Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrCCCC[N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].O>CN(C)C=O>[C:10]1(=[O:11])[NH:6][C:7](=[O:16])[C:8]2=[CH:15][CH:14]=[CH:13][CH:12]=[C:9]12
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NC(=O)c2ccccc21
Reaction time: 0.08 h
Yield: 103.8 %

Procedure:
70% Sodium hydride (827 mg) was suspended in dimethylformamide (20 ml), a solution of 4-(3-pyridinyl)-1H-imidazole (3.0 g) obtained by the method described in the publication (International Patent Publication WO00/02875) in dimethylformamide (10 ml) was added to the suspension under ice cooling, and the resulting mixture was stirred at the same temperature for 5 minutes. A solution of N-(4-bromobutyl)phthalimide (5.84 g) in dimethylformamide (10 ml) was added to the reaction mixture, and the resulting mixture was stirred at 60° C. for 4 hours. Distilled water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogencarbonate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, the resulting residue was dissolved in ethyl acetate, and hexane was added to the solution to deposit a solid. The deposited solid was collected by filtration to obtain a phthalimide compound (3.16 g). (2) By using the compound obtained in (1) mentioned above (3.16 g) as a starting material, the title compound (1.94 g) was obtained in the same manner as that of Reference Example 9, (2).
Reaction SMILES: Cl.[C:2]1([C:8]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:16]3[C@@H:12]([CH2:13][NH:14][CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[NH:38][CH:37]=[C:36]2[CH2:42][C:43](O)=[O:44]>>[C:26]1([C:8]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:16]3[C@@H:12]([CH2:13][N:14]([C:43](=[O:44])[CH2:42][C:36]4[C:35]5[C:39](=[CH:40][CH:41]=[C:33]([F:32])[CH:34]=5)[NH:38][CH:37]=4)[CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)Cc1c[nH]c2ccc(F)cc12
Reactant: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Agent: Cl
Product: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CN(C(=O)Cc3c[nH]c4ccc(F)cc34)C[C@H]21
Yield: 34.1 %

Procedure:
By working in accordance with the operating method of Use Example 4, starting from 0.8 g of (3aS, 4S, 7aS)-7,7 -diphenyl-4-(2-methoxyphenyl)-perhydroisoindol-4-ol hydrochloride and 0.39 g of (5-fluoro-3-indolyl)-acetic acid, 0.36 g of (3aS, 4S, 7aS)-7,7-diphenyl-2-[(5-fluoro-3-indolyl)-acetyl]-4-(2-methoxyphenyl)-perhydroisoindol-4-ol is obtained in the form of white crystals which melt with decomposition at 170° C.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11](=[O:23])[C:12]([NH:15]C(=O)OC(C)(C)C)([CH3:14])[CH3:13]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:15][C:12]([CH3:14])([CH3:13])[C:11]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)=[O:23]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N1CCc2ccccc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(N)C(=O)N1CCc2ccccc2C1
Yield: 83.3 %

Procedure:
A solution of 41 (0.36 g, 1.1 mmol) in TFA (5 mL) and CH2Cl2 (5 mL) was stirred at room temperature for 40 minutes. The mixture was concentrated in vacuo and the residue was dissolved in EtOAc (50 mL). Upon sequential washings with 1 N NaOH (2×50 mL) and brine (50 mL), the organic solution was dried (Na2SO4) and concentrated to afford 42 (0.20 g, 77%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@@H:10]([NH2:12])[C@H:9]([OH:13])[C@H:8]([O:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:7]=1)=[O:5])[CH3:2].[Na+:20].[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29]([O-:32])(=[O:31])=[O:30])=O>C(O)C>[Na+:20].[CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@@H:10]([N:12]=[CH:21][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([O-:32])(=[O:31])=[O:30])[C@H:9]([OH:13])[C@H:8]([O:14][CH:15]([CH2:16][CH3:17])[CH2:18][CH3:19])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@@H](O)[C@H](N)C1
Reactant: O=Cc1ccccc1S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@@H](O)[C@H](N=Cc2ccccc2S(=O)(=O)[O-])C1
Yield: 99.4 %

