Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[O-]S(C(F)(F)[F:19])(=O)=O.F[N+]1C(C)=CC(C)=CC=1C>CO>[CH3:13][O:12][C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[C:3]2[F:19])=[O:11]
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Agent: Cc1cc(C)[n+](F)c(C)c1
Solvent: CO
Product: COC(=O)c1ccc2[nH]cc(F)c2c1
Yield: 10.4 %

Procedure:
A solution of methyl 5-indole carboxylate (1.75 g, 10 mmol) and N-fluoro-2,4,6-trimethylpyridinium triflate (3.75 g, 13 mmol) in methanol (100 mL) was heated at reflux for 18 hours and concentrated. The concentrate was purified by flash column chromatography on silica gel to provide 200 mg of the desired product.
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[O:18])[CH:9]([N:19]3[C:23](=[O:24])[C:22]4=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]4[C:20]3=[O:29])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[O:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[O:38][CH2:39][CH2:40]Br.O>CN(C)C=O>[C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:40][CH2:39][O:38][CH:33]3[CH2:34][CH2:35][CH2:36][CH2:37][O:32]3)[C:10](=[O:18])[CH:9]([N:19]3[C:20](=[O:29])[C:21]4=[CH:28][CH:27]=[CH:26][CH:25]=[C:22]4[C:23]3=[O:24])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrCCOC1CCCCO1
Reactant: O=C1Nc2ccccc2C(c2ccccc2)=NC1N1C(=O)c2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1C(N2C(=O)c3ccccc3C2=O)N=C(c2ccccc2)c2ccccc2N1CCOC1CCCCO1
Reaction time: 8 h
Yield: 58.3 %

Procedure:
To a solution of (3RS)-1,3-dihydro-5-phenyl-3-phthalimido-2H-1,4-benzodiazepine-2-one (1.90 g) in N,N-dimethylformamide (30 ml) was added sodium hydride (62% suspension in mineral oil; 0.20 g) gradually with stirring under cooling in an ice-bath (<3° C.). The mixture was stirred for 10 minutes under the same conditions. To the resultant mixture was added 2-[(tetrahydropyran-2-yl)oxy]ethyl bromide (1.60 g) in one portion. The mixture was stirred at ambient temperature for one hour and at 45° C. for 4.5 hours and allowed to stand overnight. The resultant reaction mixture was poured into water and extracted with ethyl acetate twice. The extract was washed with water and dried over magnesium sulfate. Removal of the solvent gave light yellow powder, which was washed with a mixture of ethyl acetate and diethyl ether and collected by filtration to afford a mixture (1.48 g) of (3RS)-1,3-dihydro -5-phenyl-3-phthalimido-1-{2-((RS)-2-tetrahydropyranyloxy) ethyl}-2H-1,4-benzodiazepine-2-one and (3RS)-1,3-dihydro-5-phenyl-3-phthalimido-1-{2-((SR)-2tetrahydropyranyloxy)ethyl}-2H-1,4-benzodiazepine-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:17]3[C:18]([CH3:28])=[N:19][N:20]4[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][C:21]=34)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)=[CH:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][N:34]=[CH:33][C:32]=1[C:37](Cl)=[O:38].C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:17]3[C:18]([CH3:28])=[N:19][N:20]4[CH:25]=[CH:24][C:23]([CH2:26][NH:27][C:37]([C:32]5[CH:33]=[N:34][CH:35]=[CH:36][N:31]=5)=[O:38])=[CH:22][C:21]=34)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)=[CH:29][CH:30]=1
Reactant: O=C(Cl)c1cnccn1
Reactant: Cc1nn2ccc(CN)cc2c1-c1nc(Cc2ccc(Cl)cc2)c(-c2nnc[nH]2)s1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nn2ccc(CNC(=O)c3cnccn3)cc2c1-c1nc(Cc2ccc(Cl)cc2)c(-c2nnc[nH]2)s1
Temperature: 25 °C
Reaction time: 22 h
Yield: 2.5 %

