Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(O[C:8]([N:10]2[CH2:14][CH2:13][N:12](C)[C:11]2=[C:16]([N+:26]([O-:28])=[O:27])[C:17](=[O:25])[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=O)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O.O>[C:19]1([O:18][C:17](=[O:25])[C:16](=[C:11]2[NH:12][CH2:13][CH2:14][N:10]2[CH3:8])[N+:26]([O-:28])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN1CCN(C(=O)Oc2ccccc2)C1=C(C(=O)Oc1ccccc1)[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CN1CCNC1=C(C(=O)Oc1ccccc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 15.66 g of phenyl chloroformate in 25 ml of methylene chloride was added to a stirred and ice-cooled solution of 8.21 g of 1-methylimidazole in 175 ml of methylene chloride. To the resulting white suspension was added 7.15 g of 1-methyl-2-(nitromethylene)imidazolidine in portions as a solid. After stirring overnight at room temperature, the reaction mixture was washed twice with water. The organic layer was dried (MgSO4) and concentrated. The residual orange syrup was treated with water, and this mixture allowed to stand at room temperature overnight. The resulting solid was isolated by filtration. Trituration with ethyl acetate gave white powder. Recrystallization from a mixture of 60 ml of dimethyl sulfoxide and 45 ml of water gave 3-methyl-2-(1-nitro-2-oxo-2-phenoxyethylidene)-1-imidazolidinecarboxylic acid phenyl ester (1A), as a white solid, m.p.: 214°-215° C. A heterogeneous mixture of 1.92 g of 1A in 10 ml of dimethyl sulfoxide and 0.55 g of sodium carbonate in 3 ml of water was stirred at room temperature for two days. Crude, solid product was obtained by dilution with 30 ml of water and then filtration. Recrystallization from dimethyl sulfoxide: water yielded 1, as white crystals, m.p.: 234°.
Reaction SMILES: S(O[CH:6]([CH2:17][CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)[CH2:7][C:8](=[CH2:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(C)(=O)=O.O.[SH-:27].[Na+].O>CN(C)C=O>[C:12]([O:11][C:9]([CH:8]1[CH2:16][S:27][CH:6]([CH2:17][CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH2:7]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: [SH-]
Reactant: C=C(CC(CCOC1CCCCO1)OS(C)(=O)=O)C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C1CSC(CCOC2CCCCO2)C1
Reaction time: 7 h
Yield: 58.1 %

Procedure:
To a stirred solution of tert-butyl 4-mesyloxy-2-methylene-6-tetrahydropyranyloxyhexanoate (1.38 g) in dimethylformamide (20 ml), sodium hydrosulfide hydrate (0.34 g) was added under nitrogen atmosphere and ice-cooling and the mixture was stirred for 7 hours. Water was added to the mixture and extracted with diethylether. The organic layer was washed with saturated aqueous sodium bicarbonate solution, water and saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 0.67 g (58%) of 4-tert-butoxycarbonyl-2-(2-tetrahydropyranyloxyethyl)tetrahydrothiophene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:13](=[O:15])[CH3:14])=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: Nc1ccc(F)cc1C(F)(F)F
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(F)cc1C(F)(F)F
Temperature: 0 °C

