Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[H-].[Na+].Cl[C:13]1[CH:18]=[CH:17][N+:16]([O-:19])=[C:15]([CH3:20])[C:14]=1[CH3:21]>CS(C)=O>[CH3:1][C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][O:8][C:13]2[CH:18]=[CH:17][N+:16]([O-:19])=[C:15]([CH3:20])[C:14]=2[CH3:21])[CH2:4][O:3]1
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1c(OC[C@@H]2COC(C)(C)O2)cc[n+]([O-])c1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 135.9 %

Procedure:
To a dimethylsulfoxide (48 ml) solution of the ((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol (4.87 g, 39.7 mmol), sodium hydride, in oil (1.73 g, 39.6 mmol as the content was regarded as 55%) was added at room temperature. To the mixture, 4-chloro-2,3-dimethylpyridine 1-oxide (4.8 g, 30.5 mmol) was added, the mixture was stirred at 60° C. for 2 hours. After cooled to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH silica gel, elution solvent: ethyl acetate/methanol) to obtain the title compound (10.5 g, yield: 136%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=O)[CH:5]=[N:6][CH:7]=1.[OH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][N:15]2[CH3:20].[C:21](#[N:25])[CH2:22][C:23]#[N:24].N1CCCCC1>C(O)C>[NH2:25][C:21]1[O:10][C:11]2[C:19]([CH:8]([C:4]3[CH:5]=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)[C:22]=1[C:23]#[N:24])=[CH:18][CH:17]=[C:16]1[N:15]([CH3:20])[CH:14]=[CH:13][C:12]=21
Reactant: Cc1cncc(C=O)c1
Reactant: Cn1ccc2c(O)cccc21
Reactant: N#CCC#N
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cncc(C2C(C#N)=C(N)Oc3c2ccc2c3ccn2C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-methyl-pyridine-3-carbaldehyde (121 mg, 1 mmol) and 4-hydroxy-1-methyl-indole (146 mg, 0.99 mmol) in absolute ethanol (5 mL) at 0° C., was added malononitrile (67 mg, 1.01 mmol) and piperidine (0.1 mL). The clear solution was slowly warmed to room temperature and stirred overnight. The product was collected by vacuum filtration, washed with ethanol, and dried in vacuo as a yellow powder (269 mg, 86%). 1H NMR (CDCl3): 8.34 (d, J=2.1 Hz, 1H), 8.31 (dd, J=0.6, 2.1 Hz, 1H), 7.29 (m, 1H), 7.06 (d, J=3.0 Hz, 1H), 7.02 (dd, J=0.9, 8.4 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 6.57 (dd, J=0.9, 3.0 Hz, 1H), 4.85 (s, 1H), 4.72 (brs, 2H), 3.77 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: [CH:1](=[C:8]1/[C:9](=[O:17])[NH:10][C:11]2[C:16]/1=[CH:15][CH:14]=[CH:13][CH:12]=2)\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][NH:19][CH2:20]C(O)=O.[CH3:24][C:25]([CH3:29])=[CH:26][CH:27]=O>C1(C)C=CC=CC=1>[CH3:18][N:19]1[CH2:20][CH:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:17])[CH:27]1[CH:26]=[C:25]([CH3:29])[CH3:24]
Reactant: CC(C)=CC=O
Reactant: CNCC(=O)O
Reactant: O=C1Nc2ccccc2/C1=C\c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)=CC1N(C)CC(c2ccccc2)C12C(=O)Nc1ccccc12