Procedure:
A mixture of 1-{3-[4-(4-chlorobenzyl)-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-a]pyridin-5-yl}methanamine (0.0222 g, 0.0491), pyrazine-2-carboxylic acid chloride (8.0 mg, 0.056 mmol) and N,N-diisopropylethylamine (10 mg, 0.08 mmol) in dry Methylene chloride (5.0 mL) in dry N,N-dimethylformamide (1.0 mL) was sonicated for 2 min. The mixture was stirred at rt for 22 hours. N,N-diisopropylethylamine (13 mg, 0.10 mmol) and pyrazine-2-carboxylic acid chloride (9.11 mg, 0.0639 mmol) were added and the mixture was stirred at rt for 3 days. The mixture was quenched with water, then extracted with DCM (3×30 mL). The combined DCM solutions were washed with water, brine, dried over Na2SO4, filtered, and evaporated to give a crude product (80 mg). The crude product was purified by HPLC to give a solid product (0.0007 g, yield 3%). LCMS: (AA) ES+ 542, 544. 1H NMR (400 MHz, d6-DMSO) δ: 9.72-9.74 (d, J=6.53 Hz, 1H), 9.23 (s, 1H), 8.87 (s, 1H), 8.75 (s, 1H), 8.67-8.69 (d, J=6.53 Hz, 1H), 8.63 (s, 1H), 8.22 (s, 1H), 7.24-7.30 (m, 4H), 7.03-7.05 (d, J=7.28 Hz, 1H), 4.62-4.64 (d, J=6.78 Hz, 2H), 4.47 (s, 2H), 2.63 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:14]=[C:13]([CH:15](C)[CH2:16][CH:17]=O)[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32]C[CH2:30][CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH2:48]([N:55]1CCNCC1)C1C=CC=CC=1>C(Cl)Cl>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:55]([CH2:48][CH2:17][CH2:16][CH2:15][C:13]2[O:12][N:11]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[CH:14]=2)[CH2:30][CH2:29]1
Reactant: COc1ccccc1N1CCCCC1
Reactant: CC(CC=O)c1cc(-c2cccc([N+](=O)[O-])c2)no1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCCCc2cc(-c3cccc([N+](=O)[O-])c3)no2)CC1
Yield: 80.1 %

Procedure:
About 2 min after dissolving 3-[3-(3-nitrophenyl)isoxazol-5-yl]butanal (60 mg, 0.231 mmol) and 1-(2-methoxyphenyl)piperidine (44.4 mg, 0.231 mmol) in 3 mL of dry methylene chloride, were added NaBH(OAc)3 (147 mg, 0.693 mmol), cold acetic acid (15.9, 0.277 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 4.2 hr and followed the same processes as in Example 1 to obtain 80.8 mg (80.1%) of the target compound.
Reaction SMILES: [C:1](OC(Cl)(Cl)Cl)(OC(Cl)(Cl)Cl)=O.[NH2:13][C:14]1[C:23]([Br:24])=[C:22]([F:25])[CH:21]=[CH:20][C:15]=1[C:16]([NH:18][CH3:19])=[O:17].[OH2:26]>C(Cl)Cl>[Br:24][C:23]1[C:22]([F:25])=[CH:21][CH:20]=[C:15]2[C:14]=1[NH:13][C:19](=[O:26])[N:18]([CH3:1])[C:16]2=[O:17]
Reactant: CNC(=O)c1ccc(F)c(Br)c1N
Reactant: O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cn1c(=O)[nH]c2c(Br)c(F)ccc2c1=O
Reaction time: 5 h
Yield: 100 %

Procedure:
A mixture of tri-phosgene (Aldrich, St. Louis, Mo.; 0.233 g, 0.784 mmol) and 2-amino-3-bromo-4-fluoro-N-methylbenzamide (720a; 0.57 g, 2.30 mmol) in 23 mL anhydrous DCM was fitted with a water-cooled reflux condenser and drying tube, and heated to reflux overnight. LCMS indicated the reaction was about 85% conversion. Additional triphosgene (0.075 g) was added and heating continued for 5 h. The reaction was cooled and concentrated in vacuo to give 8-bromo-7-fluoro-3-methylquinazoline-2,4(1H,3H)-dione (0.63 g, 2.30 mmol, 100% yield) as a light orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.89 (1H, s), 8.03 (1H, dd, J=8.8, 5.9 Hz), 7.23 (1H, t, J=8.6 Hz), 3.26 (3H, s). MS (ESI, pos. ion) m/z: 272.9/275.0 (M+1).
Reaction SMILES: C([O:4][CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])C=C.[CH3:14][C:15]([CH3:17])=[O:16].C[N+]1([O-])CC[O:22]CC1>[Os](=O)(=O)(=O)=O.O>[OH:16][CH:15]([CH2:17][OH:22])[CH2:14][O:4][CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9]
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)=O
Reactant: C=CCOCP(=O)(OCC)OCC
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: CCOP(=O)(COCC(O)CO)OCC
Temperature: 20 °C

