Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H][H].[CH3:3][CH:4]1[CH2:9][CH2:8][O:7][C:5]1=[O:6].C1(C)C=CC=C(C)C=1>[Cu].[Cr]([O-])([O-])=O.CO>[CH3:3][CH:4]1[CH2:9][CH2:8][O:7][CH2:5]1.[CH3:3][CH:4]1[CH2:9][CH2:8][O:7][C:5]1=[O:6].[C:5]([O:7][CH3:8])(=[O:6])[CH:4]([CH3:9])[CH3:3]
Reactant: [H][H]
Agent: O=[Cr]([O-])[O-]
Agent: [Cu]
Agent: CC1CCOC1=O
Solvent: Cc1cccc(C)c1
Solvent: CO
Product: CC1CCOC1
Product: COC(=O)C(C)C
Yield: 0.5 %

Procedure:
A stainless steel-made tubular reactor to be used as a hydrogenation reactor having an inside diameter of 15 mm and a length of 300 mm was packed inside with 10 g of copper-chromite as the catalyst roughly uniformized in particle size of 10 to 20 mesh (produced by Nissan Girdler Catalyst Co.,Ltd. under the trade name: G-99C in the form of pellets). Subsequently, a catalyst reduction was carried out at 150 to 200° C. by passing through the reactor, hydrogen gas diluted with nitrogen to 0.5 to 5% by volume by the conventional method with sufficient care not to form a hot spot. Thereafter, the feed gas to the reactor was switched to pure hydrogen at a pressure of 70 kg/cm2G, a purge gas SV of 500 hr-1 and a catalyst bed temperature of 230° C. Then, the tubular reactor was charged at an upper portion thereof with a starting material for reaction consisting of a solution of 30 parts by weight of 2-methyl-γ-butyrolactone which had been obtained in Example 3 in 70 parts by weight of m-xylene at a rate of 3.3 g per hour. The effluent through a lower portion thereof was cooled and degasified to collect the reaction product. After the lapse of 5 hours from the start of the reaction, the reaction product was collected for one hour and analyzed by gas chromatography. As a result, the objective 3-methyltetrahydrofuran was obtained in a yield of 90.1% in a conversion efficiency of 2-methyl-γ-butyro-lactone of 100% in a yield of 0.5% methyl isobutyrate, while methanol was not detected in the reaction product throughout the reaction period.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:10]=[CH:11][C:12]=1OS(C(F)(F)F)(=O)=O.[N:28]1([C:34]([C:36]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=2)=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[F-].[Cs+]>C(COC)OC.C(O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:10]=[CH:11][C:12]=1[C:39]1[CH:38]=[CH:37][C:36]([C:34]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:35])=[CH:41][CH:40]=1
Reactant: CCOC(=O)CCc1ccc(OS(=O)(=O)C(F)(F)F)c(OCCCOC)c1
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCOCC1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CCO
Product: CCOC(=O)CCc1ccc(-c2ccc(C(=O)N3CCOCC3)cc2)c(OCCCOC)c1
Temperature: 25 °C
Yield: 65.9 %

Procedure:
Ethyl 3-[3-(3-methoxypropoxy)-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl]propanoate (0.8 g, 1.9 mmol) was dissolved in dimethoxyethane (12 mL) and ethanol (1.2 mL). 4-Morpholine-4-carbonylphenylboronic acid (0.50 g, 2.1 mmol) was added and argon: was bubbled in the mixture for 15 minutes. Cesium fluoride (0.6 g, 4.2 mmol) and tetrakistriphenylphosphine palladium (0.11 g, 0.1 mmol) were added and the mixture was brought to reflux under an argon atmosphere for 4 hours. After cooling to room temperature, solvents were evaporated under reduced pressure and the residue was dissolved in ethyl acetate/water (15 mL/15 mL). The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate, 7/3) to yield 0.57 g (65%) of the desired product as a yellow oil.
Reaction SMILES: C([Sn]([N:14]=[N+:15]=[N-:16])(CCCC)CCCC)CCC.[NH2:17][C:18]1[N:19]=[C:20]([CH3:33])[C:21]2[CH:27]=[C:26]([C:28]#[N:29])[C:25](=[O:30])[N:24]([CH2:31][CH3:32])[C:22]=2[N:23]=1>C1(C)C=CC=CC=1>[NH2:17][C:18]1[N:19]=[C:20]([CH3:33])[C:21]2[CH:27]=[C:26]([C:28]3[NH:16][N:15]=[N:14][N:29]=3)[C:25](=[O:30])[N:24]([CH2:31][CH3:32])[C:22]=2[N:23]=1
Reactant: CCn1c(=O)c(C#N)cc2c(C)nc(N)nc21
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCn1c(=O)c(-c2nnn[nH]2)cc2c(C)nc(N)nc21
Temperature: 140 °C
Reaction time: 20 h
Yield: 44.8 %