Procedure:
To a stirred suspension of 27.1 g (100 mmol) (3R,4S,5R)-5-amino-3-(1-ethylpropoxy)-4-hydroxycyclohexene-1-carboxylic acid ethyl ester and 20.8 g (100 mmol) 2-formylbenzenesulfonic acid sodium salt in 270 ml ethanol was heated to reflux under argon for 2 hours. The brown, turbid reaction mixture was evaporated in a rotary evaporator and the residue was treated twice with 135 ml of ethyl acetate and evaporated in a rotary evaporator at 50° C. to dryness to yield 45.88 g (99%) of (1R,5R,6S)-2-{[3-ethoxycarbonyl-5-(1-ethyl-propoxy)-6-hydroxy-cyclohex-3-enylimino]-methyl}-benzenesulfonic acid sodium salt as a yellow amorphous solid. IR (film): 3417, 2924, 2726, 1714, 1638, 1464, 1378, 1237, 1091, 970 cm−1; MS (ISP-MS): 438.3 (M+−Na) m/z.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:6](=[N:7][O:8][N:9]=2)[CH:5]=[CH:4][CH:3]=1.[Br:11]Br.[O-]S([O-])=O.[Na+].[Na+]>ClCCl.C(OCC)(=O)C.[Fe]>[Br:11][C:5]1[C:6]2[C:10](=[N:9][O:8][N:7]=2)[C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: BrBr
Reactant: Clc1cccc2nonc12
Agent: [Fe]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Clc1ccc(Br)c2nonc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
4-Chlorobenzo[c][1,2,5]oxadiazole (1.0 g, 6.5 mmol) was treated with iron powder (14 mg, 0.2 mmol), stirred and heated to 50° C. and then treated in portions with bromine (1.1 g, 7.1 mmol) to produce a homogeneous red melt solution. The flask was fitted with a reflux condenser and the temperature was raised to 85° C. and stirred for 60 min. An additional 450 mg of bromine were added, heating was continued for 1 h more and then the mixture was allowed to stand for 18 h at 20° C. The solid contents of the flask were dissolved in 15 mL dichloromethane and stirred for 30 min with 15 mL saturated Na2SO3 solution. The mixture was diluted with 30 mL ethyl acetate and the organic phase was washed with 15 mL saturated NaCl, dried (Na2SO4) and concentrated under vacuum. The material was chromatographed on silica with a 0-7% ethyl acetate-hexane gradient to give the title compound as a white solid (1.4 g; 93%): mp 81-83° C.; 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J=7.5 Hz, 1H), 7.33 (d, J=7.5 Hz, 1H); EIMS m/z 232.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:37])([CH3:36])[CH2:9][C@:10]([OH:35])([C:31]([F:34])([F:33])[F:32])[CH2:11][C:12]#[C:13][C:14]2[C:19]([NH:20]C(=O)C(F)(F)F)=[CH:18][CH:17]=[C:16]([S:27]([CH3:30])(=[O:29])=[O:28])[N:15]=2)[CH:5]=[CH:6][CH:7]=1.CN(C)C(=N)N(C)C>CS(C)=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:37])([CH3:36])[CH2:9][C@:10]([CH2:11][C:12]2[NH:20][C:19]3[C:14](=[N:15][C:16]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:17][CH:18]=3)[CH:13]=2)([OH:35])[C:31]([F:34])([F:33])[F:32])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C[C@@](O)(CC#Cc1nc(S(C)(=O)=O)ccc1NC(=O)C(F)(F)F)C(F)(F)F)c1cccc(Br)c1
Agent: CN(C)C(=N)N(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C[C@@](O)(Cc1cc2nc(S(C)(=O)=O)ccc2[nH]1)C(F)(F)F)c1cccc(Br)c1
Temperature: 70 °C
Reaction time: 7 h
Yield: 61.1 %

