Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9](I)[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:12]([CH3:14])[CH3:13].[CH3:15][N:16](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:15]#[N:16])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)c1c[nH]c2c(I)cc(Br)cc12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)c1c[nH]c2c(C#N)cc(Br)cc12
Temperature: 90 °C
Yield: 76 %

Procedure:
To a stirred solution of 5-bromo-7-iodo-3-(1-methylethyl)-1H-indole (3.05 g, 8.38 mmol) in DMF (50 mL) was added zinc cyanide (0.52 g, 4.43 mmol) and tetrakis(triphenylphosphine)palladium (0.8 g, 0.692 mmol). The reaction was purged with N2, stirred and heated at 90° C. LCMS indicated that the reaction was complete. The reaction was evaporated to dryness under vacuum. Purification by silica gel chromatography (Analogix, SF25-60 g, 0 to 10% EtOAc in hexanes) and trituration with hexanes, filtering and drying under vacuum gave the product 5-bromo-3-(1-methylethyl)-1H-indole-7-carbonitrile (1.67 g, 6.35 mmol, 76% yield) as a light yellow solid. MS (ES)+ m/e 263.0 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([C:11](OC)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1)=O.[BH4-].[Na+].[Cl-:17].[Ca+2].[Cl-].O.C(O)C>C(O)C>[ClH:17].[OH:2][CH2:3][C:5]1[C:10]([CH2:11][OH:12])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: COC(=O)c1cccnc1C(=O)OC
Reactant: [Cl-]
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cl
Product: OCc1cccnc1CO
Temperature: 5 °C

Procedure:
To a solution of pyridine-2,3-dicarboxylic acid dimethyl ester (25.0 g, 128.1 mmol) in ethanol (183 mL) was added sodium borohydride (24.2 g, 640.5 mmol). The resulting mixture was cooled to 5° C. while stirring under argon. A solution of calcium chloride (12.6 g, 113.5 mmol) in ethanol (77 mL) was added dropwise while maintaining a temperature between 10° C. and 15° C. After addition, the resulting mixture was allowed to warm to room temperature over 16 h. A mixture of 4:1 water/ethanol (100 mL) added and the resulting mixture stirred 1 hr, then evaporated in vacuo to yield a white solid, which was finely ground with mortar and pestle. The fine powder was refluxed for 3 h in ethanol (450 mL), cooled to room temperature and filtered through dicalite. The filtrate was filtered through Nylon 66, 0.45-μ filter, then treated with anhydrous hydrogen chloride gas until solution was pH 2 while cooling on ice bath. A white precipitate was isolated and washed with ethyl ether and dried to yield (2-hydroxymethyl-pyridin-3-yl)-methanol hydrogen chloride as a white solid. C7H9NO2; MS (ESI) m/z 140.1 (MH)+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][N:13]1[C@H:27]2[C@@H:17]([C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:28]=3[C:25]([CH2:26]2)=[CH:24][NH:23]4)[CH2:16][C@@H:15]([CH2:29][OH:30])[CH2:14]1.N1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O>[S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)([O:30][CH2:29][C@@H:15]1[CH2:16][C@H:17]2[C@@H:27]([CH2:26][C:25]3[C:28]4[C:22](=[CH:21][CH:20]=[CH:19][C:18]2=4)[NH:23][CH:24]=3)[N:13]([CH3:12])[CH2:14]1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1C[C@H](CO)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cc1
Temperature: 0 °C
Yield: 86.2 %

Procedure:
5.0 g of p-toluenesulfonyl chloride was added in small portions to a mixture of 5.0 g of 6-methylergolin-8β-ylmethanol and 50 ml of pyridine while stirring, and the resulting mixture was stirred for 3 hours. After completion of the reaction, 4 ml of water was added to the mixture which was then stirred for 30 minutes. The mixture was diluted with ice-water, rendered alkaline with potassium carbonate and allowed to stand. The precipitated crystals were separated by filtration, washed with water and dried to obtain 6.9 g of the titled compound as colorless crystals. The crystals thus obtained were recrystallized from dichloromethane-isopropyl acetate to obtain colorless leaflets having a melting point of 195°-199° C. (with decomposition).
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C([O-])=[O:13].[Na+].O>CO>[OH:13][CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(O)C(=O)c1ccccc1
Yield: 62.8 %

