Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([N:9]([CH2:21][C:22]#[C:23][C:24]2[CH:41]=[CH:40][C:27]([CH2:28][NH:29][C:30](=[O:39])[O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:26][CH:25]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[O:19][CH3:20])=[O:8])[NH:5][CH:6]=1.C([O-])(=O)C.[Na+]>CN(C)C=O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:7](=[O:8])[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=3[O:19][CH3:20])[CH:21]=[C:22]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([CH2:28][NH:29][C:30](=[O:39])[O:31][CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:40][CH:41]=3)[N:5]2[CH:6]=1
Reactant: COc1ccc(CN(CC#Cc2ccc(CNC(=O)OCc3ccccc3)cc2)C(=O)c2cc(Br)c[nH]2)c(OC)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(Cc3ccc(CNC(=O)OCc4ccccc4)cc3)n3cc(Br)cc3c2=O)c(OC)c1
Temperature: 120 °C

Procedure:
To a solution of EXAMPLE 37B (21.0 g, 34 mmol) in N,N-dimethylformamide (900 ml) was added sodium acetate (2.81 g, 34 mmol), tetrabutyl ammonium chloride (9.51 g, 34 mmol) and palladium(II) acetate (767 mg, 3.4 mmol). The mixture was heated at 120° C. for 30 minutes. After cooling, the reaction mixture was partitioned between ethyl acetate and brine. The organic phase was washed with water, and concentrated. The residue was purified by flash chromatography (50% ethyl acetate in hexane) to afford the title compound. LC-MS (ESI): m/z 616, 618 (M, M+2), RT: 2.38 minutes.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:5][C:6]([O:8]C(C)(C)C)=[O:7].N1C(C)=CC=CC=1C.[Si:29](OS(C(F)(F)F)(=O)=O)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].[Cl-].[NH4+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[C@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]([O:8][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])=[O:7]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)O[Si](C)(C)C(C)(C)C
Reaction time: 0.25 h

Procedure:
To a methylene chloride solution (1.0 ml) of N-t-butoxycarbonyl-L-phenylalanine methyl ester (139.5 mg, 0.5 mmol) and 2,6-lutidine (0.116 ml, 1.0 mmol), t-butyldimethylsilyltrifluoromethane sulfonate (TBDMSOTf) (0.172 ml, 0.75 mmol) was added dropwise at room temperature in a nitrogen atmosphere. After the mixture was stirred for 15 minutes, a saturated aqueous solution of ammonium chloride (2 ml) was added to quench the reaction and extraction with ether was conducted. The organic layer was dried over anhydrous magnesium sulfate and filtered. By distilling off the solvent, the titled compound was obtained in an amount of 186.8 mg.
Reaction SMILES: Cl(O)(=O)(=O)=O.C(O)C.[CH:9]1([C:12]2(N3CCCC3)[O:16][N:15]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:13]2)[CH2:11][CH2:10]1>O>[CH:9]1([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:13]=2)[CH2:11][CH2:10]1
Reactant: c1cncc(C2=NOC(C3CC3)(N3CCCC3)C2)c1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: CCO
Product: c1cncc(-c2cc(C3CC3)on2)c1

