Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3=[N:14][C:15]([CH3:26])=[CH:16][C:17](OS(C(F)(F)F)(=O)=O)=[C:12]3[C:11]([CH3:27])=[CH:10]2)=[C:4]([CH3:28])[CH:3]=1.[NH:29]1[CH2:39][CH2:38][CH:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:31][CH2:30]1.C(N(CC)C(C)C)(C)C>O>[CH2:36]([O:35][C:33]([CH:32]1[CH2:38][CH2:39][N:29]([C:17]2[CH:16]=[C:15]([CH3:26])[N:14]=[C:13]3[N:9]([C:5]4[C:4]([CH3:28])=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=4[CH3:8])[CH:10]=[C:11]([CH3:27])[C:12]=23)[CH2:30][CH2:31]1)=[O:34])[CH3:37]
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)c2c(C)cn(-c3c(C)cc(Cl)cc3C)c2n1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)C1CCN(c2cc(C)nc3c2c(C)cn3-c2c(C)cc(Cl)cc2C)CC1
Temperature: 160 °C
Yield: 79.7 %

Procedure:
A mixture of the crude trifluoromethanesulfonic acid 1-(4-chloro-2,6-dimethylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl ester (20.5 g), ethyl isonipecotate (74.4 g) and N,N-diisopropylethylamine (12.2 g) was heated at 150-170° C. for 1 hour. To the reaction mixture, water was added and extracted with ethyl acetate. The organic layer was washed with water, and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: hexane/ethyl acetate=5:1) to give 1-[1-(4-chloro-2,6-dimethylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidine-4-carboxylic acid ethyl ester (16.6 g) as a pale yellow solid.
Reaction SMILES: [NH2:1]/[C:2](/[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[C:3]1\[C:4](=[O:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[S:7]\1.S(Cl)(Cl)(=O)=[O:21].C(O)C>ClCCl.ClC(Cl)C>[NH2:1]/[C:2](/[C:13]1[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=1)=[C:3]1\[C:4](=[O:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[S:7]\1=[O:21]
Reactant: N/C(=C1/Sc2ccccc2C1=O)c1ccc(F)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: CCO
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: N/C(=C1\C(=O)c2ccccc2S1=O)c1ccc(F)cc1
Temperature: -70 °C
Reaction time: 15 h

Procedure:
2.61 gm (9.61 mmols) of (E)-2-[(amino)-4-fluorophenylmethylene]-benzo[b]thiophen-3(2H)-one were dissolved in 50 ml of dichloromethane, the solution was cooled to -70° C, and then a solution of 1.5 gm (11.1 mmols) of sulfuryl chloride in 5 ml of dichloroethane was added dropwise thereto. After 15 hours, 20 ml of 95% ethanol were added, and the reaction mixture was brought to room temperature by removal of the cooling bath. It was then neutralized with aqueous sodium carbonate, the dichloromethane phase was dried with sodium sulfate, the solvent was evaporated in vacuo, and the residue was recrystallized from glacial acetic acid/ethanol (1:4 v/v).
Reaction SMILES: [OH-].[Na+].[CH:3]1([S:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][C@@H:15]([CH2:18][CH2:19][CH:20]([OH:33])[C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][CH:22]=3)[C@@H:14]([CH2:34][C:35]([O:37]C)=[O:36])[CH2:13]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1.CC(C)=O.C(OCC)C>[CH:3]1([S:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][C@@H:15]([CH2:18][CH2:19][CH:20]([OH:33])[C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][CH:22]=3)[C@@H:14]([CH2:34][C:35]([OH:37])=[O:36])[CH2:13]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)C[C@H]1CN(CCSC2CCCCC2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: COc1ccc2nccc(C(O)CC[C@@H]3CCN(CCSC4CCCCC4)C[C@@H]3CC(=O)O)c2c1
Temperature: 60 °C
Yield: 102.8 %