Procedure:
10.0 g (0.56 mol) 4-fluoro-2-trifluoromethyl-phenylamine were stirred overnight at RT in 40 mL acetic anhydride. The reaction mixture was poured onto 300 g ice water. The precipitate formed was suction filtered, washed with 100 mL water and dried i. vac.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].[OH:12][C:13]1[N:17]=[C:16]([S:18][CH2:19][CH3:20])[S:15][N:14]=1>O1CCCC1>[CH3:8][NH:9][C:10]([N:14]1[C:13](=[O:12])[N:17]=[C:16]([S:18][CH2:19][CH3:20])[S:15]1)=[O:11]
Reactant: CN=C=O
Reactant: CCSc1nc(O)ns1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCSc1nc(=O)n(C(=O)NC)s1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
10.4 ml of triethylamine and 10 ml of methyl isocyanate were added to a solution of 20.3 g of 3-hydroxy-5-ethylthio-1,2,4-thiadiazole in 100 ml of tetrahydrofuran and the mixture was stirred at 20° C for 1 hour, cooled to -10° C and filtered. The product was crystallized from ethyl acetate to obtain 18 g of 2-(N-methylcarbamoyl)-5-ethylthio-1,2,4-thiadiazole-3-one melting at 131° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:22])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:21])([C:14]([NH:16][CH:17]([CH3:20])[CH2:18][OH:19])=[O:15])[CH2:6][CH2:5]2.[O:23]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:23][C:7]([CH3:21])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:22])[C:14]([NH:16][CH:17]([CH3:20])[CH2:18][OH:19])=[O:15]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NC(C)CO)O2
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NC(C)CO)=C(C)C1=O
Yield: 92.6 %

Procedure:
Oxidation as described in protocol B, using 102.2 mg (0.329 mmol) of 6-hydroxy-N-(1-hydroxypropan-2-yl)-2,5,7,8-tetramethylchroman-2-carboxamide and 397 mg CAN (2.45 mmol) yielded 98.5 mg of 2-hydroxy-N-(1-hydroxypropan-2-yl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow foam.
Reaction SMILES: [C:1]1([C:6]([OH:8])=O)[CH2:5][CH2:4][CH2:3][CH:2]=1.[Cl-].[CH2:10]([NH2:12])[CH3:11]>C1C=CC=CC=1>[C:1]1([C:6]([NH:12][CH2:10][CH3:11])=[O:8])[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CCN
Reactant: O=C(O)C1=CCCC1
Agent: [Cl-]
Solvent: c1ccccc1
Product: CCNC(=O)C1=CCCC1
Temperature: 30 °C
Reaction time: 10 h
Yield: 69.8 %

Procedure:
N-Cyclopentenoyl-ethylamine was prepared from cyclopentenoic acid (2 grams, 17.5 mmol) and oxallyl chloride (2.2 grams, 17.5 mmol) after stirring at 25-35° C. for 8-12 hours. To this was added a benzene solution of ethylamine (2.1 grams, 48.7 mmol) at 0° C., and this reaction mixture was stirred for 3 hours at 25-35° C., after which time the solvent was evaporated under vacuum to yield N-cyclopentenoyl-ethylamine (1.7 grams), yield: 68.9%. A solution of N-cyclopentenoyl-ethylamine (1.7 grams, 13.3 mmol) in anhydrous tetrahydrofuran (THF) (10 mL) under a nitrogen atmosphere, and lithium aluminum hydride (LiAlH4; 1.3 grams, 36.1 mmol) was added to the solution. After being stirred for 1 hour at 25-35° C., the reaction mixture was gently refluxed for 8 hours. The reaction mixture was quenched with saturated sodium sulfate solution, filtered, and the precipitate washed with diethyl ether (Et2O). The filtrate was concentrated to afford N-cyclopentylmethyl ethylamine (0.6 g, yield: 40%).
Reaction SMILES: Cl[C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C>[Pd].C(O)C>[F:12][C:11]1[CH:2]=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[C:6]([O:13][CH3:14])[CH:5]=2
Reactant: COc1ccc2cc(F)c(Cl)nc2c1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc2cc(F)cnc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.9 %

