Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]=1>[OH-].[Na+].O1CCOCC1.O>[CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]=1
Reactant: COC(=O)c1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(C)c(Cc2ccc(C(=O)O)c(-c3ccccc3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.5 %

Procedure:
Methyl 4-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-phenylbenzoate (84 mg, 0.1926 mmol) was dissolved in a mixed solution of a 1N aqueous solution of sodium hydroxide (5 ml) and 1,4-dioxane (5 ml) followed by stirring at room temperature for 16 hours. The reaction solution was diluted with water (20 ml), washed with ether, acidified with concentrated hydrochloric acid and extracted with ether. The extract was washed with water and dried and the solvent was evaporated therefrom to give the title compound (45 mg, 0.1800 mmol, 93%).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=4)[CH:11]=[C:10]([C:22]([O:24][CH3:25])=[O:23])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:27][CH2:28][CH2:29][OH:30].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH2:27][CH2:28][CH2:29][OH:30])=[CH:17][CH:16]=4)[CH:11]=[C:10]([C:22]([O:24][CH3:25])=[O:23])[C:9]=3[CH:8]=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: OCCCBr
Reactant: COC(=O)c1cc(-c2ccc(O)cc2)cc2c1cnn2C1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(-c2ccc(OCCCO)cc2)cc2c1cnn2C1CCCC1
Temperature: 100 °C
Yield: 68.5 %

Procedure:
To a stirred solution of methyl 1-cyclopentyl-6-(4-hydroxyphenyl)-1H-indazole-4-carboxylate (0.5 g, 1.48 mmol) in DMF (15 mL), 3-bromopropane-1-ol (0.616 g, 4.46 mmol) and K2CO3 (0.306 g, 2.23 mmol) were added, resulting reaction mass was heated at 100° C. for 4 h. On completion, water was added to reaction mass and extracted with ethyl acetate. Combined organic layers were dried and concentrated under reduced pressure giving crude material which was purified by column chromatography over silica gel (60-120 mesh size) to afford methyl 1-cyclopentyl-6-(4-(3-hydroxypropoxy)phenyl)-1H-indazole-4-carboxylate (0.4 g, 68.2%).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[C:19][CH2:20]OS(C)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:28][O:29][CH2:30][CH2:31][NH:32][CH3:33]>>[CH3:28][O:29][CH2:30][CH2:31][N:32]([CH3:33])[CH2:20][C:19]#[C:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:27])[F:26])=[CH:4][CH:5]=3)=[N:10][S:11][C:12]=2[CH:17]=1
Reactant: CS(=O)(=O)OCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Reactant: CNCCOC
Product: COCCN(C)CC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 17.1, Methanesulfonic acid 3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl ester and 2-Methoxyethylmethylamine were converted to yield (2-Methoxy-ethyl)-methyl-{3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-amine as light brown oil, MS: 405 (MH+).
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])=[N:10][CH:11]=1.[CH3:21]O>>[OH:5][C:6]1[CH:11]=[N:10][C:9]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([O:17][CH3:21])=[O:16])=[N:8][CH:7]=1
Reactant: O=C(O)c1cccc(-c2ncc(O)cn2)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(-c2ncc(O)cn2)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
32.7 ml (445 mmol) of thionyl chloride are added to a suspension of 88.0 g (366 mmol) of 3-(5-hydroxypyrimidin-2-yl)benzoic acid in 1.4 l of methanol, and the mixture is heated at 80° C. for 2 hours. 20 ml (276 mmol) of thionyl chloride and, after 2 hours, a further 10 ml (138 mmol) of thionyl chloride are then added. After each addition, the reaction mixture is stirred at 80° C. for 2 hours. The reaction mixture is evaporated to a volume of about 300 ml in vacuo. The precipitate formed is filtered off and dried in vacuo: methyl 3-(5-hydroxypyrimidin-2-yl)benzoate as brownish crystals; m.p. 219-223°; ESI 231 (M+H); HPLC: Rt.=2.58 min (method A).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[F:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[C:10]([OH:17])[CH:9]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([S:29]([N:32]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[C:33]3[S:34][CH:35]=[CH:36][N:37]=3)(=[O:31])=[O:30])=[CH:26][CH:27]=2)[CH:22]=[CH:21][N:20]=1>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:19]2[C:28]3[C:23](=[CH:24][C:25]([S:29]([N:32]([CH2:38][C:39]4[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=4)[C:33]4[S:34][CH:35]=[CH:36][N:37]=4)(=[O:30])=[O:31])=[CH:26][CH:27]=3)[CH:22]=[CH:21][N:20]=2)=[C:10]([OH:17])[CH:9]=1
Reactant: OB(O)c1ccc(F)cc1O
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(F)cc4O)nccc3c2)cc1
Temperature: 125 °C
Yield: 92.4 %

