Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]([CH3:25])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:11][CH:10]=2)[O:3]1.[CH3:27][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>C1COCC1>[CH3:27][N:17]([CH2:16][C@@H:15]([C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:26])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1)[CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: C[C@@H](CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: C[C@@H](CN(C)C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reaction time: 1 h
Yield: 66.3 %

Procedure:
A solution of (R)-tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propylcarbamate (9.0 g, 24.93 mmol) in anhydrous THF (120 mL) was cooled to 0° C. and NaHMDS (30 mL, 29.9 mmol) was added. The mixture was stirred for 1 h, methyl iodide (1.9 mL, 29.9) in THF (40 mL) added and stirred for 14 h. The reaction mixture was quenched with water (20 mL) and diluted with ethyl acetate (250 mL). The layers were separated and the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and the residue purified by column chromatography (silica, 0-30% ethyl acetate/heptane) to afford the desired product (6.2 g, 66%) as light yellow oil: ESI MS m/z 376 [C21H13NO4+H]+.
Reaction SMILES: [CH2:1]([C:8](=[CH2:13])[C:9]([O:11][CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][NH:15][CH3:16]>CO>[CH2:1]([CH:8]([CH2:13][N:15]([CH3:16])[CH3:14])[C:9]([O:11][CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(Cc1ccccc1)C(=O)OC
Reactant: CNC
Solvent: CO
Product: COC(=O)C(Cc1ccccc1)CN(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 30.0 g of methyl α-benzylacrylate, prepared by the method of R. B. Miller and B. F. Smith, Synth. Commun. 3, 359 (1973) in methanol (50 ml) is added to a solution of dimethylamine (71.0 g) in methanol (210 ml), and the mixture is stirred at room temperature for 48 hours. The solvent is removed under reduced pressure to give methyl 2-benzyl-3-dimethylaminopropionate as a yellow oil, used without purification in the next synthetic step; NMR: δ7.14 (s, 5H), 3.52 (s, 3H), 2.82 (m, 3H), 2.17 (s, 6H), 2.63-2.17 (m, remaining H).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1[CH:54]=[C:53]([C:55]2[CH:56]=[C:57]([NH2:61])[CH:58]=[CH:59][CH:60]=2)[CH:52]=[N:51][CH:50]=1>CN(C=O)C>[N:49]1[CH:54]=[C:53]([C:55]2[CH:56]=[C:57]([NH:61][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:58]=[CH:59][CH:60]=2)[CH:52]=[N:51][CH:50]=1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Nc1cccc(-c2cncnc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2cncnc2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 8.6 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-pyrimidin-5-yl-phenylamine (0.011 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.002 g of product in 9% yield: LCMS (ESI) m/z 360 (MH+).
Reaction SMILES: [SH:1]CCC(OC)=O.[H-].[Na+].[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[C:18]1([CH:21]([N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)[CH3:22])[CH2:20][O:19]1.Cl>CN(C)C=O.O>[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[C:18]([OH:19])([CH:21]([N:23]1[CH:27]=[N:26][CH:25]=[N:24]1)[CH3:22])[CH2:20][SH:1]
Reactant: CC(n1cncn1)C1(c2ccc(F)cc2F)CO1
Reactant: COC(=O)CCS
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(n1cncn1)C(O)(CS)c1ccc(F)cc1F
Reaction time: 0.08 h

