Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[O-]CC.[Na+].[NH2:6][C:7]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][NH:9][N:8]=1.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[NH2:6][C:7]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][N:9]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]=1
Reactant: CCOC(=O)c1c[nH]nc1N
Reactant: ClCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1N
Yield: 55.2 %

Procedure:
Sodium (1.9 g) was dissolved in anhydrous ethanol (100 ml) to prepare a solution of sodium ethoxide. To this, were added 3-amino-4-ethoxycarbonylpyrazole (12.4 g) and benzyl chloride (10 g), and the resulted mixture was refluxed for 1 h. After filtration of the hot mixture, the filtrate was concentrated to quarter volume, and cooled to crystallize. The crude product was recrystallized from an ether-water mixture to give 3-amino-1-benzyl-4-ethoxycarbonylpyrazole (10.7 g, yield 44%). To a solution of 3-amino-1-benzyl-4-ethoxycarbonylpyrazole (0.2 g) in dried toluene (30 ml), were added propyl isocyanate (0.307 ml) and triethylamine (0.11 ml), and the mixture was refluxed in a sealed tube for 8 h. The reaction mixture was evaporated under reduced pressure followed by silica-gel column chromatography (toluene : ethyl acetate=20:1) to give the title compound (0.129 g, yield 48%). 1H-NMR (CDCl3) δ ppm: 0.92 (3H, t, J=7Hz, CH2CH2CH3 ), 1.32 (3H, t, J=7Hz, COOCH2CH3 ), 1.57 (2H, 6th, CH2CH2CH3), 4.28 (2H, q, J=7Hz, COOCH2CH3), 5.14 (2H, s, CH2 --Ph), 7.25 (5H, m, CH2 --Ph), 7.91 (2H, brs, NH), 8.00 (1H, s, C5-H)
Reaction SMILES: [CH2:1]1[O:11][C:10]2[C:3](=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[O:2]1.[OH-:12].[K+]>CCO.O.[N+]([O-])([O-])=O.[Ag+]>[CH2:1]1[O:11][C:10]2[C:3](=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]([OH:12])=[O:6])[O:2]1
Reactant: O=Cc1cccc2c1OCO2
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cccc2c1OCO2
Reaction time: 2 h

Procedure:
To a solution of 0.85 g (5.66 mmol) of 2,3-methylenedioxybenzaldehyde (Aldrich) in EtOH at 0° C. was added a solution of 2.12 g (12.45 mmol) of AgNO3 in 7.5 mL of H2O. To this was then added a solution of 1.74 g (31.4 mmol) of KOH in 12 mL of H2O. After 2 h, the reaction mixture was filtered and the filter was washed with EtOH. The filtrate was concentrated and the pH was adjusted to pH=2 to 3 with 6N HCl. The title compound precipitated out and was isolated by filtration to give the title compound. 1H NMR (CDCl3) δ6.16 (s, 2H), 6.92 (t, 1H, J=8 Hz), 7.04 (d, 1H, J=8 Hz), 7.48 (d, 1H, J=8 Hz);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=1N.S(=O)(=O)(O)O.N([O-])=O.[Na+].[C-:30]#[N:31].[Na+]>O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=1[C:30]#[N:31]
Reactant: [C-]#N
Reactant: CS(=O)(=O)c1ccc(Oc2ccc(Cl)c(Cl)c2)c(N)c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2ccc(Cl)c(Cl)c2)c(C#N)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 95.8 %

Procedure:
A mixture of 5.0 g (0.0151 mole) of 2-(3,4-dichlorophenoxy)-5-(methylsulfonyl)benzenamine (Example 16), 75 ml of glacial acetic acid, 37.5 ml of water and 3.0 g (0.0306 mole) of concentrated sulfuric acid was cooled to 0° C. and 1.5 g (0.0217 mole) of sodium nitrite dissolved in 15 ml of water was added slowly. The mixture was stirred at 0° C. for 20 minutes and then added slowly to a mixture of 7.5 g (0.0838 mole) of cuprous cyanide and 30 g (0.612 mole) of sodium cyanide dissolved in 150 ml of water at 0° C. The mixture was stirred at 0° C. for 45 minutes and allowed to warm to room temperature. The mixture was then heated at 50° C. for 1 hr. The mixture was poured into water and the crystalline product collected by filtration, washed with water and dried, to obtain 4.95 g (96.1% yield) of product. Purification was accomplished by column chromatography using silica gel as the support and chloroform as the eluent followed by recrystallization from ethyl acetate, which gave purified 2-(3,4-dichlorophenoxy)-5-(methylsulfonyl)benzonitrile, mp 162°-163° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[NH:10][CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:6][CH:7]=1.[NH:16]([CH:23]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.S(Cl)(Cl)=O>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[NH:10][CH2:11][C:12]([N:16]([CH:23]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C(Nc1ccccc1)C(=O)OC(C)(C)C
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Solvent: O=S(Cl)Cl
Product: Cc1cccc(NC(=O)NCC(=O)N(c2ccccc2)C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Yield: 33.1 %

