Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][C:13](O)=O)=[CH:3]1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.[CH3:36][S:37]([NH:40][C:41]1[CH:42]=[CH:43][C:44]2[O:49][CH2:48][CH:47]([CH2:50][NH2:51])[O:46][C:45]=2[CH:52]=1)(=[O:39])=[O:38]>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][CH2:13][NH:51][CH2:50][CH:47]2[CH2:48][O:49][C:44]3[CH:43]=[CH:42][C:41]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:52][C:45]=3[O:46]2)=[CH:3]1
Reactant: Cn1cc(CCC(=O)O)c2ccccc21
Reactant: CS(=O)(=O)Nc1ccc2c(c1)OC(CN)CO2
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(CCCNCC2COc3ccc(NS(C)(=O)=O)cc3O2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
1-Methylindole-3-propionic acid (1.2 g, 6.0 mmole), 1-hydroxybenzotriazole hydrate (0.97 g, 7.2 mmole) and 1,3-diisopropylcarbodiimide (1.1 ml, 7.2 mmole) were combined in 100 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 7-methylsulfonylamino-2,3-dihydro-1,4-benzodioxin-2-methanamine (1.9 g, 7.2 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant. Fractions containing product were concentrated and washed with a minimum amount of THF to remove a by-product and to give 2.1 g (79%) of the desired product, (7-methylsulfonyl-2,3-dihydro-benzo[1,4]dioxin-2ylmethyl)-4-(1-methyl-1H-indol-3-yl)-propanamide, as a fluffy white solid.
Reaction SMILES: [C:1]1([CH:7]2[CH2:13][C:12](=[O:14])[NH:11][C:10]3[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=3[S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:19]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:19][C:13]1[C:12](=[O:14])[NH:11][C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[S:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CC(c2ccccc2)Sc2ccccc2N1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2SC(c2ccccc2)=C1Br
Reaction time: 5 h

Procedure:
A stirred solution of 25.5 g (0.1 mole) of 2,3-dihydro-2-phenyl-1,5-benzothiazepin-4(5H)-one (prepared as disclosed by Krapcho et al, J. Med. Chem., 6, 544, (1963)) in 250 ml of dimethylformamide is treated with a solution of 35 g (0.2 mole) of N-bromosuccinimide in 100 ml of dimethylformamide. The mixture is stirred at 105°-110° for 5 hours, cooled, and poured into 1.8 liters of cold H2O to precipitate a solid. After cooling overnight, the latter is filtered, washed with H2O, and air-dried; wt. 29.6 g (89%); m.p. 190°-192°; s. 180°. Following crystallization from a mixture of 30 ml of hot dimethylformamide and 60 ml of MeCN, the colorless solid weighs 17.8 g (53%); m.p. 240°-242° (dec.).
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH:11]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2O)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[CH2:6][CH2:5]1.Cl.Cl.N1(C[C@H](C2(O)CCCCC2)C2C=CC=C([O:46]C(F)(F)F)C=2)CCNCC1>>[ClH:1].[ClH:1].[CH3:3][N:4]1[CH2:5][CH2:6][N:7]([CH2:10][C@H:11]([C:23]2([OH:46])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:20])([F:21])[F:22])[CH:13]=2)[CH2:8][CH2:9]1
Reactant: OC1([C@@H](CN2CCNCC2)c2cccc(OC(F)(F)F)c2)CCCCC1
Reactant: CN1CCN(CC(c2cccc(OC(F)(F)F)c2)C2CCCC[C@H]2O)CC1
Agent: Cl
Product: CN1CCN(C[C@@H](c2cccc(OC(F)(F)F)c2)C2(O)CCCCC2)CC1