Procedure:
N-{2-[(S)-6-(3-Bromophenyl)-4-hydroxy-6-methyl-4-trifluoromethylhept-1-ynyl]-6-methanesulfonylpyridin-3-yl}-2,2,2-trifluoroacetamide (351 mg, 0.57 mmol) was dissolved in 3.4 mL of DMSO and tetramethylguanidine (0.43 mL, 3.42 mmol) was added. The mixture was stirred at 70° C. for 7 hours. Then it was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution, and brine, dried over sodium sulfate, and concentrated in vacuo. The mixture was purified by flash chromatography (gradient 0→8% MeOH in DCM). The product was further purified by crystallization (DCM) to give (R)-4-(3-bromophenyl)-1,1,1-trifluoro-2-(5-methanesulfonyl-1H-pyrrolo[3,2-b]pyridin-2-ylmethyl)-4-methylpentan-2-ol as a white solid (181 mg, 61%).
Reaction SMILES: O.OC1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O.[CH:25]1[CH:30]=[C:29]2[C:31]([C:33]3[C:38]([C:39](=[O:40])[C:28]2=[CH:27][CH:26]=1)=[C:37]([NH2:41])[C:36]([S:42]([O-:45])(=[O:44])=[O:43])=[CH:35][C:34]=3Br)=[O:32].[Na+:47].[C:48]1([S:54]([NH2:57])(=[O:56])=[O:55])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[Na+:47].[NH2:41][C:37]1[C:38]2[C:39](=[O:40])[C:28]3[C:29](=[CH:30][CH:25]=[CH:26][CH:27]=3)[C:31](=[O:32])[C:33]=2[C:34]([NH:57][S:54]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)(=[O:56])=[O:55])=[CH:35][C:36]=1[S:42]([O-:45])(=[O:44])=[O:43]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: Nc1c(S(=O)(=O)[O-])cc(Br)c2c1C(=O)c1ccccc1C2=O
Agent: [Cu+2]
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Product: Nc1c(S(=O)(=O)[O-])cc(NS(=O)(=O)c2ccccc2)c2c1C(=O)c1ccccc1C2=O
Temperature: 70 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
Copper (II) sulphate pentahydrate (0.16 g, 0.00064 mol) and lactose monohydrate (2.9 g, 0.008 mol) are added to a mixture of bromaminic acid sodium salt (38.2 g, 0.1 mol) and benzene sulphonamide (17.3 g, 0.11 mol) in water (250 ml) containing sodium carbonate (3.8 g) and sodium bicarbonate (19.0 g). The mixture which has a pH of 8.5-9.0, is heated to 70° C. and stirred at this temperature for 5 hours. The resulting mixture is diluted with water to a volume of 750 ml and cooled to 40° C. The solid product is filtered off and washed with a solution of sodium chloride (12 g) in water (1300 ml) to give a 95% yield of 1-amino-4-phenylsulphonamido-anthraquinone-2-sulphonic acid sodium salt, a product of formula I where M denotes sodium and R denotes a group of formula III.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:10][CH:11]([C:14]1[CH:31]=[CH:30][C:17]([O:18][CH:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:20](O)=[O:21])=[CH:16][CH:15]=1)[CH2:12][CH3:13]>>[CH3:1][O:2][C:3]1[C:4]([NH:9][C:20](=[O:21])[CH:19]([O:18][C:17]2[CH:30]=[CH:31][C:14]([CH:11]([CH3:10])[CH2:12][CH3:13])=[CH:15][CH:16]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCCCCCCC(Oc1ccc(C(C)CC)cc1)C(=O)O
Reactant: COc1cccnc1N
Product: CCCCCCCC(Oc1ccc(C(C)CC)cc1)C(=O)Nc1ncccc1OC

