCC1SCCCS1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The aldehyde prepared in 2G (0.937 g, 3.77 mmoles) was dissolved in methanol (20 ml) and cooled to 0° C. Sodium borohydride (0.071 g, 1.87 mmoles) was added and the mixture was stirred 30 min. Acetone was added to react with an excess of sodium borohydride and then the reaction mixture was acidified with acetic acid. The solvents were evaporated under reduced pressure. The residue was diluted with ether and washed with water. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the title alcohol as an oil in a quantitative yield. NMR (H1, CDCl3, 60MHz) characteristic peaks 4 (t, JHH =7 Hz, 1), 5.1 (dt, JHF =21 Hz, JHH =8 Hz, 1).
Reaction SMILES: [CH:1]1([C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[NH2:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].[C:18](Cl)(Cl)=[S:19]>ClCCl.O>[CH:1]1([C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=[C:18]=[S:19])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ccccc1C1CCCC1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: S=C=Nc1ccccc1C1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a biphasic solution of 2-cyclopentylaniline (0.46 g, 2.9 mmol) in dichloromethane (10 mL) and water (4.8 mL) in a 100 mL roundbottom flask equipped with a magnetic stir bar and nitrogen inlet was added sodium hydrogencarbonate (0.73 g, 8.6 mmol) followed by thiophosgene (0.21 mL, 2.8 mmol). The reaction was stirred at room temperature for 1 hour, filtered through a phase separator cartridge, and concentrated providing the 1-cyclopentyl-2-isothiocyanatobenzene as a red oil which was used without further purification. To a solution of the isothiocyanate in ethanol (5.5 mL) in a 100 mL roundbottom flask was added hydrazine hydrate (0.15 mL, 3.1 mmol), and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with hexanes and the resulting solid was collected by filtration, washed with hexanes, and dried under house vacuum to provide the title compound (0.41 g, 1.7 mmol, 63% yield) as a white solid: 1H NMR (400 MHz, CDCl3) δ 9.02 (bs, 1H), 7.52 (bs, 1H), 7.41-7.18 (m, 4H), 4.06 (bs, 2H), 3.21-3.06 (m, 1H), 2.04 (s, 2H), 1.90-1.74 (m, 2H), 1.74-1.58 (m, 4H); ESIMS m/z 236 ([M+H]+).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:18]([O:20][CH3:21])=[O:19])=[CH:9][NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:1]1([C:7]2[C:8]([C:18]([O:20][CH3:21])=[O:19])=[CH:9][N:10]([S:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:32])=[O:31])[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)c1c[nH]c(-c2ccccc2)c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cn(S(=O)(=O)c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Yield: 79 %

Procedure:
Using methyl 4,5-diphenyl-1H-pyrrole-3-carboxylate (428 mg), sodium hydride (60% in oil, 74 mg) and benzenesulfonyl chloride (0.24 mL), a procedure as in Reference Example 4 was performed to give the title compound as white crystals (yield 506 mg, 79%).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][S:9][C:4]=2[CH:3]=1.Br[CH2:14][CH2:15][CH2:16][Cl:17].CC(C)=O>>[Cl:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][S:9][C:4]=2[CH:3]=1
Reactant: O=C1CSc2cc(O)ccc2N1
Reactant: ClCCCBr
Solvent: CC(C)=O
Product: O=C1CSc2cc(OCCCCl)ccc2N1
Reaction time: 24 h
Yield: 50.4 %

Procedure:
After a mixture consisting of 7-hydroxy-3,4-dihydro-2H-1,4-benzothiazin-3-one (1.812 g, 10 mmol), 1bromo-3-chloropropane (2.362 g, 15 mmol), potassium carbate (4.146 g, 30 mmol) and acetone (40 mmol) was heated under reflux and stirring for 24 hours, insolube matter was filtered off, and the solvent was distilled off under reduced pressure. The residue was subjected to chromatography on a silica gel column (developer: chloroform) to purify the same, and was then recrystallized from acetone. The title compound (1.300 g) was obtained as yellow leaflets (yield: 50.4%).