Procedure:
To a solution of 2-bromo-1-phenylpropan-1-one (6.0 g, 28.2 mmol) in methanol (50 mL) was added sodium formate (7.66 g, 113 mmol) and the mixture was heated under reflux for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4:1) to give the title compound (2.66 g, yield 63%) as a colorless oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](=[S:11])[NH2:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:14][I:15]>CC(C)=O>[IH:15].[C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([S:11][CH3:14])=[NH:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(N)=S)cc1
Reactant: CI
Solvent: CC(C)=O
Product: CSC(=N)c1ccc(NC(C)=O)cc1
Product: I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2.7 g. (0.014 mole) of p-acetamidobenzthioamide in 100 ml. of acetone is added 2.6 ml. of methyl iodide, and the resulting reaction mixture allowed to stir at room temperature overnight. The intermediate product is filtered and dried, 4.4 g., m.p. 216°-217° C.
Reaction SMILES: [O:1]1[CH2:5][CH:2]1[CH:3]=[CH2:4].[C:6]([O:9]C(=O)C)(=[O:8])[CH3:7].C(N(CC)CC)C.[C:20](O)(=[O:22])[CH3:21]>COCCOCCOC>[C:6]([O:9][CH:2]([CH2:5][O:1][C:20](=[O:22])[CH3:21])[CH:3]=[CH2:4])(=[O:8])[CH3:7]
Reactant: CC(=O)O
Reactant: CC(=O)OC(C)=O
Reactant: C=CC1CO1
Solvent: CCN(CC)CC
Solvent: COCCOCCOC
Product: C=CC(COC(C)=O)OC(C)=O
Temperature: 125 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
A 300-mL autoclave was charged with 40 mL (0.50 mol) of 3,4-epoxy-1-butene, 62.2 g (0.61 mol) acetic anhydride, 1.8 g (0.018 mol) of triethylamine, 1.1 g (0.018 mol) acetic acid and 4.2 mL of diglyme. The autoclave was purged with nitrogen twice, then the vessel was pressurized to 8 bars (100 psig) with nitrogen. The agitator was started and an initial sample was taken. The mixture was heated to 125° C. During the course of 2 hrs, samples were taken every 15 min for analysis by GC. GC analysis of the crude mixture after 2 hrs revealed an 87% yield of 3,4-diacetoxy-1-butene with an 89% selectivity and 1.8% 3,4-epoxy-1-butene. The reaction was observed to be first order in 3,4-epoxy-1-butene with a first order rate constant of 0.024 min-1 (Table A). This example demonstrates the catalytic effect of the tertiary amine with acetic acid as the co-catalyst (Table B).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[CH2:7]=O.[CH:9](=[O:13])[CH:10]([CH3:12])[CH3:11].Cl.[OH-].[Na+]>>[CH3:11][C:10]([CH3:7])([CH:9]=[O:13])[CH2:12][N:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6]
Reactant: O=C1CCCN1
Reactant: C=O
Reactant: CC(C)C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C=O)CN1CCCC1=O
Reaction time: 8 h