Procedure:
3-Methoxy-2-aminopyridine, prepared by reduction of the corresponding nitro compound according to Example 31, was coupled with 2-(4-(1-methylpropyl)phenoxynonanoic acid according to Example 25 to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13]/[CH:14]=[CH:15]/[CH3:16])=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:24]>ClCCl.C1(C)C=CC=CC=1>[O:24]1[CH:14]([CH2:13][O:12][C:11]2[CH:17]=[CH:18][C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[CH:9][CH:10]=2)[CH:15]1[CH3:16]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C/C=C/COc1ccc(C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC1OC1COc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 22 °C
Reaction time: 18 h
Yield: 95.8 %

Procedure:
A solution of trans-4-[4-(tert-butoxycarbonyl)phenoxy]-2-butene (3.10 g, 12.48 mmol) in dry dichloromethane (50 ml) was treated at 22° C. with 3-chloroperoxybenzoic acid (4.30 g, 24.9 mmol) and the resulting mixture was stirred at 22° C. for 18 hours. The mixture was then diluted with toluene, washed with 5% sodium thiosulfate, saturated sodium bicarbonate and brine. After drying (sodium sulfate), evaporation of the solvent gave an oil that was chromatographed on silica gel. Elution with a mixture of toluene and ethyl acetate (95:5) gave 3.16 g (96%) of the title material as an oil which solidified upon standing: bp 85-90° C./0.05 torr (bulb to bulb, air bath temperature); mp 47-48° C.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[O:13]1[CH:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14]1>C(N(CC)CC)C>[ClH:1].[OH:13][CH:15]([CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:14][NH:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1
Reactant: NCCOc1ccc(O)cc1
Reactant: c1ccc(OCC2CO2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: Oc1ccc(OCCNCC(O)COc2ccccc2)cc1
Yield: 15.6 %

Procedure:
A mixture of p-(2-aminoethoxy)phenol hydrochloride, (1.89 g) triethylamine (1.01 g) and 1,2-epoxy-3-phenoxy-propane (1.5 g) was heated under reflux for 24 hours. The reaction mixture was cooled and the solvent was evaporated. The residue was partitioned between dichloromethane (100 ml) and 10% w/v potassium carbonate solution. The organic layer was separated, dried (MgSO4), and the solvent was evaporated. The residual oil was dissolved in ethyl acetate and dry hydrogen chloride was passed through the solution until no further solid precipitated. The precipitate was collected and recrystallised from methanol and ethyl acetate to give p-(2-[2-hydroxy-3-phenoxypropylamino]ethoxy)phenol hydrochloride (0.53 g) mp, 171° C.; microanalysis: found C, 60.3; H, 6.7; N, 4.0; Cl, 10.6%; required for C17H22NClO4 : C, 60.1; H, 6.5; N, 4.1; Cl, 10.5% NMR: 3.09 (dd, 1H, CHOH.CH2NH), 3.28 (dd, 1H, CHOH.CH2NH), 3.47 (t, 2H, NHCH2CH2), 4.15 (m, 2H, NHCH2CH2), 4.25 (m, 1H, CHOH), 5.01 (br s, 1H, CHOH), 6.67+6.79 (2d, 4 aromatic H), 6.92 (m, 3 aromatic H), 7.26 (t, 2 aromatic H), 9.1 (br s, NH2+ +phenolic OH). [Note: p-(2-[(2-hydroxy-3-phenoxypropylamino]ethoxy)phenol in addition to being a valuable intermediate also shows significant thermogenic properties in its own right (sub-cut.ED50 in test (b): 0.51 mg/kg; SI in test (c) >100) and is provided together with its pharmaceutically acceptable salts, and compositions, as a further feature of the invention.]
Reaction SMILES: C1(=O)CCCC1.[C:7]([O:18]CC)(=O)[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[CH2:15]([O:14][C:12]([CH:11]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:18])=[O:13])[CH3:16]
Reactant: CCOC(=O)CCCCC(=O)OCC
Solvent: O=C1CCCC1
Product: CCOC(=O)C1CCCC1=O