Procedure:
2.96 cm3 of 5N aqueous sodium hydroxide solution were added, with stirring at a temperature in the region of 20° C., to a solution of 1.9 g of methyl (3R,4R)-1-[2-(cyclohexylthio)ethyl]-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-acetate in 35 cm3 of dioxane. The solution was heated for 16 hours at a temperature in the region of 60° C. The reaction mixture was evaporated under reduced pressure (5 kPa) at a temperature in the region of 50° C. and then the residue obtained was taken up in 50 cm3 of acetone and reevaporated as above. After having taken up the residue obtained in 50 cm3 of diethyl ether and having concentrated as under the above conditions, the yellow solid obtained had 20 cm3 of water added and was acidified with an amount of citric acid sufficient to obtain a pH in the region of 4-5. The mixture was extracted with 50 cm3 of dichloromethane. The organic extract was concentrated under reduced pressure (5 kPa) at a temperature in the region of 50° C. The evaporation residue was taken up in 2 times 100 cm3 of a dichloromethane/methanol (90/10 by volume) mixture, the insoluble material was filtered off each time after the residue had been taken up. The combined filtrates were concentrated as above and then the residue obtained was taken in 50 cm3 of diethyl ether and evaporated as under the above conditions. The crystals obtained were taken up in 50 cm3 of diethyl ether, filtered off, and washed with 2 times 50 cm3 of ether. The product was finally dried under reduced pressure, first under 5 kPa and then in an oven under 10 Pa at a temperature in the region of 60° C. 1.9 g of (3R,4R)-1-[2-(cyclohexylthio)ethyl]4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-acetic acid were obtained in the form of a solid with a yellow color.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[C:5]2[O:22]C(=O)C.[OH-].[K+].Cl>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)(=[O:13])=[O:12])[CH:6]=[C:5]2[OH:22]
Reactant: COc1ccc(S(=O)(=O)n2cc(OC(C)=O)c3cc(Br)ccc32)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)n2cc(O)c3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
Acetic acid 5-bromo-1-(4-methoxybenzenesulfonyl)-1H-indol-3-yl ester (20, 150 mg, 0.353 mmol) was added to a stirring solution of 50% potassium hydroxide (2.0 mL) in methanol (6.0 mL). After stirring at 25° C. for 30 min, the reaction mixture was acidified with 1M hydrochloric acid. The organic material was extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated at reduced pressure to afford 5-bromo-1-(4-methoxy-benzenesulfonyl)-1H-indol-3-ol (21, 110.0 mg, 81% yield). MS(ESI) [M−H+]−=380.0; 382.0
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CS(O[CH2:16][C:17]1([CH2:21][CH2:22][CH3:23])[CH2:20][O:19][CH2:18]1)(=O)=O.O>CN(C)C=O>[CH2:1]([S:8][CH2:20][C:17]([CH2:16][S:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH2:21][CH2:22][CH3:23])[CH2:18][OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: CCCC1(COS(C)(=O)=O)COC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(CO)(CSCc1ccccc1)CSCc1ccccc1
Reaction time: 1 h

Procedure:
A solution of benzyl mercaptan (25.0 ml) in dry dimethylformamide (100 ml) was stirred at 0° C., under a current of nitrogen. Sodium hydride (6.0 g., 80% dispersion in oil) was added carefully and the mixture was stirred at 0° for 1 hour. 3-n-Propyloxetan-3-ylmethyl methanesulphonate (10.0 g.) was added and the mixture was stirred at 0° C. for 1 hour. The mixture was refluxed with stirring for 6 hours. The mixture was cooled and poured into water. The aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was chromatographed on silica, eluting with 1:4; diethyl ether:hexane. 2,2-Di-(benzylthiomethyl)pentan-1-ol was obtained as a pale yellow oil (15.6 g.)
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CN(C)C=O.S(Cl)([Cl:30])=O>C(Cl)Cl>[CH2:1]([O:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([Cl:30])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOc1ccccc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOc1ccccc1C(=O)Cl
Reaction time: 2 h

Procedure:
29.1 g of the dodecyloxybenzoic acid was dissolved in 300 ml of methylene chloride, 1 ml of N,N-dimethylformamide was added, and 24 g of thionyl chloride was added dropwise over about 30 min under heating and reflux. After the addition the heating and refluxing were continued for 2 hours further, and concentration was conducted, to obtain 2-dodecyloxybenzoic acid chloride.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=2)[CH:5]=[N:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>ClCCl.CCOCC>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=2)[CH:5]=[N+:4]([O-:24])[CH:3]=1
Reactant: Brc1cncc2cc3ccccc3cc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOCC
Product: [O-][n+]1cc(Br)c2cc3ccccc3cc2c1
Temperature: 25 °C