Procedure:
In a round-bottom flask with a mounted reflux condenser and under nitrogen atmosphere, 40.0 g (0.48 mol) of 2-pyrrolidinone, 39.2 g (0.48 mol) of 36% aqueous formaldehyde, and 37.3 g (0.52 mol) of isobutyraldehyde were introduced while being stirred vigorously, mixed with 10.0 g of concentrated hydrochloric acid, whereby the mixture vigorously boiled up. After boiling had subsided, the mixture was heated to boiling in an oil bath (100° C.), and was kept boiling overnight. The clear, yellow reaction mixture was neutralized with 2N NaOH, extracted twice with ethyl acetate, the combined organic phases were washed with brine, dried on MgSO4, and completely concentrated by evaporation in a rotary evaporator. The dark-yellow oil that was obtained was fractionated in a vacuum. The product distilled at an overhead temperature of 71° C. and a pressure of 2·10−2 mbar. Yield: 14.8 g (19% of theory) of a colorless and almost odorless liquid.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[N:4]=[C:5]([NH:8][C:9]2[N:14]=[CH:13][C:12]([CH:15]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)O)=[CH:11][C:10]=2[S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[S:6][CH:7]=1.O.CC1C=CC(S(O)(=O)=O)=CC=1.Cl>C1(C)C=CC=CC=1>[ClH:1].[CH3:2][C:3]1[N:4]=[C:5]([NH:8][C:9]2[C:10]([S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:11][C:12]([CH:15]=[C:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][N:14]=2)[S:6][CH:7]=1
Reactant: Cc1csc(Nc2ncc(C(O)C3CCOCC3)cc2Sc2ccccc2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1csc(Nc2ncc(C=C3CCOCC3)cc2Sc2ccccc2)n1
Temperature: 25 °C
Yield: 35 %

Procedure:
A 10 mL round-bottomed flask was charged with (6-(4-methylthiazol-2-ylamino)-5-(phenylthio)pyridin-3-yl)(tetrahydro-2H-pyran-4-yl)methanol hydrochloride (125 mg, 0.278 mmol), 4-methylbenzenesulfonic acid hydrate (5.28 mg, 0.0278 mmol), Toluene (5 mL) and heated to reflux in dean stark trap for 24 7 hours. The reaction was cooled to ambient temperature and partitioned between saturated aqueous sodium bicarbonate and CH2Cl2. The organic layer was dried with sodium sulfate, filtered and concentrated. The residue was purified on silica gel (25% EtOAc in hexanes) to afford the title compound (42 mg, 35.0% yield) as after HCl salt formation. 1H NMR (CDCl3) δ 12.24 (bs, 1H), 8.18 (m, 1H), 7.71 (m, 1H), 7.54 (m, 2H), 7.30 (m, 3H), 6.40 (s, 1H), 6.20 (s, 1H), 3.78 (t, 2H), 3.65 (t, 2H), 2.45 (s, 3H), 2.42 (m, 4H). Mass spectrum (apci) m/z=396.2 (M+H—HCl).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:34])=[C:19]([NH:21][C:22]([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[N:30]=[CH:29][CH:28]=[CH:27]3)=[O:23])[CH:20]=1>C(N(CC)CC)C>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([CH3:34])=[C:19]([NH:21][C:22]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[CH:29][CH:28]=[CH:27]4)=[O:23])[CH:20]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(N)cc1NC(=O)c1ccc2ncccc2c1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2ccc(C(F)(F)F)cc2)cc1NC(=O)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52 %

Procedure:
Using an analogous procedure to that described in Example 4, 4-trifluoromethylbenzoyl chloride was reacted with N-(5-amino-2-methylphenyl)-quinoline-6-carboxamide in the presence of triethylamine. The reaction mixture was stirred at ambient temperature for 18 hours and then evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained the title compound in 52% yield; Mass Spectrum: M+H+ 450.
Reaction SMILES: [CH2:1]([S:4]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])(=[O:6])=[O:5])[CH:2]=C.[Cl:17]Cl.[CH:19]([Cl:22])(Cl)Cl>>[Cl:17][CH:2]([CH2:19][Cl:22])[CH2:1][S:4]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])(=[O:6])=[O:5]
Reactant: C=CCS(=O)(=O)Oc1ccccc1[N+](=O)[O-]
Reactant: ClC(Cl)Cl
Reactant: ClCl
Product: O=[N+]([O-])c1ccccc1OS(=O)(=O)CC(Cl)CCl
Yield: 80.3 %

