Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([O:12][C:13](=[O:35])[CH2:14]/[C:15](=[CH:19]\[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:24]([CH3:34])[CH:23]=1)/[C:16]([OH:18])=[O:17])([CH3:11])([CH3:10])[CH3:9].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C1(N)CCCCC1>CO.O>[CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([O:12][C:13](=[O:35])[CH2:14][C@@H:15]([CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[C:24]([CH3:34])[CH:23]=1)[C:16]([OH:18])=[O:17])([CH3:10])([CH3:11])[CH3:9]
Reactant: Cc1cc(CC/C=C(\CC(=O)OC(C)(C)C)C(=O)O)ccc1-c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CO
Solvent: NC1CCCCC1
Product: Cc1cc(CCC[C@H](CC(=O)OC(C)(C)C)C(=O)O)ccc1-c1ccccc1
Temperature: 22.5 °C
Reaction time: 16 h
Yield: 64.1 %

Procedure:
A stirred solution of (E)-2-[2-(tert-butoxy)-2-oxoethyl]-5-(2-methyl-1,1′-biphenyl-4-yl)-2-pentenoic acid cyclohexylamine salt (1.1 Kg, 2.3 mol) and [(S)-2,2′-bis(diphenylphosphino-1,1′-binaphthyl]chloro(p-cymene)ruthenium chloride (2.2 g, 2.4 mmol) in methanol (8.2 liters) and water (2.8 liters) was heated to 60° C., under hydrogen (60 p.s.i.), for 40 hours and then allowed to cool to 20-25° C. (enantiomeric excess=88%). The mixture was concentrated in vacuo to a volume of 3 liters and then ethyl acetate (5 liters) was added. The mixture was distilled at constant volume of ethyl acetate until water droplets appeared in the distillate. The mixture was then cooled to 20-25° C. and then demineralised water (2.9 liters) and citric acid (485 g, 2.5 mol) were added. The organic phase was separated and washed with demineralised water (1.1 liter) and then dried azeotropically by distillation at a constant volume of 8.25 liters. Methylethyl ketone (8.25 liters) was added and the mixture was warmed to 40° C. Cyclohexylamine (228 g, 2.28 mol) was added in one portion and the mixture was allowed to cool to 20-25° C., then was stirred for 16 hours. The mixture was filtered and the residue was washed with a mixture of ethyl acetate (55 ml) and methylethyl ketone (55 ml) and then dried in vacuo at 45° C. to leave the title compound as a colourless solid (0.71 Kg, 65% yield, enantiomeric excess=98.6%, 99% pure by HPLC).
Reaction SMILES: [CH:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH:13]([CH2:15][CH3:16])[CH3:14])=[CH:8][CH:7]=1)([CH2:3][CH3:4])[CH3:2].[Na].[CH2:18]([CH:20]([CH2:23][CH2:24][CH2:25][CH3:26])[CH:21]=O)[CH3:19]>ClCCl>[CH:13]([N:12]([CH2:21][CH:20]([CH2:18][CH3:19])[CH2:23][CH2:24][CH2:25][CH3:26])[C:9]1[CH:8]=[CH:7][C:6]([N:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[CH2:21][CH:20]([CH2:18][CH3:19])[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:11][CH:10]=1)([CH2:15][CH3:16])[CH3:14]
Reactant: CCC(C)Nc1ccc(NC(C)CC)cc1
Reactant: CCCCC(C=O)CC
Agent: [Na]
Solvent: ClCCl
Product: CCCCC(CC)CN(c1ccc(N(CC(CC)CCCC)C(C)CC)cc1)C(C)CC
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.5 %

