Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]C1C=CC(O)=CC=1.ClC1C=C(O)C=CC=1.[CH3:17][N:18]1[C:23]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][O:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)[CH2:26][CH2:25]2)=[CH:22][C:21](=[O:41])[N:20]([CH3:42])[C:19]1=[O:43]>>[ClH:1].[CH3:17][N:18]1[C:23]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][O:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)[CH2:26][CH2:25]2)=[CH:22][C:21](=[O:41])[N:20]([CH3:42])[C:19]1=[O:43]
Reactant: Oc1ccc(Cl)cc1
Agent: Cn1c(N2CCN(CCCOc3cccc(Cl)c3)CC2)cc(=O)n(C)c1=O
Agent: Oc1cccc(Cl)c1
Product: Cl

Procedure:
The same treatment as in Example 3 was effected except that 4-chlorophenol was replaced with 3-chlorophenol, thereby obtaining 17.5 g of the crystals of 1,3-dimethyl-6-[4-(3-[3-chlorophenoxy]propyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [Cl:1]C1C=CC(O)=CC=1.ClC1C=CC=CC=1O.[CH3:17][N:18]1[C:23]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:40])[CH2:26][CH2:25]2)=[CH:22][C:21](=[O:41])[N:20]([CH3:42])[C:19]1=[O:43]>>[ClH:1].[CH3:17][N:18]1[C:23]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:40])[CH2:26][CH2:25]2)=[CH:22][C:21](=[O:41])[N:20]([CH3:42])[C:19]1=[O:43]
Reactant: Oc1ccc(Cl)cc1
Agent: Cn1c(N2CCN(CCCOc3ccccc3Cl)CC2)cc(=O)n(C)c1=O
Agent: Oc1ccccc1Cl
Product: Cl

Procedure:
The same treatment as in Example 3 was effected except that 4-chlorophenol was replaced with 2-chlorophenol, thereby obtaining 8.2 g of the crystals of 1,3-dimethyl-6-[4-(3-[2-chlorophenoxy]propyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2([C:25]([OH:27])=O)[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:35][OH:36].C(N(CC)CC)C>C(Cl)Cl.C1COCC1.O>[OH:36][NH:35][C:25]([C:12]1([S:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:11])=[O:10])[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)=[O:27]
Reactant: NO
Reactant: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccccc3)CC2)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)C2(C(=O)NO)CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4-(4-Methoxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acid (2.0 g, 5.1 mmol) and DMEF (2 drops) in CH2Cl2 (100 ml) at 0° C, oxalyl chloride (1.0 gm, 8 mmol) was added in a drop-wise manner. After the addition, the reaction miture was stirred at room temperature for 1 hour. Simultaneously, in a separate flask a mixture of hydroxylamine hydrochloride (2.0 gm, 29 mmol) and triethylamine (5 ml, excess) was stirred in THF:water (5:1, 30 ml) at 0° C for 1 hour. At the end of 1 hour, the oxalyl chloride reaction mixture was concentrated and the pale yellow residue was dissolved in 10 ml of CH2Cl2 and added slowly to the hydroxylamine at 0° C. The reaction mixture was stirred at room temperature for 24 hours and concentrated. The residue obtained was extracted with chloroform and washed well with water. The product obtained was purified by silica gel column chromatography and eluted with chloroform the product 4-(4-Methoxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acid hydroxyamide was isolated as a colorless solid. mp 90-95° C.; Yield, 1.2 g, 48%; MS: 405 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 2.29 (m, 3H), 2.76-2.79 (m, 2H), 3.43 (m, 4H),4.30 (s, 2H), 7.14-7.17 (d,2H), 7.50-7.73 (m, 5H), 9.37 (s,1H), 10.53 (s,1H), 11.18 (s,1H).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.[CH3:29][C:30]1([CH3:37])[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1>C1COCC1.[Cl-].[NH4+].C(OCC)(=O)C>[CH3:29][C:30]1([CH3:37])[CH2:35][CH2:34][C:33](=[CH:2][O:3][CH3:4])[CH2:32][CH2:31]1
Reactant: CC1(C)CCC(=O)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC=C1CCC(C)(C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of methoxymethyl triphenylphosphonium chloride (35.5 g, 0.104 mol) in THF (400 mL) at 0° C. was added n-BuLi (33.1 mL of a 2.8M solution in hexanes; 0.095 mol). The mixture was stirred at 0° C. for 30 min., cooled to −78° C. and a solution of 4,4-dimethyl cyclohexanone (10.0 g, 0.079 mol) in THF (100 mL) was added, dropwise. After 1 hr at −78° C. the mixture was slowly warmed to 0° C., diluted with satd ammonium chloride (400 mL) and ethyl acetate (100 mL) and stirred at room temperature for 48 hr. Layers were separated and the aqueous phase was extracted with ethyl acetate. Combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with hexanes, solids were removed by filtration and the filtrated was concentrated in vacuo. The residue was dissolved in dichloromethane (40 mL), PS-TsNHNH2 (8 g; ca. 3.7 mmol/g) and acetic acid (2 drops) were added and the mixture was stirred at room temperature for 24 hr. Resin was removed by filtration and washed (CH2Cl2, MeOH, CH2Cl2). Combined filtrate/washings were concentrated in vacuo, affording (4,4-dimethyl cyclohexylidene)methyl methyl ether as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.CCOCC.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[CH:21][C:20]=1[CH2:38][CH3:39].C(N(CC)CC)C>[Cl-].[Zn+2].[Cl-].C(OCC)(=O)C.C1CCCCC1.CC(O)(C)C.ClCCCl>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:29][CH2:30]3)=[CH:21][C:20]=2[CH2:38][CH3:39])[N:7]=1
Reactant: CCc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCCl
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: CCc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Reaction time: 1 h
Yield: 83.4 %

