Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11].C(N(CC)CC)C>ClCCl>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([S:19]([N:4]2[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][OH:9])[CH2:2][CH2:3]2)(=[O:21])=[O:20])=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: OCCN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCN(CCO)CC2)cc1
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of 415 μL (3.38 mmol) of 1-piperazineethanol in 20 mL of dichloromethane were added 500 mg (2.26 mmol) of 4-nitrobenzenesulfonyl chloride and 472 μL (3.38 mmol) of triethylamine under ice cooling, and the mixture was stirred for 30 minutes at the same temperature. The reaction mixture was diluted with dichloromethane and the organic layer was washed with water, saturated sodium bicarbonate aqueous solution and saturated saline solution and then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=30/1) to give 670 mg (94%) of the title compound.
Reaction SMILES: C(OCC)(=O)C.[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]2[C:19]([C:20]([O:22]CC3C=CC=CC=3)=[O:21])=[C:18]([CH3:30])[NH:17][C:16](=[O:31])[N:15]2[C:32](=[O:49])[NH:33][CH2:34][CH2:35][CH:36]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:11]=[CH:12][CH:13]=1>[H][H].[Pd]>[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]2[C:19]([C:20]([OH:22])=[O:21])=[C:18]([CH3:30])[NH:17][C:16](=[O:31])[N:15]2[C:32](=[O:49])[NH:33][CH2:34][CH2:35][CH:36]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: [H][H]
Reactant: CC1=C(C(=O)OCc2ccccc2)C(c2cccc(Cl)c2)N(C(=O)NCCC(c2ccccc2)c2ccccc2)C(=O)N1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)O)C(c2cccc(Cl)c2)N(C(=O)NCCC(c2ccccc2)c2ccccc2)C(=O)N1

Procedure:
10 ml of ethyl acetate was added to a mixture of 141 mg (0.237 mmol) of benzyl 4-(3-chlorophenyl)-3-(3,3-diphenylpropylcarbamoyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate and a catalytic amount of 10% palladium/carbon, and they were stirred at room temperature in hydrogen atmosphere under normal pressure overnight. The catalyst was filtered out, and the obtained filtrate was concentrated under reduced pressure. The residue was washed with hexane/ethyl acetate (1/1) and then dried under reduced pressure to obtain the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([O:15][CH3:16])[C:12](O)=[O:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>>[CH2:1]([O:8][C:9](=[O:10])[CH:11]([C:12]([Cl:19])=[O:13])[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(C(=O)O)C(=O)OCc1ccccc1
Reactant: O=S(Cl)Cl
Product: COC(C(=O)Cl)C(=O)OCc1ccccc1

Procedure:
A solution of Benzyloxy carbonyl methoxy-acetic acid (40 g) and Thionyl chloride (80 ml) was stirred at reflux temperature for 3 hours. Excess Thionyl chloride was distilled off, to the residue was added toluene (100 ml) and distilled off the solvent completely to get chloro carbonyl methoxy-acetic acid benzyl ester (40 g) as a light brown liquid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([OH:20])=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:21][CH3:22])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:23])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>CN(C)C=O>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([O:20][CH2:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:21][CH3:22])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:23])[CH:5]=1
Reactant: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)OCC(=O)OCc3ccccc3)c(Cl)c1Cl)C2
Temperature: 80 °C

