Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH:16]1[CH2:20][CH2:19][CH2:18][S:17]1>C1C=CC=CC=1>[S:17]1[CH2:18][CH2:19][CH2:20][CH:16]1[C:10]1[C:11](=[O:13])[CH2:12][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][C:9]=1[OH:14]
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Reactant: ClC1CCCS1
Solvent: c1ccccc1
Product: O=C1CC(c2ccccc2)CC(O)=C1C1CCCS1
Temperature: 25 °C

Procedure:
A mixture of 4.0 parts of 5-phenyl-1,3-cyclohexanedione and 120 parts by volume of a 5% benzene solution of 2-chlorotetrahydrothiphene was refluxed by heating while stirring. After cooling to room temperature, the reaction mixture was washed with 40 parts by volume of water and then treated three times with 30 parts by volume of a 5% aqueous solution of sodium hydroxide. The aqueous layer was collected and washed with 30 parts by volume of ether. While maintaining the temperature of the solution below 10° C., the pH of the solution was controlled between 4 and 5 with the addition of 6 N hydrochloric acid. The light orange colored crystals thus deposited were collected and purified by passing through a column containing a silica gel using a solvent mixture of chloroform and benzene (5:1) as a spreading agent to obtain 2-(2-tetrahydrothienyl)-3-hydroxy-5-phenyl-2-cyclohexen-1-one in a form of colorless fine crystals. The melting point was 141° to 142° C. The yield was 2.4 parts.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19](=[S:21])[NH2:20])=[CH:15]2)(=[O:8])=[O:7].N[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1S.Cl.C(O)CO>O>[S:21]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:20]=[C:19]1[C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8]
Reactant: Nc1ccccc1S
Reactant: NC(=S)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: Cl
Solvent: OCCO
Solvent: O
Product: O=S(=O)(Nc1cccc2cc(-c3nc4ccccc4s3)[nH]c12)c1cccs1
Temperature: 100 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
A mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.30 g), 2-aminothiophenol (0.10 mL), concentrated hydrochloric acid (0.5 mL) and ethylene glycol (6 mL) was stirred at 100° C. overnight. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (0.14 g, yield 38%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 201-202° C.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:26][C@H:27]([C:29]([OH:31])=[O:30])[CH3:28]>C[O-].[Na+].CO>[OH:18][C:17]1[C:16]2[C:11](=[CH:12][C:13]([S:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9][C:8]=1[C:6]([NH:26][C@@H:27]([CH3:28])[C:29]([OH:31])=[O:30])=[O:7]
Reactant: C[C@H](N)C(=O)O
Reactant: CCCCOC(=O)c1ncc2cc(Sc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C[C@H](NC(=O)c1ncc2cc(Sc3ccccc3)ccc2c1O)C(=O)O
Yield: 72 %

Procedure:
A mixture of 4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (0.20 g) and L-alanine (0.75 g) in 0.5 M NaOMe/MeOH (11.3 ml) was heated to reflux for 36 h. After cooling, reaction mixture was concentrated. The residue was suspended in water (50 ml) and extracted with ethyl acetate (50 ml) which was discarded. The aqueous layer was acidified by 2 N HCl aqueous solution. Extracted with ethyl acetate (2×50 ml). Combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give the title compound (0.15 g). MS-(−)-ion: M−1=367.1.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]2[CH:17]=[C:16]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:23][C:24]=3[CH3:25])[CH:15]=[CH:14][C:6]=2[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:32][C:33]1[C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:36][N:35]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:34]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:25][C:24]1[O:23][C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:21][C:20]=1[CH2:19][O:18][C:16]1[CH:15]=[CH:14][C:6]2[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:3]([CH2:2][O:32][C:33]3[C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:36][N:35]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[N:34]=3)[O:4][C:5]=2[CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc2c(-c3ccccc3)c(CCl)oc2c1
Reactant: CCOC(=O)c1cn(-c2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(-c2ccccc2)nc1OCc1oc2cc(OCc3nc(-c4ccccc4)oc3C)ccc2c1-c1ccccc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
A mixture of 4-({[2-(chloromethyl)-3-phenyl-1-benzofuran-6-yl]oxy}methyl)-5-methyl-2-phenyl-1,3-oxazole (1.16 g), ethyl 3-hydroxy-1-phenyl-1H-pyrazole-4-carboxylate (0.58 g), potassium carbonate (0.35 g) and N,N-dimethylformamide (30 mL) was stirred at 90° C. for 3 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration, and subjected to silica gel column chromatography to give ethyl 3-({6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-phenyl-1-benzofuran-2-yl}methoxy)-1-phenyl-1H-pyrazole-4-carboxylate as colorless crystals (1.19 g, 76%) from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 143-144° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH2:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1>CO.N#N.[OH-].[Pd+2].[OH-]>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH:5]1[CH2:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][CH:6]1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1
Reactant: COC(=O)CC1=C(c2cccc(OC)c2)CC(C)(C)CC1
Agent: [Pd+2]
Agent: N#N
Agent: [OH-]
Solvent: CO
Product: COC(=O)CC1CCC(C)(C)CC1c1cccc(OC)c1
Yield: 87.2 %

