Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[C:3]1([CH:10]=[CH:9][C:7]([OH:8])=[CH:6][CH:5]=1)[OH:4].Br[CH2:12][CH2:13][CH:14]=[CH2:15]>C(O)C>[CH2:15]([O:4][C:3]1[CH:10]=[CH:9][C:7]([OH:8])=[CH:6][CH:5]=1)[CH2:14][CH:13]=[CH2:12]
Reactant: Oc1ccc(O)cc1
Reactant: C=CCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=CCCOc1ccc(O)cc1

Procedure:
In a three-necked flask equipped with a dropping funnel, a mixture composed of potassium hydroxide (27 mmol) and hydroquinone (45 mmol) is dissolved in 400 ml of absolute ethanol by heating. Add 4-bromo-1-butene (Aldrich) (18 mmol) dropwise. Maintain at reflux for 4 hours. After being cooled and filtered the solvent is evaporated. The mixture is taken up in a solution of ice-cold water. That dissolves a part of the hydroquinone and leads to the appearance of a precipitate containing the desired product. Extract the product with ether. After three washings with water, the organic phase is dried over sodium sulfate then the solvent is evaporated. The phenyl is purified by chromatography on silica gel (eluent: heptane-ether 5/5). The yield of the reaction is of the order of 50%.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[H-].[Na+].F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[CH3:1][N:2]1[CH2:11][CH:10]([O:12][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1
Reactant: CN1Cc2ccccc2C(O)C1
Reactant: Fc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1Cc2ccccc2C(Oc2ccccc2)C1
Temperature: 95 °C
Reaction time: 4 h
Yield: 65.5 %

Procedure:
A solution of 2-methyl-1,2,3,4-tetrahydro-4-isoquinolinol (6.0 g, 0.037 mole) in 30 ml dry DMF is added dropwise under nitrogen to a suspension of sodium hydride 50% (98%) (2.2 g, 0.044 mole), previously washed with hexane, in 50 ml dry DMF. After one hour the mixture is slowly warmed to 75° C. at which time fluorobenzene (7.1 g. 0.074 mole) in 30 ml dry DMF is added dropwise. The reaction mixture is stirred at 95° C. for four hours then at 75° C. for about 16 hours. Most of the solvent is removed under reduced pressure and the resultant mixture is stirred in 500 ml water then extracted with chloroform. The combined organic extracts are washed twice with water and then dried (saturated NaCl, anhydrous MgSO4). Removal of solvent yields 5.8 g (65%) of an oil which is purified by dry column chromatography over silica gel using ethyl acetate as the eluent. The desired product is extracted with chloroform to yield 1.5 g (17%) of an oil of 2-methyl-4-phenoxy-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:11])=[C:8]([SH:10])[CH:9]=1.C(N(CC)CC)C.[Br:19][C:20]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=O.[OH-].[Na+]>CN1CCCC1=O>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:22]([C:21]3[CH:25]=[CH:26][CH:27]=[C:28]([O:29][CH3:30])[C:20]=3[Br:19])[S:10][C:8]=2[CH:9]=1
Reactant: COc1ccc(N)c(S)c1
Reactant: COc1cccc(C(=O)Cl)c1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COc1ccc2nc(-c3cccc(OC)c3Br)sc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.6 %