Procedure:
A mixture of 2-chloro-3-fluoro-7-methoxyquinoline (310 mg, 1.47 mmol), triethylamine (310 mg, 0.4 ml, 3.07 mmol) and 10% palladium on activated charcoal (50 mg) in dry ethanol (5 ml) was stirred under hydrogen gas at ambient temperature for 24 hours. The mixture was then filtered through celite. The celite was washed with methanol and the solvent was removed by evaporation from the combined filtrates. The crude material was purified by chromatography on silica, eluting with 10% ethyl acetate in isohexane to give 3-fluoro-7-methoxyquinoline (130 mg, 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[C:6]([CH:8]=1)[NH2:7].C(N(C(C)C)CC)(C)C.[Cl:23][C:24]1[CH:28]=[CH:27][S:26][C:25]=1[C:29](Cl)=[O:30]>ClCCl>[Cl:23][C:24]1[CH:28]=[CH:27][S:26][C:25]=1[C:29]([NH:7][C:6]1[CH:8]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[C:9]1[NH:13][N:12]=[N:11][N:10]=1)=[O:30]
Reactant: Nc1cc(Cl)ccc1-c1nnn[nH]1
Reactant: O=C(Cl)c1sccc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(Cl)ccc1-c1nnn[nH]1)c1sccc1Cl
Reaction time: 4 h
Yield: 41.5 %

Procedure:
The intermediate 5-chloro-2-(1H-tetrazol-5-yl)aniline (200 mg, 1.0 mmol) and diisopropylethylamine (310 uL, 1.7 mmol) were taken up in 5 mL of dichloromethane. To the solution was added 3-chlorothiophene-2-carboyl chloride (221 mg, 1.2 mmol). The solution was stirred for 4 hours, at which point starting material was no longer detected by LCMS analysis. Dichloromethane (10 ml) was then added to solution. This solution was extracted 3 times with an aqueous solution of 0.1 N NaOH. The aqueous extractions were combined and concentrated HCl was added to until pH=1. The resulting precipitate was filtered and washed with acetonitrile to yield final product (141.1 mg, 41%). 1H NMR (400 MHz, d6-DMSO): 11.89 (s, 1H), 8.60 (s, 1H), 8.26 (d, 1H), 8.05 (d, 1H), 7.45 (d, 1H), 7.30 (d, 1H). MS (EI) for C12H7Cl2N5OS: 340.2 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([OH:3])=[O:2].IC.[C:14](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([O:3][CH3:14])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccccc1C(=O)O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1ccccc1C=O

Procedure:
4.5 g (30 mmol) of 2-carboxybenzaldehyde, 17.1 (120 mmol) of iodomethane and 12.4 g (90 mmol) of potassium carbonate were stirred in 85 ml of acetone for 24 hours. The solvent was removed by evaporation and the residue was partioned between 50 ml of water and 50 ml of ether. The aqueous layer was washed with 3×50 ml portions of ether. The combined organic extracts were washed with 30 ml each of 1M sodium thiosufate and saturated sodium cloride solutions and dried over MgSO4. The solvent was removed by evaporation. The residue was subjected to flash chromatography (silica gel, 10% ethyl acetate/hexanes) to give the title compound as a clear colorles oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:32])=[C:11]([C:28]([F:31])=[CH:29][CH:30]=1)[CH2:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH:20]=2)[NH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:35]([Si:38](Cl)([CH:42]([CH3:44])[CH3:43])[CH:39]([CH3:41])[CH3:40])([CH3:37])[CH3:36].O>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]([F:32])=[C:11]([C:28]([F:31])=[CH:29][CH:30]=1)[CH2:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH:20]=2)[N:15]([Si:38]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:35]([CH3:37])[CH3:36])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Fc1ccc(OCc2ccccc2)c(F)c1Cc1c[nH]c2ncc(-c3cccnc3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2c(F)ccc(OCc3ccccc3)c2F)c2cc(-c3cccnc3)cnc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.8 %