Procedure:
Dissolve [2-(3-methoxy-phenyl)-4,4-dimethyl-cyclohex-1-enyl]-acetic acid methyl ester (4.3 g, 15 mmol) in methanol (135 ml), exchange with N2 3×, add palladium hydroxide 20% on activated carbon (0.84 g, 5.9 mmol). Add 60 psi of H2 at room temperature for 18 h. Filter off catalyst rinsing with methanol, concentrate filtrate to give the title compound (3.8 g, 88%): 1H NMR (CDCl3) δ 7.23-7.17 (m, 1H), 6.79-6.71 (m, 3H), 3.80 (s, 3H), 3.55-3.49 (t, 3H), 2.52-2.19 (m, 1H), 1.95-1.83 (m, 2H), 1.72-1.21 (m, 6H), 1.02 (s,3H), 0.99, (s, 3H), 0.93 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].S([O-])([O-])(=O)=O.CS[C:15]([NH2:27])=[NH+:16][CH2:17][CH2:18][S:19][CH2:20][C:21]1[N:22]=[CH:23][NH:24][C:25]=1[CH3:26].CS[C:30]([NH2:42])=[NH+:31][CH2:32][CH2:33][S:34][CH2:35][C:36]1[N:37]=[CH:38][NH:39][C:40]=1[CH3:41]>>[CH3:41][C:40]1[NH:39][CH:38]=[N:37][C:36]=1[CH2:35][S:34][CH2:33][CH2:32][N:31]=[C:30]([NH2:42])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:15]([NH2:27])=[N:16][CH2:17][CH2:18][S:19][CH2:20][C:21]1[N:22]=[CH:23][NH:24][C:25]=1[CH3:26]
Reactant: NCCCCCN
Reactant: CSC(N)=[NH+]CCSCc1nc[nH]c1C
Agent: O=S(=O)([O-])[O-]
Product: Cc1[nH]cnc1CSCCN=C(N)NCCCCCNC(N)=NCCSCc1nc[nH]c1C

Procedure:
The reaction of 1,5-diaminopentane (0.43 g) with S-methyl-N-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiouronium sulphate (2.52 g) by the method described in Example 5 afforded the title compound which was isolated as the dipicrate (1.8 g) m.p. 115°-120°.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20](Br)[CH:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:26][N:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[Sn](CCCC)(CCCC)CCCC>>[F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:28]5[N:27]([CH3:26])[CH:31]=[CH:30][CH:29]=5)[CH:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccn1C
Reactant: Fc1ccc(CCN2CCC(N3CCc4ccc(Br)cc43)CC2)cc1
Product: Cn1cccc1-c1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Yield: 16 %

Procedure:
1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-bromoindoline (0.1 g) and 1-methyl-2-tributylstannylpyrrole (0.37 g) synthesized in accordance with the method described in Tetrahedron Lett., 4407 (1986). were treated as in Production Example 13-2 to give the title compound (0.016 g) as a yellow oil (yield: 15.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>CC#N>[CH3:15][N:13]([CH3:14])[C:11](=[O:12])[CH2:10][N:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: COc1ccc(NCC(=O)N(C)C)cc1
Reactant: CCOC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CN(CC(=O)N(C)C)c1ccc(OC)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 85.6 %

