Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:25][CH2:24]2)=[CH:4][C:5]([N:20]([CH3:22])[CH3:21])=[C:6]([CH:19]=1)[C:7]([NH:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])=[O:8].C(N(CC)C(C)C)(C)C.[O:45]1[CH:49]=[CH:48][CH:47]=[C:46]1[C:50](Cl)=[O:51]>ClCCl.O>[CH3:21][N:20]([CH3:22])[C:5]1[C:6]([C:7](=[O:8])[NH:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])=[CH:19][C:2]([NH:1][C:50]([C:46]2[O:45][CH:49]=[CH:48][CH:47]=2)=[O:51])=[C:3]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:27][CH2:28]2)[CH:4]=1
Reactant: Cc1ccccc1N1CCN(c2cc(N(C)C)c(C(=O)NCCCN3CCCC3=O)cc2N)CC1
Reactant: O=C(Cl)c1ccco1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: Cc1ccccc1N1CCN(c2cc(N(C)C)c(C(=O)NCCCN3CCCC3=O)cc2NC(=O)c2ccco2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.4 %

Procedure:
To a solution of 5-amino-2-dimethylamino-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide 7c (91.7 mg, 0.19 mmol, 100 mol %) and N,N-diisopropylethylamine (0.10 ml, 0.58 mmol, 300 mol %) in dichloromethane (4.0 ml) was added furan-2-carbonyl chloride (0.02 ml, 0.23 mmol, 120 mol %) and a catalytic amount of N,N-dimethylaminopyridine. The reaction was stirred for 16 h at room temperature and then diluted with water and extracted three times with dichloromethane. The combined organics were dried over sodium sulfate and concentrated to a residue that was purified by column chromatography (dichloromethane to 10% methanol/dichloromethane) to afford furan-2-carboxylic acid [4-dimethylamino-5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide 7d (50.0 mg; 0.09 mmol, 45.6%) as an off-white solid.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH2:28]>C(O)C>[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH:28][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1
Reactant: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Reactant: CN(C)CCN
Solvent: CCO
Product: CCCOc1ccccc1-c1nc2nc(NCCN(C)C)ncc2c(=O)[nH]1

Procedure:
In a similar manner to Example 38, reaction of 7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.49 g) and N,N-dimethyl-ethylenediamine (1.24 g) in ethanol (20 ml) yielded the title compound, 0.46 g. m.p. 181-2° C. (recrystallized for methanol).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+].O>CC(C)=O>[C:17]([NH:11][C:9]1[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]([OH:16])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)c1cc(NC(=O)c2ccccc2)cc(C(C)(C)C)c1O
Reaction time: 1 h
Yield: 90.6 %

Procedure:
11.05 g (0.05 mole) 2,6-di-t-butyl-4-aminophenol is dissolved in 25 ml acetone and 7.03 g (0.05 mole) benzoyl chloride is added thereto. The reaction is exothermic. The mixture is shaken and 10 ml of 5 N sodium hydroxide is added thereto, portionwise, accompanied by agitation. A solid material separates and is allowed to stand for one hour, cooled and there is then added thereto 50 ml water. The mixture is filtered, washed with 50 ml water and then four times each time with 50 ml portions of petroleum ether to remove the red color. The solid material is air dried and there is obtained 14.72 g (a yield of 90.6%) of the 4-benzamido-2,6-di-t-butylphenol product. The solid material is dissolved in 100 ml of 90% ethanol, contacted with a charcoal adsorbent (Darco G-60) and then crystallized. The crystalline material is cooled, filtered, washed with 30 ml cold 90% ethanol and then dried in vacuo over phosphorus pentoxide. The pure product is characterized by a melting point of 209°-210° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(O)[O-].[Na+].[C-:16]#[N:17].[Na+]>O.C(O)C>[OH:10][CH:9]([CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:16]#[N:17]
Reactant: [C-]#N
Reactant: O=CCCc1ccccc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CC(O)CCc1ccccc1
Reaction time: 2 h
Yield: 47.1 %