Procedure:
To 3-(3-Benzyloxy-2,6-difluoro-benzyl)-5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (P-1455, 700.0 mg, 1.64 mmol, prepared as described in Example 24, Scheme 43a) in tetrahydrofuran (40.0 mL) was added sodium hydride (60% in mineral oil, 100.0 mg, 2.5 mmol). After 10 minutes, triisopropylsilyl chloride (0.60 mL, 0.0028 mol) was added to the reaction. The reaction was stirred at room temperature for 2 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give the compound as colorless oil (548, 0.85 g, 89%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.C([O:17][C:18](=O)[C:19]([F:22])([F:21])[F:20])C.OS(O)(=O)=O>C1(C)C=CC=CC=1>[F:20][C:19]([F:22])([F:21])/[C:18](/[OH:17])=[CH:11]/[C:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:9][CH:8]=1)=[O:12]
Reactant: CC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: O=C(/C=C(\O)C(F)(F)F)c1ccc(OC(F)(F)F)cc1
Temperature: 2 °C
Reaction time: 14 h
Yield: 83.6 %

Procedure:
25 g (122 mmol) 1-(4-Trifluoromethoxy-phenyl)-ethanone were added to a suspension of 16.5 g (147 mmol) potassium-tert-butylate in 250 ml toluene. The suspension was cooled to 2° C. and 17.5 ml (147 mmol) ethyltrifluoroacetate were added within 15 min. The mixture was stirred at ambient temperature for 14 h, cooled to 2° C. and brought to pH 6 with 10% aqueous H2SO4. Twofold extraction with tert-butyl methylether was followed by washing of the combined extracts with brine/ice water 1/1 and drying of the organic layer over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by flash chromatography (silica gel, dichloromethane) to give 30.5 g (102 mmol, 83%) of the title compound as red oil.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:6]=[CH:5][C:4]1=2.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl.N1C=CC=CC=1>[CH3:23][S:24]([NH:1][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([NH:13][S:14]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15])=[CH:8]2)(=[O:26])=[O:25]
Reactant: NCC1CCCc2cc(NS(=O)(=O)c3ccccc3)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)NCc1cccc2cc(NS(=O)(=O)c3ccccc3)ccc12
Temperature: 25 °C

Procedure:
N-(5-Aminomethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzenesulfonamide is dissolved in methylene chloride and pyridine, and the mixture is cooled in an ice bath. Methanesulfonyl chloride is added dropwise, and the reaction mixture is stirred at ice bath temperature, then allowed to warm to room temperature. The reaction mixture is quenched by addition of water and extracted with methylene chloride. The organic layer is washed with water, dried (MgSO4), filtered and concentrated under reduced pressure to give N-[5-(Methanesulfonylamino-methyl)-naphthalen-2-yl]-benzenesulfonamide. 5-(Methanesulfonylamino-methyl)-naphthalene-2-sulfonic acid phenylamide may be similarly prepared.
Reaction SMILES: [Na].[C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[N:12])=[N:9][CH:10]=1)([OH:4])=[O:3].N[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[SH:20]>C(O)C>[S:20]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:12]=[C:11]1[C:8]1[CH:7]=[CH:6][C:5]([C:2]([OH:4])=[O:3])=[CH:10][N:9]=1
Reactant: Nc1ccccc1S
Reactant: N#Cc1ccc(C(=O)O)cn1
Agent: [Na]
Solvent: CCO
Product: O=C(O)c1ccc(-c2nc3ccccc3s2)nc1

Procedure:
Sodium (7.7 mmol) is added to a flask containing 70 ml of ethanol. As soon as the sodium has dissolved, 7 mmol of 5-carboxy-2-cyanopyridine and 8.4 mmol of 2-amino-thiophenol are added and the solution is refluxed for 24 h. The solid formed is filtered off, redissolved in ethanol and water, the solution is made acidic (pH=3) with 2N HCl and evaporated. The residue is dissolved in 100 ml of hot ethyl acetate, the salts are filtered off and the filtrate on cooling gives crystals of the title compound, m.p. >300°.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=3[NH2:25])[CH2:12][CH2:11]2)=[N:2]1.[C:26](Cl)(=[O:28])[CH3:27]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=3[NH:25][C:26](=[O:28])[CH3:27])[CH2:12][CH2:11]2)=[N:2]1
Reactant: CC(=O)Cl
Reactant: Cc1cccc(CCN2CCN(c3nsc4ccccc34)CC2)c1N
Product: CC(=O)Nc1c(C)cccc1CCN1CCN(c2nsc3ccccc23)CC1
Yield: 63 %