Procedure:
In an analogous manner to Example 24, 1-{(1R)-2-(4-methylpiperazin-1-yl-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol dihydrochloride was prepared from, 1-{(1R)-2-piperazin-1-yl-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol (See Example 244). HRMS: calcd for C20H29F3N2O2+H, 387.22594. found (ESI, [M+H]+), 387.2269.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]([OH:17])[C:15]#[CH:16])[CH:5]=[C:4]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH3:23])[C:3]1=2.[OH:25][C:26]1[CH:34]=[C:33](I)[CH:32]=[CH:31][C:27]=1[C:28]([OH:30])=[O:29].[Cl-].[NH4+]>CN(C=O)C.C(N(CC)CC)C.[Cu](I)I>[OH:17][CH:14]([C:6]1[CH:5]=[C:4]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH3:23])[C:3]2[C:2]([CH3:24])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=2[CH:7]=1)[C:15]#[C:16][C:33]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[C:26]([OH:25])[CH:34]=1
Reactant: O=C(O)c1ccc(I)cc1O
Reactant: C#CC(O)c1cc(OCCOCC)c2c(c1)C(C)(C)CCC2(C)C
Agent: I[Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOCCOc1cc(C(O)C#Cc2ccc(C(=O)O)c(O)c2)cc2c1C(C)(C)CCC2(C)C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
200 mg (0.6 mmol) of 1-[5,5,8,8-tetramethyl-4-(2-ethoxyethoxy)-5,6,7,8-tetrahydronaphth-2-yl]prop-2-yn-1-ol (Example 2b) and 175 mg (0.4 mmol) of 2-hydroxy-4-iodobenzoic acid are dissolved in 5 mL of DMF and 2 mL of triethylamine. 10 mg of copper iodide and 20 mg of dichloropalladiumbis(triphenylphosphine) are added, and the reaction medium is stirred at 50° C. for 2 hours 30 minutes. The reaction medium is poured into ammonium chloride solution and extracted with ethyl acetate. The residue is purified on a column of silica (eluent: 5/5 heptane/EtOAc). The desired product is obtained in the form of a yellowish powder (m=80 mg; yield=42%; m.p.=120° C.) 1H NMR (DMSO D6): 1.13 (t, J=7.0 Hz, 3H); 1.24 (s, 6H); 1.36 (s, 6H); 1.56-1.61 (m, 4H); 3.52 (q, J=7.0 Hz, 2H); 3.76 (m, 2H); 4.07 (m, 2H); 5.51 (s, 1H); 6.15 (bs, 1H); 6.89 (s, 1H); 6.97 (m, 2H); 7.11 (s, 1H); 7.77-7.79 (m, 1H), 11.5 (bs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH2:9][CH:8]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:19][CH2:18]3)[C:7]=2[CH:27]=1.[C:28](O)(=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].O.[OH-].[NH4+]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH2:9][CH:8]([N:17]3[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][O:26][C:28](=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:21][CH2:22]3)[C:7]=2[CH:27]=1
Reactant: CCCCCCCC(=O)O
Reactant: COc1ccc2c(c1)C(N1CCN(CCCO)CC1)Cc1ccccc1S2
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCCC(=O)OCCCN1CCN(C2Cc3ccccc3Sc3ccc(OC)cc32)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 14.82 grams of 8-methoxy-10-[4-(3-hydroxypropyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepin in 50 milliliters of benzene was added 12.55 grams of caprylic acid (octanoic acid). The resulting reaction mixture was allowed to stand overnight and was then heated for 3 hours at a temperature of 60°C. After cooling, the mixture was shaken with 100 milliliters of water, 20 milliliters of concentrated aqueous ammonium hydroxide solution was then added thereto, and the mixture was extracted with a mixture of benzene and ethyl ether. The resulting extract was washed with water, dried over anhydrous potassium carbonate, and the solvent was evaporated therefrom. The residue was dissolved in 40 milliliters of acetone and added to a solution of 9.5 grams of maleic acid in 30 milliliters of acetone. On standing, 15.5 grams of crude 8-methoxy-10-]4-(3-octanoyloxypropyl)piperazino]-10,11-dihydrobenzo[b,f]thiepin di(hydrogen maleate) crystals separated therefrom. On purification by recrystallization from acetone, the di(hydrogen maleate) salt had a melting point of 130°C. The free base was recovered in the form of a viscous oil by adding the di(hydrogen maleate) to a dilute aqueous ammonium hydroxide solution and extracting the solution with benzene as described in Example 1 hereinbefore.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7]([CH2:10][C:11](O)=O)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:24]=[CH:23][C:20](C=O)=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7](/[CH:10]=[CH:11]/[C:20]2[CH:23]=[CH:24][C:17]([F:16])=[CH:18][CH:19]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C(O)CS(=O)(=O)Cc1ccc(Br)cc1
Product: O=S(=O)(/C=C/c1ccc(F)cc1)Cc1ccc(Br)cc1
Yield: 82 %