Procedure:
3-Phenylpropionaldehyde (0.40 mole) was added dropwise to a solution of sodium bisulfite (0.80 mole) in 240 mL water and 50 mL 95% ethanol at room temperature over a 30 min period. A solution of sodium cyanide (0.40 mole) in 60 mL water was added dropwise to the stirred white suspension over a 20 min period at room temperature. After continuing stirring for an additional 2 hrs, the reaction mixture was extracted with ether (4×250 mL). The extracts were combined, dried (MgSO4) and concentrated in vacuo to give 30.4 g (47%) of 2-hydroxy-4-phenylbutyronitrile as a viscous pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][NH:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:7])=[CH:4][CH:3]=1.[CH2:17](O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:17]([O:13][C:12](=[O:14])[CH2:11][CH2:10][NH:9][NH:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:16][CH:15]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCc1ccccc1
Reactant: Nc1ccc(C(=O)NNCCC(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Nc1ccc(C(=O)NNCCC(=O)OCc2ccccc2)cc1

Procedure:
N-(p-Aminobenzamido)-β-alanine is reacted with benzyl alcohol and p-toluenesulphonic acid to give N-(p-aminobenzamido)-β-alanine benzyl ester, m.p. 96°-97° C.
Reaction SMILES: [OH:1][C@H:2]([CH3:21])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)=[O:4].[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[CH3:22][S:23]([O:1][C@H:2]([CH3:21])[C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:9][CH:10]=1)=[O:4])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(COc2ccc(C(=O)[C@@H](C)O)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(COc2ccc(C(=O)[C@@H](C)OS(C)(=O)=O)cc2)cc1
Reaction time: 0.33 h
Yield: 93 %

Procedure:
The compound (1.53 g, 5.34 mmol) synthesized in the above (3) was dissolved in dichloromethane (15 mL), and with cooling with ice, methanesulfonyl chloride (0.62 mL, 8.0 mmol) and triethylamine (1.11 mL, 8.0 mmol) were added in that order. The reaction solution was stirred for 20 minutes with cooling with ice. The reaction solution was poured into aqueous saturated sodium hydrogencarbonate solution, and extracted with chloroform. The organic layer was washed with aqueous saturated ammonium chloride solution and water in that order, then dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting pale yellow solid was washed with chloroform and n-hexane to obtain the entitled compound (1.8 g, 93%) as a white solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([OH:12])=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1.O>N1C=CC=CC=1>[C:16]([NH:15][CH2:14][CH2:13][CH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([NH:2][C:22]([CH:19]3[CH2:21][CH2:20]3)=[O:23])[C:11]=2[OH:12])[CH2:7][CH2:8]1)(=[O:18])[CH3:17]
Reactant: CC(=O)NCCC1CCc2ccc(N)c(O)c21
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NCCC1CCc2ccc(NC(=O)C3CC3)c(O)c21
Reaction time: 3 h
Yield: 106.7 %

Procedure:
N-[2-(6-Amino-7-hydroxy-2,3-dihydro-1H-inden-1-yl)ethyl]acetamide hydrochloride (100 mg, 0.369 mmol) was dissolved in pyridine (4 mL), cyclopropylcarbonyl chloride (36.8 μL, 0.406 mmol) was added under ice-cooling, and the mixture was stirred for 3 hr. Water was added to the reaction solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→95/5) to give the title compound (119 mg, yield 100%).
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH2:13](O)[C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1.O>CCCCCC>[CH3:1][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:13][C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1)=[O:10])[CH3:12]
Reactant: COc1cc(CO)ccc1O
Reactant: CC(C)CCCCCCC(=O)O
Solvent: CCCCCC
Solvent: O
Product: COc1cc(COC(=O)CCCCCCC(C)C)ccc1O
Temperature: 50 °C
Reaction time: 20 h
Yield: 97.5 %