Procedure:
The procedure is as in Example 1, but 0.85 g of 2-[3-(3-methylphenyl)ureido]acetic acid, 1.25 g of di-tert-butyl 2-anilinomalonate and 0.3 cm3 of thionyl chloride are used as starting materials. The product obtained is purified by chromatography on 50 g of silica (0.04-0.063 mm) contained in a column 3 cm in diameter [eluent: methanol/dichloromethane (1.5/98.5 by volume)], using an excess pressure of 40 kPa of nitrogen and collecting 25-cm3 fractions. Fractions 6 to 15 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 35° C. and the residue obtained is crystallization from 10 cm3 of diethyl ether. 0.67 g of di-tert-butyl 2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}malonate melting at 175° C. are then obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.OC[C:27]#[C:28][CH2:29][N:30]1[C:34](=[O:35])[C:33]([CH3:46])([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH:43]([CH3:45])[CH3:44])=[CH:38][CH:37]=2)[NH:32][C:31]1=[O:47]>ClCCl>[Br:24][CH2:20][C:27]#[C:28][CH2:29][N:30]1[C:34](=[O:35])[C:33]([CH3:46])([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH:43]([CH3:44])[CH3:45])=[CH:38][CH:37]=2)[NH:32][C:31]1=[O:47]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)Oc1ccc(C2(C)NC(=O)N(CC#CCO)C2=O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)Oc1ccc(C2(C)NC(=O)N(CC#CCBr)C2=O)cc1
Yield: 87.4 %

Procedure:
Triphenylphosphine (196 mg) and carbon tetrabromide (247 mg) were added to a mixed solution of 3-(4-hydroxy-2-butynyl)-5-methyl-5-[4-(1-methylethoxy)phenyl]imidazolidine-2,4-dione (157 mg, 498 μmol) in dichloromethane (10 mL) at room temperature. After completion of the reaction, the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 165 mg of the title compound (yield: 87%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([CH:11]([C:17](OCC)=[O:18])[C:12](OCC)=[O:13])[CH:9]=[CH2:10]>>[CH2:8]([C:11]1[C:12](=[O:13])[N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]2=[N:1][C:17]=1[OH:18])[CH:9]=[CH2:10]
Reactant: Nc1ccccn1
Reactant: C=CCC(C(=O)OCC)C(=O)OCC
Product: C=CCc1c(O)nc2ccccn2c1=O
Temperature: 160 °C
Yield: 27.1 %

Procedure:
2-aminopyridine (996 mg, 10.58 mmol) and diethyl allylmalonate (2098 μl, 10.58 mmol) were combined and heated to 160° C. neat for 9 hours. The brown solution solidified upon cooling to room temperature. The solid was filtered and washed with Et2O to yield the title compound as a tan solid (580 mg, 27%) LCMS (ES+) m/z 203.02 (M+H)+.
Reaction SMILES: [C:1]1([C:7]([SH:20])([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:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[C:24]([CH3:28])([CH3:27])[CH:25]=[O:26]>C1COCC1.C1(C)C=CC=CC=1>[CH3:27][C:24]([S:20][C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:28])[CH:25]=[O:26]
Reactant: CC(C)(Br)C=O
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C=O)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.7 %