Procedure:
A solution of 4-bromobenzyl sulfonylacetic acid (0.01 mol) and 4-fluorobenzaldehyde (0.01 mol) was subjected to Procedure 1. The title compound was obtained in 82% yield.
Reaction SMILES: P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[OH-].[Na+].[CH2:11]([O:13][C:14]([C@:16]1([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C@@H:17]1[CH:19]=[CH2:20])=[O:15])[CH3:12]>O.CS(C)=O>[CH2:11]([O:13][C:14]([C@@:16]1([NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:18][C@H:17]1[CH:19]=[CH2:20])=[O:15])[CH3:12]
Reactant: C=C[C@H]1C[C@@]1(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)OCC
Temperature: 39 °C
Reaction time: 24.5 h

Procedure:
To an aqueous solution of sodium phosphate buffer (0.1M, 4.25 L, pH 8) housed in a 12 Liter jacked reactor, maintained at 39° C., and stirred at 300 rpm, was added 511 grams of Alcalase 2.4 L (about 425 mL) (Novozymes North America Inc.). When the temperature of the mixture reached 39° C., the pH was adjusted to 8.0 by the addition of 50% NaOH in water. A solution of (1R,2S)/(1S,2R)N-Boc-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester (85 g) in 850 mL of DMSO was then added over a period of 40 minutes. The reaction temperature was maintained at 40° C. for 24.5 hours during which time the pH of the mixture was adjusted to 8.0 at the 1.5 hour and 19.5 hour time points using 50% NaOH in water. After 24.5 hours, the enantio-excess of the ester was determined to be 97.2%, and the reaction was cooled to room temperature (26° C.) and stirred overnight (16 hours) at which time the enantio-excess of the ester was determined to be 100%. The pH of the reaction mixture was then adjusted to 8.5 with 50% NaOH and the resulting mixture was extracted with MTBE (2×2 L). The combined MTBE extract was washed with 5% NaHCO3 (3×100 mL), water (3×100 mL), and then concentrated in vacuo to give the enantiomerically pure (1R,2S)N-Boc-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester as light yellow solid (42.55 g; purity: 97% (210 nm, containing no acid; 100% enantiomeric excess (“ee”).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[CH3:23][NH:24][CH2:25][CH2:26][CH3:27].C(N(CC)CC)C>CS(C)=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:24]([CH3:23])[CH2:25][CH2:26][CH3:27])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCNC
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F

Procedure:
The title compound was prepared from (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example B5) (4.00 g, 11.7 mmol), N-methyl-propyl-amine (1.89 ml, 17.6 mmol) and triethylamine (5.73 ml, 41.1 mmol) in DMSO (30 mL) at RT according to the general procedure C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([C:12]1[CH:13]=[C:14]([CH:26]=[CH:27][CH:28]=1)[C:15]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)=[O:16])#[N:11].C(N(CC)CC)C>C(Cl)Cl>[C:10]([C:12]1[CH:13]=[C:14]([CH:26]=[CH:27][CH:28]=1)[C:15]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:21][CH:20]=1)=[O:16])#[N:11]
Reactant: O=C(Cl)c1ccccc1
Reactant: N#Cc1cccc(C(=O)NCc2ccc(N)cc2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cccc(C(=O)NCc2ccc(NC(=O)c3ccccc3)cc2)c1

Procedure:
A solution of 0.6 g (4.2 mmol) of benzoylchloride in 10 ml of methylene chloride is added dropwise to a solution of 1 g (4 mmol) of 3-cyano-N-(4-amino-benzyl)-benzamide and 0.6 g (6 mmol) of triethylamine in 30 ml of methylene chloride at ambient temperature. After 8 hours at ambient temperature the product which has crystallised out is dissolved in methylene chloride and methanol. After extraction with water the combined organic extracts are dried and evaporated down.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[OH:13])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2].C(N(CC)CC)C.[CH2:27]([O:29][C:30](Cl)=[O:31])[CH3:28]>O1CCCC1>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[O:13][C:30]([O:29][CH2:27][CH3:28])=[O:31])=[CH:5][C:4]=1[C:16]([F:19])([F:17])[F:18])#[N:2]
Reactant: CCOC(=O)Cl
Reactant: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)On1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(C#N)cc21
Yield: 90.6 %