Procedure:
A solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (166 mg, 0.766 mmol) in 1:1 DCE: t-BuOH (5 mL) was stirred at 0° C. under nitrogen. 1.0 M Zinc(II) chloride in ether (0.77 mL, 0.77 mmol) was added and the mixture stirred for one hour. tert-Butyl 4-(4-amino-3-ethylphenyl)piperidine-1-carboxylate (I40) (212 mg, 0.70 mmol) in 1:1 DCE: t-BuOH (5 mL) was added dropwise, and after 30 minutes triethylamine (146 μL, 1.05 mmol) in 1:1 DCE: t-BuOH (5 mL) was added and the mixture allowed to slowly come to room temperature. After 18 hours the mixture was concentrated, and chromatography (12 g silica cartridge, 0-50% ethyl acetate/cyclohexane) gave the title compound (I41) (283 mg, 84% yield) as a pale pink solid; 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J=0.6 Hz, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.15-7.07 (m, 3H), 4.25 (s, 2H), 2.80 (t, J=12.1 Hz, 2H), 2.69-2.59 (m, 3H), 1.83 (d, J=12.9 Hz, 2H), 1.69-1.59 (m, 2H), 1.49 (s, 9H), 1.23 (t, J=7.6 Hz, 3H). LCMS Method C: rt 6.94 min; m/z 429.1 [M-tBu+2H]+, 385.1 [M-Boc+2H]+; m/z 483.1 [M−H]−.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:3]=1.[C:16]1([CH3:28])[CH:21]=[CH:20][C:19]([S:22]([N:25]=C=O)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(#N)C>[C:16]1([CH3:28])[CH:17]=[CH:18][C:19]([S:22]([N:25]=[C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]([C:12]([O:14][CH3:15])=[O:13])=[CH:3]2)(=[O:23])=[O:24])=[CH:20][CH:21]=1
Reactant: COC(=O)c1cc(O)c2ccccc2n1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: CC#N
Product: COC(=O)c1cc(=NS(=O)(=O)c2ccc(C)cc2)c2ccccc2[nH]1
Temperature: 25 °C
Yield: 82.3 %