Procedure:
Tributyltin azide (660 μL, 2.41 mmol) was added to a flask charged with 2-amino-8-ethyl-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (0.184 g, 0.803 mmol) in anhydrous toluene (5.0 mL). The reaction was fitted with a reflux condenser and heated to 140° C. under a nitrogen atmosphere. After 20 h, the reaction was cooled to room temperature and the precipitate collected by vacuum filtration and washed with absolute ethanol to give 2-amino-8-ethyl-4-methyl-6-(1H-tetrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (98 mg, 45% yield) as a light brown solid: 1H NMR (400 MHz, 20% DCl in D2O): δ 6.97 (s, 1H), 2.42 (q, J=7.2 Hz, 2H), 0.953 (s, 3H), −0.73 (t, J=7.2 Hz, 3H); MS (EI) for C11H11N8O: 271.0 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[N+:25]([O-])=O)[N:9]=2)=[CH:4][CH:3]=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[NH2:25])[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc2nc(-c3ccc(Br)cc3)c(-c3ccc(Br)cc3)nc12
Solvent: C1COCCO1
Product: Nc1cccc2nc(-c3ccc(Br)cc3)c(-c3ccc(Br)cc3)nc12

Procedure:
1.01 g (2.1 mmol) of 2,3-di(4-bromophenyl)-5-nitroquinoxaline was dissolved in 30 g of dioxane, followed by purging well with argon, adding 0.3 g of 5% Pd/C (hydrous) and purging well with argon again. This system was purged with a hydrogen gas and reacted at room temperature for 24 hours. After completion of the reaction, the system was filtered. The resulting filtration residue was washed with acetone and then with dioxane and filtered again. The solvent was removed from the resulting filtrate and a reaction product was extracted with a silica gel column.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[I:22][C:23]1[N:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1.O>ClCCl>[I:22][C:23]1[N:28]=[CH:27][C:26]([C:29]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:30])=[CH:25][CH:24]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(Cl)c1ccc(I)nc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccc(I)nc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1.0 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 10 ml of triethylamine in 50 ml of dichloromethane under argon is added 3.2 g of 6-iodopyridine-3-carbonyl chloride. The mixture is stirred at room temperature for 16 hours and then poured into 100 ml of water. The organic layer is separated and washed with 2% HCl, water, saturated NaHCO3 and dried (Na2SO4). The solvent is removed under vacuum and the residue chromatographed on silica gel with ethyl acetate-hexane as solvent to give the product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[F:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[C:30](=O)[CH2:31]Br>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH:31]=[C:30]([C:29]3[CH:34]=[CH:35][CH:36]=[C:27]([F:26])[CH:28]=3)[N:20]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Reactant: O=C(CBr)c1cccc(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(-n2cc(-c3cccc(F)c3)nc2-c2ccc(Cl)cc2)cc1
Yield: 50.3 %

Procedure:
To a mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (Example 1, Step 1) (700 mg, 2.24 mmol) and sodium bicarbonate (376 mg, 4.48 mmol) in isopropanol (30 mL), 3-fluorophenacyl bromide (0.97 g, 4.48 mmol) was added. After heating the reaction mixture at 75–80° C. for 18 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with aqueous sodium bicarbonate and water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography (silica gel, hexane/ethyl acetate, 6/4) to give 2-(4-chlorophenyl)-4-(3-fluorophenyl)-1-[4-(methylsulfonyl)phenyl)-1H-imidazole (481 mg, 50%) as a white solid: mp 194–196° C. Anal. Calc'd. for C22H16N2SO2FCl: C, 61.90; H, 3.78; N, 6.56; S, 7.51. Found: C, 61.71; H, 3.59; N, 6.42; S, 7.69.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[C:4]([C:11]2[C:19]3[C:18]([NH:20][C@H:21]([C:23]4[N:28]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:27](=[O:35])[C:26]5=[C:36]([CH3:39])[CH:37]=[CH:38][N:25]5[N:24]=4)[CH3:22])=[N:17][CH:16]=[N:15][C:14]=3[N:13]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[CH:12]=2)[CH:3]=1.[N-:48]=[C:49]=[O:50].[K+]>O.C(O)(=O)C>[CH3:39][C:36]1[CH:37]=[CH:38][N:25]2[C:26]=1[C:27](=[O:35])[N:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]([C@@H:21]([NH:20][C:18]1[C:19]3[C:11]([C:4]4[CH:3]=[C:2]([NH:1][C:49]([NH2:48])=[O:50])[CH:10]=[C:9]5[C:5]=4[CH:6]=[CH:7][NH:8]5)=[CH:12][N:13]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:45])([CH3:47])[CH3:46])[C:14]=3[N:15]=[CH:16][N:17]=1)[CH3:22])=[N:24]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(N)cc5[nH]ccc35)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: [N-]=C=O
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(NC(N)=O)cc5[nH]ccc35)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 72.6 %

