Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na+].[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]([CH2:27][OH:28])=[C:13]([C:24]([O-:26])=[O:25])[CH:14]=[C:15]4[C:23]=3[C:19]3[O:20][CH2:21][O:22][C:18]=3[CH:17]=[CH:16]4)=[CH:10][C:5]=2[O:4][CH2:3]1.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[OH-].[K+]>O>[CH2:29]([O:25][C:24]([C:13]1[CH:14]=[C:15]2[C:23](=[C:11]([C:9]3[CH:8]=[CH:7][C:6]4[O:2][CH2:3][O:4][C:5]=4[CH:10]=3)[C:12]=1[CH2:27][O:28][CH2:11][C:9]1[CH:10]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:19]1[O:20][CH2:21][O:22][C:18]=1[CH:17]=[CH:16]2)=[O:26])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: O=C([O-])c1cc2ccc3c(c2c(-c2ccc4c(c2)OCO4)c1CO)OCO3
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(OCc1ccccc1)c1cc2ccc3c(c2c(-c2ccc4c(c2)OCO4)c1COCc1ccccc1)OCO3
Temperature: 140 °C
Yield: 102.5 %

Procedure:
A mixture of 3 (78 mg, 0.2 mmol) and benzyl bromide (0.38 mL, 3.2 mmol), and powdered KOH (168 mg) was heated at 140° C. for 3 h, and then cooled to room temperature. The mixture was diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The extract was washed with water (3×100 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using CH2Cl2 to give 4 (56 mg, 51%) as a colorless liquid. 1H NMR (CDCl3) δ 8.27 (s, 1H, H4), 7.51 (d, 1H, H5, J=8.4 Hz), 7.23-7.44 (m, 10H, 2×OCH2Ph), 7.22 (d, 1H, H6, J=8.4 Hz), 6.82 (d, 1H, H5′, J=7.8 Hz), 6.77 (d, 1H, H2′, J=1.5 Hz), 6.71 (dd, 1H, H6′, J=1.5, 7.8 Hz), 6.05 (AB, 2H, 3′,4′-OCH2O—, Δδ=10.2 Hz, J=1.2 Hz), 5.84 (AB, 2H, 7,8-OCH2O—, Δδ=4.8 Hz, J=1.2 Hz), 5.34 (s, 2H, 3-COOCH2Ph), 4.67 (s, 2H, 2-CH2OCH2Ph), 4.32 (s, 2H, 2-CH2OBn); MS (EI) m/z 546 [M]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:19][CH3:20])=[CH:4][C:5]2[CH:9](O)[CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:7][C:6]=2[C:17]=1[Cl:18].B(F)(F)F.CCOCC.C(O)(=O)C>O.[OH-].[Na+]>[Cl:1][C:2]1[C:3]([O:19][CH3:20])=[CH:4][C:5]2[CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:7][C:6]=2[C:17]=1[Cl:18]
Reactant: COc1cc2c(c(Cl)c1Cl)SC(c1ccccc1)C2O
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: O
Product: COc1cc2cc(-c3ccccc3)sc2c(Cl)c1Cl
Yield: 30.7 %