Procedure:
N,N′-di-sec-butyl-p-phenylenediamine (20.8 g, 94 mmol) and sodium triacetoxyhydroborate (60.0 g, 283 mmol) in dichloromethane (500 ml) was treated with 2-ethylhexanal (30.3 g, 236 mmol) and stirred at room temperature for 15 hours. TLC showed the reaction complete and the reaction mixture was decanted to a beaker and quenched by addition of saturated aqueous NaHCO3 and stirred until effervescence ceased. The organic phase was separated and washed twice with water, once with brine and then dried (MgSO4), filtered and concentrated in vaccuo to afford a red oil. The product was chromatographed (eluent 5% ethyl acetate in heptane). Relevant fractions were collected and concentrated to afford a red oil (36.16 g, 82% yield).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([CH3:14])[CH:3]=1.[C:15]1([CH:21]2[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:13][C:6]1[N:5]=[C:4]([CH3:14])[CH:3]=[C:2]([NH:27][CH:24]2[CH2:23][CH2:22][CH:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:26][CH2:25]2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: NC1CCC(c2ccccc2)CC1
Reactant: CCOC(=O)c1c(Cl)cc(C)nc1C
Product: CCOC(=O)c1c(NC2CCC(c3ccccc3)CC2)cc(C)nc1C

Procedure:
was prepared analogously to Example 8 using ethyl 4-chloro-2,6-dimethylnicotinate and 4-phenylcyclohexylamine. nD23 :1.5389.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])[CH:7]=[C:8]([CH3:10])[O:9][C:4]=2[CH:3]=1.[Na].[C:15]([NH:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32]Cl)[CH2:26][CH2:25]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(O)C>[C:15]([NH:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][O:1][C:2]2[CH:13]=[CH:12][C:5]3[C:6](=[O:11])[CH:7]=[C:8]([CH3:10])[O:9][C:4]=3[CH:3]=2)[CH2:26][CH2:25]1)(=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(NC1CCN(CCCCl)CC1)c1ccccc1
Reactant: Cc1cc(=O)c2ccc(O)cc2o1
Agent: [Na]
Solvent: CC(C)O
Product: Cc1cc(=O)c2ccc(OCCCN3CCC(NC(=O)c4ccccc4)CC3)cc2o1

Procedure:
5.3 g. (0.03 mol) 7-hydroxy-2-methyl-4H-1-benzopyran-4-one are added to a solution of 0.69 g. (0.03 mol) sodium in 75 ml. propan-2-ol and the mixture heated under reflux for 10 minutes. 8.4 g. (0.03 mol) 3-(4-Benzamidopiperidino)-propyl chloride dissolved in 25 ml. propan-2-ol are added thereto, the mixture heated under reflux for 12 hours, evaporated and the residue taken up in dichloromethane and the solution washed with dilute aqueous sodium hydroxide solution. The organic phase is evaporated and the residue recrystallised from propan-2-ol. There are obtained 6.8 g. (54% of theory) 7-[3-(4-benzamidopiperidino)propoxy]-2-methyl-4H-1-benzopyran-2-one; m.p. 173°-175° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:17][CH2:16][O:15][CH2:14]3)[N:11]=[CH:10][C:9]=2[C:18]([OH:20])=O)=[C:4]([Cl:21])[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:34][O:35][C:36]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:37]=1[CH2:38][NH2:39].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:17][CH2:16][O:15][CH2:14]3)[N:11]=[CH:10][C:9]=2[C:18]([NH:39][CH2:38][C:37]2[CH:40]=[CH:41][C:42]([O:44][CH3:45])=[CH:43][C:36]=2[O:35][CH3:34])=[O:20])=[C:4]([Cl:21])[CH:3]=1
Reactant: O=C(O)c1cnn(C2CCOC2)c1-c1ccc(Br)cc1Cl
Reactant: COc1ccc(CN)c(OC)c1
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CNC(=O)c2cnn(C3CCOC3)c2-c2ccc(Br)cc2Cl)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(±)-5-(4-bromo-2-chlorophenyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxylic acid (1 g) was dissolved in DCM (20 mL), and CDI (611 mg) was added, followed by stirring at room temperature for one hour. 2,4-dimethoxybenzylamine (0.809 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for two hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with DCM. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 10% to 40%) to give the title compound (1.26 g).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([O:29]C)=[O:28])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO.O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([OH:29])=[O:28])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccccc1COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1csc(-c2cc3cc(OCc4ccccc4C(=O)O)ccc3o2)n1
Yield: 99.7 %