Procedure:
A mixture of 3-E-3-benzylidene-1,3-dihydro-indol-2-one (10.0 mmol), N-methyl-glycine (14 mmol) and 3-methyl-but-2-enal (14 mmol) in 100 mL toluene was refluxed for 6 hours. The solvent was removed and the residue was purified on silica gel column to yield the product.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:5]2[C:16](=[O:29])[CH:17]([NH:18][C:19](=[O:28])[C:20](=[N:25][O:26][CH3:27])[C:21](=O)[CH2:22]Br)[C@H:4]2[S:3]1.[NH2:30][C:31]([NH2:33])=[S:32]>C(O)C>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:5]2[C:16](=[O:29])[CH:17]([NH:18][C:19](=[O:28])[C:20](=[N:25][O:26][CH3:27])[C:21]3[N:30]=[C:31]([NH2:33])[S:32][CH:22]=3)[C@H:4]2[S:3]1
Reactant: NC(N)=S
Reactant: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=CC(C)S[C@H]12
Solvent: CCO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=CC(C)S[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a mixture of 2,2,2-trichloroethyl 2-methyl-7-(2-methoxyimino-3-oxo-4-bromobutyramido)-3-cephem-4-carboxylate (a mixture of syn and anti isomers) (0.94 g.) and ethanol (10 ml.) was added thiourea (0.12 g.), and the mixture was stirred for 40 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was shaken with ethyl acetate and water. The ethyl acetate layer was separated, and the remaining aqueous layer was neutralized with sodium bicarbonate and then extracted with ethyl acetate. Thus obtained ethyl acetate layers were combined together, washed with water, dried over magnesium sulfate, treated with activated charcoal and then concentrated under reduced pressure. The residue was pulverized in diethyl ether, collected by filtration and then dried to give 2,2,2-trichloroethyl 2-methyl-7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), which can be represented as 2,2,2-trichloroethyl 2-methyl-7-[2-methoxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), (0.6 g.). This compound was subjected to column chromatography on silica gel using a mixed solvent of benzene, ethyl acetate and acetic acid (10:10:1) as a developer, and the eluates containing the object compound were collected, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was pulverized in diethyl ether, collected by filtration and then dried to give pale brown powder of the purified object compound (syn isomer) (0.16 g.), mp 128° to 149° C. (dec.).
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=O.[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1.N1CCCCC1.C(O)(=O)C>C(O)C>[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22](=[CH:1][C:3]3[NH:4][C:5]4[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=4[C:11]=3[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=Cc1[nH]c2c(c1CCC(=O)O)CCCC2
Solvent: C1CCNCC1
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)CCc1c(C=C2C(=O)Nc3cc(Cl)ccc32)[nH]c2c1CCCC2
Temperature: 25 °C
Yield: 79.4 %

Procedure:
A mixture of 3-(2-formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid (5.4 g), 3.7 g of 6-chloro-2-oxindole and 2.7 g of piperidine in 25 mL of ethanol was refluxed for 4 hours. Upon slow addition of acetic acid (8 mL), a precipitate formed. The mixture was refluxed for 5 minutes and cooled to ambient temperature. The precipitate was collected by vacuum filtration and washed with 20 mL of ethanol. The solids were slurry-washed in 30 mL of reflushing ethanol, cooled, collected by vacuum filtration, washed with 30 mL of ethanol and vacuum dried to give 6.5 g (80%) of 3-[2-(6-chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionic acid as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[NH:6]2.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C.[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]Br>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[N:6]2[CH2:34][C:33]1[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=1[Cl:31]
Reactant: Clc1ccccc1CBr
Reactant: O=C1Nc2cccc(Cl)c2C1=O
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C1C(=O)N(Cc2ccccc2Cl)c2cccc(Cl)c21
Yield: 94.5 %