Procedure:
A solution of 4-bromobenzo[g]isoquinoline (7-3) (390 mg, 1.5 mmol, 1. eq) in dichloromethane (25 ml) was treated with mCPBA (˜70%, 559 mg, 2.27 mmol, 1.5 eq) and the reaction mixture was stirred at room temperature until LCMS showed complete conversion. The reaction mixture was diluted with ether, and the precipitate was collected by filtration, washed with ether, and dried to give the title N-oxide 7-4. LRMS m/z: found 274.0, 276.0, calcd. (M+H) 274.0, 276.0
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[Cl:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9]>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:7]=[C:8]([NH:9][C:1]([Cl:4])=[O:2])[CH:10]=[CH:11][CH:12]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1cccc(Cl)c1
Solvent: Cc1ccccc1
Product: O=C(Cl)Nc1cccc(Cl)c1

Procedure:
The intermediate is then reacted with a secondary amine in an aprotic solvent such as toluene at temperatures from room temperature or below up to the boiling point of the solvent. An example of this process is the reaction of phosgene with 3-chloroaniline to yield the intermediate N-(3-chlorophenyl)carbamyl chloride which is then reacted with dibenzylamine to yield 1,1-dibenzyl-3-(3-chlorophenyl)urea.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([OH:9])=[O:8])[CH2:2]1.[OH-].[Na+].[CH2:12]([O:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>O>[CH2:12]([O:19][C:20]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([OH:9])=[O:8])[CH2:2]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)C1CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
To the solution of piperidine-3-carboxylic acid (1.3 g, 10 mmol) in water (20 mL) was added sodium hydroxide (1.6 g, 40 mmol). Then benzyloxycarbonyl chloride (2.02 g, 12 mmol) was added dropwise at 0° C. The mixture was stirred at 0° C. for 2 h. The resulting mixture was treated with 5N hydrochloric acid to pH=6 and extracted with ethyl acetate, the solvent was removed under reduced pressure and dried in vacuum. 2.2 g of solid of 1-(benzyloxycarbonyl)piperidine-3-carboxylic acid was obtained. LC-MS (ESI) m/z: 264 (M+1)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.[Br:7][CH2:8][C:9](Br)=[O:10].N1C=CC=CC=1.C(C1OC1)Cl>C1C=CC=CC=1>[Br:7][CH2:8][C:9]([O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1)=[O:10]
Reactant: O=C(Br)CBr
Reactant: OC1CCOC1
Solvent: c1ccncc1
Solvent: ClCC1CO1
Solvent: c1ccccc1
Product: O=C(CBr)OC1CCOC1
Reaction time: 1 h

Procedure:
In a four-neck, 2-liter flask, 42.5 g (0.48 mole) 3-hydroxy tetrahydrofuran was dissolved in 600 ml benzene. The resultant solution was cooled to below 20° C in an ice-water bath. 135.3 g (58.4 ml, 0.67 mole) bromoacetyl bromide was then added to the solution. 75.9 g (77.6 ml, 0.96 mole) pyridine was added dropwise to the solution over a 30-minute period. When the addition was complete, stirring was continued for one hour at the above temperature. The reaction mixture was then removed from the cooling bath and allowed to come to room temperature. The solution was first washed with 350 ml of water, then with 100 ml 1N HCl, and finally with 100 ml saturated NaHCO3 solution. The remaining benzene solution was dried with MgSO4 and filtered. The benzene solvent was removed by evaporation in vacuo, leaving the product oil. The yield was 70.1 g, or 69.9% of the theoretical yield of 100.3 g. The refractive index of the product was nD 30 = 1.5022. The structure of the product was confirmed by spectral evidence. Epichlorohydrin (1% by weight) was added as a stabilizer.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[CH:5](=[O:17])[C:6]1[CH:16]=[C:13]([O:14][CH3:15])[C:11]([OH:12])=[C:8]([O:9][CH3:10])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:12][C:11]1[C:13]([O:14][CH3:15])=[CH:16][C:6]([CH:5]=[O:17])=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: BrCCBr
Reactant: COc1cc(C=O)cc(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)cc(OC)c1OCCBr
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.6 %