Procedure:
Ethyl-2-oxocyclopentane carboxylate (3.9 gm 0.025 m) was fluorinated in a similar manner to that described in Example 1. Work up gave ethyl-2-fluoro-2-oxocyclopentane carboxylate [NMR(CDCl3); 19F, δF =-164.6 ppm (t) JHF =21.0 Hz. MS (EI); M+ 174]. Yield 56%. Also recognised in the reaction mixture was cyclopentanone [M.S. (EI); 84(M+)], unreacted starting material, and diethyl adipate [M.S. (CI); 203 (M+1)+ ]. Conversion 80%.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=O>C(OCC)C>[C:19]([O:18][C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C:11]1([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH2:9][OH:8])=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)C1(c2ccc(F)cc2)CCCN1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCC1(CO)c1ccc(F)cc1
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 86.8 %

Procedure:
To a suspension of lithiumaluminiumhydride (1.5 g) in dry diethyl ether (25 mL) at −20° C. was added dropwise a solution of 2-(4-fluoro-phenyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (4.25 g) in dry diethyl ether (20 mL) over 10 minutes. The reaction was stirred at −20° C. for 20 minutes and followed by TLC. After 30 minutes the reaction was quenched at −20° C. by adding saturated aqueous sodium sulfate solution dropwise until the lithium aluminium hydride reagent was fully quenched. Further solid sodium sulfate was added to the slurry and the mixture was allowed to warm to ambient temperature. The slurry was filtered and the solid was washed with further diethyl ether. The filtrate was collected and the diethyl ether was evaporated in vacuo to afford the desired 2-(4-fluoro-phenyl)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (3.37 g, MS (ES+): 296.3 (MH+)) as a colourless oil.
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].[C:7]1(C)[CH:12]=[CH:11]C=[CH:9][CH:8]=1.C(C1C=CC=CC=1)C>C1(C)C(C)=CC=CC=1>[CH2:5]1[C:6]2[C:9](=[CH:8][CH:7]=[CH:12][CH:11]=2)[CH2:2][C:1](=[O:3])[O:4]1
Reactant: CCOC(C)=O
Reactant: Cc1ccccc1
Solvent: CCc1ccccc1
Solvent: Cc1ccccc1C
Product: O=C1Cc2ccccc2CO1

Procedure:
After the reaction, recovery of isochromanones can be carried out by concentration of reaction mixture or extraction with an organic solvent such as ethyl acetate, toluene, xylene and ethylbenzene. When the reaction mixture is separated into two layers, i.e., a water layer and a product layer, depending on the target isochromanones, it is possible to separate and remove the water layer. In particular, when the product is 3-isochromanone, the product layer is liquid at 85° C. or higher, so that solubility in water is low and the target compound can be recovered by separation operation. Further, distillation and purification under reduced pressure can give rise to highly pure 3-isochromanone.
Reaction SMILES: O[CH:2]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[CH:3]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:11]>C(O)C.[Pd]>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:2][CH:3]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:11]
Reactant: COc1cccc(C(O)C2CCCCCCC2=O)c1
Agent: [Pd]
Solvent: CCO
Product: COc1cccc(CC2CCCCCCC2=O)c1
Reaction time: 10 h
Yield: 42.6 %

Procedure:
A mixture of 2-{hydroxy-(3-methoxyphenyl)methyl}-cyclooctanone (6.0 g) and 10% Pd/C (2 g) in ethanol (120 ml) was stirred under H2 for 10 hours. The catalyst was filtered off and filtrate was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 2-(3-methoxybenzyl)cyclooctanone (2.4 g).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=O.O.[NH2:13][NH2:14]>CO>[NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[N:13][NH2:14]
Reactant: NN
Reactant: O=C1Nc2ccccc2C1=O
Solvent: CO
Solvent: O
Product: NN=C1Nc2ccccc2C1=O