Procedure:
A solution containing 1.43 g. of perchloric acid (70%) in 5 ml. of absolute ethanol is added dropwise with stirring to a solution of 2.57 g. of 3-[5-cyclopropyl-5-(1-pyrrolidinyl)-2-isoxazolin-3-yl]-pyridine in 25 ml. of absolute ethanol. The resulting solution is diluted with 25 ml. of water and then heated vigorously on a steam bath for 0.5 hours. The hot solution is poured directly onto 200 g. of ice. The precipitate is collected by filtration, washed well with water and air dried. This gives a white solid, melting point 72°-75°C. and the nmr spectrum δ6.82 (DMSO-d6, s, 4-isoxazolyl H).
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[C:7]([CH3:9])[N:8]=1)=[N+:2]=[N-:3].C(N(CC)C(C)C)(C)C.[C:29]([O:33][CH2:34][CH3:35])(=[O:32])[C:30]#[CH:31]>O1CCCC1.[Cu]I>[CH2:13]([NH:12][C:10]([C:6]1[S:5][C:4]([N:1]2[CH:31]=[C:30]([C:29]([O:33][CH2:34][CH3:35])=[O:32])[N:3]=[N:2]2)=[N:8][C:7]=1[CH3:9])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1nc(N=[N+]=[N-])sc1C(=O)NCc1ccccc1
Reactant: C#CC(=O)OCC
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(-c2nc(C)c(C(=O)NCc3ccccc3)s2)nn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
To a solution of 2-azido-N-benzyl-4-methylthiazole-5-carboxamide (1.00 g, 3.67 mmol) in tetrahydrofuran (30 mL) was added copper(I) iodide (0.70 g, 3.67 mmol), N,N-diisopropylethylamine (1.28 mL, 7.32 mmol) and ethyl propiolate (0.45 g, 4.58 mmol). The reaction mixture was stirred at ambient temperature for 18 hours and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate:petroleum ether, 1:1) to afford the title compound as a white solid in 61% yield (0.83 g): 1H NMR (300 MHz, CDCl3) δ 8.87 (s, 1H), 7.36-7.26 (m, 5H), 6.17 (br s, 1H), 4.63 (d, J=6.0 Hz, 2H), 4.47 (q, J=6.0 Hz, 2H), 2.70 (s, 3H), 1.42 (t, J=6.0 Hz, 3H); MS (ES+) m/z 372.3 (M+1).
Reaction SMILES: [NH4+:1].[Cl:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]([O:19][CH3:20])=[C:13]([S:15](Cl)(=[O:17])=[O:16])[CH:14]=1)=[O:8]>O1CCCC1>[Cl:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]([O:19][CH3:20])=[C:13]([S:15]([NH2:1])(=[O:17])=[O:16])[CH:14]=1)=[O:8]
Reactant: COc1ccc(C(=O)CCCCCl)cc1S(=O)(=O)Cl
Reactant: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CCCCCl)cc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 25% aqueous ammonium solution was added dropwise to a solution of 5-(5-chloropentanoyl)-2-methoxybenzenesulfonyl chloride (3.00 g) obtained in Reference Example 65 in tetrahydrofuran (50 ml) under ice-cooling. After stirring at room temperature for 30 minutes, the solvent was evaporated under reduced pressure, extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as colorless crystals (2.54 g) having a melting point of 135 to 136° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[NH:5][CH3:6].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(#N)C>[CH2:11]([N:5]([CH3:6])[C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[C:8]([Cl:10])[CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: CNc1cc(Cl)cc(Cl)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(Cc1ccccc1)c1cc(Cl)cc(Cl)c1

Procedure:
The mixture of 3,5-dichloro-N-methylaniline (345 mg) and excess amount of benzyl bromide and triethylamine in acetonitrile (7 ml) was refluxed for 4 hours. The reaction mixture was separated with ethyl acetate and water, and the organic layer was washed with water, dried and concentrated in vacuo to give N-benzyl-3,5-dichloro-N-methylaniline (532 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]([NH:22][C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1)=[O:21])[C:6]([CH2:8]P(=O)(OC)OC)=[O:7].[N:32]1[CH:37]=[CH:36][C:35]([CH:38]=O)=[CH:34][CH:33]=1.[OH-].[Na+].C(O)(=O)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6](=[O:7])[CH:8]=[CH:38][C:35]2[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]([NH:22][C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1)=[O:21]
Reactant: O=Cc1ccncc1
Reactant: COc1cc(C(=O)CP(=O)(OC)OC)ccc1OCC(=O)Nc1nc2ccccc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc(C(=O)C=Cc2ccncc2)ccc1OCC(=O)Nc1nc2ccccc2s1
Reaction time: 5 h
Yield: 79.7 %