Procedure:
A mixture of 5.0 g of 6,7-dichloro-2,3-dihydro-3-hydroxy-5-methoxy-2-phenylbenzo[b]thiophene, 10 ml of boron trifluoride etherate and 20 ml of glacial acetic acid is refluxed for 1 hour. The mixture is cooled, diluted with water and basified with dil sodium hydroxide solution. Extraction with dichloromethane followed by column chromatography over silica (50% dichloromethane in hexane) gives 1.45 g of 6,7-dichloro-5-methoxy-2-phenylbenzo[b]thiophene, mp 144°-145°.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.C([O:19][C:20](=O)[CH:21]=[C:22]([C:30]1[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=1)C.Cl>C1COCC1>[Br:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]([C:30]2[CH:31]=[CH:32][C:33]([Br:36])=[CH:34][CH:35]=2)=[CH:21][CH2:20][OH:19])=[CH:24][CH:25]=1
Reactant: CCOC(=O)C=C(c1ccc(Br)cc1)c1ccc(Br)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCC=C(c1ccc(Br)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
A 1M solution of DIBAL-H in toluene (150 ml, 150 mmol) was added dropwise, at −70° C. over 30 min, to a stirred solution of 3,3-bis-(4-bromophenyl)-acrylic acid ethyl ester (24.5 g, 59.7 mmol) in dry THF (400 ml) and stirred for 30 min. The mixture was warmed to room temperature, and stirred for 1.5 h. The mixture was poured into 1N HCl (700 ml) with vigorous stirring and the product extracted with ethyl acetate (3×200 ml). The combined organic extracts were washed with brine, dried (MgSO4), and evaporated to give the crude product as an off-white solid, which was purified by column chromatography on silica gel (15% ethyl acetate in n-heptane eluent). The purified product was diluted in boiling heptane, filtered and the filtrate cooled, giving 15.8 g (72%) 3,3-bis-(4-bromophenyl)prop-2-en-1-ol as an crystalline solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[CH3:18][O:19][C:20](=[O:23])[CH2:21][NH2:22].O>C1COCC1>[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:22][CH2:21][C:20]([O:19][CH3:18])=[O:23])=[O:14])=[CH:11][CH:10]=1
Reactant: COC(=O)CN
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CNC(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
Saturated aqueous potassium carbonate (190 mL) and 4-methoxybenzoyl chloride (60.8 g, 358 mmol) were added to a solution of glycine methyl ester (30.0 g, 239 mmol) in THF (100 mL) at 0° C. The reaction mixture was stirred for 3 h at 0° C. and then poured into water (100 mL). The resulting mixture was extracted with EtOAc (200 ml×2). The combined extracts were dried over anhydrous sodium sulfate and concentrated to afford methyl 2-(4-methoxybenzamido)acetate (46.2 g, 86% yield) as a colorless solid, which was used directly without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([O:26][CH3:27])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH3:15])=[CH:9][CH:8]=1)=O.CO.[ClH:30].C(OCC)C>O1CCCC1>[ClH:25].[ClH:30].[CH3:1][NH:2][CH2:3][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([O:26][CH3:27])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH3:15])=[CH:11][CH:12]=1
Reactant: CNC(=O)COc1ccc(CC(C)NCC(OC)c2cccc(Cl)c2)cc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: CNCCOc1ccc(CC(C)NCC(OC)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of N-[2-(4-methylaminocarbonylmethoxyphenyl)-1-methylethyl]-2-methoxy-2-(3-chlorophenyl)ethanamine (0.50 g; 85:15 mixture of diastereoisomers) in dry tetrahydrofuran (20 ml) was added borane-methyl sulphide complex (2 ml), under nitrogen. The solution was boiled under reflux for 3 hours, and after cooling to room temperature, methanol (6 ml) was added. This solution was allowed to stand overnight at room temperature, boiled under reflux for 1 hour, cooled, and hydrogen chloride gas passed through for 10 minutes. After dilution with diethyl ether, cooling to 0° C. and filtering, N-[2-(4-(2-methylaminoethoxy)phenyl)-1-methylethyl]-2-methoxy-2-(3-chlorophenyl)ethanamine dihydrochloride, mp 270°-273° C. (methanol-ethyl acetate), was obtained as a single diastereoisomer.
Reaction SMILES: COC1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:5][CH:4]=1.[N:31]1C=CC(C=O)=CC=1>>[N:31]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:5][CH:4]=1
Reactant: O=Cc1ccncc1
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Product: O=C(NCCNCc1ccncc1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]amide using 4-pyridinecaboxaldehyde instead of 4-methoxy benzaldehyde. LCMS (ESI) 393 (M+H) 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.35-8.42 (2H, m) 8.00 (1H, d, J=5.61 Hz) 7.65 (1H, d, J=5.42 Hz) 7.46 (1H, d, J=5.47 Hz) 7.36-7.41 (2H, m) 7.24 (1H, d, J=3.56 Hz) 6.86 (1H, d, J=5.66 Hz) 6.55 (1H, d, J=3.56 Hz) 3.82 (2H, s) 3.51 (2H, t, J=6.25 Hz) 2.79 (2H, t, J=6.17 Hz)
Reaction SMILES: C[C:2]1[CH:7]=[CH:6]C(S(O)(=O)=O)=[CH:4][CH:3]=1.[C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][NH2:23])=[C:18]([OH:24])[CH:17]=1)(=[O:14])[CH3:13].C(OC1C=CC(N)=C(O)C=1)(=O)C.C(CC(=O)C)(=O)C>>[C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:7]([CH3:6])=[CH:2][C:3]([CH3:4])=[N:23]2)=[C:18]([OH:24])[CH:17]=1)(=[O:14])[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(=O)Oc1ccc(NN)c(O)c1
Agent: CC(=O)Oc1ccc(N)c(O)c1
Solvent: CC(=O)CC(C)=O
Product: CC(=O)Oc1ccc(-n2nc(C)cc2C)c(O)c1
Yield: 52.8 %