Procedure:
Partially dissolve 4-chloro isatin (118 mg, 0.65 mmol) in acetonitrile (4 mL). Add 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (0.207 ml, 0.72 mmol) and after 5 min add 2-chlorobenzyl bromide (0.084 mL, 0.65 mmol). After 4 h dilute with ethyl acetate (50 mL) and wash with 1N HCl (2×20 mL), water, and brine. Dry (Na2SO4), filter and concentrate in vacuo to give 188 mg (94%) of the title compound as crude material as a red solid. MS (ES): m/z=306 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:9]([CH:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[OH:12])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:31](=O)[CH3:32].[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:35].[Na+]>CO.C(O)(=O)C.C(=O)([O-])O.[Na+].[OH-].[Na+]>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[CH:11]([OH:12])[C:9]1[N:8]([CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[C:7]2[C:2]([N:1]([CH2:31][CH3:32])[CH2:34][CH3:35])=[CH:3][CH:4]=[CH:5][C:6]=2[N:10]=1
Reactant: CC(C)(C)OC(=O)NCCn1c(C(O)c2ccc(Cl)cc2Cl)nc2cccc(N)c21
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCN(CC)c1cccc2nc(C(O)c3ccc(Cl)cc3Cl)n(CCNC(=O)OC(C)(C)C)c12
Yield: 73.7 %

Procedure:
To a solution of tert-butyl (2-{7-amino-2-[(2,4-dichlorophenyl)(hydroxy)methyl]-1H-benzimidazol-1-yl}ethyl)carbamate (5.00 g, 11.1 mmol) in methanol (110 mL) and acetic acid (5.5 mL) was added acetoaldehyde (4.15 mL, 66.6 mmol) at 0° C. The resultant mixture was stirred at 0° C. for 30 min. To the reaction mixture was added sodium triacetoxyborohydride (14.1 g, 66.5 mmol) at 0° C. After the resultant mixture was stirred at room temperature for 3 h, the mixture was diluted with aqueous sodium hydrogen carbonate and 8N aqueous sodium hydroxide, and extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture to give a colorless solid (4.15 mg, 8.18 mmol, 74%).
Reaction SMILES: CCCCCC.[H-].[K+].[CH3:9][C:10]1[NH:11][C:12]2[C:17]([C:18]=1[CH3:19])=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:30])=[C:25]([N:27]=[C:28]=[S:29])[CH:26]=1>C1COCC1>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:30])=[C:25]([NH:27][C:28]([N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]([CH3:19])=[C:10]2[CH3:9])=[S:29])[CH:26]=1
Reactant: Cc1ccc(Cl)cc1N=C=S
Reactant: Cc1[nH]c2ccccc2c1C
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(Cl)cc1NC(=S)n1c(C)c(C)c2ccccc21
Reaction time: 16 h
Yield: 66.1 %

Procedure:
A stirred slurry of hexane washed potassium hydride (1.38 g, 34.5 mmol) in 10 mL of dry THF was treated dropwise with a solution of 2,3-dimethylindole (5.0 g, 34.5 mmol) in 30 mL THF. The mixture was stirred until a clear solution was obtained. A solution of 5-chloro-2-methylphenylisothiocyanate (6.3 g, 34.5 mmol) in 5 mL THF was slowly added and stirring was continued for 16 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between EtOAc and 1N HCl. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residual solid was triturated with Et2O-hexane overnight to provide 7.5 g of the title compound as a light yellow solid, m.p. 115° C. (67% of theory).
Reaction SMILES: CC(C)([O-:4])C.[K+].C(OCC)(=O)C(OCC)=O.[O:17]([CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.OS(O)(=O)=O>O1CCCC1>[C:30]1(=[O:4])[C:31]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][CH2:24][CH2:25][C:26]=2[C:27](=[O:28])[O:29]1
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)CCCOc1ccccc1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(=O)C(=O)OCC
Product: O=C1OC(=O)C2=C1CCOc1ccccc12
Reaction time: 8 h