Procedure:
To a stirred solution of 2-(4-methoxyphenylamino)-N,N-dimethylacetamide (19) (10.7 g, 51.2 mmol) in MeCN (80 mL) and DIPEA (13.4 ml, 77 mmol) was added ethyl bromoacetate (6.84 ml, 61.4 mmol) the reaction was stirred at 60° C. for 16 h. The volatiles were removed in vacuo, and the crude mixture was dissolved in EtOAc (150 mL), washed with 1M HCl (aq.) (150 mL), brine (150 mL), dried (MgSO4), filtered and solvents removed in vacuo to afford a purple oil. The residue was purified by silica gel chromatography (120 g, 60-100% EtOAc in isohexane) to afford ethyl 2-((2-(dimethylamino)-2-oxoethyl)(4-methoxyphenyl)amino)acetate (X) (12.9 g, 85%) as a purple oil: m/z 295.4 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 6.81-6.71 (m, 2H), 6.60-6.47 (m, 2H), 4.24-3.96 (m, 6H), 3.66 (s, 3H), 2.99 (br s, 3H), 2.83 (br s, 3H), 1.19 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]45[O:29][C:26]([CH2:30][CH2:31][C:32]([O:34]C)=[O:33])([CH2:27][CH2:28]4)[CH2:25][CH2:24]5)=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([C:5]1[O:9][C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]45[O:29][C:26]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])([CH2:27][CH2:28]4)[CH2:25][CH2:24]5)=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCC12CCC(c3ccc(-c4ccc(Nc5nnc(C(C)(C)C)o5)cc4)cc3)(CC1)O2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1nnc(Nc2ccc(-c3ccc(C45CCC(CCC(=O)O)(CC4)O5)cc3)cc2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
To a solution of methyl 3-(4-(4′-((5-(tert-butyl)-1,3,4-oxadiazol-2-yl)amino)-[1,1′-biphenyl]-4-yl)-7-oxabicyclo[2.2.1]heptan-1-yl)propanoate (100 mg, 0.21 mmol) in THF (3.4 mL) and methanol (0.85 mL) was added 1N NaOH solution (0.63 mL, 0.63 mmol) and the reaction was let stir at rt for 2 h. The resulting yellow reaction mixture was partially concentrated by rotary revaporation (rt water bath) to remove THF. The resulting yellow mixture was diluted with methanol, filtered and purified on preparative HPLC (10-50% acetonitrile:5 mM NH4OH) and lyophilized to afford 83 mg (86%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.36 (s, 9H), 1.56-1.82 (m, 6H), 2.01-2.10 (m, 2H), 2.10-2.19 (m, 2H), 2.30-2.39 (m, 2H), 7.43 (d, J=8.6 Hz, 2H), 7.60 (d, J=8.6 Hz, 2H), 7.62-7.67 (m, 4H) 10.51 (br. s., 1H). 13C NMR (100 MHz, DMSO-d6): δ ppm 174.5, 165.9, 159.5, 141.7, 138.3, 138.2, 133.1, 127.1, 125.8, 125.4, 117.1, 86.1, 85.5, 37.9, 34.9, 31.7, 30.2, 30.1, 27.8. ESI-MS m/z: 462.1 [M+H]+, retention time 1.13 min (condition E). HR/MS [M+H]+: found 462.2371. calc. 462.2393. RT: 1.96 (Condition L).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[C:13](=[O:14])[N:12]2[C:7]([S:8][CH2:9][CH2:10][CH2:11]2)=[N:6][C:5]=1[CH3:15].[BrH:16]>C(O)(=O)C>[Br:16][CH2:2][CH2:3][C:4]1[C:13](=[O:14])[N:12]2[C:7]([S:8][CH2:9][CH2:10][CH2:11]2)=[N:6][C:5]=1[CH3:15]
Reactant: Cc1nc2n(c(=O)c1CCO)CCCS2
Reactant: Br
Solvent: CC(=O)O
Product: Cc1nc2n(c(=O)c1CCBr)CCCS2
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 20 parts of 3,4-dihydro-7-(2-hydroxyethyl)-8-methyl-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one, 50 parts of acetic acid and 180 parts of a hydrobromic acid solution 67% in acetic acid was stirred and heated to reflux. Stirring was continued overnight at reflux temperature. The reaction mixture was evaporated and the solid residue was triturated in 2-propanone. The product was filtered off and dried, yielding 24 parts (100%) of 7-(2-bromoethyl)-3,4-dihydro-8-methyl-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one; monohydrobromide; mp. 215° C. (intermediate 8).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].[C:13](=S)=[S:14].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]2[O:5][C:13]([SH:14])=[N:2][CH:3]=2)=[CH:7][CH:8]=1
Reactant: S=C=S
Reactant: NCC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Sc1ncc(-c2ccc(Cl)cc2)o1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 172.9 %