Procedure:
330 mg of the title compound was prepared in a manner similar to Example 54b) by using 4-hydrazinyl-3-hydroxyphenyl acetate 4-methylbenzenesulfonate (0.9 g), which was prepared from 4-amino-3-hydroxyphenyl acetate (1.0 g) in a manner similar to Example 54a), and acetylacetone (0.9 g).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[C:12]1([CH2:18][CH2:19][NH2:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>ClCCl>[C:8]([NH:20][CH2:19][CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:10])[CH3:9]
Reactant: NCCc1ccccc1
Reactant: CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCc1ccccc1
Reaction time: 2 h

Procedure:
Triethylamine (1.26 ml, 9.08 mmol), followed by acetyl chloride (0.64 ml, 9.08 mmol) was added to a solution of 2-phenylethylamine (1.04 ml, 8.25 mmol) in dichloromethane (16 ml) at 0° . After 2 hours, the solution was poured into water and extracted thoroughly with ethyl ether. Evaporation of the dried (magnesium sulfate) extracts gave an oil, which was purified on silica using 80% ethyl acetate/hexane. The title amide was obtained as a colorless solid.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][CH:5]([CH:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[CH2:19][CH2:20][N:12]([C:13]=34)[C:11]3[CH:21]=[CH:22][CH:23]=[CH:24][C:10]=3[NH:9]2)[CH2:4][CH2:3]1.N1C(C)=CC(C)=CC=1C.[Cl:34]C(OC(Cl)C)=O>ClCCl>[ClH:34].[NH:2]1[CH2:3][CH2:4][CH:5]([CH:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[CH2:19][CH2:20][N:12]([C:13]=34)[C:11]3[CH:21]=[CH:22][CH:23]=[CH:24][C:10]=3[NH:9]2)[CH2:6][CH2:7]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: CN1CCC(C2Nc3ccccc3N3CCc4cccc2c43)CC1
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: Cl
Product: c1ccc2c(c1)NC(C1CCNCC1)c1cccc3c1N2CC3
Temperature: 50 °C

Procedure:
To a 1 L, 3-necked round bottom flask equipped with a reflux condenser, nitrogen inlet, magnetic stirring bar and addition funnel were fed 6-(1-methylpiperidin-4-yl)-1,2,6,7-tetrahydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine (19.3 gm), collidine (622 gm) and dichloromethane (500 ml). The mixture was heated to a gentle reflux and alpha-chloroethyl chloroformate (19 gm) was added dropwise over a period of 30 minutes at refluxing temperature. The resultant solution was refluxed for 2 hours and thereafter cooled to about 50° C. The solution was concentrated to a solid-oil mixture and thereafter extracted with ether (about 2 L). The insolubles were filtered off and the ethereal solution was concentrated and dried on a rotary evaporator (high vacuum pump at about 80° C.) until little collidine was left. The crude product (43 gm) was identified as the bis-alpha-chloroethyl carbamate of the desired product.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:20])[CH2:14][CH:15]=2)=[CH:5][CH:4]=1.OO.S(=O)(O)[O-:31].[Na+].[C:35]([CH:38]([CH:40]([C:42]([O-:44])=[O:43])[OH:41])[OH:39])([O-:37])=[O:36]>C(O)(=O)C.CCOCC>[OH:39][CH:38]([CH:40]([OH:41])[C:42]([OH:44])=[O:43])[C:35]([OH:37])=[O:36].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:20])[CH2:12][CH:11]=2)=[O:31])=[CH:5][CH:4]=1
Reactant: O=C(CCCN1CC=C(Sc2ccc(Cl)cc2)CC1)c1ccc(F)cc1
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Reactant: O=S([O-])O
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C(CCCN1CC=C(S(=O)c2ccc(Cl)cc2)CC1)c1ccc(F)cc1
Product: O=C(O)C(O)C(O)C(=O)O
Reaction time: 144 h