Procedure:
A mixture of 4-tert-butyl-2-[5-(2-methoxycarbonylphenylmethoxy)benzofuran-2-yl]thiazole (0.28 g) and 4N aqueous sodium hydroxide (1.0 ml) in methanol (5 ml) was stirred under reflux 5.5 hours. After being cooled, the resulting solution was concentrated under reduced pressure to give a residue. The residue was dissolved in water and adjusted to pH 4 with diluted aqueous hydrochloric acid to give crystals. The crystals were filtered and washed with water to give 4-tert-butyl-2-[5-(2-carboxyphenylmethoxy)benzofuran-2-yl]thiazole (0.27 g).
Reaction SMILES: O.C(O[C:7](=[O:10])[CH:8]=[O:9])CCC.[CH3:11][NH:12][C:13]([NH2:15])=[O:14]>C(O)(=O)C>[OH:10][CH:7]1[N:12]([CH3:11])[C:13](=[O:14])[NH:15][C:8]1=[O:9]
Reactant: CNC(N)=O
Reactant: CCCCOC(=O)C=O
Solvent: CC(=O)O
Solvent: O
Product: CN1C(=O)NC(=O)C1O
Yield: 80 %

Procedure:
15.0 g of glyoxylic acid n-butyl ester monohydrate and 7.4 g of N-methylurea were refluxed in an 80% aqueous solution of acetic acid for 1 hour. After the solvent was removed by distillation, a small amount of methanol was added to the residue and the insoluble matter was filtered off. The filtrate was then evaporated to dryness under reduced pressure. The resulting crude crystals were recrystallized from ethyl acetate to give 10.4 g of 5-hydroxy-1-methylhydantoin (compound 1) in the form of white crystals.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1.[Li]CCCC.[Br:15]Br>C1COCC1.C1CCCCC1>[Br:15][C:4]1[S:3][C:2]([CH3:1])=[N:6][C:5]=1[C:7]([OH:9])=[O:8]
Reactant: BrBr
Reactant: Cc1nc(C(=O)O)cs1
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: Cc1nc(C(=O)O)c(Br)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Methyl-thiazole-4-carboxylic acid (13.0 g, 90.8 mmol) was dissolved in 750 ml THF and cooled to −75° C. n-BuLi (1.6M in THF; 120 ml, 190.7 mmol) was added dropwise in 30 minutes. The red suspension was stirred for 15 min. at −75° C. and 30 min. at 0° C. A solution of bromine (5.1 ml, 100 mmol) in 20 ml cyclohexane was added dropwise at −75° C. and stirring was continued at room temperature for 2 hrs. The reaction mixture was quenched with 20 ml water, evaporated and acidified with 2N HCl to pH 2. The aqueous layer was extracted two times with ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product (16.4 g, 81%) [MS: m/e=223.0 (M+H+)] was used without any further purification for the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:19])[N:11]([CH3:18])[CH:12]=[CH:13][C:14]=1[C:15]([OH:17])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:20][C:21]1[S:22][CH2:23][CH2:24][N:25]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:10](=[O:19])[N:11]([CH3:18])[CH:12]=[CH:13][C:14]=1[C:15]([SH:22]1[CH2:23][CH2:24][NH:25][C:21]1=[S:20])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: SC1=NCCS1
Reactant: Cn1ccc(C(=O)O)c(OCc2ccccc2)c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cn1ccc(C(=O)[SH]2CCNC2=S)c(OCc2ccccc2)c1=O
Reaction time: 4 h
Yield: 80 %