Procedure:
To a solution of diethyl allyloxymethylphosphonate (4.2 g. 20.2 mmol) in an acetone (50 ml) and water (25 ml) mixture, was added osmium tetroxide (1 crystal) and 4-methylmorpholine-N-oxide (3.8 g, 32.3 mmol). The reaction mixture was stirred at 20° C. under nitrogen until no more starting alkene was present (6 days). The solvents were evaporated under high vacuum and the residue chromatographed on silica eluting with chloroform-methanol 10:1 affording diethyl 2,3-dihydroxypropoxymethylphosphonate (4.2 g, 86%) as a clear liquid. νmax (film) 3400, 1650 , 1230, 1100, 1030 and 960 cm-1 ; δH (CDCl3) 1.35(6H, t, J7.3 Hz, 2×CH2CH3), 3.20(2H, s, D2O exchangeable, 2×OH), 3.62(5H, m, CH2OH+CHOH+CH2OCH2P), 3.79(2H, d, 8.2 Hz, CH2P), 4.14(4H, m, 2×CH2CH3); m/z 243 (MH+, 13%); Found: C,38.50; H,7.70%; C8H19O6P.0.4H2O requires C,38.52; H,7.94%.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:34]([Cl:35])=[CH:33][C:11]([C:12]([NH:14][C:15]2[S:16][C:17]([CH2:26][N:27]([CH2:29][CH2:30][CH2:31][CH3:32])[CH3:28])=[C:18]([C:20]3[S:21][CH:22]=[C:23]([Cl:25])[CH:24]=3)[N:19]=2)=[O:13])=[CH:10][N:9]=1.C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45].O>C1COCC1>[CH2:29]([N:27]([CH2:26][C:17]1[S:16][C:15]([NH:14][C:12](=[O:13])[C:11]2[CH:33]=[C:34]([Cl:35])[C:8]([NH:7][CH2:6][CH2:5][NH:4][S:44]([CH3:43])(=[O:46])=[O:45])=[N:9][CH:10]=2)=[N:19][C:18]=1[C:20]1[S:21][CH:22]=[C:23]([Cl:25])[CH:24]=1)[CH3:28])[CH2:30][CH2:31][CH3:32]
Reactant: CCCCN(C)Cc1sc(NC(=O)c2cnc(NCCN)c(Cl)c2)nc1-c1cc(Cl)cs1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCN(C)Cc1sc(NC(=O)c2cnc(NCCNS(C)(=O)=O)c(Cl)c2)nc1-c1cc(Cl)cs1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
100 mg of 6-[(2-aminoethyl)amino]-N-[5-{[butyl(methyl)amino]methyl}-4-(4-chlorothiophen-2-yl)thiazol-2-yl]-5-chloronicotinamide trihydrochloride was suspended in 5 ml of THF, and 85 μl of triethylamine was added, followed by cooling to 0° C. 13 μl of methanesulfonyl chloride was added to the solution, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water, and extracted with chloroform. The organic layer was washed with water and with brine, and then dried over magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (chloroform:MeOH =10:1) to obtain 75 mg of N-[5-{[butyl(methyl)amino]methyl}-4-(4-chlorothiophen-2-yl)thiazol-2-yl]-5-chloro-6-({2-[(methylsulfonyl)amino]ethyl}amino)nicotinamide.
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH:3]([N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][CH:5]=1>[Ni].CO>[N:13]1([CH:3]([C:4]2[CH:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=2)[CH:2]([CH3:18])[CH3:1])[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: CC(C)C(c1ccc([N+](=O)[O-])cc1)n1ccnc1
Agent: [Ni]
Solvent: CO
Product: CC(C)C(c1ccc(N)cc1)n1ccnc1
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of 12 parts of intermediate 40, namely 1-[2-methyl-1-(4-nitrophenyl)-propyl]-1H-imidazole, and 79 parts of methanol was hydrogenated for 1 hour at room temperature and 2.105Pa with 3 parts of Raney nickel. The catalyst was filtered off and the filtrate was evaporated, yielding 12 parts (100%) of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl]benzenamine (interm. 41).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[CH:10](=O)[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:13].C(OCC)(=O)C>CCCCCC>[OH:13][C:12]1[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=1[CH:10]=[N:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9]
Reactant: O=Cc1ccccc1O
Reactant: Cc1cc(O)ccc1N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(O)ccc1N=Cc1ccccc1O
Temperature: 25 °C
Reaction time: 19 h
Yield: 93 %