Procedure:
A solution of 7.5 g of 4-{4-[(4-chlorophenyl)thio]-1,2,3,6-tetrahydro-1-pyridinyl}-1-(4-fluorophenyl)-1-butanone hydrochloride, 1.8 g of 30% hydrogen peroxide in 100 ml of acetic acid is allowed to stand at room temperature for 6 days. A small quantity of sodium bisulfite is added after which the acetic acid is removed in vacuo. The residue is neutralized with dilute sodium carbonate solution, and the product extracted into chloroform. The solvent is evaporated to give an oil. The tartrate salt is generated in ether and triturated with boiling ethyl acetate to yield a white powder, m.p. 159°-160° C.
Reaction SMILES: CS[C:3]([N:7]1[CH2:11][C:10]([CH3:13])([CH3:12])[CH:9]=[N:8]1)=[N:4][CH2:5][CH3:6].[Cl:14][C:15]1[CH:16]=[C:17]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>C(#N)C>[Cl:14][C:15]1[CH:16]=[C:17]([S:23]([N:26]=[C:3]([N:7]2[CH2:11][C:10]([CH3:12])([CH3:13])[CH:9]=[N:8]2)[NH:4][CH2:5][CH3:6])(=[O:24])=[O:25])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(S(N)(=O)=O)cc1Cl
Reactant: CCN=C(SC)N1CC(C)(C)C=N1
Solvent: CC#N
Product: CCNC(=NS(=O)(=O)c1ccc(OC)c(Cl)c1)N1CC(C)(C)C=N1
Yield: 0.4 %

Procedure:
0.75 g (1 mol equiv.) N-Ethyl-4,4-dimethyl-4,5-dihydro-pyrazole-1-carboximidothioic acid methyl ester and 0.94 g (1.05 mol equiv.) 3-chloro-4-methoxy-benzenesulfonamide were added to 10 mL acetonitrile. The reaction mixture was refluxed overnight and volatiles were removed in vacuo. The residue was taken up in ethyl acetate and extracted with 2N NaOH. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. Purification by flash chromatography on silica gel (Et2O) afforded 1.43 g (97%) 3-chloro-N-[(4,4-dimethyl-4,5-dihydro-pyrazol-1-yl)-ethylamino-methylene]-4-methoxy-benzenesulfonamide. 1H NMR (400 MHz, CDCl3) δ 1.17 (t, J=7.3 Hz, 3H), 1.22 (s, 6H), 3.43-3.52 (m, 2H), 3.77 (br.s., 2H), 3.95 (s, 3H), 6.75 (s, 1H), 6.96 (d, J=8.6 Hz, 1H), 6.70-6.90 (br.s., 1H) 7.82 (dd, J=8.6, 2.3 Hz, 1H), 7.95 (d, J=2.3 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][C:11]1[CH:15]=[CH:14][NH:13][N:12]=1.[C:16]1([CH2:22][C:23](=O)[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:22]([C:23]1[NH:10][C:11]2=[N:12][NH:13][CH:14]=[C:15]2[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[Cl:1])[C:24]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)CC(=O)Cc1ccccc1
Reactant: O=Cc1ccccc1Cl
Product: CCOC(=O)C1=C(Cc2ccccc2)Nc2n[nH]cc2C1c1ccccc1Cl

Procedure:
The title compound was prepared from 2-chlorobenzaldehyde, 3-aminopyrazole and ethyl 4-phenylacetoacetate in the same manner as in Example 1.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH3:28])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][C:14]([C:18]([O:20]CC)=[O:19])=[C:15]([CH3:17])[N:16]=2)=[CH:8][C:7]=1[N:23]1[CH:27]=[N:26][N:25]=[N:24]1.[OH-].[Na+].Cl.O>O1CCCC1.CO>[OH:1][CH2:2][CH:3]([CH3:28])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][C:14]([C:18]([OH:20])=[O:19])=[C:15]([CH3:17])[N:16]=2)=[CH:8][C:7]=1[N:23]1[CH:27]=[N:26][N:25]=[N:24]1
Reactant: CCOC(=O)c1sc(-c2ccc(OCC(C)CO)c(-n3cnnn3)c2)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(OCC(C)CO)c(-n3cnnn3)c2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.5 %