Procedure:
To a suspension of (S)-2-(1-((5-(6-amino-1H-indol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.08 mmol) in 403 μl water and 208 μl acetic acid was added potassium isocyanate (17 mg, 0.21 mmol) according to the method described in Preparation 181. The residue was purified using SP1® Purification System (0% to 100% hexane-ethyl acetate) to obtain 40 mg (75% yield) of the title compound.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][C:8]1[C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:31]=[C:32]([C:43]([OH:45])=O)[CH:33]=[C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=2)[CH:35]=1)=[O:5])C.[CH3:46][NH2:47]>>[C:4]([CH2:6][CH2:7][C:8]1[C:9]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:35]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=3)[CH:33]=[C:32]([C:43](=[O:45])[NH:47][CH3:46])[CH:31]=2)=[CH:10][CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])([OH:3])=[O:5]
Reactant: CN
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3cccc(F)c3)c2)c1CCC(=O)OCC
Product: CNC(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2cccc(F)c2)c1

Procedure:
The title compound was prepared according to the general procedure described in Steps 7 and 8 of Method C starting from 5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-3′-fluoro-biphenyl-3-carboxylic acid and methylamine.
Reaction SMILES: [CH3:1][NH2:2].C[O:4][C:5](=O)[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8](F)[CH:7]=1.[CH3:17]O>>[CH3:1][N:2]1[C:8]2[CH:7]=[C:6]([CH:5]=[O:4])[CH:11]=[CH:10][C:9]=2[N:12]=[CH:17]1
Reactant: CO
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CN
Product: Cn1cnc2ccc(C=O)cc21

Procedure:
The title compound was synthesized in a similar manner as described for intermediate J using methyl amine solution in MeOH instead of 2-pyrrolidin-1-yl-ethylamine to react with 3-fluoro-4-nitro-benzoic acid methyl ester (xiv) (tR 1.56 min (conditions 8), MH+=161).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Br)[CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:35]1[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36]1.C(N(CC)CC)C>CN(C=O)C.[I-].[Na+]>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:11]=[CH:10][C:15]4[C:14]([CH:13]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:16]=4)[CH:18]=[C:19]([C:27]3[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=3)[CH2:33][N:35]3[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: Nc1ncnn2c(-c3cccc(CBr)c3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: OC1CCNC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ncnn2c(-c3cccc(CN4CCC(O)C4)c3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 55 °C
Yield: 22.1 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-[3-(bromomethyl)phenyl]pyrrolo[2,1-f][1,2,4]triazin-4-amine (125 mg, 025 mmol) in DMF (1 mL) was added 3-pyrrolidinol (26 μL, 0.27 mmol), triethylamine (103 μl, 0.74 mmol), and sodium iodide (0.4 mg, 0.002 mmol). The reaction was heated (55° C.) for 17 h and then cooled to rt. The crude reaction mixture was purified via preparative HPLC using a gradient elution from 15% to 50% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 28 mg (22%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1 H), 7.92-8.00 (m, 3 H), 7.83 (d, 1 H), 7.69 (d, 1 H), 7.25-7.44 (m, 7 H), 7.22 (dd, 1 H), 7.14 (s, 1 H), 5.67 (s, 2 H), 4.68 (d, 1 H), 4.09-4.21 (m, 1 H), 3.60 (q, 2 H), 2.65-2.72 (m, 1 H), 2.58 (q, 1 H), 2.37-2.46 (m, 1 H), 2.32 (dd, 1 H), 1.93-2.03 (m, 1 H), 1.48-1.59 (m, 1 H); ES-MS m/z 516.20 [M+H]+, HPLC RT (min) 2.53.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([OH:24])[CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C)C=O.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([O:24][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc(C2CCCN(C(=O)OCc3ccccc3)C2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cc(C2CCCN(C(=O)OCc3ccccc3)C2)ccc1C
Temperature: 60 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
To a solution of 3-(3-hydroxy-4-methyl-phenyl)-piperidine-1-carboxylic acid benzyl ester (Example 11; 2.08 g, 6.39 mmol) in 15 mL dimethylformamide was added cesium carbonate (4.17 g, 12.78 mmol) and ethyl bromoacetate (1.42 mL, 12.78 mmol). The mixture was heated to 60° C. under N2 with stirring for 3 h and cooled to ambient temperature. The resultant brown suspension was diluted with 300 mL water and extracted with diethyl ether (2×200 mL). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was flash chromatographed with 15% ethyl acetate/hexanes to yield 1.42 g (54%) of the desired 3-(3-ethoxycarbonylmethoxy-4-methyl-phenyl)-piperidine-1-carboxylic acid benzyl ester as a clear oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:17])[C:5]2[C:10]([CH3:11])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[CH2:24]([N:3]1[C:4](=[O:17])[C:5]2[C:10]([CH3:11])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:8][C:6]=2[N:7]=[C:2]1[CH3:1])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1sc2nc(C)[nH]c(=O)c2c1C
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1sc2nc(C)n(Cc3ccccc3)c(=O)c2c1C
Yield: 45 %