Procedure:
According to the procedure of Wright, Synthesis, 1984, 1058, methyl 4-hydroxy-2-quinolinecarboxylate (2.03 g, 0.01 m) and p-toluenesulfonyl isocyanate (1.97 g, 0.01 m) were mixed in reagent grade acetonitrile at RT. The heterogeneous mixture was heated at reflux until the evolution of COz had ceased (ca 2-3 hours). During this time a yellow solid formed. After cooling to RT, the yellow solid was collected by filtration, washed with acetonitrile, and dried to give methyl 4-(p-toluenesulfonylimino)-1,4-dihydroquinoline-2-carboxylate (2.93 g, 82%), melting point of 264°-265° C. (dec.), as a yellow solid.
Reaction SMILES: [CH:1]1([C:7](=[O:9])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:10]Br.S([O-])([O-])=O.[Na+].[Na+]>CO>[Br:10][CH2:8][C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:9]
Reactant: BrBr
Reactant: CC(=O)C1CCCCC1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(CBr)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a solution (50 mL) of 1-cyclohexylethanone (25.0 g) in methanol was added bromine (10.1 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. Saturated sodium sulfite aqueous solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-10% ethyl acetate/hexane) to give the title object compound (25.8 g, 63%) as a colorless oil.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(Cl)(=O)CCCCCCC/C=C\CCCCCCCC>>[CH2:13]([NH:27][CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: CCCCCCCCCCCCCCN
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Product: CCCCCCCCCCCCCCNC1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O

Procedure:
N-Tetradecyl-N-(D-galactopyranosyl)amine is prepared from 30 g of D-galactose and 53 g of tetradecylamine as described in Example 44. The galactoxylamine is reacted with oleoyl chloride by the process described in Example 11.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([OH:31])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35]O.O1C2C=CC(C3(C(NC4C=CC(C(OCCCO)C5C=CC=CC=5OC)=CN=4)=O)CC3)=CC=2OC1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([O:31][CH2:35][CH2:34][N:33]([CH3:37])[CH3:32])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CN(C)CCO
Reactant: COc1ccccc1C(O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Agent: COc1ccccc1C(OCCCO)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Product: COc1ccccc1C(OCCN(C)C)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((2-(dimethylamino)ethoxy)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-(hydroxy(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide and 2-(dimethylamino)ethanol in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((3-hydroxypropoxy)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[C:6]([F:12])[CH:5]=1)=[O:3].[C:13](=O)([O:17]CC)[O:14][CH2:15][CH3:16].[H-].[Na+]>>[Cl:10][C:9]1[CH:8]=[C:7]([Cl:11])[C:6]([F:12])=[CH:5][C:4]=1[C:2]([CH2:1][C:13]([O:14][CH2:15][CH3:16])=[O:17])=[O:3]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1cc(F)c(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(=O)c1cc(F)c(Cl)cc1Cl

Procedure:
Condensation of 2,4-dichloro-5-fluoroacetophenone 2 with diethyl carbonate in the presence of NaH yielded ethyl 2,4-dichloro-5-fluorobenzoylacetate 3. Treatment of the latter with triethyl orthoformate in acetic anhydride gave the carbon homologue enol ether intermediate 4 which was allowed to react with a slight excess of cyclopropylamine in methylene chloride at room temperature to give the enaminoketoester 5. Cyclization of the latter with 1 molar equivalent of NaH in refluxing dioxane yielded ethyl 1,4-dihydro-4-oxo-quinoline-3-carboxylate 6 which was then hydrolysed with aqueous NaOH to give 1-cyclopropyl-6-chloro-7-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (IM) 7. See also Scheme 1 below (Maurer, F. and Grohe, K., DE 3 435 392 through Chem. Abst., Vol. 105, No.5, 1984, pp. 97158e). Compound data:
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([SH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[C:16]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[N:17]=1>CN(C)C=O>[C:8]1([CH2:7][S:14][C:16]2[C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=[C:18]([C:26]([F:27])([F:29])[F:28])[N:17]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: SCc1ccccc1
Reactant: COC(=O)c1ccc(C(F)(F)F)nc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(F)(F)F)nc1SCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 6.55 g (0.0584 mol) of potassium-t-butoxide in 60 mL dry dimethylformamide under nitrogen at 0° C. was added 6.84 mL (0.0584 mol) of benzyl mercaptan in 20 mL dimethylformamide while maintaining the temperature below 15° C. A solution of 15.83 g (0.053 mol) of the product from Example 2a or 2b in 20 mL dry dimethylformamide was added dropwise maintaining the temperature at 0° C. and then stirred another 30 minutes at 0° C. The reaction was poured into ice water and extracted with ether. The combined organic layers were washed with water, brine, dried over magnesium sulfate and evaporated to afford 17.84 g (100%). 1H NMR is similar to Example 3. IR (neat) 1725, 1675, 1575, 1135, 850 cm-1.
Reaction SMILES: [BrH:1].C([N:9]1[CH2:18][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([OH:26])[CH:20]=2)[C:16]2[C:11](=[C:12]([N+:28]([O-])=O)[C:13]([OH:27])=[CH:14][CH:15]=2)[CH2:10]1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[BrH:1].[NH2:28][C:12]1[C:13]([OH:27])=[CH:14][CH:15]=[C:16]2[C:11]=1[CH2:10][NH:9][CH2:18][CH:17]2[C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([OH:26])[CH:20]=1
Reactant: O=[N+]([O-])c1c(O)ccc2c1CN(Cc1ccccc1)CC2c1ccc(O)c(O)c1
Agent: [Pd]
Agent: Br
Solvent: CCO
Product: Nc1c(O)ccc2c1CNCC2c1ccc(O)c(O)c1
Yield: 112.9 %