Procedure:
A solution was prepared by dissolving 34.1 mg of ethyl 2-[4-(3-hydroxy-2-methylpropoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylate in 1.0 mL of a mixed solution of tetrahydrofuran/methanol=1/1. A reaction mixture solution prepared by adding 0.2 mL of 2 M sodium hydroxide aqueous solution to the solution was stirred at room temperature for 3 hours. After the addition of 0.2 mL of 2 M hydrochloric acid to the reaction mixture solution under stirring, 3 mL of water was added and extraction was performed using 4 mL of ethyl acetate. The organic layer was concentrated, followed by purifying by a conventional method to obtain 15.4 mg of 2-[4-(3-hydroxy-2-methylpropoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylic acid.
Reaction SMILES: C1(N=[N:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([N:29]=NC5C=CC=CC=5)=[CH:25][CH:24]=4)[N:19]=[C:18]([NH:37][C:38]4[CH:43]=[CH:42][C:41]([N:44]=NC5C=CC=CC=5)=[CH:40][CH:39]=4)[N:17]=3)=[CH:11][CH:10]=2)C=CC=CC=1.O.NN.NC1C=CC=CC=1>[Pd].C(O)C(C)C>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:21]=[C:20]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([NH2:29])=[CH:27][CH:28]=3)[N:19]=[C:18]([NH:37][C:38]3[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=3)[N:17]=2)=[CH:11][CH:10]=1
Reactant: c1ccc(N=Nc2ccc(Nc3nc(Nc4ccc(N=Nc5ccccc5)cc4)nc(Nc4ccc(N=Nc5ccccc5)cc4)n3)cc2)cc1
Agent: [Pd]
Agent: NN
Solvent: CC(C)CO
Solvent: Nc1ccccc1
Solvent: O
Product: Nc1ccc(Nc2nc(Nc3ccc(N)cc3)nc(Nc3ccc(N)cc3)n2)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
In one 100 milliliter, four-neck, round-bottom flask equipped with a thermo-couple, a condenser, a mechanical stirrer, and a nitrogen sweep were placed 3.34 grams (0.005 mole) of 2,4,6-tris-[4-(phenylazo)phenylamino]-1,3,5-triazine, 50 grams of isobutanol, 1.66 grams (0.033 mole) of hydrazine hydrate and 0.15 gram of 5 percent palladium on carbon (approximately 60 percent wet). Over a period of two hours, the mixture was heated to 70° C., and held an additional ten hours at 70° C. The reduction was followed by high performance liquid chromatography by observing the disappearance of the starting tris-azo compound and the conversion of the intermediate di- and mono-azo compounds to the tris-amino compound and the formation of the by-product aniline. The title compound was isolated by filtration at 60° C. The filter cake was washed with 10 milliliters of isobutanol, dried to a constant weight to give 100 percent yield (2 grams) of 2,4,6-tris-[4-aminoanilino]-1,3,5-triazine. The melt point was 297°-299° C. The infrared spectrum was consistent with the structure. Relative area HPLC analysis showed it to be 97.8 percent pure. The filtrate was distilled to recover 1.1 grams of aniline, 78.6 percent of theory.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH2:4][CH:5]=[CH:6][N:7]=1.[CH2:8](I)[CH2:9][CH3:10].C(OCC)(=O)C.[OH-].[K+]>CN(C)C=O.CO>[CH2:8]([N:7]1[CH:6]=[CH:5][CH2:4][S:3][C:2]1=[NH:1])[CH2:9][CH3:10]
Reactant: NC1=NC=CCS1
Reactant: CCCI
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CO
Product: CCCN1C=CCSC1=N
Temperature: 50 °C
Reaction time: 8 h
Yield: 22.5 %

Procedure:
1.3 g (11.4 mmol) of 2-amino-6H-1,3-thiazine was dissolved in 4 ml of dimethylformamide, and 2.4 g (14.1 mmol) of n-propyl iodide was added thereto. The mixture was heated at 50° C. for one hour and then stirred at room temperature overnight. To the reaction solution, 100 ml of ethyl acetate was added, and the mixture was stirred and then left to stand still. Then, the ethyl acetate layer was separated and removed by decantation. Then, the residual oily substance was dissolved in 50 ml of methanol, and 30 ml of a methanol solution containing 0.75 g (11.4 mmol) of 85% potassium hydroxide, was added thereto at room temperature. The mixture was further stirred at the same temperature for one hour, and then methanol was distilled off under reduced pressure. To the residue, 60 ml of chloroform was added, and insoluble matters were removed by filtration. Then, the filtrate was concentrated under reduced pressure. The residual oily substance was purified by alumina column chromatography (eluent: chloroform) to obtain 0.4 g of 3,6-dihydro-3-n-propyl-2H-1,3-thiazin-2-imine as an oily substance.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]C.[CH:13]([OH:15])=O.[OH:16]O>C(O)C>[CH2:13]([OH:15])[CH:11]([OH:16])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: OO
Reactant: C=CCCCCCCCCCC
Reactant: O=CO
Solvent: CCO
Product: CCCCCCCCCCC(O)CO