Procedure:
8-Methylnonanoic acid (1.00 g, 5.80 mmol), vanillyl alcohol (851 mg, 5.52 mmol), and Novozym 435 (50 mg) were measured and placed in a flask (25 ml). The mixture in the flask free of a plug was heated with stirring in an oil bath at 50° C. for 20 hours. After 2 to 3 hours of stirring with heating, attachment of water on the wall of the upper part of the flask was observed. The reaction mixture was returned to room temperature, hexane (25 ml) was added, and Novozym 435 and a small amount of precipitated vanillyl alcohol were removed by filtration. Hexane (25 ml) was added to the filtrate, and the mixture was washed with 5% aqueous citric acid solution (25 ml) and saturated brine (25 ml), and dried over anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to give a mixture (1.66 g) of dihydrocapsiate and 8-methylnonanoic acid as a colorless oil. As a result of the analysis, the yield of dihydrocapsiate was 89.7%, and the purity was 99.5 area % by HPLC. The mixture contained 8.0 wt % of 8-methylnonanoic acid relative to dihydrocapsiate.
Reaction SMILES: [CH3:1][N:2]([C@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)C(OC(C)(C)C)=O.[CH:45]1([C:51](Cl)=[O:52])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>>[CH3:1][N:2]([C@H:10]1[CH2:14][C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:12]([CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:26][CH2:27]2)[CH2:11]1)[C:51]([CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1)=[O:52]
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](N(C)C(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Reactant: O=C(Cl)C1CCCCC1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](N(C)C(=O)C3CCCCC3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 31 in Step A and cyclohexanoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:15]([NH:17][C:18]2[S:19][C:20]([S:23]C#N)=[CH:21][N:22]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S[CH2:33][C@@H:34]([C@@H:36]([CH2:38][SH:39])O)O.Cl[CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:15]([NH:17][C:18]2[S:19][C:20]([S:23][CH2:41][CH2:42][N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)=[CH:21][N:22]=2)=[O:16])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4].[CH:26]1([N:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:6]([C:38]3[S:39][CH:33]=[CH:34][CH:36]=3)=[O:7])[CH2:9][CH2:10]2)[C:15]([NH:17][C:18]2[S:19][C:20]([S:23][CH2:41][CH2:42][N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)=[CH:21][N:22]=2)=[O:16])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)Nc2ncc(SC#N)s2)C2CCCCC2)CC1
Reactant: O[C@H](CS)[C@@H](O)CS
Reactant: ClCCN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC(N(C(=O)Nc2ncc(SCCN3CCOCC3)s2)C2CCCCC2)CC1
Product: O=C(c1cccs1)N1CCC(N(C(=O)Nc2ncc(SCCN3CCOCC3)s2)C2CCCCC2)CC1

Procedure:
4-{1-Cyclohexyl-3-[5-(2-morpholin-4-yl-ethylsulfanyl)-thiazol-2-yl]-ureido}-piperidine-1-carboxylic acid tert-butyl ester was prepared as described in general procedure (H) and (I) using 4-[1-cyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-ureido]-piperidine-1-carboxylic acid tert-butyl ester, dithioerythritol and N-(2-chloroethyl)-morpholine. Removal of the Boc group and N-acylation using thiophene-2 carboxylic acid as described in general procedure (G), steps 3 and 4 gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:13])[CH2:9][CH2:10][CH:11]=[O:12])=[CH:4][CH:3]=1.[CH2:14]([Mg]I)[CH2:15][CH3:16].S(=O)(=O)(O)O>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH2:9][CH2:10][CH:11]([OH:12])[CH2:14][CH2:15][CH3:16])=[CH2:13])=[CH:6][CH:7]=1
Reactant: CCC[Mg]I
Reactant: C=C(CCC=O)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: C=C(CCC(O)CCC)c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 77.5 %