Procedure:
A vial containing a suspension of Cs2CO3 (0.292 g, 0.897 mmol), (4-fluoro-2-hydroxyphenyl)boronic acid (0.045 g, 0.292 mmol) and 1-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate JJJ; 0.1 g, 0.224 mmol) in DME (2.5 ml) and water (0.375 ml) was degassed with nitrogen and tetrakis(triphenylphosphine)palladium (0.026 g, 0.022 mmol) was added. The vial was sealed and heated under microwave irradiation at 125° C. for 30 min. The aqueous layer was discarded using a pipette and the organic layer was concentrated and purified by silica gel chromatography (25 g column, eluting with Hex:EtOAc (0 to 50%)). Pure fractions were combined and concentrated to obtain 1-(4-fluoro-2-hydroxyphenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.108 g, 0.207 mmol, 92% yield) as light yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[CH2:15]([N:19]=[C:20]=[O:21])[CH2:16][CH2:17][CH3:18].C(N(CC)CC)C>C(Cl)Cl>[CH:3]1[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]=2[CH:13]=[CH:14][C:2]=1[O:1][C:20](=[O:21])[NH:19][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Oc1ccc2oc3ccccc3c2c1
Reactant: CCCCN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCNC(=O)Oc1ccc2oc3ccccc3c2c1
Yield: 54.4 %

Procedure:
A solution of 2-hydroxydibenzofuran (1.47 g, 7.98 mmol), butyl isocyanate (1.26 mL, 11.2 mmol) and triethylamine (0.89 mL, 6.39 mmol) in 50 mL of methylene chloride was stirred under N2 at room temperature for 1 hour. The solvent was removed under reduced pressure to give a solid. Recrystallization from diethyl etherhexane gave 1.23 g (54%) of the title compound as a white crystalline solid, mp 124°-126° C.
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C1COCC1.[CH2:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1)[CH2:16][CH3:17].Cl>[Zn].C(OCC)(=O)C>[F:8][C:2]([F:9])([CH:22]([OH:23])[C:21]1[CH:24]=[CH:25][C:18]([CH2:15][CH2:16][CH3:17])=[CH:19][CH:20]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCCc1ccc(C=O)cc1
Reactant: CCOC(=O)C(F)(F)Br
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1ccc(C(O)C(F)(F)C(=O)OCC)cc1
Reaction time: 1 h
Yield: 98 %

Procedure:
To a reaction vessel under a nitrogen atmosphere, 4.4 g of well-dried zinc, 10.3 g of ethyl bromodifluoroacetate (e-14) and 25 ml of THF were added, and the resultant mixture was cooled to 0° C. and stirred for 1 hour. The solution was slowly added dropwise in a temperature range of 20° C. to 25° C. to another reaction vessel under a nitrogen atmosphere in which 5.0 g of 4-propylbenzaldehyde (e-23) and 50 ml of THF were put, and the resultant mixture was further subjected to heating reflux for 4 hours. After cooling the resultant reaction mixture to 25° C., 200 ml of 1 N HCl aqueous solution and 200 ml of ethyl acetate were added to separate the mixture into an organic layer and an aqueous layer, and an extraction operation was performed. The resultant organic layer was isolated, and washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then the resultant solution was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, the resultant residue was purified by a preparative isolation operation by means of column chromatography using a mixed solvent of heptane and ethyl acetate (heptane:ethyl acetate=20:1 in a volume ratio) as an eluent and silica gel as a filler, the resultant product was dried, and thus 9.0 g of ethyl 2,2-difluoro-3-hydroxy-3-(4-propylphenyl)propanoate (e-24) was obtained. A yield based on compound (e-23) was 97.8%.
Reaction SMILES: [CH3:1][N:2]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)[CH3:3].BrC#[N:16].C(Cl)Cl>CCOCC>[CH3:3][N:2]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)[C:1]#[N:16]
Reactant: N#CBr
Reactant: CN(C)c1cccc2ccccc12
Solvent: CCOCC
Solvent: ClCCl
Product: CN(C#N)c1cccc2ccccc12
Yield: 48 %