Procedure:
A mixture containing [(5,6-dichloro-9a-ethyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetic acid (Example 20, Step D) (1.07 g, 0.003 mole), potassium carbonate (0.41 g, 0.003 mole) and benzyl bromoacetate (0.69 g, 0.003 mole) in dimethylformamide (35 ml) is heated at 80° C. for two hours. Then this mixture is filtered and the filtrate is concentrated in vacuo. The residue is dissolved in methylene chloride, washed with aqueous sodium bicarbonate and than water, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a viscous oil which is triturated with ether to give 1.06 g. of product.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][C@@H:8]([CH3:33])[C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17](=[O:32])[NH:18][C@@H:19]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][C:25]([Br:31])=[CH:26][CH:27]=3)[N:22]=2)[CH3:20])[NH:12]1)=[O:10])(C)(C)C.Cl.[CH:36]1([CH:39]([OH:43])C(O)=O)[CH2:38][CH2:37]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl.O1CCOCC1>[Br:31][C:25]1[CH:24]=[C:23]2[C:28]([CH:29]=[CH:30][C:21]([C@H:19]([NH:18][C:17]([C@@H:13]3[CH2:14][CH2:15][CH2:16][N:11]([C:9](=[O:10])[C@@H:8]([NH:7][C:6](=[O:5])[CH:39]([CH:36]4[CH2:38][CH2:37]4)[OH:43])[CH3:33])[NH:12]3)=[O:32])[CH3:20])=[N:22]2)=[CH:27][CH:26]=1
Reactant: O=C(O)C(O)C1CC1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)C(O)C1CC1)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Temperature: 0 °C
Yield: 30.8 %

Procedure:
((S)-2-{(S)-3-[(R)-1-(7-Bromo-quinolin-2-yl)-ethylcarbamoyl]-tetrahydro-pyridazin-1-yl}-1-methyl-2-oxo-ethyl)-carbamic acid tert-butyl ester, (1.07 g, 2.00 mmol) was suspended in dichloromethane (20 mL) and the mixture was cooled to 0° C. with stirring. 4 M Hydrogen chloride in 1,4-dioxane (11 mL) was added and the reaction mixture stirred for 90 minutes and then evaporated. Residual water was azeotroped off with toluene and the residue was suspended in dichloromethane (20 mL) and cyclopropyl-hydroxy-acetic acid (255 mg, 2.20 mmol) was added. The mixture was cooled to 0° C. with stirring and N,N-diisopropylethylamine (775 mg, 1.05 mL, 6.00 mmol) was added followed by (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (1.06 g, 2.40 mmol). The reaction was allowed to warm to ambient temperature and stirred for 18 h. 1M Hydrochloric acid was added and the organic layer was washed with saturated sodium bicarbonate solution, passed through a hydrophobic frit and evaporated. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate/methanol 1:0 to 9:1 to afford the title compound (328 mg) as a white foam. The original aqueous extracts were re-extracted with dichloromethane/methanol (9:1, 2×) and the organic extracts dried over anhydrous sodium sulfate, filtered and evaporated. The residue purified by silica gel chromatography eluting with a gradient of ethyl acetate/methanol 1:0 to 17:3 to afford the title compound (378 mg) as a white foam. The two foams were combined (706 mg, 66%). 1H NMR (300 MHz, CDCl3) δ 0.46-0.73 (m, 4H), 1.04-1.18 (m, 1H), 1.49-1.59 (m, 6H), 1.53-1.78 (m, 2H), 1.95-2.04 (m, 1H), 2.25-2.34 (m, 1H), 2.64-2.82 (m, 1H), 3.44-3.55 (m, 2H), 3.60-3.84 (m, 1H), 4.50-4.60 (m, 1H), 5.23-5.33 (m, 1H), 5.48-5.55 (m, 1H), 7.36-7.41 (m, 1H), 7.62-7.73 (m, 2H), 8.13-8.19 (m, 2H), 8.47-8.51 (m, 1H). LCMS (m/z) [M+H] 532.0, 534.0 Tr=2.07 min. LCMS (m/z) 532.0, 533.9 [M+H], Tr=2.12 min.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[N:23]([CH2:28][CH3:29])[N:24]=[C:25]([CH3:27])[CH:26]=4)=[O:21])=[CH:15][CH:14]=3)=[O:12])[CH:8]=2)[NH:3]1.[CH:30](OCC)=[O:31].[O-]CC.[Na+].Cl>C(O)C>[OH:31][CH:30]=[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]4[N:23]([CH2:28][CH3:29])[N:24]=[C:25]([CH3:27])[CH:26]=4)=[O:21])=[CH:17][CH:18]=3)=[O:12])[CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)CC(=O)N3)cc1
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)C(=CO)C(=O)N3)cc1
Temperature: 78 °C
Yield: 75.1 %