Procedure:
A solution of 4-(4-chlorophenyl)pent-4-enal (2.0 g) in dry diethyl ether (25 ml) was added to a stirred solution of propylmagnesium iodide [from 1-iodopropane (2.72 g) and magnesium turnings (0.48 g)] in dry diethyl ether (50 ml) under an atmosphere of nitrogen (exotherm). After stirring for 1 hour the reaction mixture was poured into a mixture of ice and dilute sulphuric acid, then extracted with ether. The extracts were washed with water, dried over magnesium sulphate, and concentrated under reduced pressure to give 2-(4-chlorophenyl)-5-hydroxyoct-1-ene (1.9 g, 77%) as a yellow oil.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH3:7])[CH2:4][OH:5])[CH3:2].[H-].[Na+].[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15](F)[C:12]=1[C:13]#[N:14]>C1COCC1>[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([O:5][CH2:4][CH:3]([CH2:6][CH3:7])[CH2:1][CH3:2])[C:12]=1[C:13]#[N:14]
Reactant: N#Cc1c(N)cccc1F
Reactant: CCC(CC)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)COc1cccc(N)c1C#N
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
To a solution of 2-ethylbutan-1-ol (1.02 g, 10.0 mmol) in dry THF (60 mL) was carefully added NaH (60% in mineral oil, 480 mg, 12.0 mmol) in small portions at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. under nitrogen for 2 hrs. To this solution was added 2-amino-6-fluorobenzonitrile (1.36 g, 10.0 mmol), and the reaction solution was stirred at 0° C.-RT for 2 hrs, and then at 65° C. overnight under nitrogen. The reaction was cooled down to room temperature then quenched with brine, and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4. Filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: 20% EtOAc in hexanes) to give the title compound as colorless oil (1.29 g, 59%). 1H NMR (400 MHz, CDCl3) δ 0.93 (t, J=8 Hz, 6H), 1.55-1.43 (m, 4H), 1.73-1.65 (m, 1H), 3.90 (d, J=4 Hz, 2H), 4.10 (brs, 2H), 6.25 (d, J=8 Hz, 1H), 6.34 (d, J=8 Hz, 1H), 7.20 (t, J=8 Hz, 1H).
Reaction SMILES: Br.BrCCCN.FC1C=CC(C[N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=[C:16]2[NH:24]C2CCN(CCN=C=S)CC2)=CC=1.C(=O)([O-])[O-:37].[Na+].[Na+]>O1CCCC1>[OH2:37].[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[NH2:24]
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc(Cn2c(NC3CCN(CCN=C=S)CC3)nc3ccccc32)cc1
Agent: Br
Agent: NCCCBr
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc2ccccc2[nH]1
Product: O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2.2 parts of 3-bromo-1-propanamine hydrobromide, 4.1 parts of 1-[(4-fluorophenyl)methyl]-N-[1-(2-isothiocyanatoethyl)-4-piperidinyl]-1H-benzimidazol-2-amine, 2.2 parts of sodium carbonate and 135 parts of tetrahydrofuran was stirred overnight at room temperature. The reaction mixture was further stirred and refluxed for 3 hours. The mixture was filtered and the filtrate was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume), saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 2.5 parts of 1-[(4-fluoro-phenyl)methyl]-N-[1-[2-[(5,6-dihydro-4H-1,3-2-yl)amino]ethyl]-4-piperidinyl[-1H-benzimidazol-2-amine monohydrate; mp 121.4° C. (compound 117).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](F)=[C:6]([CH:19]=1)[C:7]([C:9](=[CH:15][N:16]([CH3:18])C)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8].N[C@@H:22]1[CH2:27]C[CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]1.C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CN(C=O)C>[Br:1][C:2]1[CH:19]=[C:6]2[C:5](=[N:4][CH:3]=1)[N:16]([C@@H:18]1[CH2:27][CH2:22][CH2:23][N:24]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:25]1)[CH:15]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:7]2=[O:8]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Br)cnc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cn([C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c2ncc(Br)cc2c1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
Ethyl 2-(5-bromo-2-fluoronicotinoyl)-3-(dimethylamino)acrylate (Intermediate 3, 2.0 g, 5.79 mmol), (R)-tert-butyl 3-aminopiperidine-1-carboxylate (1.160 g, 5.79 mmol, CNH technologies), and potassium carbonate (2.042 g, 7.38 mmol, Aldrich) were combined in THF (10.0 mL). The reaction was heated at 60° C. for 2 hrs. After 2 h, DMF (5.0 mL) was added. The reaction was heated at 90° C. for 14 h. The reaction mixture was cooled to 0° C. and 1N HCl was slowly added until pH was around 4. The resulting precipitate was filtered, washed with water and dried overnight to yield a light yellow solid (2.10 g, 75%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[CH:11]=[C:12]([OH:16])C=C[CH:15]=1.FC1C=C(O)C=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:12](=[O:16])[CH2:11][CH:10]([CH3:15])[O:8]2)=[CH:6][CH:7]=1
Reactant: Oc1cccc(Cl)c1
Reactant: Oc1cccc(Br)c1
Agent: Oc1cccc(F)c1
Product: CC1CC(=O)c2ccc(Br)cc2O1
Yield: 30 %

Procedure:
By the method of Preparations L1 and L2, and 3-bromophenol, 3-chlorophenol and 3-fluorophenol were converted, respectively, to 7-bromo-2-methylchroman-4-one (30% yield; oil); 7-chloro-2-methylchroman-4-one (35% yield; oil;
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:30]=[CH:29][C:8]([O:9][CH2:10][C:11](=[O:28])[CH:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:17][CH:16]=2)[CH3:13])=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH3:38][S:39]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11](=[O:28])[CH:12]([O:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[CH:19][CH:20]=2)[CH3:13])=[CH:29][CH:30]=1)(=[O:41])=[O:40]
Reactant: CC(Oc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)COc1ccc(CCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)COc1ccc(CCCOS(C)(=O)=O)cc1
Reaction time: 0.75 h
Yield: 97.8 %