Procedure:
To potassium tert-butoxide (1.35 g, 12 mmol) in tetrahydrofuran (30 mL) was added diethyl oxalate (2.2 g, 15 mmol) and ethyl 4-phenoxybutanoate (2.08 g, 10 mmol) in tetrahydrofuran (30 mL) at 0° C. dropwise. The mixture was allowed to stir overnight, concentrated, quenched with 1 N HCl(aq), extracted with ethyl acetate, and concentrated. A fraction of this material (308 mg, 1 mmol) was added to concentrated H2SO4 at 0° C. The mixture was stirred for 1.5 hours and was poured onto ice chips. The precipitate was collected to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.44 (dd, J=1.5, 8.1 Hz, 1H), 7.48 (t, J=8.1 Hz, 1H), 7.25 (t, J=7.8 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 4.28 (t, J=5.1 Hz, 2H), and 3.02 (t, J=5.1 Hz, 2H).
Reaction SMILES: [C:1]([C:4]1[C:5]([F:23])=[C:6]([F:22])[C:7]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].C1C(=O)N([I:31])C(=O)C1.C(O)(C(F)(F)F)=O>CN(C=O)C.CCOC(C)=O>[C:1]([C:4]1[C:5]([F:23])=[C:6]([F:22])[C:7]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([I:31])=[CH:17][C:16]=2[F:21])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(C(C)=O)c(F)c(F)c1Nc1ccccc1F
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(C)=O)c(F)c(F)c1Nc1ccc(I)cc1F
Reaction time: 8 h

Procedure:
To a solution of methyl 5-acetyl-2-(2-fluorophenylamino)-3,4-difluorobenzoate (0.47 mmol, 0.16 g) in DMF (10 ml) was added NIS (0.56 mmol, 0.13 g) and TFA (0.10 ml), and the reaction was stifled at room temp overnight. The crude was diluted with EtOAc and washed with H2O. The organic fraction was dried over MgSO4 and concentrated under reduced pressure to yield the desired product in 90% (0.23 g).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5]([S:8][CH3:9])=[N:6][N:7]=1.ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)Cl>[NH2:1][C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5]([S:8]([CH3:9])=[O:20])=[N:6][N:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nnc(N)c(=O)n1C
Solvent: ClCCl
Product: Cn1c(S(C)=O)nnc(N)c1=O
Yield: 59.2 %

Procedure:
1.7 g of 6-amino-4-methyl-3-methylthio-1,2,4-triazin-5-one are dispersed in 200 ml of methylene chloride, and 1.8 g of 3-chloroperbenzoic acid are added in portions at 15°-20° C. A clear yellow solution is thereby formed and is evaporated at 40° C. in vacuo. The solid residue is treated with ethyl acetate, whereupon the 3-chlorobenzoic acid formed in the reaction dissolves completely. The undissolved pure product is filtered off to give 1.1 g of 6-amino-4-methyl-3-methylsulfinyl-1,2,4-triazin-5-one with a melting point of 189° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Br:44][C:45]1[CH:46]=[C:47]([NH2:55])[C:48]2[CH:49]=[N:50][N:51]([CH3:54])[C:52]=2[CH:53]=1>CN(C=O)C.O>[Br:44][C:45]1[CH:53]=[C:52]2[C:48]([CH:49]=[N:50][N:51]2[CH3:54])=[C:47]([NH:55][C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)=[O:10])[CH:46]=1
Reactant: Cn1ncc2c(N)cc(Br)cc21
Reactant: Cc1cccc(C(=O)O)n1
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: O
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)Nc2cc(Br)cc3c2cnn3C)n1
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
6-Methyl-2-pyridinecarboxylic acid (74 mg, 0.54 mmol) and HATU (250 mg, 0.65 mmol) were dissolved in DMF (4 ml) and then DIPEA (0.23 ml) was then added. The mixture was stirred under nitrogen for 30 min. 6-bromo-1-methyl-1H-indazol-4-amine (135 mg, 0.60 mmol) was then added and stirring was continued under nitrogen overnight. Addition of water was followed by extraction of the resultant mixture with DCM (2×10 ml). The organics were combined and concentrated in vacuo then the residue was purified by chromatography on silica eluting with a gradient of 0-100% ethyl acetate in DCM. Fractions containing desired material were combined and concentrated in vacuo to afford the title compound (120 mg).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH:2]=[CH2:3].[C:11]1([N:17]=[C:18]=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH:2]=[CH2:3].[C:11]1([NH:17][C:18]([O:10][CH2:5][CH3:4])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C=Nc1ccccc1
Agent: C=CCc1ccccc1O
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccccc1