Procedure:
2-amino-1-(4-chlorophenyl)ethanone hydrochloride (0.80 g, 3.88 mmol) and carbon disulfide (0.47 mL, 0.59 g, 7.76 mmol) was suspended in ethanol (10 mL). To this was slowly added a solution of sodium carbonate (0.44 g, 4.08 mmol) in water (4 mL) at ambient temperature. After heating to 80° C. ext. temp. for 18 h the cold mixture was filtered. The filtrate was diluted with acetic acid (40 mL) and stirred for 15 min. at room temperature. Evaporation of the solvents in vacuo gave 1.42 g of a crude 5-(4-chlorophenyl)oxazole-2-thiol which was of ca. 61% purity (HPLC-MS) and used as is in the next step. The crude oxazole-2-thiol compound (1.42 g, max. 3.88 mmol) was suspended in phosphorous oxychloride (5 mL). To this was added dropwise triethyl amine (1.15 mL, 0.84 mg, 8.27 mmol) and the mixture heated to 105° C. ext. temperature for 4 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with aq. sat. bicarbonate (100 mL) and water (50 mL). Drying (sodium sulfate) and concentration in vacuo yielded crude product (615 mg), which was purified by column chromatography (SiO2, 5-40% ethyl acetate in heptanes) to give pure 2-chloro-5-(4-chlorophenyl)oxazole (105 mg, 0.49 mmol, 13%, purity 96% HPLC-MS).
Reaction SMILES: [F:1][C:2]([F:25])([C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[C:3](Cl)=[O:4].[N+:26]([C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][OH:32])([O-:28])=[O:27].C(N(CC)CC)C.Cl.C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]([F:25])([C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[C:3]([O:32][CH2:31][C:30]1[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=1[N+:26]([O-:28])=[O:27])=[O:4]
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=[N+]([O-])c1ccccc1CO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(OCc1ccccc1[N+](=O)[O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 0.5 h

Procedure:
Perfluorooctanoyl chloride (21.6 g, 0.05 mol) was added slowly with stirring to a solution of 2-nitrobenzyl alcohol (7.65 g, 0.05 mol) and triethylamine (5.2 g, 0.05 mol) in 100 ml benzene. During the addition, the temperature was allowed to rise to 50° C. and the triethylamine hydrochloride began to precipitate. After the addition was complete, the reaction was stirred an additional 30 minutes. The reaction was filtered and the filtrate evaporated in vacuo to give an oil which crystallized on cooling in an ice bath (m.p. 34°-35° C.). Benzene washings of the material retained on the filter paper gave a second fraction of oil which crystallized on cooling. Total yield was 11.97 g.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][CH:8]([CH3:11])[CH2:9][SH:10].Cl[C:13]1[S:14][C:15]([S:23](=[O:26])(=[O:25])[NH2:24])=[CH:16][C:17]=1[C:18](OCC)=[O:19]>C(O)C>[CH3:11][CH:8]1[NH:7][C:18](=[O:19])[C:17]2[CH:16]=[C:15]([S:23](=[O:25])(=[O:26])[NH2:24])[S:14][C:13]=2[S:10][CH2:9]1
Reactant: CCOC(=O)c1cc(S(N)(=O)=O)sc1Cl
Reactant: CC(N)CS
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: CC1CSc2sc(S(N)(=O)=O)cc2C(=O)N1
Reaction time: 24 h
Yield: 72.5 %

Procedure:
To a mixture of potassium tert-butoxide (8.56 g, 0.076 mol) in ethanol (75 mL) was added 2(R,S)-aminopropanethiol (3.1 g, 0.0246 mol) and ethyl 2-chloro-5-sulfamoylthiophene-3-carboxylate (5.98 g, 0.022 mol). The mixture was heated at reflux for 24 hours, and then allowed to stand at room temperature for 24 hours. Following removal of most of the solvent by vacuum concentration, the mixture was acidified to pH 3 with dilute hydrochloric acid. The resulting solids were removed by filtration and dried to give 4.44 g of the title compound, mp 184°-187° C.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][NH:11][CH3:12].[Cl:13][C:14]1[C:15]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=2)=[N:16][C:17]([Cl:20])=[CH:18][CH:19]=1>N1C=CC=CC=1>[Cl:13][C:14]1[C:15]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:31])[N:11]([O:10][CH3:9])[CH3:12])=[CH:25][CH:24]=2)=[N:16][C:17]([Cl:20])=[CH:18][CH:19]=1
Reactant: CNOC
Reactant: O=C=Nc1ccc(OCc2nc(Cl)ccc2Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CON(C)C(=O)Nc1ccc(OCc2nc(Cl)ccc2Cl)cc1
Temperature: 60 °C