Procedure:
A solution of 0.4 g (1.48 mmol) 7-cyano-1-hydroxy-6-trifluoromethylquinoxaline-2,3(1H,4H)-dione in 50 ml dry tetrahydrofuran was added 0.2 ml (1.50 mmol) dry triethylamine and 0.15 ml (1.58 mmol) ethylchloroformate. The mixture was refluxed for 45 min., and then evaporated in vacuo. The residue was stirred with water to give 0.46 g (91%) of 7-cyano-1-ethoxycarbonyloxy-6-trifluoromethylquinoxaline-2,3(1H,4H)-dione. M.p. 190° C. decomp. 1H-NMR (DMSO-d6): 8.33 (1H, s), 7.73 (1H, s), 2.9 (2H, q), 1.2 (3H, t).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5].C([O-])(=O)C.[K+:12].[C:13]1(=O)[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>C(O)(=O)C>[K+:12].[C:13]1(=[O:18])[N:1]([CH2:2][CH2:3][S:4]([O-:7])(=[O:6])=[O:5])[C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCS(=O)(=O)O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)[O-]
Yield: 84.1 %

Procedure:
A mixture containing 30 g of taurine, 25 g of potassium acetate and 90 ml of acetic acid is brought to reflux for 10 minutes and 37.8 g of phthalic anhydride are then added. The mixture is heated to reflux for two and a half hours and then filtered, and the product is washed with AcOH and then with 2-propanol; it is rinsed with ether and then dried under vacuum to obtain 59.14 g of the expected product.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][CH:9]=1>N1C=CC=CC=1>[CH2:5]([O:4][C:2]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:12][CH:13]=1)=[O:3])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(-n2cccc2)cc1
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(-n2cccc2)cc1
Reaction time: 1.5 h

Procedure:
Ethyl chloroforrnate (0.38 ml) was added dropwisc to a stirred solution of 1-(4-aminophenyl)pyrrole (0.56 g, 3.54 mmol , Corelli et al., Farmaco. Ed. Sci., 1983, 38, 219) in pyridine (5 ml) at 5-10° C. for 15 minutes. The cooling bath was removed and stirring continued for 1.5 hours. The mixture was evaporated and the residue was purified by flash column chromatography on silica gel, eluting with a gradient of 1-4% MeOH in dichloromethane to give the title product (0.43 g) as a solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[CH3:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][N:15]1[CH2:20][CH2:21][CH2:22][NH2:23].CO.[BH4-].[Na+]>ClCCl>[CH3:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][N:15]1[CH2:20][CH2:21][CH2:22][NH:23][CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: CC1CCCCN1CCCN
Reactant: O=Cc1ccc2ccccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC1CCCCN1CCCNCc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Naphtaldehyde 1 g (6.4 mmol), 3-(2-methyl-piperidin-1-yl)-propylamine 0.99 g (6.4 mmol), in 25 mL of dry dichloromethane was added 5 g of molecular sieve. The reaction was stirred overnight at room temperature. The molecular sieve was filtered and dichloromethane was concentrated under vacuum. To the mixture was added 15 mL of dry methanol and sodium borohydride 0.3 g (8 mmol) after 30 minutes reaction goes to completion, methanol was concentrated under vacuum, and was diluted with chloroform, organic layer was washed with 2 times 20 mL water, followed with brine. The organic layer was dried over magnesium sulfate and concentrated under vacuum. The compound was purified using silica gel chromatography elution, with 3.5% methanol in chloroform, yield 0.6 g oil.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4](Cl)=[O:5].[O:13]1[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1>>[CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([CH:15]1[C:16](=[O:19])[CH2:17][CH2:18][O:13][CH2:14]1)=[O:5]
Reactant: COC(C(=O)Cl)c1ccccc1
Reactant: O=C1CCOCC1
Product: COC(C(=O)C1COCCC1=O)c1ccccc1
Yield: 14.5 %