Procedure:
To a solution of 3-benzyloxy-4-carboxy-1-methyl-2(1H)-pyridinone (1.05 g, 4 mmol), 2-mercaptothiazoline (0.50 g, 4.2 mmol) and a catalytic amount of 4-dimethylaminopyridine (DMAP) in dry methylene chloride (50 mL), N,N'-dicyclohexylcarbodiimide (DCC) (0.86 g, 4.2 mmol) is added. Alter stirring for 4 hours, the dicyclohexylurea (DCU) solids are removed by filtration, the yellow filtrate is rotary evaporated to give a yellow solid. Crystallization from isopropanol-methylene chloride gives the title compound (1.16 g, 80.4%) as bright yellow crystalline plates, m.p. 149°-150° C. 1H NMR (250 MHz, CDCl3) δ2.867 (t, 2H, J=7.32), 3.594 (s, 3H), 4.313 (t, 2H, J=7.33), 5.301 (s, 2H), 6.107 (d, 1H, J=6.99), 7.126 (d, 1H, J=7.00), 7.31-7.45 (m, 5H). Anal for C17H16N2O3S2Calcd. (found): C, 56.64 (56.36); H, 4.47 (4.47); N, 7.73 (7.73); S, 17.78 (17.41).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]=1[CH3:13].CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:30].[N:31]1([CH2:37][CH2:38][CH2:39][N:40]2[CH2:46][C:45]3[CH:47]=[C:48](/[CH:51]=[CH:52]/[C:53](O)=[O:54])[CH:49]=[N:50][C:44]=3[NH:43][C:42](=[O:56])[CH2:41]2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[ClH:30].[CH3:1][N:2]([CH2:3][C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]=1[CH3:13])[C:53](=[O:54])/[CH:52]=[CH:51]/[C:48]1[CH:49]=[N:50][C:44]2[NH:43][C:42](=[O:56])[CH2:41][N:40]([CH2:39][CH2:38][CH2:37][N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)[CH2:46][C:45]=2[CH:47]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN(CCCN1CCOCC1)CC(=O)N2
Reactant: CNCc1sc2ccccc2c1C
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(CCCN2CCOCC2)CC(=O)N3)sc2ccccc12
Yield: 56 %

Procedure:
According to the procedure of Example 1, except substituting methyl-(3-methyl-benzo[b]thiophen-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-[4-(3-morpholin-4-yl-propyl)-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.20 g, 56%) was prepared as an off-white powder: 1H NMR (300 MHz, DMSO-d6) δ 10.88 (br s, 1H), 10.48 (br s, 1H), 8.58 (s, 1H), 8.31 (s, 1H), 7.88-7.86 (m, 1H), 7.75-7.72 (m, 1H), 7.60-7.55 (m, 1H), 7.42-7.30 (m, 3H), 5.16-4.89 (m, 2H), 3.98 (br s, 2H), 3.92-3.79 (m, 4H), 3.63 (br s, 2H), 3.37-3.33 (m, 6H), 3.18-3.10 (m, 2H), 2.94 (s, 1H), 2.63 (br s, 2H), 2.42 (s, 3H), 1.92 (br s, 2H); MS (ESI) m/e 534 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([PH:4](=[O:6])[OH:5])[CH3:3].Cl[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]>O1CCOCC1.O>[C:12]1([CH2:11][O:10][C:8]([NH:1][CH:2]([PH:4](=[O:5])[OH:6])[CH3:3])=[O:9])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(N)[PH](=O)O
Solvent: C1COCCO1
Solvent: O
Product: CC(NC(=O)OCc1ccccc1)[PH](=O)O
Temperature: 20 °C
Yield: 73.8 %