Procedure:
To a solution of 24.3 g of 2-nitrophenyl 2-propenesulfonate in 80 ml of chloroform was added 7.1 g of chlorine absorbed in 20 ml of chloroform dropwise with stirring below 0°C. After the addition, the mixture was stirred for two hours at room temperature. By distillation of the solvent and fractionation, 25.2 g of 2-nitrophenyl 2,3-dichloropropanesulfonate, B.P 167°-169°C/0.015 mmHg, was obtained in a yield of 80.3%.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8](O)=[C:7]([CH3:13])[C:6]=1[CH3:14])(=[O:3])[CH3:2].[CH3:15][C:16](=C)[CH2:17]O.C=O.[C:22]([OH:25])(=[O:24])[CH3:23]>>[CH3:23][C:22]1([OH:25])[CH:16]([CH3:17])[CH2:15][C:9]2[C:8](=[C:7]([CH3:13])[C:6]([CH3:14])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[C:10]=2[CH3:11])[O:24]1
Reactant: CC(=O)Oc1c(C)cc(O)c(C)c1C
Reactant: CC(=O)O
Reactant: C=C(C)CO
Agent: C=O
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CC(C)C(C)(O)O2
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A pressure-proof reaction vessel equipped with a stirrer was charged with 17.5 g (0.09 mole) of 4-acetoxy-2,3,5-trimethylphenol, 32.5 g (0.45 mole) of 2-methyl-2-propen-1-ol, 3.7 g (0.099 mole) of 80% paraformaldehyde and 2.7 g (0.045 mole) of acetic acid, and the mixture was reacted, with stirring, at 150° C. for 3 hours. However, the desired product 2,5,7,8-tetramethyl-6-acetoxy-2-hydroxy-methylchroman could not be obtained at all.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[CH3:17][N:18]([CH3:21])C=O>>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][O:7][C:1]1[CH:6]=[CH:5][C:4]([CH2:3][C:2]2[CH:17]=[N:18][CH:21]=[CH:6][CH:1]=2)=[CH:3][CH:2]=1)[CH3:16]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccccc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)COc1ccc(Cc2cccnc2)cc1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
A mixture of 0.70 g of the phenol compound(prepared as described in Example 9), 0.30 g of sodium hydride (content 63%) and 14 ml of N,N-dimethylformamide was stirred at 100° C. for 20 minutes, and stirred with 0.64 g of ethyl bromoacetate at 70° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water, and extracted with diethyl ether. The extract was washed with water, and a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a 0.5% V/V solution of ethanol in chloroform as eluent to give 0.166 g of the title compound having the following physical characteristics:
Reaction SMILES: O[C:2]1([OH:20])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:16]([O-:18])=[O:17])[C:8]=2[NH:12][C:13](=[O:15])[CH3:14])[C:3]1=[O:19].[Se]=O.CC(O)=O.[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1)([CH3:29])[CH3:28]>O1CCOCC1>[OH:20][C:2]1([C:33]2[CH:34]=[CH:35][C:30]([CH:27]([CH3:29])[CH3:28])=[CH:31][C:32]=2[O:36][CH3:37])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:16]([O-:18])=[O:17])[C:8]=2[NH:12][C:13](=[O:15])[CH3:14])[C:3]1=[O:19]
Reactant: COc1cccc(C(C)C)c1
Reactant: CC(=O)Nc1c([N+](=O)[O-])ccc2c1C(=O)C(O)(O)C2=O
Agent: O=[Se]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COc1cc(C(C)C)ccc1C1(O)C(=O)c2ccc([N+](=O)[O-])c(NC(C)=O)c2C1=O
Reaction time: 12 h
Yield: 14 %

Procedure:
N-(2,2-dihydroxy-5-nitro-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide (2.60 g, 11.1 mmol) was completely dissolved in anhydrous dioxane (20 ml). This solution was added with selenium oxide (2.70 g, 24.4 mmol) and AcOH (1.5 ml). The reaction mixture was heated for 7 hrs under reflux. After filtration at high temperature, the filtrate was concentrated to afford 1.79 g (100%). Trifluoroacetic solution of the resulting product was added with isopropyl-3-methoxybenzene (1.66 g, 11.1 mmol), followed by stirring for 12 hrs. The remainder was extracted with ethyl acetate, and concentrated organic layer was purified using column chromatography (ethylacetate 100%) to afford the title compound (0.64 g, 14%).
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[Na+].[Cl:31][C:32]1[CH:33]=[CH:34][C:35]2[N:36]([N:38]=[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:40]=2)[N:37]=1>O1CCCC1>[ClH:31].[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([N:38]=[C:39]([C:41]5[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=5)[N:40]=4)[N:37]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Clc1ccc2nc(-c3ccccc3)nn2n1
Reactant: OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cl
Product: c1ccc(-c2nc3ccc(OCCCN4CCC(OC(c5ccccc5)c5ccccc5)CC4)nn3n2)cc1
Temperature: 0 °C
Yield: 44 %