Procedure:
1,2-Dibromoethane (47 mL, 0.55 moles) was added to a mixture of syringaldehyde (10 g, 55 mmoles) and potassium carbonate (38 g, 275 mmoles) in DMF (150 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (0.5 L) and extracted with ethyl acetate (3×300 mL). The combined organic phases were washed with saturated sodium chloride (500 mL), dried over MgSO4 and evaporated in vacuo to afford 3.44 g (22%) of 4-(2-bromoethoxy)-3,5-dimethoxybenzaldehyde.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:30]=[CH:29][C:12]2[N:13]=[C:14]([CH2:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[N:15]([CH2:16][CH2:17][CH3:18])[C:11]=2[CH:10]=1.[CH3:31][N:32]1[CH:36]=[CH:35][N:34]=[C:33]1[CH:37]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[CH2:6][N:7]([CH2:37][C:33]1[N:32]([CH3:31])[CH:36]=[CH:35][N:34]=1)[CH2:8][C:9]1[CH:30]=[CH:29][C:12]2[N:13]=[C:14]([CH2:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[N:15]([CH2:16][CH2:17][CH3:18])[C:11]=2[CH:10]=1
Reactant: Cn1ccnc1C=O
Reactant: CCCn1c(CCCCN2CCCCC2)nc2ccc(CNCc3ncc[nH]3)cc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCn1c(CCCCN2CCCCC2)nc2ccc(CN(Cc3ncc[nH]3)Cc3nccn3C)cc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 105.8 %