Procedure:
Methyl 3-mercaptopropionate (0.88 ml) was added to N,N-dimethylformamide (14 ml) containing 60% sodium hydride in oil (0.32 g) under ice-cooling. After 5 minutes, a solution of 2-(2,4-difluorophenyl)-2-[1-(1H-1,2,4-triazol-1-yl)ethyl]oxirane (0.67 g) in N,N-dimethylformamide (3.5 ml) was added over 5 minutes with ice-cooling. After 15 minutes, the reaction mixture was poured into water (150 ml), neutralized with hydrochloric acid and extracted with ethyl acetate (50 ml×3). The organic layers were combined, washed with saturated aqueous sodium chloride solution (30 ml× 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (3 cm×10 cm) and elution was carried out with ethyl acetate-hexane (1:1). The desired fraction was concentrated and diethyl ether was added to the residue to give crude crystals (0.25 g) of 2-(2,4-difluorophenyl)-1-mercapto-3-[(1H)-1,2,4-triazol-1-yl]-2-butanol (of low polarity; compound 116, diastereomer B). The crystals were recrystallized from a mixture of chloroform and diethyl ether to give 0.21 g of compound 116. The mother liquor of the above crude crystals was further subjected to silica gel chromatography (2 cm×12 cm) and elution was carried out with ethyl acetate-hexane (1:1). The desired fraction was concentrated and diethyl ether and hexane were added to the residue to give crude crystals (0.25 g) of 2-(2,4-difluorophenyl)-1-mercapto-3-[(1H)-1,2,4-triazol-1-yl]-2-butanol (of high polarity; compound 115, diastereomer A). The crystals were recrystallized from a mixture of chloroform and diethyl ether to give crystals of compound 115 (0.11 g). Compound 115 (diastereomer A) m.p. 112°-117° C. (colorless prism)
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:23][C@H:22]([CH2:24][O:25][CH3:26])[C@@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[I:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][NH2:32].Cl>>[I:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][NH:32][C:2]1[C:3]2[N:4]=[CH:5][N:6]([C:7]=2[N:8]=[CH:9][N:10]=1)[C@@H:11]1[O:23][C@H:22]([CH2:24][O:25][CH3:26])[C@@H:17]([OH:18])[C@H:12]1[OH:13]
Reactant: NCc1cccc(I)c1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Product: COC[C@H]1O[C@@H](n2cnc3c(NCc4cccc(I)c4)ncnc32)[C@H](O)[C@@H]1O

Procedure:
Method B. The reaction was carried out with 6-chloro-9-(2,3-di-O-acetyl-5-O-methyl-β-D-ribofuranosyl)-purine (60, 363 mg, 0.94 mmol) and 3-iodobenzylamine.HCl (1.41 mmol, 380 mg). The mixture was purified by column chromatography (eluens 5% MeOH in CH2Cl2). Yield 397 mg (0.80 mmol, 85%), mp 155–157° C.; Rf 0.54 (eluens 10% MeOH in CH2Cl2); 1H NMR (DMSO-d6) δ 8.40 (bs, 1H, NH), 8.33 (s, 1H, H-8), 8.21 (s, 1H, H-2), 7.70 (s, 1H, CCHCI), 7.57 (d, 1H, J=6.52 Hz, CCHCHCH), 7.34 (d, 1H, J=5.15 Hz, CCHCH), 7.08 (t, 1H, J=8.93 Hz, CCHCH), 5.89 (d, 1H, J=4.12 Hz, H-1′), 5.50–5.47 (m, 1H, OH-2′), 5.27–5.25 (m, 1H, OH-3′), 4.68–4.56 (m, 3H, H-2′, NHCH2), 4.14–4.13 (m, 1H, H-3′), 4.01–3.98 (m, 1H, H-4′), 3.57–3.53 (m, 2H, H-5′), 3.31 (s, 3H, OCH3); MS m/z 498 (M+H)+; Anal. (C18H20N5O4) C, H, N.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[OH:10][CH2:11][CH2:12][O:13][C:14](=[O:28])[NH:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][NH:21][C:22](=[O:27])[O:23][CH2:24][CH2:25][OH:26]>CC(C)=O.O>[OH:10][CH2:11][CH2:12][O:13][C:14]([NH:15][CH2:16][CH2:17][N:18]([C:8]1[N:1]=[C:2]([N:18]([CH2:17][CH2:16][NH:15][C:14]([O:13][CH2:12][CH2:11][OH:10])=[O:28])[CH2:19][CH2:20][NH:21][C:22]([O:23][CH2:24][CH2:25][OH:26])=[O:27])[N:4]=[C:5]([Cl:6])[N:7]=1)[CH2:19][CH2:20][NH:21][C:22]([O:23][CH2:24][CH2:25][OH:26])=[O:27])=[O:28]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: O=C(NCCNCCNC(=O)OCCO)OCCO
Solvent: O
Solvent: CC(C)=O
Product: O=C(NCCN(CCNC(=O)OCCO)c1nc(Cl)nc(N(CCNC(=O)OCCO)CCNC(=O)OCCO)n1)OCCO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 50 g water in a 3-neck flask equipped with stirrer and a thermometer, were added 9.2 g (0.05 m) of cyanuric chloride, dissolved in 50 g acetone below 10° C. To the white slurry of cyanuric chloride, 27.9 g of bis(2-hydroxyethyl)(iminodiethylene)biscarbamate (HEC), NH(CH2CH2NHCO2CH2CH2OH)2 dissolved in 50 g of water was added over a period of 15 minutes. During the addition, the reaction temperature was maintained below 12° C. After complete addition of HEC, the slurry turned into a clear solution. To this was added 10% caustic to maintain the reaction pH at about 7 and the reaction mixture was allowed to warm up to 25° C. At 25° C., as the reaction progressed, a white crystalline solid slowly separated out. After 4 hrs. at 25°-35° C., the solids were separated by filtration, washed with water and recrystallized from ethanol. The product yield was 24 g and m.p. 174° C. The structure of the product was confirmed by nuclear magnetic resonance (nmr) and fast atomic bombardment (fab), mass spectrometry to be that of FORMULA I: ##STR20##
Reaction SMILES: [CH2:1]=[O:2].[C:3]1([CH3:12])[CH:8]=[CH:7][C:6]([S:9]([OH:11])=[O:10])=[CH:5][CH:4]=1>>[OH:2][CH2:1][S:9]([C:6]1[CH:7]=[CH:8][C:3]([CH3:12])=[CH:4][CH:5]=1)(=[O:11])=[O:10]
Reactant: C=O
Reactant: Cc1ccc(S(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)CO)cc1

Procedure:
Formaldehyde and p-toluenesulfinic acid were reacted together to produce hydroxymethyl-p-tolylsulfone according to the following procedure:
Reaction SMILES: O[C:2]1[C:7]([CH3:8])=[N:6][C:5]([Br:9])=[CH:4][N:3]=1.P(Br)(Br)([Br:12])=O>>[Br:12][C:2]1[C:7]([CH3:8])=[N:6][C:5]([Br:9])=[CH:4][N:3]=1
Reactant: O=P(Br)(Br)Br
Reactant: Cc1nc(Br)cnc1O
Product: Cc1nc(Br)cnc1Br
Temperature: 175 °C

Procedure:
A mixture of 2-hydroxy-3-methyl-5-bromopyrazine and phosphorus oxybromide is heated at about 175° C. for several hours with constant stirring. After hydrolysis of the solution on ice the crude product is extracted with ether and distilled. The distillate is refluxed with phosphorus tribromide for several hours and, after cooling, the solution is hydrolyzed on ice and the product extracted with ether, the ether removed in vacuo to give 2,5-dibromo-3-methylpyrazine.
Reaction SMILES: [C:1]([N:4]1[C:8]2=[N:9][CH:10]=[CH:11][C:12](I)=[C:7]2[CH:6]=[C:5]1[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:3])[CH3:2].[CH3:22][N:23](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([N:4]1[C:8]2[N:9]=[CH:10][CH:11]=[C:12]([C:22]#[N:23])[C:7]=2[CH:6]=[C:5]1[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(=O)n1c(CCc2ccccc2)cc2c(I)ccnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(=O)n1c(CCc2ccccc2)cc2c(C#N)ccnc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
A mixture of 1-acetyl-4-iodo-2-(2-phenylethyl)-1H-pyrrolo[2,3-b]pyridine (1.00 g, 2.56 mmol), zinc cyanide (246 mg, 1.41 mmol), tetrakis(triphenylphosphine)palladium(0) (148 mg, 0.128 mmol) and N,N-dimethylformamide (20 mL) was stirred under an argon atmosphere at 80° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-0/1), and crystallized from hexane to give the title compound (472 mg, yield 64%) as colorless crystals.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:18])[O:9][C:10]3[C:15]([C:16]=2[OH:17])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:19]1([CH2:24][CH2:25]Cl)[CH2:23][CH2:22][CH2:21][CH2:20]1>>[N:19]1([CH2:24][CH2:25][O:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[O:9][C:8](=[O:18])[C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: ClCCN1CCCC1
Reactant: O=c1oc2ccccc2c(O)c1-c1ccccc1
Product: O=c1oc2ccccc2c(OCCN2CCCC2)c1-c1ccccc1
Yield: 46 %

Procedure:
In accordance with Example 1, 10 g. (0.042 mol) of 3-phenyl-4-hydroxy-coumarin are caused to react with 9.3 g. (0.055 mol) of 2-pyrrolidino-1-chlorethane. After evaporation of the methyl isobutyl ketone, the pasty residue is taken up under heat in 150 ml. of a 5% solution of sodium bicarbonate, this being followed by cooling and extraction with chloroform. The substance obtained is dried over Na2SO4 and the chloroform is evaporated under vacuum. A brown oil is obtained. Weight 6.5 g.; yield 46% (theoretical yield 14.1 g.).
Reaction SMILES: FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1.[CH2:16]([O:19][N:20]=[C:21]([C:45]1[N:46]=[C:47]([NH:50]C(OC(CC)(C)C)=O)[S:48][CH:49]=1)[C:22]([NH:24][CH:25]1[C:43](=[O:44])[N:27]2[C:28]([C:40]([OH:42])=[O:41])=[C:29]([CH2:32][S:33][C:34]3[N:38]([CH3:39])[N:37]=[N:36][N:35]=3)[CH2:30][S:31][C@H:26]12)=[O:23])[CH:17]=[CH2:18]>>[CH2:16]([O:19][N:20]=[C:21]([C:45]1[N:46]=[C:47]([NH2:50])[S:48][CH:49]=1)[C:22]([NH:24][CH:25]1[C:43](=[O:44])[N:27]2[C:28]([C:40]([OH:42])=[O:41])=[C:29]([CH2:32][S:33][C:34]3[N:38]([CH3:39])[N:37]=[N:36][N:35]=3)[CH2:30][S:31][C@H:26]12)=[O:23])[CH:17]=[CH2:18]
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1csc(NC(=O)OC(C)(C)CC)n1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 57.2 %

Procedure:
Trifluoroacetic acid (4 ml.) and anisole (2 ml.) were added under ice-cooling to 7-[2-allyloxyimino-2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.9 g.) and the mixture was stirred for 40 minutes at ambient temperature. The reaction mixture was post-treated according to a similar manner to that of Example 17 to give 7-[2-allyloxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.425 g.).
Reaction SMILES: Br[C:2]1[N:40]=[C:5]2[N:6]=[C:7]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][N:23]4[CH2:28][CH2:27][CH:26]([C:29]5[N:33]=[C:32]([C:34]6[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=6)[NH:31][N:30]=5)[CH2:25][CH2:24]4)=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[CH3:41][NH2:42]>>[CH3:41][NH:42][C:2]1[N:40]=[C:5]2[N:6]=[C:7]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][N:23]4[CH2:28][CH2:27][CH:26]([C:29]5[N:33]=[C:32]([C:34]6[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=6)[NH:31][N:30]=5)[CH2:25][CH2:24]4)=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1
Reactant: CN
Reactant: Brc1nc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)c(-c3ccccc3)cn2n1
Product: CNc1nc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)c(-c3ccccc3)cn2n1
Temperature: 110 °C

Procedure:
150 mg 2-bromo-6-phenyl-5-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)[1,2,4]triazolo[1,5-a]pyrimidine (prepared as described under example 52) is dissolved in 8 ml of a methylamine solution (2M in THF). The reaction mixture is heated under microwave irradiation to 110° C. for 8 hours. The solvent is evaporated and the residue is purified by RP HPLC (water, 10 mM NH4COOH, pH 3.7/ACN) to yield the desired compound.
Reaction SMILES: [C:1]1([C@@H:7]([CH3:11])[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:32])[C:18]=1[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1)=[O:21]>>[Cl:32][C:17]1[CH:16]=[N:15][CH:14]=[C:13]([Cl:12])[C:18]=1/[CH:19]=[C:20](\[O:21][C:8](=[O:9])[C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:11])/[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)cc1OC
Reactant: C[C@@H](C(=O)Cl)c1ccccc1
Product: COc1ccc(/C(=C/c2c(Cl)cncc2Cl)OC(=O)[C@H](C)c2ccccc2)cc1OC
Yield: 21 %

Procedure:
The compound was obtained starting from 2-(R)-phenyl-propionyl chloride and 2-(3,5-dichloro-pyridin-4-yl)-1-(3,4-dimethoxy-phenyl) -ethanone, following the procedure of Example 7 (0.22 g, 0.48 mmol, 21% yield).
Reaction SMILES: [C:1]([SH:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].CO.Cl[CH2:27][CH2:28][N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[CH:30]1>C(O)C>[C:1]([S:20][CH2:27][CH2:28][N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[CH:30]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: ClCCn1cnc2ccccc21
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: c1ccc(C(SCCn2cnc3ccccc32)(c2ccccc2)c2ccccc2)cc1
Yield: 38 %

Procedure:
To a solution of trityl mercaptan (9.7 g, 35 mmol) in ethanol (90 ml) was added, at 0° C., a sodium methoxide-methanol solution (28%) (7.1 ml). To the reaction mixture was added 1-(2-chloroethyl)benzimidazole (6.32 g, 35 mmol), which was heated for 2 hours under reflux. Insoluble substances were filtered off, and the filtrate was concentrated under reduced pressure. The concentrate was subjected to a silica gel column chromatography (3.0×40 cm: ethyl acetate:hexane=1:1→2:1) to give 1-(2-tritylthioethyl)benzimidazole (5.6 g, 38%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].[C:19](Cl)(=[O:23])[O:20][CH2:21][CH3:22]>O.CC(C)=O>[CH2:21]([O:20][C:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2)=[O:23])[CH3:22]
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)Nc1ccc2c(c1)CCC(=O)N2

Procedure:
6-Amino-3,4-dihydrocarbostyril (60 g) is added to a solution of potassium carbonate (128 g) in water (300 ml) and acetone (300 ml), and thereto is added dropwise ethyl chlorocarbonate (46 ml) with stirring under ice-cooling. After the addition, the mixture is further reacted at the same temperature for 30 minutes. After the reaction, the reaction mixture is poured into water, and the resulting precipitate is separated by filtration, washed with water and further with diethyl ether. After drying, the crystal thus obtained is purified by silica gel column chromatography (solvent; chloroform:methanol=100:1) and then recrystallized from ethanol to give 6-ethoxycarbonylamino-3,4-dihydrocarbostyril (68.5 g), as colorless prisms, m.p. 193°-194° C.
Reaction SMILES: [ClH:1].N[N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2.Cl.O.[C:20]1([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH2:34][C:35](=O)[CH3:36])[CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[ClH:1].[C:20]1([N:26]2[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][C:34]3[C:17]4[C:4]5=[C:5]([CH:14]=[CH:15][CH:16]=4)[CH2:6][CH2:7][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=4[N:3]5[C:35]=3[CH3:36])[CH2:30][CH2:31]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NN1c2ccccc2CCc2ccccc21
Reactant: CC(=O)CCCN1CCN(c2ccccc2)CC1
Agent: Cl
Solvent: O
Product: Cc1c(CCN2CCN(c3ccccc3)CC2)c2cccc3c2n1-c1ccccc1CC3
Yield: 47.4 %

Procedure:
A suspension of 5-amino-10,11-dihydro-5H-dibenz[b,f]azepine hydrochloride (5.0g.) and 5-(4-phenyl-1-piperazinyl)-2-pentanone monohydrate monohydrochloride (6.2g.) in absolute alcohol (100 ml.) was heated on a water bath at 50° to 60°C. in a nitrogen atmosphere for one hour. The mixture was cooled and the solids were collected by filtration, washed with ethyl alcohol, suspended in aqueous methyl alcohol, collected by filtration, washed with water, ethyl alcohol and ether to give 2-[(4-phenyl-1-piperazinyl)-ethyl]-1-methyl-6,7-dihydroindolo-[1,7-ab][1]benzazepine hydrochloride (4.4g.), m.p. 280°-288°C.(dec.). By treatment of this hydrochloride salt in water with an equivalent of ammonium hydroxide and isolation using standard procedures there is obtained the free base 2-[(4-phenyl-1-piperazinyl)-ethyl]-1-methyl-6,7-dihydroindolo[1,7-ab][1]benzazepine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)=[CH:4][CH:3]=1.[CH:23](=O)[CH3:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCCl>[CH2:23]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)=[CH:4][CH:3]=1)[CH3:24]
Reactant: CC=O
Reactant: C[C@H]1CN(Cc2ccc(N)cc2)CCN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.7 %

Procedure:
1,1-dimethylethyl (2S)-4-[(4-aminophenyl)methyl]-2-methyl-1-piperazinecarboxylate (D2) (0.30 g, 1 mmol), acetaldehyde (0.055 mL, 1 mmol), sodium triacetoxyborohydride (0.417 g, 2 mmol) and triethylamine (0.151 mL, 1.1 mmol) were combined in dry 1,2-DCE (15 mL) and stirred under Ar at room temperature for 48 hours. Saturated NaHCO3 (15 mL) was added and reaction mixture stirred for a further 2 hours. The aqueous layer was then extracted with DCM (×3) and the combined organic layers were dried (Na2SO4) and concentrated in vacuo. The crude material was purified by column chromatography eluting with 0-100% ether/petroleum ether to give the title compound (0.239 g). δH (CDCl3, 400 MHz) 7.11 (2H, d), 6.56 (2H, dd), 4.16 (1H, br.s), 3.78 (1H, d), 3.51 (1H, br.s), 3.42 (1H, d), 3.29 (1H, d), 3.15 (2H, q), 3.08 (1H, td), 2.75 (1H, d), 2.59 (1H, d), 2.06 (1H, dd), 1.93 (1H, m), 1.45 (9H, s), 1.25 (3H, t), 1.21 (3H, d). MS (ES+): 234.2, no molecular ion (MH+) observed.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH3:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:20][C:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1(c2ccccc2)CCNCC1
Yield: 110.8 %

Procedure:
To a cooled suspension of 10% Pd-C (0.5 g) in 10 mL methanol was added a solution of 1-benzyl-4-methyl-4-phenyl piperidine (4.5 g, 17.0 mmol) in 40 mL of methanol and the resulting suspension was hydrogenated in a Parr bomb under 250 psi of hydrogen for two days. The suspension was filtered through a pad of celite and the solvent was removed from the filtrate to obtain 4-methyl-4-phenyl piperidine as a yellow solid (3.3 g, 99% yield).
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([O:22][C:23](=[O:26])[NH:24][CH3:25])[CH2:20][NH2:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Cl:27][CH2:28][CH2:29][CH2:30][S:31](NCC(OC)CSCCCCCCCCCCCCCCCC)(=[O:33])=[O:32]>>[Cl:27][CH2:28][CH2:29][CH2:30][S:31]([NH:21][CH2:20][CH:19]([O:22][C:23](=[O:26])[NH:24][CH3:25])[CH2:18][S:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:33])=[O:32]
Reactant: CCCCCCCCCCCCCCCCSCC(CN)OC(=O)NC
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC(=O)NC

Procedure:
3-Hexadecylthio-2-methylcarbamoyloxypropylamine IVc1 is allowed to react and worked up by the same procedure as described in (4). m.p. 84.5°-85.5° C. The summary of the experimental condition and the physical data of the prodcut are listed in the Table 7.