Procedure:
2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-amide (0.735 g, 1.89 mmol) and ethyl formate (0.454 mL, 3.78 mmol) were dissolved in anhydrous ethanol (3.80 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (3.53 mL, 9.46 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale orange precipitate. The suspension was filtered yielding an orange solid as the pure 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-amide (0.594 g, 1.42 mmol, 75%).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[CH:10](O)[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>CC#N>[CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1C(O)c1ccc(O)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CC#N
Solvent: CCOCC
Product: CCCCc1oc2ccccc2c1Cc1ccc(O)cc1
Reaction time: 0.17 h
Yield: 89.3 %

Procedure:
At −10° C., to a stirred solution of 4-[(2-butyl-benzofuran-3-yl)-hydroxy-methyl]-phenol (2.78 g, 9.39 mmol) in CH3CN was added portionwise triethylsilane (two×1.50 mL, 18.78 mmol total, @ 0.5 h interval). To the reaction was added BF3.Et2O (1.19 mL, 9.39 mmol) and the reaction was stirred for 10 min. The reaction was quenched with sat. aq. KCO3 and extracted with CH2Cl2. The organic extracts were washed with brine (3×), dried (MgSO4) and concentrated. Purification on silica gel gave 2.35 g (89%) the title compound as a white solid, mp 67-70° C. (DMSO-d6) 8 0.87 (t, 3H), 1.31 (sextet, 2H), 1.62 (quintet, 2H), 2.78 (t, 2H), 3.84 (s, 2H), 6.64 (d, 2H), 7.02 (d, 2H), 7.09 (dt, 1H), 7.16 (dt, 1H), 7.31 (d, 1H), 7.42 (d, 1H), 9.16 (s, 1H). IR (KBr) 3300, 2950, 1610, 1510 and 1450 cm−1. mass spectrum (EI) m/z 280 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:14])=O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([Cl:14])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1ccccc1C(=O)O
Solvent: CN(C)C=O
Product: COc1ccccc1C(=O)Cl

Procedure:
A mixture of 2-methoxybenzoic acid (45.6 g, 0.3 mol), thionyl chloride (53.5 g, 33 ml, 0.45 mol) and dimethylformamide (two drops) was refluxed for an hour. Excess thionyl chloride was then distilled off under reduced pressure. Benzene (50 ml) was added to the residue and the solvent was distilled off until the weight of the residue remained unchanged (about 51 g).
Reaction SMILES: Br[C:2]1[C:3](=[O:18])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[CH3:17])[CH:5]=[CH:6][CH:7]=1.[F-].[Cs+].[CH2:21](B1OC(C)(C)C(C)(C)O1)[CH:22]=[CH2:23]>C1COCC1.ClCCl.O>[CH2:23]([C:2]1[C:3](=[O:18])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[CH3:17])[CH:5]=[CH:6][CH:7]=1)[CH:22]=[CH2:21]
Reactant: C=CCB1OC(C)(C)C(C)(C)O1
Reactant: Cc1cc([N+](=O)[O-])ccc1-n1cccc(Br)c1=O
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: C=CCc1cccn(-c2ccc([N+](=O)[O-])cc2C)c1=O