Procedure:
The compound (429.5 mg) obtained in Example 61-4 was dissolved in methanol (21.5 ml) and added with 1-methyl-2-imidazole carboxaldehyde (173.6 mg) and sodium cyanoborohydride (132.1 mg). After the solution was adjusted to pH 4 with acetic acid, the whole was stirred at room temperature for 4 days. The reaction solution was concentrated under reduced pressure. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution and a saturated saline solution. Then, the resultant was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining a hydrochloride (559.2 mg) of the subject compound as a pale-yellow solid.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.[C:41]([O:45][CH3:46])(=[O:44])[CH:42]=[CH2:43].C(N(CC)CC)C>C(O)C>[CH3:46][O:45][C:41](=[O:44])[CH2:42][CH2:43][NH:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: C=CC(=O)OC
Solvent: CCN(CC)CC
Solvent: CCO
Product: C=C(C)[C@@H]1CC[C@]2(NCCC(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Yield: 64.4 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (20 mg, 0.037 mmol), methyl acrylate (0.013 mL, 0.147 mmol) and triethylamine (0.026 mL, 0.184 mmol) in ethanol (1 mL) was refluxed for 5 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure to provide the desired product as a yellow oil (15 mg 65%). LCMS: m/e 630.43 (M+H)+, 3.81 min (method 10).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Cl:21])[CH:11]=[C:6]([C:7](OC)=[O:8])[CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:12]1[CH:13]=[C:4]([CH2:3][OH:2])[CH:5]=[C:6]([CH2:7][OH:8])[CH:11]=1
Reactant: COC(=O)c1cc(OCCCCCCCl)cc(C(=O)OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc(CO)cc(OCCCCCCCl)c1
Temperature: -25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
6.5 g (19.8 mmol) 5-[(6-chlorohexyl)oxy]isophthalic acid dimethyl ester were dissolved in 65 ml tetrahydrofuran in an atmosphere of argon. The colourless solution was cooled to −25° C. and then 42 ml (41.6 mmol) of a 1 molar solution of lithiumaluminiumhydrid in tetrahydrofuran were added dropwise over a period of 30 minutes. The reaction mixture was carefully quenched in sequence first with 5 ml of methanol and then with 50 ml of a 1 molar solution of HCl in water. The suspension was stirred for 1 hour at room temperature and subsequently filtered through speedex. The solid residue was washed carefully with 100 ml of tert.-butyl-methylether. The organic phase of the filtrate was separated, washed with 100 ml of a saturated sodium bicarbonate solution and 100 ml of water, dried over magnesium sulfate, filtered and concentrated in vacuum. Column chromatography of the crude product on 250 g of silica gel using dichloromethane:methanol (9:1) as eluent gave 5 g (93%) of [3-[(6-chlorohexyl)oxy]-5-[hydroxymethyl]phenyl]methanol as a white solid.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[C:2]=[S:3].[CH2:24]([NH:28][CH2:29][CH2:30][CH2:31][OH:32])[CH2:25][CH2:26][CH3:27]>ClCCl>[CH2:24]([N:28]([CH2:29][CH2:30][CH2:31][OH:32])[C:2]([NH:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[S:3])[CH2:25][CH2:26][CH3:27]
Reactant: COc1ccc(N2CCN(c3ccc(N=C=S)cc3)CC2)cc1
Reactant: CCCCNCCCO
Solvent: ClCCl
Product: CCCCN(CCCO)C(=S)Nc1ccc(N2CCN(c3ccc(OC)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
A mixture of 10 parts of 1-(4-isothiocyanatophenyl)-4-(4-methoxyphenyl)piperazine, 6.3 parts of 3-(butylamino)-1-propanol and 130 parts of dichloromethane was stirred for 3 hours at room temperature. The reaction mixture was evaporated and the residue was triturated in 2-propanone. The product was filtered off and dried, yielding 12.7 parts (92%) of N-butyl-N-(3-hydroxypropyl)-N'-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]thiourea; mp. 153.9° C. (44).
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[C@:14]2([CH3:15])[C@@:9]([OH:17])([CH2:10][C:11](=[O:16])[CH2:12][CH2:13]2)[CH2:8][CH2:7]1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([O:4][CH2:5][C@@H:6]1[C@:14]2([CH3:15])[C@@:9]([OH:17])([CH2:10][C@@H:11]([OH:16])[CH2:12][CH2:13]2)[CH2:8][CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1CC[C@]2(O)CC(=O)CC[C@]12C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)OC[C@H]1CC[C@]2(O)C[C@@H](O)CC[C@]12C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
To a solution of 5.00 g of (1S,3aS,7aR)-1-acetoxymethyl-3a-hydroxy-7a-methyl-5-perhydroindenone (see Prepn. 3) in 50 ml of methanol cooled at 0° C., 0.77 g of NaBH4 were added and the mixture was stirred for 1 hr. It was then diluted with 10 ml of 5% aqueous NaH2PO4.H2O, concentrated in vacuo and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by flash-chromatography (SiO2) with n-hexane/chloroform/acetone 4:3:3 as the eluant to give 2.18 g of (1S,3aS,5S,7aR)-1-acetoxymethyl-7a-methylperhydroinden-3a,5-diol as a white foam.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[N:11]1([C:14]2[CH:19]=[C:18]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(-c3cccs3)ncn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1csc(-c2cc(N3CCNCC3)ncn2)c1

Procedure:
A solution of 4-(6-thiophen-2-yl-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (30 mg, 0.08 mmol) in 1:1 TFA/CH2Cl2 (3 mL) was stirred for 2 h, and then was concentrated to yield the title compound, as its corresponding TFA salt.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:17][CH:16]=[C:15]([CH2:23][OH:24])[CH:14]=2)=[CH:9][CH:8]=1)[CH3:2]>O1CCCC1.[O-2].[O-2].[Mn+4]>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:18]([O:19][CH:20]([CH3:21])[CH3:22])=[CH:17][CH:16]=[C:15]([CH:23]=[O:24])[CH:14]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOCCOc1ccc(-c2cc(CO)ccc2OC(C)C)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: CCOCCOc1ccc(-c2cc(C=O)ccc2OC(C)C)cc1
Yield: 81.2 %

Procedure:
A solution of [4′-(2-ethoxyethoxy)-6-isopropoxybiphenyl-3-yl]methanol (0.90 g, 2.72 mmol) and manganese dioxide (2.7 g, 31.1 mmol) in tetrahydrofuran (40 mL) was stirred at room temperature for 2 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:19-3:7) to give the title compound (725 mg) as colorless needle crystals. yield 81%.