Procedure:
A mixture of 252 mg of ethyl 2,5-dimethyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate, 138 mg of potassium carbonate, 15 mL of acetonitrile and 1 mL of benzyl chloride was heated under reflux overnight. After condensing the reaction mixture under reduced pressure, the residue was purified on silica gel column chromatography (chloroform:methanol=100:1) to provide 153 mg (45%) of the title compound.
Reaction SMILES: [S-2:1].[Na+].[Na+].Cl[C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[CH:6][C:7]#[N:8].Cl[CH2:16][C:17]#[N:18].C[O-].[Na+]>CN(C=O)C.CO.O>[NH2:8][C:7]1[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:1][C:16]=1[C:17]#[N:18]
Reactant: N#CCCl
Reactant: N#CC=C(Cl)c1ccccc1
Reactant: [S-2]
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: N#Cc1sc(-c2ccccc2)cc1N
Temperature: 65 °C
Reaction time: 2 h
Yield: 6.1 %

Procedure:
To a suspension of sodium sulfide (0.95 g, 12.23 mmol) in DMF (12.5 mL) was added a solution of 3-chloro-3-phenylprop-2-enenitrile (2 g, 12.23 mmol) in DMF (5 mL) at rt for 5 min and stirred the mixture at 60-70° C. for 2 h. Then chloroacetonitrile (0.77 mL, 12.23 mmol) was added dropwise to the reaction mixture and again stirred at 60-70° C. for 2 h. Then, a solution of sodium methoxide (0.66 g, 12.23 mmol) in methanol (5 mL) was added dropwise and stirring was continued for 1 h at the same temperature. The mixture was allowed to rt and poured into cold water and stirred for 15 min. The solid separated was filtered, washed with water and dried. The solid was recrystallized from hexane-chloroform to give the product as a pale brown color solid (150 mg, 8%), nip 158-160° C. 1H NMR (400 MHz, CDCl3): δ 7.52-7.54 (2H, m), 7.37-7.41 (3H, m), 6.75 (1H, s), 4.48 (2H, s); LC-MS (negative ion mode): m/z 199 (M−H)−.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH2:11][CH2:12][N:13](CC2C=CC=CC=2)[CH2:14][CH:15]=1.[Cl:23]C(OCCCl)=O>ClCCl>[ClH:23].[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH2:11][CH2:12][NH:13][CH2:14][CH:15]=1
Reactant: O=C(Cl)OCCCl
Reactant: C1=C(c2cc3ccccc3s2)CCN(Cc2ccccc2)C1
Solvent: ClCCl
Product: C1=C(c2cc3ccccc3s2)CCNC1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
To a solution of 4-(benzothiophen-2-yl)-1-benzyl-1,2,3,6-tetrahydropyridine (3.5 g, 0.01 mol) in anhydrous dichloromethane (50 ml) cooled in ice was added chloroethyl chloroformate (1.61 ml, 0.013 mol). The reaction was stirred at room temperature for 11/2 hours and concentrated in vacuo. The residue was suspended in methanol (25 ml) and stirred under reflux for 1 hour. The reaction mixture was cooled, and the resultant solid isolated by filtration, to afford the title compound as a pale yellow solid (2.1 g, 84%). δH (DMSO-d6), 2.80 (2H, m, HNCH2CH2), 3.34 (2H, m, HNCH2CH2), 3.77 (2H, m, HNCH2CH2), 6.21 (1H, m, HNCH2CH), 7.35 (2H, m, ArH), 7.49 (1H, s, ArH), 7.81 (1H, m, ArH), 7.92 (1H, m, ArH).
Reaction SMILES: Br[CH:2]([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[N:13]1(C(OCC)=O)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C.[OH-].[Na+]>C(OCC)C.C(OCC)(=O)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH:2]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH3:12])=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1CCNCC1
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C(=O)c1ccc(Cl)cc1)N1CCNCC1