Procedure:
To a solution of dimethyl {[3-methoxy-4-(2-benzothiazolylaminocarbonylmethoxy)benzoyl]methyl}phosphonate (1.7 g) and pyridine-4-aldehyde (0.5 g) in tetrahydrofuran (30 ml) is added a 5% aqueous sodium hydroxide solution (6 ml) under ice-cooling, and the mixture is stirred for 5 hours. The mixture is neutralized with acetic acid, and the precipitated crystals are collected by filtration, and then recrystallized from dichloromethane-ethanol-diethyl ether to give 2-{2-methoxy-4-[3-(4-pyridyl)acryloyl]phenoxymethylcarbonylamino}benzothiazole (1.3 g).
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[C:12]([O:17][CH:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26]C2CCCCO2)=[CH:22][CH:21]=1)[CH3:19])(=[O:16])[CH2:13][CH2:14][CH3:15]>CO>[C:12]([O:17][CH:18]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[CH3:19])(=[O:16])[CH2:13][CH2:14][CH3:15]
Reactant: CCCC(=O)OC(C)c1ccc(OC2CCCCO2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CCCC(=O)OC(C)c1ccc(O)cc1
Yield: 11 %

Procedure:
In 150 ml of methanol was dissolved 0.1 mole of the R-form of 1-(4-(tetrahydro-2-pyranyloxy)phenyl)ethyl butyrate, to which 1.1 g of pyridinum, p-toluenesulfonate, and the mixture was subjected to reaction at room temperature for 2 hours. Then, methanol was distilled under reduced pressure, 200 ml of ether was added thereto, and it was washed with water. The resulting ether layer was dried with anhydrous magnesium sulfate, and ether was distilled under reduced pressure to give R-form of 1-(4-hydroxyphenyl)ethyl butyrate (yield: 11%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[OH-].[Na+].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:21])=[O:20])[CH:9]=[CH:10][C:3]=12
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Brc1ccnc2[nH]ccc12
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1ccc2c(Br)ccnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-1H-pyrrolo[2,3-b]pyridine (6.9 g, prepared according to the method described in Organic Letters, 2003, vol. 5, 5023-5025) and benzyltriethylammonium chloride (210 mg) in methylene chloride (150 mL), sodium hydroxide (4.3 g) and benzenesulfonyl chloride (5.5 mL) were added under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour and filtered through “Celite” (registered trademark), and the filtrate was concentrated. The resulting residue was purified by a purification system CombiFlash CompanionXL (manufactured by Isco, Co., Ltd., column: RediSep 120 g; hexane:ethyl acetate=95:5→60:40) to obtain the title compound (9.8 g) having the following physical properties.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:24])[C:10]1[C:15]([S:16][CH3:17])=[CH:14][C:13]([C:18]([F:21])([F:20])[F:19])=[CH:12][C:11]=1[O:22][CH3:23].[C:25]1(=O)[CH2:28][CH2:27][CH2:26]1>>[CH:25]1([NH:1][C@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[NH:8][C:9](=[O:24])[C:10]2[C:15]([S:16][CH3:17])=[CH:14][C:13]([C:18]([F:20])([F:21])[F:19])=[CH:12][C:11]=2[O:22][CH3:23])[CH2:28][CH2:27][CH2:26]1
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)N[C@@H]1CCCC[C@@H]1N
Reactant: O=C1CCC1
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)N[C@@H]1CCCC[C@@H]1NC1CCC1

Procedure:
The title compound, colorless amorphous, MS: m/e=417.2 [(M+H)+], was prepared in accordance with the general method of example 11 from cis-N-(2-amino-cyclohexyl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide (intermediate I) and cyclobutanone.
Reaction SMILES: [ClH:1].[CH2:2]([N:9]1[C:16](=[O:17])[C@@H:15]2[C@@H:11]([CH2:12][N:13](CC3C=CC=CC=3)[CH2:14]2)[C:10]1=[O:25])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N#N>CO.O.[Pd]>[ClH:1].[CH2:2]([N:9]1[C:10](=[O:25])[C@@H:11]2[C@@H:15]([CH2:14][NH:13][CH2:12]2)[C:16]1=[O:17])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1[C@H]2CN(Cc3ccccc3)C[C@H]2C(=O)N1Cc1ccccc1
Agent: [Pd]
Agent: Cl
Agent: N#N
Solvent: O
Solvent: CO
Product: O=C1[C@H]2CNC[C@H]2C(=O)N1Cc1ccccc1
Reaction time: 12 h
Yield: 82 %