Procedure:
A solution of (3R and 3S)-1-[4-(3-hydroxypropyl)phenoxy]-3-[4-(tert-butoxycarbonyl)phenoxy]-2-butanone (1.57 g, 3.8 mmol) in dry dichloromethane (25 ml) was cooled to 0-50° C. and treated with triethylamine (1.1 ml, 7.9 mmol) followed by methanesulfonyl chloride (0.5 mL, 6.46 mmol) added dropwise over 2 minutes. After 45 minutes at 0-5° C., the reaction mixture was quenched by addition of ethyl acetate and saturated sodium bicarbonate. The organic phase was washed with brine and dried (anhydrous magnesium sulfate) and evaporated. Chromatography of the residual oil on silica gel (elution toluene-ethyl acetate, 9:1) gave 1.83 g (97%) of the title material as an oil.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.[C-:28]#[N:29].[Na+].O>COCCOC>[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([O:13][CH:12]([C:11]2[CH:14]=[CH:15][CH:16]=[C:9]([C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)[C:28]#[N:29])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=Cc1cccc(C(=O)c2ccccc2)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)OC(C#N)c2cccc(C(=O)c3ccccc3)c2)cc1
Reaction time: 0.67 h
Yield: 66.8 %

Procedure:
m-Benzoylbenzaldehyde (4.20 g) and 3.80 g of p-toluenesulfonyl chloride were dissolved in 13 ml of 1,2-dimethoxyethane (DME), and the solution was stirred at -15° to -10° C. An aqueous solution of sodium cyanide (1.08 g/15 ml) was added dropwise to the solution over 10 minutes. The mixture was stirred at -15° to -10° C. for 2 hours and then at room temperature for 40 minutes. Water (60 ml) was added, and the mixture was extracted with 60 ml of methylene chloride three times. The extract was washed with 70 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (silica gel; benzene and methylene chloride) to afford 5.21 g (yield 67%) of O-(p-toluenesulfonyl)-m-benzoylmandelonitrile as colorless crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[NH:10][CH:11]=[N:12]2>C(O)(C)C>[N:1]1([C:8]2[N:16]=[CH:15][N:14]=[C:13]3[C:9]=2[NH:10][CH:11]=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CC(C)O
Product: c1nc(N2CCNCC2)c2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To an isopropanol solution (50 mL) of piperazine (5.57 g, 64.7 mmol), 6-chloropurine (1.00 g, 6.47 mmol) was added, followed by stirring at room temperature for 1.5 hours and then heating under reflux for 2.5 hours. The reaction solution was concentrated, saturated brine was added thereto, the mixture was extracted with chloroform and THF in that order, the extract was dried over anhydrous sodium sulfate, and then the solvent was evaporated to give the target compound. Thereafter, the water layer after extraction was allowed to stand, and then the precipitated crystals were recovered by filtration to give the target compound (1.07 g in total, 5.25 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[N:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][N:11]=2)[CH:5]=[C:6]([F:9])[C:7]=1Br.[Cu][C:22]#[N:23].CN1CCCC1=O.Cl>[Fe](Cl)(Cl)Cl.O>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[N:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][N:11]=2)[CH:5]=[C:6]([F:9])[C:7]=1[C:22]#[N:23]
Reactant: CCCCCc1cnc(-c2cc(F)c(Br)c(F)c2)nc1
Reactant: N#C[Cu]
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCCCc1cnc(-c2cc(F)c(C#N)c(F)c2)nc1
Yield: 42.4 %

Procedure:
0.7 g of 2-(3',5'-difluoro-4'-bromophenyl)-5-pentylpyrimidine, 0.5 g of copper (I) cyanide and 3.5 ml of N-methylpyrrolidone were mixed in a flask and refluxed for 5 hours. The solution was poured into a solution including 1.7 g of iron (III) chloride, 0.4 ml of concentrated hydrochloric acid and 1.7 ml of water. The solution was extracted with chloroform and washed with water and an aqueous 10% solution of potassium hydroxide. The chloroform was distilled off. The residue was treated through a silica gel column using chloroform as the solvent and recrystallized from methanol to yield 0.25 g of 2-(3',5'-difluoro-4'-cyanophenyl)-5-pentylpyrimidine. The crystal--isotropic liquid transfer point (C-I Point) of the compound was 65.3° C.