Procedure:
In a 2 neck round bottom flask, equipped with a magnetic stir bar and reflux condenser, was placed N,N-dimethyl-1-naphthylamine (4.35 g, 25.4 mmol, and BrCN (2.99 g, 28.2 mmol) in a single portion. This suspension was placed in an oil bath (preheated, 90° C.) and allowed to stir and reflux under N2 for 21 hours. During this time a gas was given off, detected by bubbler placed over the reflux condenser. The reaction was followed by TLC, using methylene chloride as the solvent and viewed under UV. After the 21 hours, the mixture was cooled, 100 ml of ether was added and the insoluble quaternary salt (669 mg) was filtered off. The ether filtrate was extracted with an aqueous 5M HCl solution (4×, 30 ml) and washed with water (5×, 20 ml). The ether was dried over anhydrous granular K2CO3, filtered, then concentrated to dryness, then distilled by bulb to bulb distillation at reduced pressure to afford the yellow oil of the N-methyl-N-(1-naphthyl)cyanamide (2.22 g, 48%. b.p. 180° C./1.5 mm Hg (Cressman, Homer, W. J., Org. Synth. collective vol.3, 608), 170°-171° C./1 mm Hg).
Reaction SMILES: [CH3:1][CH:2]([CH3:43])[CH2:3][CH2:4][N:5]([CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])[C:6]([C:8]1[CH:9]=[CH:10][C:11]2[N:15]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)[N:13]([CH2:26][CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:12]=2[CH:37]=1)=[O:7]>C(OCC)(=O)C.CO.[Pd]>[NH2:23][C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:14]2[N:13]([CH2:26][CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])[C:12]3[CH:37]=[C:8]([C:6]([N:5]([CH2:4][CH2:3][CH:2]([CH3:43])[CH3:1])[CH2:38][CH2:39][CH:40]([CH3:41])[CH3:42])=[O:7])[CH:9]=[CH:10][C:11]=3[N:15]=2)=[CH:22][CH:21]=1
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccc2nc(Nc3ccc([N+](=O)[O-])cc3)n(CCCNC(=O)OC(C)(C)C)c2c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccc2nc(Nc3ccc(N)cc3)n(CCCNC(=O)OC(C)(C)C)c2c1
Temperature: 20 °C
Reaction time: 15 h
Yield: 87 %

Procedure:
Tert-butyl 3-{6-{[bis(3-methylbutyl)amino]carbonyl}-2-[(4-nitrophenyl)amino]-1H-benzimidazol-1-yl}propylcarbamate (580 mg) in solution in a mixture of ethyl acetate/methanol 3:1 (40 ml), and 10% palladium on carbon (58 mg) are introduced into an autoclave. After stirring for 15 hours under a hydrogen atmosphere (3 bar) at a temperature of approximately 20° C., the catalyst is eliminated by filtration on celite and the filtrate is concentrated under reduced pressure at 40° C. in order to produce the expected compound in the form of a foam (480 mg; 87% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](Cl)=[O:15].[NH3:17]>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH2:17])=[O:15]
Reactant: N
Reactant: COCCCCCCCCCCCC(=O)Cl
Solvent: C1CCOC1
Product: COCCCCCCCCCCCC(N)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the title product from Example 11 (1.1 g, 4.3 mmol) in 70 mL of anhydrous tetrahydrofuran was added 20 mL of freshly distilled liquid ammonia in a Parr shaker which was sealed and shaken at room temperature for 16 hours. After filtering and concentration, the crude residue was dissolved in anhydrous methanol and passed through a basic ion exchange resin and eluted with anhydrous methanol. Concentration afforded the title compound (780 mg) as a white solid, m.p. 83.9-85.6° C. (DSC). The structure was supported by NMR, infrared spectroscopy, elemental analysis, and mass spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:5]=[C:6]([Br:8])[CH:7]=1.N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClC(Cl)C>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][S:24]([CH3:23])(=[O:26])=[O:25])[CH:3]=[C:4]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(Br)cc(C(=O)c2cccnc2)c1
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: CS(=O)(=O)Nc1cc(Br)cc(C(=O)c2cccnc2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
To a stirred solution of 0.200 grams of (3-amino-5-bromo-phenyl)-pyridin-3-yl-methanone (0.72 mmol) in 10 mL of dichloroethane was added 0.87 mL (10.82 mmol) of pyridine followed by the addition of 0.56 mL (7.2 mmol) of methanesulfonyl chloride. The reaction was stirred at 80° C. for 2 hours. The volatiles were removed under reduced pressure affording material which was flash chromatographed (25% EtOAc/hexane to 1:1 EtOAc:hexane to 100% EtOAc) to give 0.150 grams of N-[3-bromo-5-(pyridine-3-carbonyl)-phenyl]-methanesulfonamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[CH2:22]([N:24]1[C:28]([C:29](O)=[O:30])=[CH:27][C:26]([C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)=[N:25]1)[CH3:23]>>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:29]([C:28]4[N:24]([CH2:22][CH3:23])[N:25]=[C:26]([C:32]5[S:33][CH:34]=[CH:35][CH:36]=5)[CH:27]=4)=[O:30])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: CCn1nc(-c2cccs2)cc1C(=O)O
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Product: CCn1nc(-c2cccs2)cc1C(=O)Nc1ccc(C)c(-c2ccc(C(=O)NCC3CC3)cc2)c1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-1-ethyl-3-(thiophen-2-yl)pyrazole-5- carboxamide was prepared from 5′-amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide and 1-ethyl-3-(thiophen-2-yl)pyrazole-5- carboxylic acid using method D. NMR; δH CDCl3 8.02,(1H, b), 7.86-7.83,(3H, m), 7.57,(1H, dd), 7.47,(1H, d), 7.40,(2H, d), 7.34,(1H, m), 7.30-7.26,(3H, m), 7.07,(1H, m), 4.63,(2H, q), 3.35,(2H, m), 2.24,(3H, s), 1.08,(1H, m), 0.58,(2H, m), 0.30,(2H, m). LCMS: retention time 3.81 min, MH+485.
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)=[O:2].[CH3:12][N:13]=[C:14]=[S:15].O>C(O)C>[CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:14]([NH:13][CH3:12])=[S:15])=[CH:7][CH:6]=1)=[O:2]
Reactant: Nc1ccc(NNC=O)cc1
Reactant: CN=C=S
Solvent: CCO
Solvent: O
Product: CNC(=S)Nc1ccc(NNC=O)cc1