Procedure:
3-(2-Methoxy-2-phenylacetyl)dihydro-2H-pyran-4(3H)-one (54 mg, 14.5%) was synthesised from 2-methoxy-2-phenylacetyl chloride and dihydro-2H-pyran-4(3H)-one according to the general procedure for the preparation of diketones. MS (ES−) m/z 247.1 (M−H)−
Reaction SMILES: [N+:1]([CH:4]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]2[CH2:16][CH2:17][CH:5]1[CH:6]=[CH:7]2)([O-:3])=[O:2].[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20].O1CCOCC1>C(O)(C)(C)C>[N+:1]([C:4]1([CH2:20][CH2:19][C:18]([O:22][CH3:23])=[O:21])[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]2[CH2:16][CH2:17][CH:5]1[CH:6]=[CH:7]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])C1C2C=CC(CC2)C1c1ccccc1
Reactant: C=CC(=O)OC
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Product: COC(=O)CCC1([N+](=O)[O-])C2C=CC(CC2)C1c1ccccc1

Procedure:
Variant B: 0.18 mole of 2-nitro-3-phenyl-bicyclo[2.2.2]-oct-5-ene, 0.18 mole of methyl acrylate and 3.8 ml of Triton B in 50 ml of tert.-butanol and stirred for 24 hours, a further 0.18 mole of methyl acrylate and 70 mlof dioxan are then added and the mixture is heated to the reflux temperature for 24 hours. After cooling, the reaction mixture crystallizes. A little ethanol is added, the mixture is neutralized with 2N hydrochloric acid and the crystal sludge is filtered. Recrystallization of the crystals from isopropanol with the addition of animal charcoal gives crystals of melting point 127°-131° C.
Reaction SMILES: P(O[CH2:9][CH3:10])(OCC)OCC.[Cl:11][C:12]1(Cl)[C:16]([Cl:17])=[C:15]([Cl:18])[C:14]([Cl:19])=[C:13]1[Cl:20]>O>[Cl:11][C:12]1[C:16]([Cl:17])([CH2:9][CH3:10])[C:15]([Cl:18])=[C:14]([Cl:19])[C:13]=1[Cl:20]
Reactant: CCOP(OCC)OCC
Reactant: ClC1=C(Cl)C(Cl)(Cl)C(Cl)=C1Cl
Solvent: O
Product: CCC1(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl
Yield: 96.4 %