Procedure:
To a solution of 1.7 g (15.6 mmol) of 1-aminoethyl phosphinic acid in 35 ml of a mixture of dioxane and water, in the presence of an equivalent of soda (624 mg), there is added, 0° C., dropwise and simultaneously, a solution of 3.1 g (18.3 mmol) of benzyl chloroformate in 9 ml of dioxane and, so as to maintain the pH of the reaction about 9, a solution of 1 g of soda in 8.7 ml of water. At the end of the addition, the mixture is maintained at a temperature about 20° C. for 2 hours. The aqueous phase is then washed 3 times with 20 ml of diethyl ether. The aqueous phase is acidified, at 0° C., with brisk agitation, with 11 ml of a 6N hydrochloric acid solution. An abundant white precipitate forms, which is filtered, washed with water and dried. There is recovered 2.8 g of product (yield=73.9%).
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[N:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)[NH2:2].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:23]2[C@H:32]3[C@H:27]([CH2:28][CH2:29][CH2:30][CH2:31]3)[C:26](=[O:33])N(CCO)N=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:23]2[C@H:32]3[C@H:27]([CH2:28][CH:29]=[CH:30][CH2:31]3)[C:26](=[O:33])[N:1]([C:3]3[CH:4]=[N:5][C:6]4[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=4[N:8]=3)[N:2]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(C2=NN(CCO)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: NNc1cnc2ccccc2n1
Product: COc1ccc(C2=NN(c3cnc4ccccc4n3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound C and 2-hydrazino-1,4-benzodiazine as described for compound 35. Purified by chromatography and crystallized from diethyl ether. M.p. 154°-156° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[CH:15][C:14]=2[Cl:20])[CH2:9][CH2:8]1)=[O:6].[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([BH3-])#N.[Na+]>CO>[CH2:21]([NH:1][CH2:2][CH2:3][NH:4][C:5]([CH:7]1[CH2:8][CH2:9][N:10]([C:13]2[C:14]([Cl:20])=[CH:15][N:16]=[CH:17][C:18]=2[Cl:19])[CH2:11][CH2:12]1)=[O:6])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCCNC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C(NCCNCc1ccccc1)C1CCN(c2c(Cl)cncc2Cl)CC1
Reaction time: 2 h
Yield: 30 %

Procedure:
To a solution of N-(2-aminoethyl)-1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide E13 (50 mg, 0.16 mmol) in MeOH (5 mL) was added benzaldehyde (16 μL, 0.16 mmol). After stirring for 2 h, sodium cyanoborohydride (20 mg, 0.32 mmol) was added and the mixture was stirred for a further 20 h. The solvent was removed under reduced pressure, the residue was dissolved in EtOAc (20 mL), washed with a saturated solution of sodium hydrogencarbonate (25 mL), brine (25 mL), dried (MgSO4) and the solvent was removed under reduced pressure. The crude product was purified by preparative tlc on silica gel (CH2Cl2, MeOH, 9:1) to furnish the title compound as a colourless oil (19 mg, 30%), umax (CHCl3)/cm−1 3015, 2850, 1659, 1558, 1512, 1236, 1146, 1036, 934; m/z (ESI) C20H25Cl2N4O requires 407.1400, found [M+H]+ 407.1401.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][N:30]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[O:22])=[CH:17][CH:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:6].[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH:25]1([CH2:24][NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:11]([CH3:14])=[CH:12][CH:13]=[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:28]=[CH:29][N:30]=[C:2]([N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)[CH:3]=4)[CH:9]=3)=[CH:16][CH:17]=2)=[O:22])[CH2:27][CH2:26]1
Reactant: C1CCNCC1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Product: Cc1ccc(NC(=O)c2ccnc(N3CCCCC3)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-piperidin-1- ylisonicotinamide was prepared from 2-chloro-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isonicotinamide and piperidine using method A. NMR; δH [2H6]—DMSO 10.29,(1H, s), 8.62,(1H, t), 8.22,(1H, d), 7.93,(2H, d), 7.71,(1H, dd), 7.65,(1H, d), 7.44,(2H, d), 7.30,(1H, d), 7.20,(1H, s), 6.99,(1H, d), 3.58,(4H, m), 3.16,(2H, t), 2.20,(3H, s), 1.60-1.54,(6H, m), 1.04,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.43 min, MH+469.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:21]=[C:22]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)[CH:23]=[CH:24][CH:25]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH:36](/B(O)O)=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:34]=[CH:35][C:2]([CH:36]=[CH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:3][CH:4]=2)[N:8]([C:20]2[CH:21]=[C:22]([N:26]3[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]3)[CH:23]=[CH:24][CH:25]=2)[CH:9]=1
Reactant: CCCCCC/C=C/B(O)O
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)c2)S(=O)(=O)N1
Product: CCCCCCC=Cc1ccc(Cc2nc(-c3ccc(Cl)cc3Cl)cn2-c2cccc(N3CC(=O)NS3(=O)=O)c2)cc1