Procedure:
1-Formyl-2-(4-aminophenyl)hydrazine (1.51 g, 0.01 mole) and methyl isothiocyanate (0.73 g, 0.01 mole) were mixed in ethanol (20 ml) and the mixture was refluxed for 30 minutes. The mixture was chilled in ice, and water was added to precipitate the product. The product came out of solution in an oily form, but solidifed upon scratching and standing. The solid material was filtered off and washed thoroughly with ether. The product was dried to give a white crystalline powder. Yield 1.3 g (58%), m.p. 176°-178° C.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([C:14]([N+:19]([O-:21])=[O:20])=[C:15]([CH3:18])[C:16]=2[F:17])[NH:10][CH:11]2[CH2:13][CH2:12]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(O[CH:25]=[C:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])C>>[CH:11]1([N:10]([CH:25]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:9]2[C:14]([N+:19]([O-:21])=[O:20])=[C:15]([CH3:18])[C:16]([F:17])=[C:7]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)[CH:8]=2)[CH2:12][CH2:13]1
Reactant: Cc1c(F)c(N2CCNCC2)cc(NC2CC2)c1[N+](=O)[O-]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CN(c1cc(N2CCNCC2)c(F)c(C)c1[N+](=O)[O-])C1CC1)C(=O)OCC
Temperature: 150 °C

Procedure:
To 3-(1-piperazinyl)-4-fluoro-5-methyl-6-nitro-N-cyclopropylaniline (1.57 g) is added diethyl ethoxymethylenemalonate (1.45 ml) and the mixture is heated at 150° C. for 25 hours. After cooling, the reaction product is purified by silica-gel column-chromatography (dichloromethane:methanol=100:1) to give diethyl [N-cyclopropyl-N-[3-(1-piperazinyl)-4-fluoro-5-methyl-6-nitrophenyl]aminomethylene]malonate (1.50 g). The product is dissolved in acetic anhydride (7.9 ml) and thereto conc. sulfuric acid (3.16 ml) is added dropwise at 50°-60° C., followed by stirring for 30 minutes. The resultant mixture is poured into ice-water, neutralized, extracted with dichloromethane and the extract is dried. The solvent is distilled off under reduced pressure. Purification by silica-gel column-chromatography (dichloromethane:methanol=10:1) to give ethyl 7-(1-piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (26 mg).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][C:3]1=[O:14].C(N(CC)CC)C.[C:22](Cl)(=[O:25])[CH2:23][CH3:24]>CN(C=O)C>[O:9]=[C:8]1[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][C:3](=[O:14])[CH:2]1[NH:1][C:22](=[O:25])[CH2:23][CH3:24]
Reactant: CCC(=O)Cl
Reactant: NC1C(=O)Nc2ccccc2NC1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(=O)NC1C(=O)Nc2ccccc2NC1=O
Reaction time: 8 h