Procedure:
4-(Diphenylmethoxy)-1-piperidinepropanol (487 mg) was dissolved in dried tetrahydrofuran (10 ml), followed by addition of sodium t-butoxide (144 mg). The mixture was refluxed under heating for 40 minutes. After the mixture was cooled, 6-chloro-2-phenyl[1,2,4]triazolo[1,5-b]pyridazine (315 mg) was added thereto. This mixture was refluxed under heating for 4 hours. After the mixture was cooled, ice-water was added thereto, followed by extraction with a mixture of ethyl acetate and tetrahydrofuran (2:1). The extract was washed with an aqueous sodium chloride saturated solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with a mixture of ethyl acetate and methanol (10:1). Fractions containing the objective compound were collected, concentrated and dissolved in ethyl acetate (10 ml), followed by addition of 4N HCl in ethyl acetate solution (0.25 ml) and concentrated under reduced pressure. The resulting crystals were recrystallized from ethanol to yield the title compound (0.334 g).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:10][O:11][C:12]1[CH:23]=[CH:22][C:15]([C:16]([O:18][CH2:19][CH2:20]Cl)=[O:17])=[CH:14][CH:13]=1>>[CH3:10][O:11][C:12]1[CH:23]=[CH:22][C:15]([C:16]([O:18][CH2:19][CH2:20][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[C:2]2[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:17])=[CH:14][CH:13]=1
Reactant: COc1ccc(C(=O)OCCCl)cc1
Reactant: c1ccc2[nH]cnc2c1
Product: COc1ccc(C(=O)OCCn2c(-c3ccccc3)nc3ccccc32)cc1
Yield: 71 %

Procedure:
The procedure of Synthesis Example 10 was repeated except that benzimidazole was used instead of the 1-aza-18-crown-6, and 2-chloroethyl 4-methoxybenzoate was used instead of the 2-chloroethyl benzoate, to give 2-(2-phenyl-1H-benzimidazol-1-yl)ethyl 4-methoxybenzoate in a yield of 71%.
Reaction SMILES: C([Li])CCC.Cl.Br[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.CCOCC.[O:19]=[C:20]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]1>CCCCCC>[OH:19][C:20]1([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]1
Reactant: Brc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccncc2)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1.600 M of n-Butyllithium in hexane (0.810 mL) was added to a solution of 4-bromopyridine hydrochloride (210 mg, 1.1 mmol) in ether (5 mL, 0.05 mol) at −78° C. The solution was stirred at −78° C. for 30 min. and then tert-butyl 3-oxopyrrolidine-1-carboxylate (200 mg, 0.001 mol) was added and the temperature was maintained at −78° C. for 3 hours. The reaction mixture was quenched with water, extracted with AcOEt. The organic layer was dried with MgSO4, and concentrated to afford the desired product.
Reaction SMILES: [C:1](#[N:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:7]([CH2:9]N)[OH:8]>O.O.C([O-])(=O)C.[Cd+2].C([O-])(=O)C>[CH2:2]([C:1]1[O:8][CH2:7][CH2:9][N:6]=1)[CH2:3][CH2:4][CH3:5]
Reactant: NCCO
Reactant: CCCCC#N
Agent: CC(=O)[O-]
Agent: [Cd+2]
Solvent: O
Product: CCCCC1=NCCO1
Temperature: 124 °C
Reaction time: 48 h