Procedure:
336 g (2.00 mol) of 1-dodecene were reacted with 236 g of formic acid and 185 g of a 50% strength aqueous H2O2 solution in accordance with Example 4. 412 g of ethanol were employed for the Marlon AS3 acid-catalyzed transesterification, and the main fraction obtained after the workup by distillation was 99.5% pure, virtually odorless 1,2-dodecanediol.
Reaction SMILES: [N+](C1C=CC([O:10][C:11]([N:13]2[CH:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=3)[C:17]([C:27]([O:29][CH3:30])=[O:28])=[C:16]([CH2:31][O:32][CH3:33])[NH:15][C:14]2=[O:34])=O)=CC=1)([O-])=O.[C:35]1([C:41]2([C:51]3[N:52]([CH3:56])[CH:53]=[CH:54][CH:55]=3)[CH2:46][CH2:45][N:44]([CH2:47][CH2:48][CH2:49][NH2:50])[CH2:43][CH2:42]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[CH3:30][O:29][C:27]([C:17]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)[N:13]([C:11](=[O:10])[NH:50][CH2:49][CH2:48][CH2:47][N:44]2[CH2:43][CH2:42][C:41]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)([C:51]3[N:52]([CH3:56])[CH:53]=[CH:54][CH:55]=3)[CH2:46][CH2:45]2)[C:14](=[O:34])[NH:15][C:16]=1[CH2:31][O:32][CH3:33])=[O:28]
Reactant: COCC1=C(C(=O)OC)C(c2ccc(F)c(F)c2)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1
Reactant: Cn1cccc1C1(c2ccccc2)CCN(CCCN)CC1
Solvent: ClCCl
Product: COCC1=C(C(=O)OC)C(c2ccc(F)c(F)c2)N(C(=O)NCCCN2CCC(c3ccccc3)(c3cccn3C)CC2)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
To a solution of 6-(3,4-difluorophenyl)-4-methoxymethyl-2-oxo-3,6-dihydro-2H-pyrimidine-1,5-dicarboxylic acid 5-methyl ester 1-(4-nitrophenyl)ester (24 mg, 0.05 mmol) in 2 ml of CH2Cl2 was added 3-[4-phenyl-4-(1-methylpyrrol-2-yl)-piperidin-1-yl]-propylamine (15 mg, 0.05 mmol) and resulting solution was stirred for 2 h at 25° C. Reaction mixture was concentrated in vacuo to provide an oil which was subjected to column chromatography over silica gel (5% MeOH/CHCl3) to yield 22 mg (69%) of the desired product, which was converted to HCl salt and recrystallized from EtOAC-Et2O to afford 16 mg of the product as a white solid: mp 139-142° C.
Reaction SMILES: [C:1]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([N+:17]([O-:19])=[O:18])=[C:10]([O:15][CH3:16])[CH:11]=2)[CH2:6]1)(=[O:4])[CH:2]=[CH2:3].[CH:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([CH3:22])[CH3:21]>CO>[CH3:21][CH:20]([N:23]1[CH2:28][CH2:27][N:26]([CH2:3][CH2:2][C:1]([N:5]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][C:9]([N+:17]([O-:19])=[O:18])=[C:10]([O:15][CH3:16])[CH:11]=3)[CH2:6]2)=[O:4])[CH2:25][CH2:24]1)[CH3:22]
Reactant: C=CC(=O)N1CCc2cc(OC)c([N+](=O)[O-])cc2C1
Reactant: CC(C)N1CCNCC1
Solvent: CO
Product: COc1cc2c(cc1[N+](=O)[O-])CN(C(=O)CCN1CCN(C(C)C)CC1)CC2
Temperature: 65 °C
Yield: 45.1 %

Procedure:
A solution of 2-acryloyl-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroisoquinoline (425 mg, 1.62 mmol) in methanol (5 mL) was treated with 1-isopropylpiperzine (1.0 mL, 7.0 mmol, Oakwood Products) and heated at 65° C. in a sealed tube for 16 h. The mixture was cooled, concentrated, and partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was separated, dried over magnesium sulfate, filtered, and purified by chromatography on SiO2 (dichloromethane to 25% methanol/dichloromethane) to give 2-{3-[4-(1-methylethyl)-1-piperazinyl]propanoyl}-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroisoquinoline (285 mg, 0.731 mmol, 45%). ESIMS (M+H)+=391.