Procedure:
700 mg of 2-benzyl-4-(3,4-dihydroxyphenyl)-7-hydroxy-8-nitro-1,2,3,4-tetrahydroisoquinoline hydrobromide was dissolved in 14 ml of ethanol, and by adding thereto 0.07 g of 10% palladium-carbon, hydrogenation reaction was performed at 40° C. The reaction was over, the reaction mixture was filtered, and concentrated. The residue obtained was changed to precipitates by treatment with chloroform, the precipitates were collected by filtration and dried, affording 590 mg of 8-amino-4-(3,4-dihydroxyphenyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[N+:8]([CH3:11])([O-:10])=[O:9].[OH-].[Na+].Cl>CO.O>[N+:8]([CH:11]=[CH:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)([O-:10])=[O:9]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccco1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])C=Cc1ccco1
Temperature: -5 °C
Reaction time: 1 h
Yield: 63.3 %

Procedure:
In a 1L 3-necked flask equipped with a mechanical stirrer, thermometer and a dropping funnel was placed 2-furaldehyde 32I (48 g, 0.5 mol) and nitromethane (30.5 g, 0.5 mol) in methanol (100 mL). The resulting mixture was cooled to −5° C. A solution of sodium hydroxide (21 g, 0.525 mol) in water (75 mL) was added at such a rate to maintain internal temperature at 0° C. (45 min). The resulting paste was stirred at 0° C. for 1 hr and then ice cold water (100 mL) was added to get a homogeneous mixture. This mixture was poured into a stirring cold solution of hydrochloric acid (100 mL of concentrate hydrochloric acid in 150 mL of water)over 20 min. After 30 min, yellow solid was collected, washed with water (250 mL) and treated with 2 g of charcoal (Norit A) in boiling ethanol (75 mL). Hot filtered through a pad of celite (7 g) in a steam jacketed Buchner funnel. The pad was washed with hot ethanol (15 mL). The filtrate was placed in a fridge for 1 hr and then yellow solid was collected and air dried to give 44 g (63% yield) of 33I. Hplc analysis showed a purity of 98%. NMR (CDCl3) δ 7.8(q, 2H), 7.8(S br, 1H), 7.1(d, 1H), 6.7–6.9(m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Ni].O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Reaction time: 14 h
Yield: 96.9 %

Procedure:
To a suspension of 1.46 g (4.8 mmol) of 4-(4-nitrophenyl)-piperazine-1-carboxylic acid tert-butyl ester (Example 11) and 1 g of Raney Nickel in 50 mL of tetrahydrofuran is added hydrogen to an initial pressure of 54.5 psi. The reaction is shaken for 14 hours and then filtered. The filtrate is concentrated to give 1.29 g (97%) of the product as a solid.
Reaction SMILES: [C:1]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([NH:19]C(OCC)=O)[CH2:15][CH2:14]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>C(O)C.O>[C:1]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([NH2:19])[CH2:15][CH2:14]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)NN1CCN(CCCCC(=O)c2ccccc2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NN1CCN(CCCCC(=O)c2ccccc2)CC1