Procedure:
Triphenylmethylmercaptan (362.94 g, 1.31 mol, 100 mol %) dissolved in anhydrous THF (2 L) was cooled in an ice bath under argon. Sodium hydride (60% in oil; 54.39 g, 1.35 mol, 104 mol %) was added in portions over 20 min. 2-bromo-2-methylpropanal (206.06 g, 1.36 mol, 104 mol %; see Stevens & Gillis, 1957, J. Amer. Chem. Soc. 79: 3448-51) was then added slowly over 20 min. The reaction mixture was allowed to warm to room temperature and stirred for 12 hours. The reaction was quenched with water (1 L) and extracted with diethyl ether (3×1 L). The ether extracts were combined, washed with saturated NaCl solution (500 mL), dried over Na2SO4 and filtered. The solvent was removed under reduced pressure to afford a thick orange oil. The crude oil was dissolved in toluene (200 mL) and diluted to 2 L with hot hexanes. The mixture was filtered through a sintered glass funnel and cooled at -5° C. for 12 hours. The white crystalline solid which formed was removed by filtration to afford 266.36 g (59% yield) of the title compound. The melting point of the resulting compound was determined to be 83-85° C. Nuclear magnetic resonance characterization experiments yielded the following molecular signature:
Reaction SMILES: [SH2:1].[C:2]([O:6][C:7](=[O:19])[CH:8]([P:11]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12])[N+:9]#[C-:10])([CH3:5])([CH3:4])[CH3:3]>O1CCCC1.[Cu]>[C:2]([O:6][C:7](=[O:19])[CH:8]([NH:9][CH:10]=[S:1])[P:11]([O:13][CH2:14][CH3:15])([O:16][CH2:17][CH3:18])=[O:12])([CH3:4])([CH3:3])[CH3:5]
Reactant: S
Reactant: [C-]#[N+]C(C(=O)OC(C)(C)C)P(=O)(OCC)OCC
Agent: [Cu]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(NC=S)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
Dry hydrogen sulphide gas is passed for 10 minutes into a solution, cooled to 0° C., of 277 mg (1 mmol) of diethylphosphono-isocyanoacetic acid tert.-butyl ester in 5 ml of dry tetrahydrofurane (filtered through aluminium oxide). After adding a few crystals of copper-II acetylacetonate, the reaction vessel is closed and left to stand overnight at room temperature. The reaction mixture is filtered and the filtrate is evaporated in vacuo. The residue is chromatographed on silica gel thick layer plates with toluene/ethyl acetate, 1:1, and gives thioformamido-diethylphosphonoacetic acid tert.-butyl ester in the form of a colourless oil: IR spectrum (in methylene chloride): characteristic bands at 3.13; 3.35; 5.75; 7.01; 8.10; 8.70 and 9.75μ.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[C:21]([C:28]3[NH:36][C:35]4[CH2:34][CH2:33][NH:32][C:31](=[O:37])[C:30]=4[CH:29]=3)[CH:22]=[CH:23][CH:24]=2)[N:19]=1>CN(C=O)C>[O:37]=[C:31]1[C:30]2[CH:29]=[C:28]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:20]=3[N:19]=[C:18]([O:1][CH:2]3[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]3)[CH:27]=[CH:26]4)[NH:36][C:35]=2[CH2:34][CH2:33][NH:32]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cccc(-c4cc5c([nH]4)CCNC5=O)c3n2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Similar to the method described in Example 103, tert-butyl 4-hydroxypiperidine-1-carboxylate (Aldrich; 357 mg, 1.77 mmol) was added to a suspension of NaH (70.9 mg, 1.77 mmol) in DMF (2.0 mL) and the resulting light yellow solution was stirred at RT for 10 min. 2-(2-Chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 66 mg, 0.22 mmol) was added and the resulting dark red solution was stirred at RT for 5 min, then heated at 70° C. for 2.5 h. The mixture was cooled to RT and partitioned between EtOAc (100 mL) and saturated aq. NH4Cl (50 mL). The organic layer was separated, sequentially washed with water (40 mL) and brine (40 mL), and then dried over MgSO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-10% MeOH in DCM) gave tert-butyl 4-((8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinolin-2-yl)oxy)piperidine-1-carboxylate as an orange oil. m/z (ESI, +ve ion) 463.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:23])[C:5]2[C:10]([CH2:11][NH:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=3)=[CH:9][O:8][C:6]=2[N:7]=1.[CH2:24]=O.[C-]#N.[Na+].Cl>C(#N)C>[NH2:1][C:2]1[N:3]=[C:4]([NH2:23])[C:5]2[C:10]([CH2:11][N:12]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=3)[CH3:24])=[CH:9][O:8][C:6]=2[N:7]=1
Reactant: Nc1nc(N)c2c(CNc3ccc4ccccc4c3)coc2n1
Reactant: C=O
Agent: Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CC#N
Product: CN(Cc1coc2nc(N)nc(N)c12)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a suspension of compound 424 (0.10 g, 0.32 mmol), 30% (w/w) aqueous solution of formaldehyde (0.1 ml) and NaCN BH3 (0.063 g) in acetonitrile (10 ml) was added dropwise concentrated hydrochloric acid until the suspension dissolved. The solution was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure and the residue dissolved in a minimum amount of distilled water and the pH of the solution adjusted to 7 with concentrated NH4OH. The resulting suspension was sonicated, cooled to 5° C. and filtered. The residue was washed with cold water (2×3 ml), stirred in MeOH (5 ml) for 12 h and filtered. The residue was washed with MeOH (2×3 ml) to afford 0.065 g (64%) of compound 429 as a light yellow solid.