Procedure:
A solution of triethyl phosphite (182.8 g., 1.1 mole) in 200 ml. of petroleum ether (pentane range) was charged to the equipment of the preceding example, which was immersed into a rock-salt-ice mixture. When the temperature of the solution reached 0°C. hexachlorocyclopentadiene (272.8 g., 1.0 mole), dissolved in 100 ml. of light petroleum ether, was added slowly to the well stirred solution at such a rate that the temperature of the mixture did not exceed +5°C. The addition required 10 hours. The clear, brown solution was poured with good stirring into a 5 liter 3 neck flask containing 2 liters of water and, after 1 hour of stirring, the product was steam distilled. After the separation of the low boiling petroleum ether 1,2,3,4,5-pentachloro-5-ethyl-cyclopentadiene, completely free of any phosphorus compound, distilled over as a pale yellow heavy oil, nD25 1.5398, the infrared spectrum of which matched perfectly that of the previous example. The product weighed 257.0 g., which corresponds to a 96.4% yield.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[CH3:7][Si:8]([CH3:44])([C:38]([CH3:43])([CH3:42])[CH:39]([CH3:41])[CH3:40])[O:9][C@H:10]1[CH2:27][C@H:26]([O:28][Si:29]([CH2:34][CH3:35])([CH2:32][CH3:33])[CH2:30][CH3:31])[C@@:25]2([CH3:36])[C:12](=[CH:13][CH:14]=[C:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[CH2:17][CH2:18][C:19]2=O)[CH2:11]1.C(O)(=O)C>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1(C)C=CC=CC=1>[CH3:44][Si:8]([CH3:7])([O:9][C@H:10]1[CH2:27][C@H:26]([O:28][Si:29]([CH2:30][CH3:31])([CH2:32][CH3:33])[CH2:34][CH3:35])[C@@:25]2([CH3:36])[C:12](=[CH:13][CH:14]=[C:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[CH2:17][CH2:18]/[C:19]/2=[CH:1]/[CH3:2])[CH2:11]1)[C:38]([CH3:43])([CH3:42])[CH:39]([CH3:40])[CH3:41]
Reactant: CC[Si](CC)(CC)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C(C)C)CC2=CC=C3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Reactant: CC(C)(C)[O-]
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: C/C=C1/CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C(C)C)C[C@H](O[Si](CC)(CC)CC)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
A 2-L three-necked flask equipped with a mechanical stirrer and an Ar-inlet tube was charged with 90.0 g (242 mmol) of ethyl triphenylphosphonium bromide and 480 mL of toluene. To the suspension, 27.2g (242 mmol) of potassium t-butoxide was added. After stirring at room temperature for 2 hr, the orange-red mixture was cooled with an ice-water bath. Then, 96.8 g (173 mmol) of (1α,3β)-3-[[dimethyl(1,1,2-trimethylpropyl)silyl]oxy]-1-[(triethylsilyl)oxy]androsta-5,7-dien-17-one was added with the aid of 30 mL of toluene. The mixture was stirred at room temperature overnight, and the reaction was quenched by the addition of 3.96 mL of acetic acid (69 mmol). After stirring for an additional hour, the suspension was filtered through a Celite pad. The filter cake was washed with 2×130 mL of toluene. The combined filtrate and washes were concentrated, and the residual toluene was removed by co-evaporation with 180 mL of methanol followed by drying under high vacuum. The residue was then dissolved in a mixture of 350 mL of hexane and 350 mL of 95% methanol. The hexane layer was washed with 180 mL of 95% methanol. The combined methanol layers were extracted with 2×150 mL of hexane. The combined hexane solutions were dried over sodium sulfate (Na2SO4), and concentrated. The residual hexane was removed by co-evaporation with 30 mL of methanol. The resulting solid residue was suspended in 175 mL of methanol, and the suspension was stirred for 1 hr to obtain a powdery material. After the suspension was stored in a refrigerator overnight, the precipitate was filtered and washed with 2×175 mL of 95% methanol. Drying under high vacuum gave 91.1 g (92.9% yield) of (1α,3β,17Z)-dimethyl[[1-[(triethylsilyl)oxy]pregna-5,7,17(20)-trien-3-yl]oxy](1,1,2-trimethylpropyl)silane as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[C:19]([O:20]C(=O)C)=[CH:18][C:5]2[CH:6]=[C:7]([C:9](=[O:17])[CH2:10][N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[O:8][C:4]=2[C:3]=1[CH3:24].[BH4-].[Na+].O>CO>[OH:17][CH:9]([C:7]1[O:8][C:4]2[C:3]([CH3:24])=[C:2]([CH3:1])[C:19]([OH:20])=[CH:18][C:5]=2[CH:6]=1)[CH2:10][N:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: CC(=O)Oc1cc2cc(C(=O)CN3CCOCC3)oc2c(C)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1c(O)cc2cc(C(O)CN3CCOCC3)oc2c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.2 %

Procedure:
A solution of acetic acid 6,7-dimethyl-2-(2-morpholin-4-yl-acetyl)-benzofuran-5-yl ester (35 mg), prepared as in Example 17, in MeOH (10 mL) was stirred while NaBH4 (40 mg) was added, and the mixture was stirred at room temperature for an additional 4 h. The mixture was poured into water, and extracted with ethylacetate. The organic layer was dried over MgSO4 and evaporated. The residue was purified by silica gel column eluting with 5% MeOH in DCM to give 21 mg of 2-(1-hydroxy-2-morpholin-4-yl-ethyl)-6,7-dimethyl-benzofuran-5-ol as an oil. Conversion into HCl salt gave a yellow solid. 1H NMR (CD3OD, 300 MHz) δ: 6.77 (s, 1H), 6.67 (s, 1H), 5.29 (dd, J=10.4, 3.3 Hz, 1H), 4.04(m, 2H), 3.85(q, 2H), 3.70–3.50 (m, 4H), 3.30(m, 2H), 2.40(s, 3H), 2.20(s, 3H) ppm. 13C NMR (CD3OD, 75 MHz) (as HCl salt) δ: 154.72, 151.88, 149.40, 125.02, 121.67, 120.21, 104.51, 102.50, 63.77, 63.69, 61.70, 60.19, 53.82, 51.28, 11.24, 11.10 ppm. M/S 292 (M+H+).