Procedure:
Triethylamine (4.55 grams; 0.045 mole) was added to a solution of O,N-dimethylhydroxylamine hydrochloride (4.1 grams; 0.042 mole) in 40 ml. of dry pyridine. 3,6dichloro-2-((4-isocyanatophenoxy)methyl)pyridine (12.4 grams; 0.042 mole) was added thereto and the resulting mixture heated for 20 minutes at about 60° C. The reaction mixture was then mixed with ice and the resulting precipitate recovered by filtration and recrystallized from a benzene-hexane (90:10) mixture. As a result of such operations, the desired N'-(4-((3,6-dichloro-2-pyridinyl)methoxy)phenyl)-N-methoxy-N-methyl urea compound was recovered as a crystalline solid having a melting point of 152°-153.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]([C:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[S:26][CH:25]=1)[C:20]([O:22][CH3:23])=[O:21]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]([C:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[S:26][CH:25]=2)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)C(N)c1csc2ccccc12
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: COC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1csc2ccccc12

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(benzothiophen-3-yl)acetate (prepared from 2-amino-2-(benzothiophen-3-yl)acetic acid [CAS 95834-94-9] using General Procedure H), the title compound was prepared as a solid (mp 185-186° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C:7]2=[O:25])([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[C:7]2=[O:25]
Reactant: O=C(CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O)OCc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)C(=O)N(CC(=O)OCc1ccccc1)C2=O
Yield: 94.5 %

Procedure:
To a suspension of benzyl 2-(5-nitro-1,3-dioxoisoindolin-2-yl)acetate (1.2 g, 3.528 mmol) in a mixture of ethanol (23 ml) and water (11.5 ml), iron powder (1.182 g, 21.16 mmol) and ammonium chloride (0.132 g, 2.468 mmol) were added, and the mixture was heated to reflux for 1 hour. The insoluble was filtered off and the filtrate was evaporated to dryness. The residue was dissolved in ethyl acetate and washed with water and brine (×3). The organic phase was dried over Na2SO4 and the solvent was removed to give benzyl 2-(5-amino-1,3-dioxoisoindolin-2-yl)acetate (1.035 g, 3.335 mmol, 94.5% yield, MS/ESI+ 310.9 [MH]+). This product was used in the following step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH2:10])=[CH:5][C:4]=1[N+:11]([O-])=O.C(O)(=O)C>ClCCl.[Zn]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH2:10])=[CH:5][C:4]=1[NH2:11]
Reactant: C=Cc1ccc(OC)c([N+](=O)[O-])c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: C=Cc1ccc(OC)c(N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a solution of 1-methoxy-2-nitro-4-vinyl-benzene (100 mg) in dichloromethane (2 mL) was added zinc dust (large excess), followed by acetic acid (0.5 mL) and the resulting mixture was stirred at room temperature for 30 minutes. The solid was filtered, washed with dichloromethane and discarded. The filtrate was evaporated under reduced pressure and the residue was purified by flash chromatography (hexane/EtOAc, 90/10) to give 50 mg of 2-methoxy-5-vinyl-phenylamine.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[CH:5]1[CH:6]=[CH:7][C:8]2N[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH:12]=[CH:11][C:9]=2[CH:10]=1>C(O)(=O)C.P(=O)(O)(O)O>[CH:5]1[CH:6]=[CH:7][C:8]2[N:1]([C:2]([NH2:4])=[O:3])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][C:9]=2[CH:10]=1
Reactant: C1=Cc2ccccc2Nc2ccccc21
Reactant: NC(N)=O
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Product: NC(=O)N1c2ccccc2C=Cc2ccccc21
Temperature: 27.5 °C

Procedure:
To a suspension of urea (80 g, 1.333 mols) in acetic acid (100 ml), phosphoric acid (8 ml) was added, followed by iminostilbene (20 g, 0.103 mols), under stirring at 25-30° C. The resulting reaction mixture was worked up according to the method of Example 1 to produce carbamazepine, which was identical to the product of Example 1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[C:9]1([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([CH:30]=O)[CH:24]=[CH:23]3)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClC(Cl)C>[C:9]1([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([CH2:30][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:24]=[CH:23]3)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=Cc1ccc2cc(OCCCCc3ccccc3)ccc2c1
Reactant: C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: c1ccc(CCCCOc2ccc3cc(CN4CCCCC4)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution in 6-(4-phenylbutoxy)-2-formylnaphthalene (50 mg) in dichloroethane (0.5 mL), piperidine (20 μL) and triacetoxy sodium borohydride (72 mg) were added, followed by stirring at room temperature for 18 hours. The reaction mixture was added with a 1N aqueous sodium hydroxide solution, and then the mixture was extracted with chloroform. After concentrating the organic layer, the obtained residue was purified by silica gel column chromatography (dichloroform:methanol:acetic acid=120:10:1) to give the title compound (60 mg) having the following physical properties.