Procedure:
A mixture of 13.5 g. of 2-allyl-phenol, 13.1 g. of phenylisocyanate and 0.5 g. of pyridine is kept at 100° C. for five minutes. Petroleum ether is added whereupon the precipitated crystals are filtered off with suction and washed with petroleum ether to give 2-allyl-phenol-phenyl-urethane, melting at 108° C. to 109° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH3:8])(=[O:6])[CH2:4][SH:5].[Br:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14](F)[C:11]=1[CH:12]=O.O>CS(C)=O>[CH3:8][O:7][C:3]([C:4]1[S:5][C:14]2[CH:15]=[CH:16][CH:17]=[C:10]([Br:9])[C:11]=2[CH:12]=1)=[O:6]
Reactant: O=Cc1c(F)cccc1Br
Reactant: COC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cc2c(Br)cccc2s1
Reaction time: 0.25 h

Procedure:
To a suspension of sodium hydride (55%, 1.11 g) in dimethyl sulfoxide (20 mL) was added methyl thioglycolate (1.53 mL) at room temperature, and the mixture was stirred for 15 minutes. A solution of 2-bromo-6-fluorobenzaldehyde (3.43 g) in dimethyl sulfoxide (4 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was poured into water with ice and precipitated crystalline solid was collected by filtration, washed with water and dried under reduced pressure to give 2-methoxycarbonyl-4-bromobenzo-[b]thiophene (1.52 g). This material was suspended in a mixed solvent of methanol (20 mL) and water (10 mL) and sodium hydroxide (0.91 g) was added to the suspension. The mixture was stirred for at 50° C. for 5 hours. The reaction mixture was cooled with ice bath, and the reaction mixture was acidified by adding 2 mol/L hydrochloric acid. The precipitated crystalline solid was collected by filtration, washed with water and dried under reduced pressure to give 2-carboxybenzo[b]thiophene (1.27 g). To this material were added copper powder (0.42 g) and quinoline (10 mL), and the mixture was stirred at 190° C. for 1 hour. After the reaction mixture was cooled to room temperature, 2 mol/L hydrochloric acid (40 mL) and ethyl acetate (20 mL) were added to the reaction mixture, and the mixture was stirred for 15 minutes. Insoluble material in the mixture was removed by filtration, and the organic layer of the filtrate was separated. The aqueous layer of filtrate was extracted with ethyl acetate. The organic layers were combined, and the combined organic layer washed with 2 mol/L hydrochloric acid, water and brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane) to give the title compound (0.55 g).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7](Cl)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([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.[CH2:27]([O:29][C:30]([C:32]1[CH:33]=[N:34][NH:35][CH:36]=1)=[O:31])[CH3:28].O.C(OCC)(=O)C>CN(C=O)C>[CH2:27]([O:29][C:30]([C:32]1[CH:33]=[N:34][N:35]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:36]=1)=[O:31])[CH3:28]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reaction time: 1 h
Yield: 79.5 %

Procedure:
Under N2 atmosphere, potassium tert-butoxide (9.60 g, 85.5 m mol) and trityl chloride (21.9 g, 78.5 m mol) were added successively to a solution of 4-(ethoxycarbonyl)pyrazole (10.0 g, 71.3 m mol) in DMF (100 ml) at 0° C. After stirred for 1 hour, the mixture was poured into water/ethyl acetate. The aqueous layer was separated, and the organic layer was washed with water, brine and dried over magnesium sulfate. After evaporation of the solvent, the resulting precipitate was recrystallized from ethyl acetate to afford 4-ethoxycarbonyl-1-(trityl)pyrazole (21.7 g).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[CH:6]=O.[N:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N+:13]=[N-:14].Cl>CO>[Cl:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[CH:6]=[C:15]([N:12]=[N+:13]=[N-:14])[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)CN=[N+]=[N-]
Reactant: O=Cc1ccc(F)c(Cl)c1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COC(=O)C(=Cc1ccc(F)c(Cl)c1)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.3 %