Procedure:
Concentrated hydrochloric acid (28.4 mL, 341 mmol) was added to a suspension of 3,7-dibenzyl-3,7-diazabicyclo[3.3.0]octan-2,4-dione (109.0 g, 341 mmol; from step (a) above) in CH3OH under a N2 atmosphere. To the resulting solution there was added 10% Pd/C (w/w; 5 g). The N2 atmosphere was exchanged for H2 (1 atm of pressure) and the reaction was stirred for 12 h. The reaction was diluted with H2O (160 mL), filtered through a pad of cellulose to remove the catalyst and the filtrate concentrated in vacuo to afford a solid. Triturating with absolute EtOH afforded 74.6 g (82%) of the sub-title compound as an off-white solid after drying in a vacuum oven at 50° C./66.5 Pa (0.5 mm Hg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13][C:12]=2[CH2:11]1.N1C=CN=C1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C)C=O>[Si:26]([O:20][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[NH2:1])[CH2:19][CH2:18]2)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: COc1ccc(C2CCc3cc(O)ccc3C2)c(N)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc(C2CCc3cc(O[Si](C)(C)C(C)(C)C)ccc3C2)c(N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
To a solution of 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (850 mg) in N,N-dimethylformamide (10 ml) were sequentially added imidazole (500 mg) and tert-butyldimethylsilyl chloride (480 mg), and the solution was stirred for 1 hour at room temperature. The solution ws extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (805 mg).
Reaction SMILES: Br[C:2]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[Li]C(C)(C)C.[B:19](OCCCC)([O:25]CCCC)[O:20]CCCC>CCOCC>[CH:11]([C:10]1[CH:9]=[CH:8][C:7]2[NH:6][N:5]=[CH:4][C:3]=2[C:2]=1[B:19]([OH:25])[OH:20])([CH3:13])[CH3:12]
Reactant: CCCCOB(OCCCC)OCCCC
Reactant: CC(C)c1ccc2[nH]ncc2c1Br
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CC(C)c1ccc2[nH]ncc2c1B(O)O
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of 4-bromo-5-isopropyl-1H-indazole (1.6 g, 6.9 mmol) in Et2O (4 mL) is added slowly to a suspension of KH (1.0 g of 30% dispersion in mineral oil, 7.7 mmol) in Et2O (20 mL) at 0° C. and the mixture is stirred for 20 min. After cooling to −78° C., t-BuLi (8.9 mL of 1.7 M in Hex, 15 mmol) is added and the resulting mixture is stirred for 40 min at −78° C. To this is added B(On-Bu)3 (5.6 mL, 21 mmol) and the mixture is stirred for 24 h at room temperature. The reaction mixture is quenched with 1N H3PO4 and extracted with Et2O. The combined Et2O layers are back-extracted with 1N NaOH (3×10 mL). The combined NaOH extracts are acidified with 1N H3PO4 and extracted with EtOAc. The EtOAc extracts are washed with saturated brine, dried (MgSO4), and concentrated to yield 5-isopropyl-1H-indazole-4-boronic acid. 1H NMR (CDCl3) 7.85 (s, 1H), 7.42 (d, 1H), 7.37 (d, 1H), 3.6 (br s, 2H), 2.88 (m, 1H), 1.32 (d, 6H).
Reaction SMILES: Cl.[N:2]1([CH:7]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)[CH2:8][CH2:9][CH3:10])[CH:6]=[CH:5][N:4]=[CH:3]1.Cl.[CH3:21]O>>[CH3:21][O:16][C:15](=[O:17])[C:14]1[CH:18]=[CH:19][C:11]([CH:7]([N:2]2[CH:6]=[CH:5][N:4]=[CH:3]2)[CH2:8][CH2:9][CH3:10])=[CH:12][CH:13]=1
Reactant: CO
Reactant: CCCC(c1ccc(C(=O)O)cc1)n1ccnc1
Agent: Cl
Product: CCCC(c1ccc(C(=O)OC)cc1)n1ccnc1