Procedure:
To a 500 milliliter round bottom flask equipped with a water condenser, magnetic stirrer and drying tube was added 12.32 grams (0.10 mole) of 4-amino-3-methylphenol, 12.21 grams (0.10 mole) of salicylaldehyde and 250 milliliters of ethyl acetate. The resulting reaction mixture was stirred for 19 hours at room temperature and ambient pressure. After the stirring period, the reaction mixture was washed twice with saturated brine solution and decolorized with activated charcoal. The reaction mixture was then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a yellow oil which solidified on standing. The resulting solidified material was slurried in hexane, collected by filtration and dried to yield 21.12 grams (0.093 moles) of 4-(2-hydroxybenzylideneamino)-3-methylphenol in the form of a yellow solid having a melting point of 95°-97° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])[CH3:4].[CH2:23]([O:25][CH2:26][CH2:27]Cl)[CH3:24].O>CN(C=O)C.C(OCC)(=O)C>[CH2:3]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:24][CH2:23][O:25][CH2:26][CH3:27])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])[CH3:4]
Reactant: CCOCCCl
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOCCn1cc(C2CCN(C(=O)OCC)CC2)c2ccccc21
Temperature: 22.5 °C
Reaction time: 16 h
Yield: 90.5 %

Procedure:
0.75 g of a60% suspension of sodium hydride in mineral oil were suspended in 20 mL of dry DMF and 4 g of 4-(1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester were added to the mixture. 1.91 g of 2-chloroethyl ethyl ether were added dropwise at room temperature and the mixture was stirred for 16 hours at 20-25° C. Water was carefully added and ethyl acetate was used as solvent extractor. The organic layer was separated and washed with water. The solvent was removed under reduced pressure affording 4.58 g of a colorless oil. The product was then crystallised from methyl-t-butyl ether/hexane giving a off white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[C:12]([NH:21][CH2:22][CH2:23][OH:24])[CH:13]=[C:14](Br)[CH:15]=3)[C:10](=[O:25])[C:9]=2[CH:8]=[C:7](Br)[CH:6]=1.CN(C)C=O.[C:32]1([S-:38])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Na+]>CO>[OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[C:12]([NH:21][CH2:22][CH2:23][OH:24])[CH:13]=[C:14]([S:38][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:15]=3)[C:10](=[O:25])[C:9]=2[CH:8]=[C:7]([S:38][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=1
Reactant: O=C1c2cc(Br)cc(NCCO)c2C(=O)c2cc(Br)cc(NCCO)c21
Reactant: [S-]c1ccccc1
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1c2cc(Sc3ccccc3)cc(NCCO)c2C(=O)c2cc(Sc3ccccc3)cc(NCCO)c21
Temperature: 120 °C

Procedure:
24 g of 1,5-bis(2-hydroxyethylamino)-3,7-dibromoanthraquinone are introduced at RT into 100 ml of dimethylformamide (DMF). After the addition of 16.3 g of sodium thiophenolate, the mixture is heated to 120° C. and maintained at that temperature for one hour. After cooling the mixture to RT, 100 ml of methanol are added thereto. The precipitate is filtered off, washed with a methanol/water mixture (1:1) and dried in vacuo.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(N=C=[O:25])CCC.[CH3:26][C:27]1C=C[CH:30]=[CH:31][C:32]=1C>CCCCCC>[CH2:31]([C:30]([N:6]1[C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:10][C:4]=2[N:3]=[C:2]1[SH:1])=[O:25])[CH2:32][CH2:27][CH3:26]
Reactant: CC(C)(C)OC(=O)Nc1ccc2nc(S)[nH]c2c1
Reactant: Cc1ccccc1C
Reactant: CCCCN=C=O
Solvent: CCCCCC
Product: CCCCC(=O)n1c(S)nc2cc(NC(=O)OC(C)(C)C)ccc21
Temperature: 147.5 °C
Yield: 95 %