Procedure:
21.4 g of the resulting 4-(4-benzoylbutyl)-1-(ethoxycarbonylamino)piperazine was dissolved in 180 ml of ethanol, and a solution of 36.2 g of potassium hydroxide in 36 ml of water was added. The mixture was heated under reflux for 3 hours. The reaction mixture was cooled, and 136 ml of 4N hydrochloric acid was added to form a 4-(4-benzoylbutyl)-1-aminopiperazine solution.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[Cl:26].C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:23]4[CH:22]=[CH:21][C:20]([Cl:19])=[C:25]([Cl:26])[CH:24]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(Cl)c(Cl)c4)cc3CC[C@@H]12
Yield: 64.1 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 3,4-dichlorophenylboronic acid (149 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 16 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 156 mg (64%) of the title compound as a foam. mp 129°-135°. FDMS: m/e=374. α[D]589 =+68.66 (c=1.03, chloroform).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
To a solution of 4-bromobenzylalcohol (2 g, 10.7 mmol) in DCM (30 mL) at 0° C. was added Et3N (2.2 mL, 16.0 mmol) followed by methanesulfonyl chloride (910 μL, 11.8 mmol). The reaction was allowed to warm to room temperature, stirred for 2 hours and then quenched with water. Saturated aqueous NaHCO3 was added, the product was extracted with DCM, the combined organic extracts were filtered through a phase separator cartridge and concentrated to give methanesulfonic acid 4-bromo-benzyl ester (2.67 g, 10 mmol, 94%). A solution of the crude product (2.67 g, 10 mmol) in DMSO (40 mL) was stirred at room temperature for 16 hours with potassium thioacetate (1.26 g, 11 mmol). The reaction was treated with water and extracted with DCM, filtered through a phase separator, concentrated and purified by silica gel column chromatography (0-50% DCM in cyclohexane) to give thioacetic acid S-(4-bromo-benzyl) ester (1.81 g, 7.39 mmol, 69%). 1H NMR (300 MHz, CDCl3): δ 7.41 (d, 2 H), 7.16 (d, 2 H), 4.05 (s, 2 H), 2.35 (s, 3 H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[O:8].[NH4+:9].[OH-]>O>[OH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([NH2:9])=[O:1]
Reactant: O=CCCCCCO
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Product: NC(=O)CCCCCO
Temperature: 90 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
5.28 Grams (45 mmols) of 6-hydroxyhexanal was charged to a 100 milliliter Schlenk flask and dissolved in 10 milliliters of deionized water by heating to 85-95° C. in a water bath. The resulting solution was charged to the Parr autoclave containing 35 milliliters of NH4OH. The reactor was placed under 400 psi air, heated to 80° C. and a 500 psi air purge was established. Reaction was allowed to proceed for 3 hours. At that time, reaction conversion was virtually complete and 6-hydroxycaproamide was formed in 35% yield.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH:17]([CH3:19])[CH3:18]>CN(C=O)C>[CH:17]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([CH3:19])[CH3:18]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C=O)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
To a solution of 2 g (16.38 mmol) of 4-hydroxybenzaldehyde in 100 mL of DMF, 2.72 g (19.69 mmol) of K2CO3, 2.74 g (16.52 mmol) of KI and 3.94 mL (39.38 mmol) of 2-iodopropane was added under argon. The mixture was stirred at 80° C. overnight, concentrated and the residue obtained was partitioned between CHCl3 and H2O. The phases were separated, the aqueous phase was extracted with CHCl3 and the combined organic phases were dried over MgSO4 and concentrated. The crude product obtained was purified by chromatography on silica gel using EtOAc/hexane mixtures of increasing polarity as eluent, to give 2.08 g of the title compound of the example as an oil (77% yield).