Procedure:
A solution of 2-bromo-4′-chloropropiophenone, (741 mg, 3 mmol); ethyl 1-piperazinecarboxylate (474 mg, 3 mmol); triethylamine (0.42 mL, 3 mmol) in diethyl ether (10 mL) was heated at reflux for 3 hours (reaction was monitored by Thin Layer Chromatography (TLC)). The reaction mixture was cooled and further diluted with ethyl acetate and washed with water, brine and dried over Na2SO4. After evaporation of the solvent in vacuo, the crude viscous liquid was treated with conc. HCl (15 mL) at refluxing temperature for 48 hrs. The cooled reaction mixture was made alkaline by addition of 50% NaOH and extracted with ethyl acetate. The combined extracts were washed with water, brine and dried over Na2SO4. After evaporation of the solvent 4′chloro-2-(piperazin-1-yl)propiophenone was obtained as a semisolid which was reacted without further purification.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8]1[CH:13]=CC=C[CH:9]=1.C=CC>CC(C)=O>[CH:8]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:13])[CH3:9].[C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccccc1
Solvent: CC(C)=O
Solvent: Oc1ccccc1
Solvent: C=CC
Product: CC(C)c1ccccc1

Procedure:
In industry, phenol is normally prepared by means of benzene alkylation with propylene to give isopropyl benzene, oxidation to the corresponding tert-hydroperoxide and subsequent cleavage to phenol and acetone in the presence of an acid catalyst.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][CH3:3].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>O1CCOCC1.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.O>[C:5]1([N:4]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:1][CH2:2][CH3:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCCNc1ccccc1
Reactant: CCOC(=O)CBr
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: O
Solvent: C1COCCO1
Product: CCCN(CC(=O)OCC)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of N-propylaniline (60 g) and ethyl bromoacetate (83.6 ml) in dioxane (60 ml), diazabicycloundecene (DBU;113 ml) was added dropwise under ice-cooling. After stirring for 1 hour at room temperature, the reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layer was washed with successive, 1N hydrochloric acid, water and saturated sodium chloride in order. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give 87.9 g (90%) of the objective compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][OH:18])[CH:12]=1>>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH:12]=1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: OCc1cccnc1
Product: O=[N+]([O-])c1cnccc1OCc1cccnc1
Yield: 78.5 %

Procedure:
In accordance with the same procedures as in Preparation 2, except for using 4-chloro-3-nitropyridine prepared in Step 1 of Preparation 1 and 3-pyridyl carbinol, the titled compound was obtained as a yellow solid. (Yield: 78.5%)
Reaction SMILES: Br[CH2:2][C:3]1[C:7]([Cl:8])=[N:6][S:5][N:4]=1.[NH2:9][CH2:10][CH2:11][SH:12].[O-]CC.[Na+]>C(O)C>[Cl:8][C:7]1[C:3]([CH2:2][S:12][CH2:11][CH2:10][NH2:9])=[N:4][S:5][N:6]=1
Reactant: NCCS
Reactant: Clc1nsnc1CBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: NCCSCc1nsnc1Cl

Procedure:
3-Methyl(1,2,5)thiadiazole is chlorinated for 4 days in acetonitrile at 25° to give 4-chloro-3-methyl(1,2,5)thiadiazole (oil) which is treated with N-bromosuccinimide in carbon tetrachloride to give 3-bromomethyl-4-chloro(1,2,5)thiadiazole (oil), the 100 MHz n.m.r. in CDCl3 had singlet at 4.66δ. 3-Bromomethyl-4-chloro(1,2,5)thiadiazole was treated with cysteamine and sodium ethoxide in ethanol to give 2-(4-chloro-3(1,2,5)thiadiazolylmethylthio)ethylamine (oil). A 60 MHz n.m.r. spectrum (CDCl3) gave a singlet at 3.91 attributed to the Het--CH2 --S protons.