Procedure:
In a flask which had been dried by heating, 1.50 g (4.85 mmol) of the compound from Example 12A, 1.44 g (9.46 mmol) of caesium fluoride and 0.56 g (0.48 mmol) of tetrakis-(triphenylphosphine)palladium(0) are initially charged in 30 ml of degassed THF. A solution of 2.04 g (12.1 mmol) of 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in 5 ml of degassed THF is added dropwise, and the mixture is heated at reflux overnight. The mixture is then diluted with dichloromethane, and water is added. After phase separation, the aqueous phase is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulphate and concentrated. The product is purified by chromatography on silica gel, giving 1.18 g (62% of theory) of the title compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:18][CH3:19])[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH2:16][CH2:15][CH:14]2[CH:10]1CC(=O)C2)[CH3:2].COCCCCCCCC1(C2CCCCCCC2)CCCCCCC1=O.[CH2:46]([O:48][CH:49]([CH2:59][CH3:60])[CH2:50][CH2:51][CH2:52][CH2:53][CH:54]1[CH2:58][CH2:57][CH:56]=[CH:55]1)[CH3:47].[Cl:61][C:62]([Cl:65])=[C:63]=[O:64]>>[Cl:61][C:62]1([Cl:65])[CH:56]2[CH:55]([CH:54]([CH2:53][CH2:52][CH2:51][CH2:50][CH:49]([O:48][CH2:46][CH3:47])[CH2:59][CH3:60])[CH2:58][CH2:57]2)[C:63]1=[O:64].[Cl:61][C:62]1([Cl:65])[C:63](=[O:64])[CH:15]2[CH:16]1[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([O:3][CH2:1][CH3:2])[CH2:18][CH3:19])[CH2:10][CH2:14]2
Reactant: CCOC(CC)CCCCC1C=CCC1
Reactant: O=C=C(Cl)Cl
Reactant: CCOC(CC)CCCCC1CCC2CC(=O)CC12
Agent: COCCCCCCCC1(C2CCCCCCC2)CCCCCCC1=O
Product: CCOC(CC)CCCCC1CCC2C(=O)C(Cl)(Cl)C12
Product: CCOC(CC)CCCCC1CCC2C1C(=O)C2(Cl)Cl

Procedure:
Disclosed is a method of synthesizing a compound, such as 6-(5-ethoxyhept-1-yl)bicyclo[3.3.0]octan-3-one or methoxyheptyl bicyclooctanone, from 3-(5-ethoxyhept-1-yl)cyclopentene or other starting material. Such a method comprises reacting 3-(5-ethoxyhept-1-yl)cyclopentene with dichloroketene to form a first mixture comprising 7,7-dichloro-4-(5-ethoxyhept-1-yl)bicyclo[3.2.0]heptan-6-one and 6,6-dichloro-4-(5-ethoxyhept-1-yl)bicyclo[3.2.0]-heptan-7-one. The first mixture is reacted with acetic acid and zinc to form a second mixture comprising 4-(5-ethoxyhept-1-yl)bicyclo[3.2.0]heptan-6-one and 4-(5-ethoxyhept-1-yl)bicyclo-[3.2.0]heptan-7-one. The second mixture is reacted with trimethylsulfonium iodide to form a third mixture comprising 2-(5-ethoxyhept-1-yl)spiro[bicyclo[3.2.0]heptane-6,2′-oxirane]. The third mixture is reacted with lithium iodide to form 6-(5-ethoxyhept-1-yl)bicyclo[3.3.0]octan-3-one.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>C(#N)C>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:11][NH:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[O:18])=[CH:15][CH:14]=1
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CC#N
Product: O=C(NNc1ccc([N+](=O)[O-])cc1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4-Nitrophenylhydrazine (32.0 g, 0.21 mole) was slurried in acetonitrile (500 ml) and the mixture was cooled to 0° C. A solution of 4-chlorobenzoyl chloride (17.5 g, 0.10 mole) in acetonitrile (25 ml) was added dropwise to the cooled slurry. The reaction mixture was allowed to stand overnight. The mixture was filtered and the solid was washed with acetonitrile, then thoroughly with water. The product was recrystallized from acetonitrile and decolorized with charcoal to give a pale yellow solid. Yield 24.8 g (85%) m.p. 245.5°-248.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][OH:9].C(=O)(O)[O-].[Na+].Cl[C:16]([O:18][CH3:19])=[O:17]>C(Cl)Cl>[OH:9][N:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[C:16](=[O:17])[O:18][CH3:19]
Reactant: Cc1ccccc1NO
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)N(O)c1ccccc1C