Procedure:
Chem. Educ. 1993, 70 (4), p. 332 discloses that 2-oxindoles are prepared by a two-step reaction, the first step of which comprises reacting isatin with hydrazine hydrate in anhydrous methanol to give the intermediate isatin hydrazone and isolating and purifying the intermediate. In the second step, the purified and dried intermediate is subjected to a Wolf-Kishner reduction in an anhydrous ethanol solution in the presence of a strong base such as sodium ethoxide. The yields achieved by this preparation method are up to about 69%. However, the disadvantage of this variant is the necessity of isolating, purifying and drying the intermediate before the reduction step can take place. A further disadvantage is the use of expensive, anhydrous ethanol as solvent because of the readiness of sodium ethoxide to react with water. A further preparation variant is described by Synth. Commun. 1994, 24 (20), p. 2835-41. In this variant, isatin is first dissolved in pure hydrazine and then reacted with pure hydrazine under reflux to give 2-oxindole in yields of up to 76%. However, this method requires a large quantity of pure hydrazine which serves as solvent and as reagent. When pure hydrazine is used, there is known to be a risk of explosion on heating or on reaction with oxidizing agents, so that particular safety measures have to be taken. An improvement suggested by U.S. Pat. No. 5,973,165 comprises preparing 2-oxindoles by reacting isatin with hydrazine hydrate in the presence of a weak base as catalyst and in a polar solvent. In order to obtain the desired end product in pure form, after the end of the reaction, 2-oxindole (purity about 97%) is first extracted, the extract is dried and then dissolved in a suitable solvent, and activated carbon is then added to the solution to decolorize it. After filtering off the activated carbon, 2-oxindole is crystallized out of the solution and obtained in a purity of 99.5%. The yields which are obtained by this process according to Example 1 are around 85%, but otherwise from 52 to 72%.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:10]2[C:11]([CH3:17])=[C:12]([C:14]([OH:16])=O)[O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH3:18][O:19][C:20](=[O:42])[C@@H:21]([NH:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=2)=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH:22]([CH3:24])[CH3:23].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.[Cl-].[Na+].O>[CH3:18][O:19][C:20](=[O:42])[C@@H:21]([NH:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:36]=[CH:37][C:38]([NH:41][C:14]([C:12]3[O:13][C:9]4[CH:8]=[CH:7][CH:6]=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[C:10]=4[C:11]=3[CH3:17])=[O:16])=[CH:39][CH:40]=2)=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH:22]([CH3:24])[CH3:23]
Reactant: Cc1c(C(=O)O)oc2cccc(OC(C)C)c12
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4cccc(OC(C)C)c4c3C)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
To 200 mg (0.91 mmol) 4-isopropoxy-3-methyl-benzofuran-2-carboxylic acid in 4 mL of DMF was added 329 mg (1 eq) of (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester, 482 mg (1.2 eq) of BOP, and 0.19 mL of N,N-diisopropylethylamine. The mixture was stirred at room temperature overnight. Brine was added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and water. Removal of the solvent in vacuo gave the crude product, which was purified by column chromatography on silica gel to give 395 mg (69% yield) of (S)-2-{4′-[(4-Isopropoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid methyl ester as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH2:12][C:13](O)([C:15]([F:18])([F:17])[F:16])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:22][CH:21]=3)[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nc(C(F)(F)F)cn2-c2ccc(S(C)(=O)=O)cc2)cc1Cl

Procedure:
A mixture of 2-(3-chloro-4-methoxyphenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-4,5-dihydro-1H-imidazole (10 mmol) and p-toluenesulfonic acid monohydrate (1 mmol) in toluene (100 mL) is heated to reflux for 72 hours. The reaction mixture is cooled and the solvent removed under reduced pressure. The crude residue is redissolved in methylene chloride and washed with water, aqueous sodium bicarbonate and brine. After drying (Na2SO4), filtration and concentration in vacuo, the crude mixture is chromatographed on silica gel using toluene/ethyl acetate to give pure 2-(3-chloro-4-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole.