Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].[Si:7](Cl)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].P([O-])([O-])([O-])=O>C1COCC1>[Si:7]([O:3][CH2:2][CH2:1][OH:4])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCO
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCO
Temperature: 20 °C
Reaction time: 0.75 h
Yield: 67.2 %

Procedure:
Ethylene glycol (2.00 g) in anhydrous THF (60 ml) under nitrogen was treated portionwise with sodium hydride (60% dispersion in mineral oil, 1.29 g) and the mixture stirred at 20° C. for 45 min. Tert-butyl dimethylsilyl chloride (4.86 g) was added and the mixture stirred at 20° C. for 45 min. Phosphate buffer (60 ml, pH6.5) was added and the mixture stirred for 20 min before extracting with ether (60 ml). The organic layer was then washed with water (60 ml) and brine (60 ml), before drying over Na2SO4, filtering, and removing the solvent in vacuo. This was purified by flash chromatography on silica. Elution with 1:4 EtOAc/cyclohexane followed by solvent evaporation in vacuo gave the title compound (3.82 g). TSP+ve 194 MNH4+.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[C:16]([C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[C:20]([OH:22])=[O:21])=O)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:27][N:28]([CH3:38])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]([CH3:37])[CH3:36])[CH:30]=1.C(OC(=O)C)(=O)C.Cl>>[CH3:36][N:35]([CH3:37])[C:31]1[CH:30]=[C:29]([N:28]([CH3:38])[CH3:27])[CH:34]=[CH:33][C:32]=1[C:16]1([C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:18]2[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:20](=[O:21])[O:22]1
Reactant: O=C(O)c1ccccc1C(=O)c1c(-c2ccccc2)[nH]c2ccccc12
Reactant: CN(C)c1cccc(N(C)C)c1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: CN(C)c1ccc(C2(c3c(-c4ccccc4)[nH]c4ccccc34)OC(=O)c3ccccc32)c(N(C)C)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 4.82 g (0.014 mole) of the 2-[(2-phenyl-3-indolyl)carbonyl]benzoic acid from part A above, 3.60 g (0.02 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine, and five ml of acetic anhydride was slowly heated until a purple color formed and maintained at this temperature for approximately two hours. After cooling to room temperature, sufficient 3 N hydrochloric acid was added to the mixture to effect solution and stirring was continued for approximately 1.5 hours. The resulting solution was filtered and the pH adjusted to five by the addition of sodium acetate. The precipitate which separated from the solution was collected by filtration and dried to obtain 3-[2,4-bis(dimethylamino)phenyl]-3-(2-phenyl-3-indolyl)phthalide (Formula III: R0 =R1 =R2 =R3 =R6 =Y1 =H; R=CH3 ; R4 =N(CH3)2 ; R5 =C6H5). After recrystallization from toluene and hexane, the off white-colored solid melted at 153°-155° C. Significant infrared maxima were observed at 3380 cm-1 (NH; m) and 1750 cm-1 (C=O; s). The nuclear magnetic resonance spectrum was consistent with the structure. A toluene solution of this product spotted on silica gel developed an intense grape-red-colored image.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([CH:21]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:22]([NH:24][N:25]1[C:29](=[O:30])[C:28]2([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[NH:27][C:26]1=[O:36])=[O:23])[CH2:12][CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].[H][H]>CO.[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:22]([NH:24][N:25]1[C:29](=[O:30])[C:28]2([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[NH:27][C:26]1=[O:36])=[O:23])[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: [H][H]
Reactant: CC(C)CC(C(=O)NN1C(=O)NC2(CCCCC2)C1=O)[C@H](CC=Cc1ccccc1)C(=O)NOC1CCCCO1
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN1C(=O)NC2(CCCCC2)C1=O)[C@H](CCCc1ccccc1)C(=O)NOC1CCCCO1

Procedure:
A solution of 0.25 g of (E)-2(R(-[1(S)-[(tetrahydro-2(RS)pyranyloxy)carbamoyl]4-phenyl-3-butenyl]-4-methyl-N-(2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)valeramide in 5 ml of methanol containing 0.025 g of 10% palladium-on-carbon catalyst was shaken in a hydrogen atmosphere for 2 hours. The catalyst was filtered off to give a solution of 0.25 g of 2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenylbutyl]-4-methyl-N-(2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)valeramide in methanol that was used directly in the process step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:10](=[N:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:33]I.O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:20][CH2:21][CH2:22][N:23]([CH3:33])[C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[C:10](=[N:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCCn1c(-c2ccc(Br)cc2)csc1=Nc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCCn1c(-c2ccc(Br)cc2)csc1=Nc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
t-Butyl 3-[4-(4-bromophenyl)-2-(phenylimino)thiazol-3(2H)-yl]-propylcarbamate (250 mg) was dissolved in N,N-dimethylformamide (2 ml), and thereto was added sodium hydride (26 mg, 60% dispersion in oil) under nitrogen atmosphere in an ice bath, and the mixture was stirred for 15 minutes. To the reaction mixture was added methyl iodide (41 μl), and the mixture was warmed to room temperature, and stirred for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with a saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [n-hexane:ethyl acetate (10:1)] to give the title compound (249 mg) as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5]Cl.[I:13][C:14]1[CH:15]=[C:16]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[NH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[I:13][C:14]1[CH:15]=[C:16]([C:19](=[O:24])[C:20]([F:21])([F:22])[F:23])[N:17]([CH2:5][C:4]2[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([CH3:1])[CH:3]=2)[CH:18]=1
Reactant: O=C(c1cc(I)c[nH]1)C(F)(F)F
Reactant: Cc1cc(CCl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Cn2cc(I)cc2C(=O)C(F)(F)F)ccc1[N+](=O)[O-]
Yield: 33.4 %

Procedure:
3-Methyl-4-nitrobenzyl chloride (0.63 g), 4-iodo-2-(trifluoroacetyl)pyrrole (0.89 g) and potassium carbonate (0.57 g) were stirred in DMF (10 ml) at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate and washed with water and saturated aqueous solution of sodium chloride. After drying the organic layer with magnesium sulfate, the solvent was distilled off under the reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 4-iodo-1-(3-methyl-4-nitrobenzyl)-2-trifluoroacetyl-1H-pyrrole (0.45 g).
Reaction SMILES: [CH2:1]1[CH:11]2[N:5]([C:6]3[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=3[S:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=32)[CH2:4][CH2:3][NH:2]1.[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[CH:21]=[CH2:22]>C(O)C>[CH2:25]([O:24][C:20](=[O:23])[CH2:21][CH2:22][N:2]1[CH2:3][CH2:4][N:5]2[C:6]3[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=3[S:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]2[CH2:1]1)[CH3:26]
Reactant: C=CC(=O)OCC
Reactant: c1ccc2c(c1)Sc1ccccc1N1CCNCC21
Solvent: CCO
Product: CCOC(=O)CCN1CCN2c3ccccc3Sc3ccccc3C2C1
Reaction time: 24 h

Procedure:
A mixture of 1,3,4,14b-tetrahydro-2H-dibenzo[b,f]pyrazino[1,2-d][1,4]thiazepine (1.5 g, 5.6 mmol), ethyl acrylate (0.61 g, 6.1 mmol) and ethanol (40 ml) was heated at reflux temperature for 5 minutes and then left to stand for 24 h at room temperature, affording crude 3-(1,3,4,14b-tetrahydro-2H-dibenzo[b,f]pyrazino[1,2-d][1,4]thiazepin-2-yl)propionic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:25])=[C:6]([CH:24]=1)[CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:15][CH2:14][N:13](C(=O)C(F)(F)F)[C:12]=2[CH:23]=1.[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:25])=[C:6]([CH:24]=1)[CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:15][CH2:14][NH:13][C:12]=2[CH:23]=1
Reactant: O=C(N1CCOc2ccc(Cc3cc(Br)ccc3Cl)cc21)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Clc1ccc(Br)cc1Cc1ccc2c(c1)NCCO2
Reaction time: 8 h
Yield: 91 %

Procedure:
To a stirred solution of 1-[6-(5-bromo-2-chloro-benzyl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-2,2,2-trifluoro-ethanone (8.6 g, 19.8 mmol) in ethanol (40 mL) was added NaBH4 portion wise and the reaction mixture was stirred overnight. The excess of NaBH4 was quenched by adding aq. HCl. Ethanol was evaporated and the residue was partitioned between dichloromethane and water. Organic layer was washed with brine, water, dried over sodium sulfate followed by evaporation of solvent furnished 6-(5-bromo-2-chloro-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine (6.1 g).
Reaction SMILES: Br.Br[CH2:3][C:4]1[N:5]=[C:6]2[C:11](=[N:12][CH:13]=1)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]2[NH2:15].[CH3:16][NH:17][C:18]1[CH:39]=[CH:38][C:21]([C:22]([NH:24][C@H:25]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:23])=[CH:20][CH:19]=1>>[CH3:32][CH2:31][O:30][C:28]([CH2:27][CH2:26][C@H:25]([NH:24][C:22]([C:21]1[CH:38]=[CH:39][C:18]([N:17]([CH2:3][C:4]2[N:5]=[C:6]3[C:7]([NH2:15])=[N:8][C:9]([NH2:14])=[N:10][C:11]3=[N:12][CH:13]=2)[CH3:16])=[CH:19][CH:20]=1)=[O:23])[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29]
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(NC)cc1)C(=O)OCC
Reactant: Nc1nc(N)c2nc(CBr)cnc2n1
Agent: Br
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(N(C)Cc2cnc3nc(N)nc(N)c3n2)cc1)C(=O)OCC

Procedure:
reacting this 6-bromomethyl-2,4-diaminopteridine hydrobromide with diethyl N-[4-(N-methylamino)-benzoyl]glutamate to give diethyl methotrexate, and
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:33])[N:17]3[C:22](=[C:23]([C:25]([O:27]C)=[O:26])[CH:24]=2)[C:21]2[N:29]=[CH:30][N:31]([CH3:32])[C:20]=2[CH:19]=[CH:18]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16](=[O:33])[N:17]3[C:22](=[C:23]([C:25]([OH:27])=[O:26])[CH:24]=2)[C:21]2[N:29]=[CH:30][N:31]([CH3:32])[C:20]=2[CH:19]=[CH:18]3)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3c(ncn3C)c12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1cnc2c1ccn1c(=O)c(-c3ccc(OCc4ccccc4)cc3)cc(C(=O)O)c21
Yield: 92.3 %

Procedure:
2.44 g (5.5 mmol) of methyl 8-(4-benzyloxy-phenyl)-3-methyl-7-oxo-3,7-dihydro-imidazo[4,5-a]quinolizine-10-carboxylate in 50 ml of ethanol were treated with a solution of 1.4 g (21 mmol) of potassium hydroxide (content 86%) in 50 ml of water. After boiling under reflux for 4 hours 200 ml of water were added and the mixture was adjusted to pH 1-2 with 2N hydrochloric acid while cooling with ice. The precipitate obtained was filtered off, washed with water and dried. There were obtained 2.16 g (92%) of 8-(4-benzyloxy-phenyl)-3-methyl-7-oxo-3,7-dihydro-imidazo [4,5-a]quinolizine-10-carboxylic acid as yellow crystals with m.p. 227°-229° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[C:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=1)(=[O:22])[CH3:21]>>[C:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([S:30][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)=[CH:26][CH:25]=1)(=[O:22])[CH3:21]
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: CC(=O)Nc1ccc(S)cc1
Product: CC(=O)Nc1ccc(SCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-acetamido-thiophenol.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6](OCCCCCCCC)[CH:5]=[CH:4][C:3]=1[C:17]1[N:22]=[C:21](C2C=CC(OCCCCCCCC)=CC=2O)[N:20]=[C:19](C2C=CC(OCCCCCCCC)=CC=2O)[N:18]=1.OC1C=C(OCCCCCCCC)C=CC=1C1N=C(C2C=CC(C)=CC=2C)N=C(C2C=CC(C)=CC=2C)N=1.OC1C=C(O)C=CC=1C1N=C(C2C=CC(C)=CC=2C)N=C(C2C=CC(C)=CC=2C)N=1.OC1C=C(OCCC)C=CC=1C1N=C(C2C=CC(OCCC)=CC=2O)N=C(C2C=CC(C)=CC=2C)N=1.OC1C=C(OCCCCCCCC)C=CC=1C1N=C(C2C=CC(C)=CC=2)N=C(C2C=CC(C)=CC=2)N=1.OC1C=C(OCCCCCCCCCCCC)C=CC=1C1N=C(C2C=CC(C)=CC=2C)N=C(C2C=CC(C)=CC=2C)N=1.OC1C=C(OCC(O)COCCCC)C=CC=1C1N=C(C2C=CC(C)=CC=2C)N=C(C2C=CC(C)=CC=2C)N=1.OC1C=C(OCC(O)COCCCCCCCC)C=CC=1C1N=C(C2C=CC(C)=CC=2C)N=C(C2C=CC(C)=CC=2C)N=1>>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][N:20]=[CH:21][N:22]=1
Reactant: CCCCCCCCOc1ccc(-c2nc(-c3ccc(OCCCCCCCC)cc3O)nc(-c3ccc(OCCCCCCCC)cc3O)n2)c(O)c1
Agent: CCCCCCCCCCCCOc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(C)cc3C)n2)c(O)c1
Agent: CCCCCCCCOCC(O)COc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(C)cc3C)n2)c(O)c1
Agent: CCCCCCCCOc1ccc(-c2nc(-c3ccc(C)cc3)nc(-c3ccc(C)cc3)n2)c(O)c1
Product: Oc1ccccc1-c1ncncn1

Procedure:
2,4,6-tris(2-hydroxy-4-octyloxyphenyl)-1,3,5-triazine, 2-(2-hydroxy-4-octyloxyphenyl)-4,6-bis(2,4-dimethylphenyl)-1,3,5-triazine, 2-[2,4-dihydroxyphenyl-4,6-bis(2,4-dimethylphenyl]-1,3,5-triazine, 2,4-bis(2-hydroxy-4-propyloxyphenyl)-6-(2,4-dimethylphenyl)-1,3,5-triazine, 2-(2-hydroxy-4-octyloxyphenyl)-4,6-bis(4-methylphenyl)-1,3,5-triazine, 2-[2-hydroxy-4-dodecyloxyphenyl)-4,6-bis(2,4-dimethylphenyl]-1,3,5-triazine, 2-[2-hydroxy-4-(2-hydroxy-3-butyloxypropoxy)phenyl]-4,6-bis (2,4-dimethylphenyl)-1,3,5-triazine, 2-[2-hydroxy-4-(2-hydroxy-3-octyloxypropoxy)phenyl]-4,6-bis (2,4-dimethylphenyl)-1,3,5-triazine and mixtures thereof, and the like.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[O:14][C:15]([Br:18])=[CH:16][CH:17]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)#[N:2].[Sn]([N:23]=[N+:24]=[N-:25])(C)(C)C>>[NH:23]1[C:1]([CH2:3][C:4]2[CH:5]=[C:6]([NH:10][C:11]([C:13]3[O:14][C:15]([Br:18])=[CH:16][CH:17]=3)=[O:12])[CH:7]=[CH:8][CH:9]=2)=[N:2][N:25]=[N:24]1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: N#CCc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: O=C(Nc1cccc(Cc2nnn[nH]2)c1)c1ccc(Br)o1

Procedure:
Nitrile (83) (162 mg, 0.53 mmol) was treated with Me3SnN3 using Method K. The residue was purified by column chromatography, flushing with heptane (200 ml) and eluting with 50% EtOAc in heptane to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3]([NH2:5])=[S:4].[CH:7]([O:20][C:21]([C:23]1[N:24]2[CH:27]([S:28][CH2:29][C:30]=1[CH:31]=[CH:32]N(C)C)[CH:26]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:25]2=[O:44])=[O:22])([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>>[CH:7]([O:20][C:21]([C:23]1[N:24]2[CH:27]([S:28][CH2:29][C:30]=1[C:31]1[S:4][C:3]([N:2]([CH3:6])[CH3:1])=[N:5][CH:32]=1)[CH:26]([NH:36][C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[C:25]2=[O:44])=[O:22])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN(C)C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1
Reactant: CN(C)C(N)=S
Product: CN(C)c1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)C3SC2)s1
Yield: 58.3 %

Procedure:
The working method of Example 2 is followed, but replacing the thiourea by N,N-dimethylthiourea (5.25 g) and starting with 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(2-dimethylamino-vinyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (E-form) (21.4 g). The product obtained is chromatographed on a column (diameter: 4.5 cm) containing silica gel (0.2-0.06 mm)(500 cc), elution being carried out with methylene chloride (5 liters) and then with mixtures of methylene chloride and ethyl acetate, namely 99:1 by volume (5 liters) followed by 97:3 by volume (7.5 liters), and 500 cc fractions being collected; fractions 13 to 34 are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. The residue is triturated with isopropyl ether (100 cc) and 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(2-dimethylamino-thiazol-5-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (13.8 g) is obtained in the form of a yellow solid.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][CH:5]([CH2:19][CH2:20][CH3:21])[CH2:6][CH2:7][CH:8](C(OCC)=O)[C:9]([O:11]CC)=[O:10].S(=O)(=O)(O)O>O>[CH3:3][O:4][CH:5]([CH2:19][CH2:20][CH3:21])[CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: CCCC(CCC(C(=O)OCC)C(=O)OCC)OC
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCC(CCCC(=O)O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
Then, 180 g of 85% KOH was dissolved in 180 ml of water, and 190 g of the above ethyl 5-methoxy-2-ethoxycarbonylcaprylate was dropped at 20°-30° C. in 60 min., followed by 30 min. of stirring and 2 hours of refluxing. After cooling, the mixture was held below 20° C., and a solution of 288 g of conc. sulfuric acid in 406 g of water was dropped in 90 min., followed by 30 min of stirring and 3 hours of refluxing at 90°-95° C. After being cooled to room temperature, the product was extracted with ether. The ether layer was washed with 5%-NaOH aqueous solution and added to the aqueous layer. The aqueous layer was acidified with 6N-hydrochloric acid and extracted with ether, followed by washing with saturated saline water, distilling-off of the ether and vacuum distillation to obtain 53 g of 5-methoxycaprylic acid in the form of a colorless clear liquid.
Reaction SMILES: C(OC([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[NH:32][C:31]3[CH:33]=[C:34]([C:37]([OH:39])=[O:38])[CH:35]=[CH:36][C:30]=3[N:29]=2)[CH2:24][CH:23]1[C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[CH:41]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.C(OC(C)C)(C)C.[ClH:54].O1CCOCC1>>[ClH:54].[ClH:54].[F:46][C:42]1[CH:41]=[C:40]([CH:23]2[CH:22]([CH2:21][NH:8][C@@H:9]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][CH:12]=3)[CH3:10])[CH2:27][CH2:26][N:25]([C:28]3[NH:32][C:31]4[CH:33]=[C:34]([C:37]([OH:39])=[O:38])[CH:35]=[CH:36][C:30]=4[N:29]=3)[CH2:24]2)[CH:45]=[CH:44][CH:43]=1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCN(c2nc3ccc(C(=O)O)cc3[nH]2)CC1c1cccc(F)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)OC(C)C
Product: C[C@@H](NCC1CCN(c2nc3ccc(C(=O)O)cc3[nH]2)CC1c1cccc(F)c1)c1cccc2ccccc12

Procedure:
A solution of 19 mg of 2-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]-1H-benzimidazole-6-carboxylic acid in 1.00 mL of 4 M hydrogen chloride/1,4-dioxane solution was stirred at room temperature for 2 hours. Diisopropyl ether was added thereto, and the resulting precipitate was collected by filtration, and dried under reduced pressure to obtain 15 mg of 2-[3-(3-fluorophenyl)-4-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)piperidin-1-yl]-1H-benzimidazole-6-carboxylic acid dihydrochloride.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: COc1ccc(CBr)cc1
Product: COc1ccc(CN2CC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)cc1
Yield: 19 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 1-(bromomethyl)-4-methoxybenzene. Yield 19%. MS M+H calculated 396.1; found 396.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.07 uM.
Reaction SMILES: C(OC(=O)[CH:5]([C:8]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[C:11]([C:21](=[O:39])[N:22]([CH2:24][C:25]2[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=2)[CH3:23])=[CH:10][N:9]=1)[C:6]#[N:7])C.[Cl-].[Li+]>CS(C)=O>[F:37][C:35]([F:36])([F:38])[C:27]1[CH:26]=[C:25]([CH:30]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:28]=1)[CH2:24][N:22]([CH3:23])[C:21](=[O:39])[C:11]1[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[CH:13][C:8]([CH2:5][C:6]#[N:7])=[N:9][CH:10]=1
Reactant: CCOC(=O)C(C#N)c1cc(-c2ccccc2C)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Product: Cc1ccccc1-c1cc(CC#N)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 120 °C
Yield: 70.1 %

Procedure:
A mixture of 650 mg (1.15 mmol) (RS)-{5-[(3,5-bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4-o-tolyl-pyridin-2-yl}-cyano-acetic acid ethyl ester and 0.20 g (4.6 mmol) lithium chloride in wet dimethyl sulfoxide was stirred at 120° C. over night. After cooling the mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The layers were separated and the aqueous layer was extracted with two portions of ethyl acetate. The combined organic extracts were washed with two portions of water, dried with magnesium sulfate and concentrated to give 595 mg of crude product. Flash chromatography afforded 396 mg (69.9%) of the title compound as a white solid.
Reaction SMILES: C(O[C:4](=[NH:15])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])C.[CH3:16][C:17]1[S:21][C:20]([C:22]([NH:24][NH2:25])=[O:23])=[CH:19][CH:18]=1>C(Cl)(Cl)Cl>[NH2:15][C:4](=[N:25][NH:24][C:22]([C:20]1[S:21][C:17]([CH3:16])=[CH:18][CH:19]=1)=[O:23])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7]
Reactant: CCOC(=N)CS(=O)(=O)c1ccccc1
Reactant: Cc1ccc(C(=O)NN)s1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C(=O)NN=C(N)CS(=O)(=O)c2ccccc2)s1
Yield: 91.2 %

Procedure:
1.75 g (0.0077 Mol) of 2-(phenylsulfonyl)-ethanimidic acid ethyl ester was stirred together with 1.2 g (0.0077 mol) 5-methyl-thiophen-2-carboxylic acid hydrazide in 14 ml chloroform for 24 hours at 50° C. The resulting precipitate was filtered off and dried. 2.37 g of 5-methyl-thiophen-2-carboxylic acid (1-amino-2-benzenesulfonyl-ethylidene)-hydrazide was obtained as off-white crystals. Mp.: 222° C. (dec.).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[NH2:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][NH:23][CH2:24]2>CN(C=O)C>[NH2:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][N:23]([C:10]1[CH:11]=[C:12]3[C:7]([C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=1[F:14])[CH2:24]2
Reactant: Nc1cccc2c1CNC2
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3Cc4cccc(N)c4C3)cc21
Yield: 54.9 %

Procedure:
177 mg of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 282 mg of 4-amino-isoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 2 to produce 141 mg of the target compound.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:16][OH:17])=[CH:6]1)(=[O:4])=[O:3].C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH3:1][S:2]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([CH:16]=[O:17])=[CH:6]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)n1cc(CO)cc1-c1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Product: CS(=O)(=O)n1cc(C=O)cc1-c1ccccc1
Yield: 75.6 %

Procedure:
Using [1-(methylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]methanol (220 mg), tetra-n-propylammonium perruthenate (31 mg), N-methylmorpholine N-oxide (177 mg) and molecular sieves 4A powder (500 mg), a procedure as in Reference Example 6 was performed to give the title compound as a brown oil (yield 165 mg, 76%).