Procedure:
To a 250 ml 3-neck RBF, stirring under nitrogen atmosphere, was charged 16.1 g (1.0 eq., 0.13 moles) N-2-methylphenylhydroxyamine in 40 ml methylene chloride and 16.8 g (1.5 eq., 0.20 moles) sodium bicarbonate neat. With a pipet added 13.1 g (1.05 eq, 0.37 moles) methyl chloroformate neat to the mixture at -5° C. to +5° C. The reaction mixture was stirred at 0° C. for 30 min. following the addition and the reaction was monitored by GC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[CH3:16][C@@:17]1([CH2:20][N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])[CH2:19][O:18]1.C(N(CC)CC)C>C(O)C.ClCCl>[NH3:9].[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:19][C@:17]([OH:18])([CH3:16])[CH2:20][N:21]2[C:22](=[O:31])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]2=[O:30])[CH2:8][CH2:7]1
Reactant: C[C@@]1(CN2C(=O)c3ccccc3C2=O)CO1
Reactant: Clc1ccc(OC2CCNCC2)cc1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@](O)(CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1)CN1C(=O)c2ccccc2C1=O
Product: N
Temperature: 25 °C
Yield: 133.8 %
Yield: 2 %

Procedure:
A solution of 4-(3,4-dichlorophenoxy)piperidine (0.985 g, 4 mmoles), 2-[[(2R)-2-methyloxiranyl]methyl]-1H-isoindole-1,3(2H)-dione (0.869 g, 4 mmoles) and triethylamine (0.809 g, 1.12 ml, 8 mmoles) in ethanol (20 ml) was stirred at 50° C. for 5 h. The resulting solution was cooled to room temperature and concentrated in vacuo to leave a crude yellow gum. Flash chromatography (silica, 2% of 7N methanolic ammonia in dichloromethane as eluant) afforded the subtitle compound as a yellow oil (1.24 g).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]2[C:3]=1[C:4]([CH2:14][CH2:15][NH2:16])=[CH:5][NH:6]2.[F:17][C:18]([F:30])([F:29])[CH2:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(O)C>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]2[C:3]=1[C:4]([CH2:14][CH2:15][NH:16][CH2:24][C:23]1[CH:26]=[CH:27][CH:28]=[C:21]([O:20][CH2:19][C:18]([F:17])([F:29])[F:30])[CH:22]=1)=[CH:5][NH:6]2
Reactant: NCCc1c[nH]c2c(F)c(F)c(F)c(F)c12
Reactant: O=Cc1cccc(OCC(F)(F)F)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Fc1c(F)c(F)c2c(CCNCc3cccc(OCC(F)(F)F)c3)c[nH]c2c1F

Procedure:
By a method similar to Example 763, using 2-(4,5,6,7-tetrafluoro-1H-indol-3-yl)ethylamine (484 mg, 2.08 mmol), ethanol (45 mL), 3-(2,2,2-trifluoroethoxy)benzaldehyde (425 mg, 2.08 mmol), anhydrous sodium sulfate (3.5 g) sodium borohydride (236 mg, 6.24 mmol) to give the free base of the title compound as a straw colored solid. Recrystallize from methylene chloride to obtain the title compound: mp 107.2–108.2° C. 1H NMR (400 MHz, dmso-d6): 11.92 (br s, 1H), 7.32 (s, 2H), 6.95–6.99 (m, 2H), 6.87 (dd, 1H, J=2.4, 8.0 Hz) 4.68 (q, 2H, J=8.8 Hz), 3.70 (s, 2H), 2.88 (t, 2H, J=7.2 Hz) 2.75 (t, 2H, J=7.2 Hz). MS (ES+): m/e 421.1 (M+1). CHN (for C19H15F7N2O.1HCl.0.20H2O) caled: C, 53.83, H 3.66, N 6.61, found: C, 53.75, H 3.33, N 6.
Reaction SMILES: C([Li])(CC)C.C1CCCCC1.CCCCCC.[CH2:18]([O:25][C:26]1[CH:27]=[C:28]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[C:29]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[O:30])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN(C)CCN(C)C.CN([CH:52]=[O:53])C>C1COCC1>[CH2:18]([O:25][C:26]1[C:27]([CH:52]=[O:53])=[C:28]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[C:29]([N:31]([CH2:32][CH3:33])[CH2:34][CH3:35])=[O:30])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCN(CC)C(=O)c1ccc(OC)c(OCc2ccccc2)c1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(OC)c(OCc2ccccc2)c1C=O
Temperature: -70 °C
Reaction time: 4 h
Yield: 27.5 %