Procedure:
Starting from 2-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-6-methyl-phenylamine (65 mg, 0.185 mmol) and acetyl chloride (14 μL, 0.194 mmol) and following the procedure as outlined in Example 1, 46 mg of N-{2-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-6-methyl-phenyl}-acetamide was isolated as a pink foam in 100% purity @ 254 nm; LCMS (APCI): 395 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1.[CH3:26][C:27](=[O:30])[CH:28]=[CH2:29]>O(CC)CC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:29][CH2:28][C:27](=[O:30])[CH3:26])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: C=CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC(=O)CCOc1ccc(F)cc1
Reaction time: 96 h
Yield: 39.7 %

Procedure:
To a stirred solution of 134 parts of 4-fluorophenol and 2 parts of 4-methylbenzenesulfonic acid in 1080 parts of benzene were added 42 parts of 3-buten-2-one. Stirring was continued for 4 days at room temperature. 700 Parts of 1,1'-oxybisethane were added and the whole was washed four times with 500 parts of a cold sodium hydroxide solution 1N and with water. The organic phase was dried, filtered and evaporated. The oily residue was purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The oily residue solidified upon cooling. The product was suspended in cold petroleumether. The product was filtered off and dried at room temperature, yielding 43.4 parts (39.7%) of 4-(4-fluorophenoxy)-2-butanone (intermediate 26).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]([CH2:20][O:21][Si](C(C)(C)C)(C)C)[CH2:14][CH2:13]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]([CH2:20][OH:21])[CH2:14][CH2:13]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc2c(c1)CCC(CO[Si](C)(C)C(C)(C)C)C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc2c(c1)CCC(CO)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In tetrahydrofuran (10 ml), (2RS)-6-(N-tert-butoxycarbonylaminomethyl)-2-(tert-butyldimethylsilyloxymethyl)-1,2,3,4-tetrahydronaphthalene (1.09 g) was dissolved. Tetrabutylammonium fluoride (a 1.0 M tetrahydrofuran solution, 4.0 ml) was added to the resulting solution, followed by stirring at room temperature for 2 hours. After concentration under reduced pressure, the reaction mixture was diluted with dichloromethane, washed with water an dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (hexane:ethyl acetate=3:1 to 2:1), whereby a colorless solid (0.77 g, 98%) was obtained. A portion of the solid was recrystallized from a mixed solvent of hexane and ethyl acetate, whereby colorless crystals were obtained.
Reaction SMILES: [CH3:1][S:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][O:6][C:5]2[CH:14]=[CH:15][C:16]([C:18]([OH:20])=[O:19])=[CH:17][C:4]1=2.[OH:21]O>C(O)(=O)C>[CH3:1][S:2]([CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][O:6][C:5]2[CH:14]=[CH:15][C:16]([C:18]([OH:20])=[O:19])=[CH:17][C:4]1=2)=[O:21]
Reactant: OO
Reactant: CSC1c2ccccc2COc2ccc(C(=O)O)cc21
Solvent: CC(=O)O
Product: CS(=O)C1c2ccccc2COc2ccc(C(=O)O)cc21
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
Dissolve with warming 380 mg. of 6,11-dihydro-11-methylthiodibenz[b,e]oxepin-2-carboxylic acid in 38 ml. of glacial acetic acid. Place the reaction mixture in an oil bath at 40° C. and add 1.5 ml. of 30% hydrogen peroxide. Stir the mixture at 40° C. for 3 1/2 hours until the solution clears. Dilute with 300 ml. of water and separate the precipitate by filtration to obtain the title product.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH:22]=O)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:24]1[CH2:32][CH2:31][CH:27]([C:28]([NH2:30])=[O:29])[CH2:26][CH2:25]1>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)C>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3([CH2:22][N:24]4[CH2:32][CH2:31][CH:27]([C:28]([NH2:30])=[O:29])[CH2:26][CH2:25]4)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: NC(=O)C1CCNCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCO
Product: NC(=O)C1CCN(CC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)CC1
Yield: 58.9 %