Procedure:
Combine 3-amino-1H-1,5-benzodiazepine-2,4-(3H, 5H)-dione (5.7 g, 30.0 mmol) and triethyl amine(3.33 g, 33.0 mmol) in 120 mL DMF and add propionyl chloride (3.05 g, 33.0 mmol) dropwise at RT. After stirring overnight, remove DMF under reduced pressure, suspend the residue in a mixed solvent (CHCl3/i-PrOH=3/1, 400 mL). Collect an off-white solid via suction filtration to give the title compound. Wash the filtrate with NaHCO3 (sat.2×100 mL) and dry with Na2SO4. Concentrate the organic solvent down to a residue, treat with ether, collect the solid as title compound: mass spectrum (APCI) (m/e): 248.1 (M+1). 1H NMR (400 MHz, DMSO-d6): 10.70 (s, 2H), 8.19 (d, 1H, J=7.2 Hz), 7.23–7.15 (m, 4H), 4.73 (d, 1H, J=8.0 Hz), 2.27 (q, 2H, J=8.0 Hz), 0.94 (t, 3H, J=8.0 Hz).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:50]1[CH:55]=[CH:54][CH:53]=[C:52]([C:56]2[CH:57]=[C:58]([NH2:62])[CH:59]=[CH:60][CH:61]=2)[CH:51]=1>CN(C=O)C>[N:50]1[CH:55]=[CH:54][CH:53]=[C:52]([C:56]2[CH:57]=[C:58]([NH:62][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:59]=[CH:60][CH:61]=2)[CH:51]=1
Reactant: Nc1cccc(-c2cccnc2)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
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: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4cccnc4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 83.6 %

Procedure:
DIEA (43.5 μL, 0.25 mmol) was added to 8-methoxy-3-carboxy-coumarin (50.0 mg, 0.23 mmol) and HATU (95.0 mg, 0.25 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-pyridin-3-yl-phenylamine (38.7 mg, 0.23 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 71.6 mg of product in 84% yield: LCMS (ESI) m/z 373 (MH+).
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH3:18])[C:7]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.CO.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:29])C=CC=CC=1>ClCCl>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16]([CH3:17])=[O:29])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH3:18])[C:7]2=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CSc1ncc2cc(C)c(=O)n(C3CCCC3)c2n1
Solvent: ClCCl
Solvent: CO
Product: Cc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Reaction time: 16 h
Yield: 84.8 %

Procedure:
8-Cyclopentyl-6-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (2.56 g, 9.30 mmol) was dissolved in dichloromethane (17 mL) and methanol (17 mL) to which 2-benzenesulfonyl-3-phenyl-oxaziridine was added and the reaction mixture was stirred for 16 hours. The solvent was removed and diethyl ether added. The precipitated solid was collected by filtration to give 8-cyclopentyl-2-methanesulfinyl-6-methyl-8H-pyrido[2,3-d]pyrimidin-7-one as a white solid (2.30 g, 84.8%). 1H NMR δ(400 MHz, CDCl3) 8.85 (s, 1H), 7.54 (s, 1H), 5.99, (m, 1H), 2.95 (s, 3H), 2.27 (d, J=1.2 Hz, 3H), 2.24 (m, 2H), 2.13 (m, 2H), 1.94 (m, 2H), 1.70 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3][C:2]1=[O:8].N1CCC=CCC1=O.[H-].[Na+].[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C1COCC1.O>[CH2:30]([N:1]1[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3][C:2]1=[O:8])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19]
Reactant: CCCCCCCCCCCCBr
Reactant: O=C1C=CCCCN1
Agent: O=C1CC=CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCN1CCCC=CC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 11.4 g (0.102 mol) of a mixture of azacyclohept-3-ene-2-one and azacyclohept-4-ene-2-one in THF was added dropwise to a suspension of 4.8 g (107 mmol) of sodium hydride (50% oil dispersion) in THF. The mixture was stirred at room temperature for 1 hour, 25.4 g (0.102 mol) of dodecyl bromide was added, and the solution was refluxed for 5 hours. The mixture was cooled, water was added, and the solvent was removed in vacuo. The residue was dissolved in CH2Cl2, washed with water, the organic phase dried over MgSO4 and concentrated in vacuo to yield an oil which was Kugelrohr distilled to give 15.5 g of crude product. This material was subjected to flash chromatography (silica gel; 9:1 petroleum ether/ether V/V) to give 1-dodecylazacyclohept-3-ene-2-one, Rf =0.5, GC (column: 48 inch, 2% OV 101; conditions: injector, detector 320° C., program; 140° C. for 3 min, then to 190° C. in 30° C./min) GC retention time, 7.74 min.