Procedure:
A mixture of about 83.1 grams (1.00 mole) valeronitrile, about 64.8 grams (1.05 mole) ethanolamine, and about 6.2 grams (0.025 mole) cadmium acetate dihydrate is heated at about 124 degrees C. to about 128 degrees C. and stirred under nitrogen for about two days. The product is then distilled under vacuum. The fraction boiling at about 67 degrees C. to about 75.5 degrees C. at about 28 mmHg is collected.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23]1=[CH:27][C:28]([O:32][CH2:33][CH:34]3[CH2:39][O:38][CH2:37][CH2:36][O:35]3)=[N:29][C:30](=[O:31])[N:22]1[CH2:21][CH2:20]2)=O)(C)(C)C>C1COCC1.CN(C=O)C>[O:35]1[CH2:36][CH2:37][O:38][CH2:39][CH:34]1[CH2:33][O:32][C:28]1[CH:27]=[C:23]2[C:24]3[C:19]([CH2:20][CH2:21][N:22]2[C:30](=[O:31])[N:29]=1)=[CH:18][C:17]([C:9]1[NH:8][C:16]2[C:11]([CH:10]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:26][CH:25]=3
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc3c(c2)CCn2c-3cc(OCC3COCCO3)nc2=O)cc2ccccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=c1nc(OCC2COCCO2)cc2n1CCc1cc(-c3cc4ccccc4[nH]3)ccc1-2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Compound 12 (57 mg, 0.11 mmol) was dissolved in a mixture of DCM/TFA (1/1, 2 mL) and the reaction was stirred at RT for 6 h. The mixture was evaporated to dryness to recover compound 13 as a TFA salt.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[CH:22]=[CH:23][C:24]2[N:25]([C:27]([S:30][CH3:31])=[N:28][N:29]=2)[N:26]=1>>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:27]([S:30][CH3:31])=[N:28][N:29]=3)[N:26]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: CSc1nnc2ccc(Cl)nn12
Product: CSc1nnc2ccc(N3CCN(C(c4ccccc4)c4ccccc4)CC3)nn12

Procedure:
A mixture of 1-benzhydrylpiperazine and 6-chloro-3-methylsulfanyl-1,2,4-triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 2 to give 6-(4-benzhydrylpiperazin-1-yl)-3-methylsulfanyl-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[C:5]([F:14])[CH:4]=1.[B:15](OC)([O:18]C)[O:16]C.Cl>C1COCC1.C(OCC)(=O)C>[F:14][C:5]1[CH:4]=[C:3]([B:15]([OH:18])[OH:16])[CH:8]=[CH:7][C:6]=1[O:9][C:10]([F:13])([F:12])[F:11]
Reactant: Fc1cc(Br)ccc1OC(F)(F)F
Reactant: COB(OC)OC
Agent: Cl
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OB(O)c1ccc(OC(F)(F)F)c(F)c1
Temperature: 55 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
Well-dried magnesium (3.05 g) and THF (20.0 ml) were put in a reaction vessel under a nitrogen atmosphere, and heated to 55° C. Then, 1-bromo-3-fluoro-4-trifluoromethoxybenzene (T-13; 25.0 g) dissolved in THF (100 ml) was slowly added dropwise thereto in the temperature range of 47° C. to 60° C., and stirred for additional 60 minutes. The obtained Grignard reagent was added dropwise to trimethyl borate (14.0 g) in a THF (100 ml) solution in the temperature range of −74° C. to −65° C., and stirred for additional 180 minutes while allowing temperature to come to 25° C. After the reaction mixture had been cooled to −30° C., 6N-hydrochloric acid (90 ml) was slowly added dropwise and stirred for additional 180 minutes while temperature was allowed to come to 25° C. Then, the reaction mixture was poured into a vessel containing ice-water (250 ml) and 3,000 ml, and mixed. Ethyl acetate (300 ml) was added to separate the mixture into organic and aqueous layers, and an extraction operation was carried out. The obtained organic layer was fractionated, washed sequentially with water, a saturated aqueous solution of sodium bicarbonate and brine, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, whereby 11.7 g of 3-fluoro-4-trifluoromethoxy phenylboronic acid (T-14) was obtained. The yield based on the compound (T-13) was 54%.