Procedure:
To a slurry of 2-mercapto-5-(tert-butoxycarbonyl) aminobenzimidazole (11.46 g, 43.19 mmol) in o-xylene (50 mL) pre-heated to 100° C. was added n-butyl isocyanate (7.3 mL, 64.79 mmol) via syringe. The mixture was then heated at 145-150° C. for 1.5 h, then cooled to room temperature and diluted with hexane (200 mL). The solid was collected by suction filtration and dried under vacuum to afford 1-butylcarbonyl-2-mercapto-5-(tert-butoxycarbonyl)aminobenzimidazole (14.19 g, 95%). 1H-NMR (DMSO)δ: 0.94 (t, J=7.2 Hz, 3H), 1.20-1.60 (m, 4H, 2CH2), 1.51 (s, 9H), 3.37-3.43 (m, 2H, CH2N), 7.19-7.23 (dd, J=9.0 and 1.9 Hz, 1H, Ar-H), 7.64 (s, 1H), 7.96 (d, J=9.0 Hz, 1H, Ar-H), 9.59 (s, 1H), 10.22 (t, J=5.4 Hz, 1H, NHCH2). Elemental Analysis calc (found %: C, 56.0 (55.8); H, 6.6 (5.7) and N, 15.4 (15.3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:20])[C:5]([NH:12][S:13]([NH:16][CH:17]([CH3:19])[CH3:18])(=[O:15])=[O:14])=[C:6]([CH:11]=1)[C:7](OC)=[O:8].CO.C[O-].[Na+].C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[NH:12][S:13](=[O:15])(=[O:14])[N:16]([CH:17]([CH3:19])[CH3:18])[C:7](=[O:8])[C:6]=2[CH:11]=1
Reactant: COC(=O)c1cc(Cl)cc(C)c1NS(=O)(=O)NC(C)C
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Solvent: O
Product: Cc1cc(Cl)cc2c1NS(=O)(=O)N(C(C)C)C2=O
Reaction time: 5 h

Procedure:
Methyl 5-chloro-3-methyl-2-((((1-methylethyl)amino)sulfonyl)amino)benzoate (26.31 grams; 0.08 mole) was mixed with 200 milliliters (ml) of methanol and sodium methoxide (8.84 grams; 0.164 mole) added thereto. The resulting reaction mixture was heated at the reflux temperature thereof for a period of 5 hours. The solvent was then removed in vacuo leaving a solid brown residue which was dissolved in 200 ml. of water. Sodium bicarbonate (20 grams) was added to the aqueous mixture and the resulting oily layer separated from the aqueous layer. The aqueous layer was acidified with dilute hydrochloric acid and the mixture extracted with ether. The ether extract was reduced in volume by evaporation in vacuo to give a light yellow oil which was dissolved in benzene, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give a light yellow powder. Recrystallization of the powder from methylene chloride and hexane gave the desired 6-chloro-8-methyl-3-(1-methylethyl)-1H-2,1,3-benzothiadiazin-4(3H)-one-2,2-dioxide product as a white crystalline solid having a melting point of 142°-144°C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:16][CH3:17])=[CH:5][C:6]=1[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14].O1CCN([CH:24]=[CH:25][N+:26]([O-:28])=[O:27])CC1.Cl.CC(C)=O>O>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]([C:6]1[CH:5]=[C:4]([CH2:16][CH3:17])[S:3][C:2]=1[NH:1][CH:24]=[CH:25][N+:26]([O-:28])=[O:27])=[O:15]
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(N)s1
Reactant: O=[N+]([O-])C=CN1CCOCC1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CCc1cc(C(=O)c2ccccc2Cl)c(NC=C[N+](=O)[O-])s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
A mixture of 2-amino-3-(2-chlorobenzoyl)-5-ethylthiophene (5.30 g), 1-morpholino-2-nitroethene (3.16 g), 6N HCl (5 ml) and acetone (25 ml) was stirred at room temperature for one hour. Water was added to the mixture, which was extracted with ethene acetate. The extract was washed with water and dried over MgSO4, and then the solvent was distilled off to obtain 3-(2-chlorobenzoyl)-2-(2-nitroethenylamino)-5-ethylthiophene as crystals (5.65 g, 84.1%). The crystals were recrystallized from acetone to obtain yellow plates, mp: 125°-126° C.
Reaction SMILES: [C:1]1(C)[C:2]([C:7]#[N:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[NH4+].[Cl-].[N-:12]=[N+:13]=[N-:14].[Na+].[CH3:16]N(C=O)C>>[C:5]1([CH3:16])[CH:6]=[CH:1][C:2]([C:7]2[NH:8][N:14]=[N:13][N:12]=2)=[CH:3][CH:4]=1
Reactant: Cc1ccccc1C#N
Reactant: [N-]=[N+]=[N-]
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: Cc1ccc(-c2nnn[nH]2)cc1