Procedure:
4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde (500 mg, 1.58 mmol), isonipecotamide (434 mg, 3.03 mmol), absolute ethanol (20 ml), activated 3 Å molecular sieves (500 mg), titanium (IV) isopropoxide (2.31 ml, 7.88 mmol) and STAB (2.84 g, 13.6 mmol) were reacted in accordance with the general procedure D. The isolated crude product was purified by column chromatography on silica eluting with DCM:MeOH:NH3 (97:2:1) to give the title compound as a colorless solid (400 mg, 59%). 1H NMR (400 MHz, CDCl3) δ7.20 (d, 2H), 6.85 (d, 2H), 5.45 (br s, 2H), 4.01 (t, 2H), 3.79-3.69 (m, 2H), 3.57-3.46 (m, 2H), 2.63 (t, 2H), 2.53 (br s, 4H), 2.35 (s, 2H), 2.31 (br s, 1H), 2.14-1.72 (m, 14H), 1.67-1.51 (m, 4H).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[O:22])=[CH:20][C:13]=3[N:12]=2)=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].C(N(C(C)C)C(C)C)C.Cl[C:40]([O:42][CH3:43])=[O:41]>C(Cl)Cl>[CH3:43][O:42][C:40]([NH:4][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[O:22])=[CH:20][C:13]=3[N:12]=2)=[CH:7][CH:6]=1)=[NH:3])=[O:41]
Reactant: COC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc(C(=N)N)cc1)n2C
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc(C(=N)NC(=O)OC)cc1)n2C
Reaction time: 0.5 h

Procedure:
0.26 g of 2-(4-amidino-phenyl)-5-[(2-methoxycarbonyl-ethyl)-aminocarbonyl]-1-methyl-benzimidazole-hydrochloride are suspended in 50 ml of methylene chloride and, whilst cooling with ice, 0.5 ml of N-ethyl-diisopropylamine and 0,067 ml of methyl chloroformate are added. The mixture is stirred at ambient temperature, after half an hour a further 0.5 ml of N-ethyl-diisopropylamine and 0.03 ml of methyl chloroformate are added and, after another half hour, a further 0.1 ml of N-ethyl-diisopropylamine and 0.03 ml of methyl chloroformate. The mixture is stirred for a further half hour, evaporated down in vacuo and purified by column chromatography (silica gel; eluant:ethyl acetate/ethanol=100:2.5 to 100:12.5). Yield: 0.12 g (40% of theory), Rf value: 0.41 (silica gel; ethyl acetate/ethanol=8:2)
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]2=[C:5]([C:12]([O-:14])=O)[N:4]=1.[CH3:17][NH2:18]>>[CH3:17][NH:18][C:12]([C:5]1[N:4]=[C:3]([C:2]([F:1])([F:16])[F:15])[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]=12)=[O:14]
Reactant: CN
Reactant: O=C([O-])c1nc(C(F)(F)F)n2c1CNCC2
Product: CNC(=O)c1nc(C(F)(F)F)n2c1CNCC2
Temperature: 60 °C
Reaction time: 6 h

Procedure:
Methyl 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate 3b (500 mg, 2 mmol) was dissolved in 8 mL of methylamine solution (20% to 30%) was added in a 20 mL sealed tube. After stirring at 60° C. for 6 hours, the reaction mixture was concentrated under reduced pressure to obtain the crude N-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydro imidazo[1,5-a]pyrazine-1-carboxamide 13a (498 mg) as a white solid. The product was used directly in the next reaction without purification.