Procedure:
5-{3-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using trans-1-octen-1-ylboronic acid (47 mg, 0.3 mmol) to give 5-{3-[4-(2,4-dichloro-phenyl)-2-(4-oct-1-enyl-benzyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [F:1][C:2]1[C:3]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH2:8][CH:7]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:6][CH2:5]2.[CH2:28](Br)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>CCOCC>[F:1][C:2]1[C:3]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:25][CH:26]=2)=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH2:8][CH:7]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:6][CH2:5]2
Reactant: CCCCCCCCC1CCc2c(cc(F)c(F)c2-c2ccc(O)cc2)C1
Reactant: CCCCCCCCBr
Solvent: CCOCC
Product: CCCCCCCCOc1ccc(-c2c(F)c(F)cc3c2CCC(CCCCCCCC)C3)cc1

Procedure:
From 6,7-difluoro-5-(4-hydroxyphenyl)-2-octyl-1,2,3,4-tetrahydronaphthalene and 1-octyl bromide by means of the Williamson ether synthesis.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH2:5].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[CH3:1][O:2][C:3](=[O:9])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH:5][S:18]([C:15]1[CH:14]=[CH:13][C:12]([O:11][CH3:10])=[CH:17][CH:16]=1)(=[O:20])=[O:19]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(OC)cc1)C(C)C
Yield: 90 %

Procedure:
In a similar manner to that in Example 1(2)-b, a reaction was carried out using (±)-valine methyl ester and 4-methoxybenzenesulfonyl chloride to afford the desired compound (yield 90%) as a white powder.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12]([CH3:20])[CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl>[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:20])[CH2:13][N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=Cc1ccc(C(C)(C)C)cc1)CN1CCCCC1
Agent: [Pd]
Agent: Cl
Product: CC(Cc1ccc(C(C)(C)C)cc1)CN1CCCCC1

Procedure:
To a solution of 4.5 g of 1-[3-(p-tert.butyl-phenyl)-2-methyl-2-propenyl]-piperidine in 125 ml of alcohol are added 1.7 ml of 32% hydrochloric acid and subsequently 1.5 g of 5% palladium/carbon and the mixture is then hydrogenated. After completion of the hydrogen uptake, the catalyst is filtered, the filtrate is treated with 200 ml of 10% sodium hydroxide and extracted with ether. The combined ether extracts are washed neutral with water, dried and evaporated. By distillation there is obtained pure 1-[3-(p-tert.butyl-phenyl)-2-methyl-propyl]-piperidine of boiling point 104° C./0.032 Torr.
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:21]C)=[C:11]4[O:12][C@H:13]5[C@@H:14]([OH:20])[CH:15]=[CH:16][C@@H:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.Cl.N1C=CC=CC=1.[OH-].[Na+]>O>[CH:8]1[C:7]2[CH2:19][C@H:18]3[N:2]([CH2:3][CH2:4][C@@:5]45[C@H:17]3[CH:16]=[CH:15][C@H:14]([OH:20])[C@@H:13]4[O:12][C:11]([C:6]=25)=[C:10]([OH:21])[CH:9]=1)[CH3:1]
Reactant: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5

Procedure:
Rapoport et al. (J.A.C.S. 5485 and 5900 73 1951) have claimed a 22% yield of morphine from codeine employing pyridine hydrochloride as the cleavage agent. 1.00g codeine was heated with pyridine hydrochloride for six minutes under nitrogen. The reaction mixture was dissolved in 20ccm water, basified with 10ccm 4N NaOH and extracted with chloroform to yield 0.210g morphine.