Procedure:
1.0 of 4-[1-(1-imidazolyl)-butyl]-benzoic acid, hydrochloride (of example 2) is dissolved in 30 ml of methanol, hydrochloric-acid gas is introduced for 10 minutes, refluxed for 30 minutes and concentrated by evaporation. The residue is distilled on a bulb tube, boiling point 190° C./0.03 mbar. 0.55 g of 4-[1-(1-imidazolyl)-butyl]-benzoic acid methyl ester is obtained.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[NH:20][C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:23]OS(=O)(=O)OC.CO>CN(C=O)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:20]([CH3:23])[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COCCCc2nc3cccnc3[nH]2)cc1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1c(CCCOCc2ccccc2)nc2cccnc21

Procedure:
Under an argon atmosphere, to a solution of 2-[3-(benzyloxy)propyl]-3H-imidazo[4,5-b]pyridine (2 g) in DMF (40 mL) was added 60% sodium hydride (0.299 g), and the mixture was stirred under ice-cooling for 30 min. Then, dimethylsulfuric acid (0.75 mL) was added, and the mixture was stirred at room temperature for 17 hr. To the reaction mixture was added methanol (5 mL), and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (1.2 g).
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[K+]>O.C(O)C>[CH2:9]([O:7][C:6]1[C:1]([CH3:8])=[CH:2][CH:3]=[CH:4][CH:5]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClCc1ccccc1
Reactant: Cc1ccccc1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccccc1OCc1ccccc1
Yield: 76.4 %

Procedure:
o-Cresol (50 g), 70 g of benzyl chloride and 38.5 g of potassium hydroxide were boiled in a mixture of 100 ml of water and 500 ml of ethanol for 4 hours. The solvent was then distilled off and the residue was shaken with 500 ml each of water and diethyl ether. The diethyl ether layer was washed with 10% sodium hydroxide and water in that order, and distilled under reduced pressure to give 70 g of an O-benzylcresol fraction boiling at 130°-133° C./5 mmHg.
Reaction SMILES: Cl[C:2](=[N:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:17]([F:19])[F:18])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:20]12CC(C=C1)C=[CH:21]2.C(N(CC)CC)C>C1(C)C=CC=CC=1.C1(C)C(C)=CC=CC=1>[F:18][CH:17]([F:19])[O:16][C:13]1[CH:14]=[CH:15][C:10]([N:9]2[CH:21]=[CH:20][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:8]2)=[CH:11][CH:12]=1
Reactant: CCOC(=O)C(Cl)=NNc1ccc(OC(F)F)cc1
Reactant: C1=CC2C=CC1C2
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccn(-c2ccc(OC(F)F)cc2)n1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
Ethyl 2-chloro-2-(2-(4-(difluoromethoxy)phenyl)hydrazono)acetate (585 mg, 2 mmol) was dissolved in toluene (4 ml) and 2,5-norbornadiene (906 mg, 1 ml, 9.83 mmol) and triethylamine (587 mg, 808 μl, 5.8 mmol) were added. The reaction mixture was stirred at 70° C. for 30 min and the reaction mixture was allowed to stir at room temperature overnight. The solid was filtered off and washed with toluene. The organic fraction was evaporated and the residue obtained was dissolved in xylene (12 ml) and refluxed for 2 hours. The solvent was evaporated and the residue was purified by column chromatography (50 g Silicagel, dichloromethane) to yield 387 mg (69%) of a light yellow solid. MS (ISP): 283.1 ([M+H]+).
Reaction SMILES: C[CH2:2][O:3]CC.CO.[CH3:8][C:9]([O:12][CH3:13])([CH3:11])[CH3:10]>>[CH2:8]=[C:9]([CH3:11])[CH3:10].[CH3:2][OH:3].[CH3:8][C:9]([O:12][CH3:13])([CH3:11])[CH3:10]
Reactant: CCOCC
Solvent: CO
Solvent: COC(C)(C)C
Product: C=C(C)C