Procedure:
Tolunitrile (103 mg, 1.0 mmol) was refluxed with NH4Cl (70 mg, 1.3 mmol), and NaN3 (85 mg, 1.3 mmol) in 3 mL of DMF overnight. The resulting 5-p-tolyl tetrazole was purified via RP-HPLC.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][C:13]([CH3:19])([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][C:13]([CH3:19])([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1(C)CC=CC(NC(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1(C)CCCC(NC(=O)OC(C)(C)C)C1
Reaction time: 48 h

Procedure:
Methyl 5-(tert-butoxycarbonylamino)-1-methylcyclohex-3-enecarboxylate, 52f, (5.59 g, 20.75 mmol) was dissolved in 100 mL, of MeOH. To the stirred solution was added 5% palladium on carbon (1.11 g, 10.38 mmol) and the reaction was stirred under a hydrogen balloon for 2 days. The reaction was filtered through celite, and the filtrate was concentrated in vacuo and used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:10][C:11]1[C:12](O)=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15]>CO.ClCCl>[NH2:1][C:2]1[C:7]([CH:8]2[NH:10][C:11]3[CH:20]=[CH:19][CH:18]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[C:12]=3[O:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)c1cccc(N)c1O
Reactant: Nc1ncccc1C=O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cccc2c1OC(c1cccnc1N)N2
Temperature: 50 °C
Reaction time: 10 h
Yield: 27.7 %

Procedure:
A 2-aminopyridine-3-carbaldehyde (650 mg) was added to a stirred solution of methyl 3-amino-2-hydroxy-benzoate (890 mg) in methanol (10 ml) and dichloromethane (5 ml). The resulting solution was stirred at 50° C. for 10 hours. The crude product was purified by flash chromatography on silica gel eluting with 1 to 2% methanol in dichloromethane. The solvent was evaporated to dryness to afford methyl 2-(2-amino-3-pyridyl)-2,3-dihydro-1,3-benzoxazole-7-carboxylate (400 mg) as a pale yellow solid. Manganese(IV) oxide (4629 mg) was added to a solution of this yellow solid (400 mg) in dichloromethane (5 ml) and tetrahydrofuran (10 ml), the mixture was stirred at 25° C. for 15 hours. The mixture was filtered and the filtrate was adsorbed on silica gel and purified by flash chromatography on silica gel eluting with 30 to 50% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford methyl 2-(2-amino-3-pyridyl)-1,3-benzoxazole-7-carboxylate (345 mg) as a pale yellow solid. NMR Spectrum: (CDCl3) 4.06 (s, 3H), 6.79 (dd, 1H), 6.89 (bs, 2H), 7.43 (dd, 1H), 7.92 (dd, 1H), 8.00 (dd, 1H), 8.26 (dd, 1H), 8.44 (dd, 1H); Mass spectrum: M+H+ 270;
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.Cl.O>C(Cl)Cl.CCOCC>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([NH:1][CH:2]2[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]2)=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: CN1CCC(N)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: CN1CCC(Nc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 100 °C
Yield: 56.2 %

Procedure:
A mixture of 4-amino-1-methylpiperidine (4.82 g, 32.3 mmol) and 4-fluoronitrobenzene (4.56 g, 32.3 mmol) is heated at 100° C. on an oil bath over a period of 7 hours. After cooling, the reaction mixture is mixed with 2N hydrochloric acid (20 ml) and water (20 ml) and shaken with ether. The acidic layer is neutralized with conc. ammoniac solution and shaken with methylene chloride. The methylene chloride layer is washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is crystallized from ether-petroleum ether to give 4-(4-nitroanilino)-1-methylpiperidine (4.27 g) as crystals melting at 153° to 155° C. The yield is 56%.