Procedure:
While cooling with an ice bath 1.35 g of sodium were dissolved in 30 ml of methanol and subsequently a solution of 4.65 g of 3-chloro-4-fluorobenzaldehyde and 6.75 g of methyl azidoacetate in 10 ml of methanol were added within 20 min. The reaction mixture was stirred at room temperature for 3 hours and then neutralized with 2N HCl. The mixture was extracted with ethyl acetate, washed with water and saturated sodium chloride solution and the organic phase was dried over sodium sulfate. The solvent was removed and the residue was chromatographed over 250 g of silica gel with n-hexane-toluene 2:1. There were obtained 2.5 g (33%) of methyl 3-chloro-4-fluoro-a-azidocinnamate as yellow crystals with m.p. 72°-74°.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:10]([Br:11])=[CH:9][C:8]([F:12])=[CH:7][C:6]=1[Br:13].[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([Br:13])=[CH:7][C:8]([F:12])=[C:9]([N+:14]([O-:16])=[O:15])[C:10]=1[Br:11]
Reactant: Fc1cc(Br)c(OCCCl)c(Br)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(F)cc(Br)c(OCCCl)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To a solution of 1-(2-chloroethoxy)-2,6-dibromo-4-fluorobenzene (65.8 g, 0.20 mol) in concentrated sulfuric acid (165 mL) maintained at room temperature using a water bath was slowly added a solution of nitric acid in sulfuric acid (10 mL HNO3 in 165 mL H2SO4). The reaction was allowed to stir at room temperature for 1 hour then poured into ice (1.5 L) and extracted with methylene chloride (2×300 mL). The combined organic layers were washed with aqueous sodium bicarbonate (150 mL) and dried over anhydrous magnesium sullfate, filtered, and the solvent removed under vacuum to afford 73.3 g (97.1%) a white crystalline solid: mp 56°-57 MS EI m/e 375/377/379/381; 1H NMR (CDCl3) δ 3.91 (2H, t, J=5.9 Hz), 4.29 (2H, d, J=5.9 Hz), 7.54 (8.1 Hz).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[CH:10]=[CH:11][O:12][C:4]=2[CH2:3]1.[Br:13][C:14]1[C:15]([Cl:21])=[C:16](F)[CH:17]=[CH:18][CH:19]=1>>[ClH:21].[Br:13][C:14]1[C:15]([Cl:21])=[C:16]([O:9][CH:6]2[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][C:4]3[O:12][CH:11]=[CH:10][C:5]2=3)[CH:17]=[CH:18][CH:19]=1
Reactant: Fc1cccc(Br)c1Cl
Reactant: CN1CCC(O)c2ccoc2C1
Product: CN1CCC(Oc2cccc(Br)c2Cl)c2ccoc2C1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 7-methyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 19) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and 3-bromo-2-chloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:3]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19].C1(C)C=CC=CC=1>CN(C)C=O>[CH3:17][N:18]([CH3:20])/[CH:19]=[CH:1]\[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)Nc1cc(C)c([N+](=O)[O-])cn1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc(/C=C\N(C)C)c([N+](=O)[O-])cn1
Temperature: 90 °C
Yield: 63 %

Procedure:
To a solution of N-(4-methyl-5-nitropyridin-2-yl)acetamide (1 g, 5 mmol, Step a) in dry dimethylformamide (10 mL), dimethylformamide dimethyl acetal (1.5 mL, 11 mmol) was added and the resulting reaction mixture was heated at 90° C. for 3 hours. The reaction mixture was cooled to room temperature, toluene was added and evaporated under vacuum followed by triturating with diethyl ether and filtration to afford N-{4-[(Z)-2-(dimethylamino)ethenyl]-5-nitropyridin-2-yl}acetamide (0.8 g, 63%).