Procedure:
1.3 M sec-butyl-lithium in cyclohexane/hexane (54 ml, 0.07 moles) was dropped into a solution under nitrogen of 3-benzyloxy-N,N-diethyl-4-methoxy-benzamide (20 g, 0.064 moles), obtained as described in example 31, tetramethylethylendiamine (10.56 ml, 0.07 moles) in THF (2.25 1) under stirring in a dry ice bath at −70° C. After 2 hours at constant temperature, DMF (21.75 ml, 0.28 moles) was added. The temperature was kept constant for 4 hours then left overnight. The mixture was poured into a NaH2PO4/Na2HPO4 buffer solution (1 l) at pH=7, the phases were separated, the organic one was washed with water (1 l), dried and brought to dryness. The crude was chromatographed (eluent: benzene:ethyl acetate 1:1) to give 6 g of the title compound (yield: 27.4%).
Reaction SMILES: [Cl:1][C:2]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][C@@H:5]1[CH3:18])=[O:3].[F:19][C:20]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][OH:23]>>[ClH:1].[CH3:18][C@H:5]1[CH2:6][NH:7][CH2:8][C@@H:9]([CH3:10])[N:4]1[C:2]([O:23][CH2:22][C:21]1[CH:24]=[CH:25][CH:26]=[C:27]([F:28])[C:20]=1[F:19])=[O:3]
Reactant: OCc1cccc(F)c1F
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)Cl
Product: C[C@@H]1CNC[C@H](C)N1C(=O)OCc1cccc(F)c1F
Product: Cl

Procedure:
2,3-Difluorobenzyl cis-2,6-dimethylpiperazine-1-carboxylate hydrochloride was prepared from cis 1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine and 2,3-difluorobenzyl alcohol according to the methods described for Examples 52 and 54 to give the product as a white solid (0.1846 g, 57% overall); (Found: C, 52.4; H, 6.0; N, 8.6%. C14H18F2N2O2.HCl requires C, 52.4; H, 6.0; N, 8.7%); δH (400 MHz, DMSO-d6) 10.07 (1H, br), 9.33 (1H, br), 7.44 (1H, m), 7.28 (2H, m), 5.21 (2H, s), 4.30 (2H, m), 3.14 (2H, d, J 13.2 Hz), 3.06 (2H, m), and 1.31 (6 H, d, J 7.2 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Mg].[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH2:11]([N:18]1[CH2:23][CH2:22][C:21]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)([OH:24])[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccc(Br)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1
Reaction time: 0.45 h

Procedure:
4-Bromoanisole (13 ml, 0.1038 mol) in THF (13.5 ml) is added to a mixture of magnesium (2.24 g, 92.2 mmol) in dry THF (20 ml). When the magnesium is consumed the reagent mixture (XIII) is cooled in a ice/water bath and a mixture of 1-benzyl-4-piperidone (XII, 15 ml, 80.9 mmol) in THF (35 ml) is added dropwise over 21 minutes. The bath is then removed and the mixture stirred for 27 minutes, then poured into saturated aqueous sodium bicarbonate. The mixture is extracted several times with ether and the combined organic extracts are dried over magnesium sulfate, concentrated and the resulting material chromatographed on silica gel eluting with methanol/dichloromethane (4/96) containing ammonium hydroxide (0.4%). Impure fractions are combined and rechromatographed as above to give 1-benzyl-4-(4-methoxyphenyl)piperidin-4-ol (XIV), NMR (CDCl3) 1.74, 2.14, 2.46, 2.78, 3.58, 3.80, 6.88, 7.31 and 7.44 δ.