Procedure:
Another embodiment of the present invention is the use of pervaporation membranes to separate alcohols from ethers and/or hydrocarbons in a process for producing high purity alkenes by the decomposition of ethers. FIG. 4 depicts such a process for producing high purity isobutene by the decomposition of MTBE, although the present invention can be applied to other ether decomposition reactions. An impure C4 feed stream 70 is combined with a methanol feed stream 71 and recycled methanol stream 72 and fed to an MTBE synthesis system 74. The MTBE synthesis system 74 produces a MTBE product stream 76. A portion of the MTBE product stream 76 is collected as final MTBE product stream 78, while another portion of the MTBE product stream 76 is taken off at stream 80 and is heated and vaporized in the heat exchanger 81 and subsequently fed to a decomposition reactor 82 containing a fixed bed of acid cation exchange resin. The decomposition reactor 82 decomposes the MTBE feed to produce an effluent stream 83 containing isobutene/methanol/MTBE, which is cooled and condensed in heat exchanger 84 to produce a liquid mixture 85 which is subsequently fed through a pervaporation membrane system 86. The isobutene/methanol/MTBE mixture is separated by the pervaporation membrane system 86 to produce a high purity methanol permeate vapor 87 and a methanol-depleted liquid concentrate reject stream 88. The high purity methanol permeate vapor stream 87 is withdrawn from the membrane system, cooled and condensed if necessary, and subsequently recycled to the MTBE synthesis reactor 74 as stream 72. The methanol-depleted liquid concentrate reject stream 88 from the pervaporation membrane system 86 is fed to a distillation column 89 to undergo separation. The high purity isobutene stream 90 is taken as overhead product, and a high purity MTBE stream 91 is taken as bottom product and recycled to the feed to the MTBE decomposer 82. A liquid side draw containing isobutene/MTBE/methanol is taken from the distillation column 89 as stream 93 and is fed through a pervaporation membrane 94 where it is separated to form a high purity methanol vapor permeate stream 95 and isobutene/MTBE stream 96. The high purity methanol vapor permeate stream 95 is subsequently combined with the methanol permeate stream from the first pervaporation membrane system 86 and recycled as combined methanol stream 72 to the MTBE synthesis step 74. The isobutene/MTBE reject stream 96 from pervaporation membrane system 94 is returned to the distillation column 89 for further separation.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[CH:5][N:4]=1)#[N:2].[CH:12]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]([CH3:19])[CH:13]=1.[OH-].[Na+].O>CC(C)=O>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([O:18][C:17]2[CH:12]=[CH:13][C:14]([CH3:19])=[CH:15][CH:16]=2)=[CH:5][N:4]=1)#[N:2]
Reactant: Cc1ccc(O)cc1
Reactant: N#Cc1ncc(Cl)nc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(Oc2cnc(C#N)c(C#N)n2)cc1
Yield: 41.5 %

Procedure:
2,3-Dicyano-5-chloropyrazine (0.83 g; 0.005 mole) was dissolved in 25 ml of acetone. The solution was cooled to 0° to 5° C., and with stirring, a solution prepared from 0.54 g (0.005 mole) of p-cresol, 0.21 g (0.005 mole) of sodium hydroxide, 1 ml of water and 15 ml of acetone was added dropwise over the period of 15 minutes. The mixture was stirred at 0° to 5° C. for 1 hour. After the reaction, the solvent was removed by concentration under reduced pressure. The residue was extracted with 100 ml of chloroform. The chloroform solution was washed with 30 ml of a 1N aqueous solution of sodium hydroxide and 30 of water and dried over anhydrous calcium chloride. Then, the solvent was distilled off. Recrystallization of the crude product from ethanol afforded 0.49 g (yield 41%) of 2,3-dicyano-5-(p-methylphenoxy)pyrazine.