Procedure:
5-Methoxy-2-aminobenzenethiol hydrochloride (83 g, 4.33 mmol) was dissolved in 1-methyl-2-pyrrolidinone (10 mL). After triethylamine (0.60 mL, 4.33 mmol) was added, the mixture was stirred at room temperature for 10 min. 2-Bromo-3-methoxybenzoyl chloride (1.08 g, 4.33 mmol) in 1-methyl-2-pyrrolidinone (10 mL) was then added and the mixture was heated at 100° C. for 40 min. The mixture was cooled to room temperature and 1N NaOH was added to PH 9. The mixture was extracted with ethylacetate and combined ethylacetate were washed with brine, concentrated. After chromatographic purification gave 6-methoxy-2-(2-bromo-3-methoxy-phenyl)-benzothiazole (0.98 g, 65% yield) as a yellow solid. Mass spec: MH+=350.
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:2]=[O:3].Cl.O1CCOCC1.[CH3:17][C:18]([OH:23])([CH2:21][CH3:22])[CH2:19][CH3:20]>ClCCl>[CH2:19]([C:18]([CH3:17])([O:23][C:2]([NH:1][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:3])[CH2:21][CH3:22])[CH3:20]
Reactant: CCOC(=O)CN=C=O
Reactant: CCC(C)(O)CC
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)CNC(=O)OC(C)(CC)CC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
0.500 ml (4.01 mmol) of ethyl isocyanatoacetate was dissolved in dichloromethane. 0.05 ml of 4 N hydrochloric acid/1,4-dioxane solution was added to the obtained solution, and they were stirred at room temperature for 5 minutes. 0.547 ml (4.41 mmol) of 3-methyl-3-pentanol was added to the reaction mixture, and they were stirred overnight. After the concentration under reduced pressure, ethyl acetate was added to the reaction mixture, and they were washed with saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was washed with diethyl ether. The filtrate was concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [Mg].C(O[CH2:5][CH3:6])C.Cl[CH2:8][Si:9]([CH2:14]Cl)([CH2:12][CH3:13])[CH2:10][CH3:11].[CH:16]1[CH:21]=[CH:20][C:19]([N:22]([C:29]2[CH:34]=[CH:33][C:32](Br)=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=1>Cl[Ni]Cl.O>[C:23]1([N:22]([C:6]2[CH:5]=[CH:34][CH:29]=[CH:30][CH:31]=2)[C:19]2[CH:18]=[CH:17][C:16]([CH2:8][Si:9]([CH2:14][C:16]3[CH:21]=[CH:20][C:19]([N:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)([CH2:12][CH3:13])[CH2:10][CH3:11])=[CH:21][CH:20]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOCC
Reactant: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: CC[Si](CC)(CCl)CCl
Agent: Cl[Ni]Cl
Agent: [Mg]
Solvent: O
Product: CC[Si](CC)(Cc1ccc(N(c2ccccc2)c2ccccc2)cc1)Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 78 %

Procedure:
0.6 g (24.9 mmol) of metallic magnesium was placed in a 200-ml four-necked flask equipped with a mechanical stirrer, a condenser, a nitrogen-inlet tube and a dropping funnel, and the inside atmosphere was replaced with nitrogen. 100 ml of diethyl ether was added and stirring was initiated. To this solution, 20 ml of a diethyl ether solution of 3.7 g (20 mmol) of bis(chloromethyl)diethylsilane was gradually added dropwise. When about 5 ml was added, mild reflux began. Under reflux conditions, the remainder of the diethyl ether solution was added. After completion of the addition, reflux was continued for 1 more hour. The Grignard solution thus obtained was cooled to room temperature, and then 6 mg of NiCl2 (dppe) was added at room temperature. Further 20 ml of a diethyl ether solution of 13.0 g (40 mmol) of 4-bromotriphenylamine was gradually added dropwise under ice cooling. After completion of the addition, the reaction mixture was stirred under reflux conditions for 8 hours. Then, the mixture was cooled on ice water bath, and 50 ml of water was added for hydrolysis. The ether layer was extracted and washed with a saturated aqueous solution of sodium hydrogen carbonate and then with two portions of water, followed by drying with anhydrous sodium sulfate. After drying, the diethyl ether was distilled off to yield a white solid, which was then recrystallized with n-hexane/toluene (3/1) to yield 19.7 g of the desired product (yield 78%).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([N:13]2[C:18](=[O:19])[CH2:17][CH2:16][CH2:15][C@@H:14]2[C:20]([O:22][CH2:23]C)=[O:21])CO)=[CH:6][CH:5]=1.O.C(OCC)(=O)C>CO>[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:23][O:22][C@@H:20]([OH:21])[CH:14]3[CH2:15][CH2:16][CH2:17][C:18](=[O:19])[N:13]23)=[CH:8][CH:9]=1
Reactant: CCOC(=O)[C@H]1CCCC(=O)N1[C@@H](CO)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CCCC2[C@H](O)OCC(c3ccc(F)cc3)N12
Reaction time: 0.67 h
Yield: 73.6 %

Procedure:
Sodium borohydride (70.9 mg) was added to a solution of ethyl (R*)-1-[(R*)-1-(4-fluorophenyl)-2-hydroxyethyl]-6-oxopiperidine-2-carboxylate (290 mg) in methanol (5.0 mL) under ice-cooling, and the reaction solution was stirred for one hour and 40 minutes. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 183 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.C(NC(C)C)(C)C.[C:13]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(Br)C=C>O1CCCC1>[CH2:3]([CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:13]([O:30][CH2:31][CH3:32])=[O:29])[CH:2]=[CH2:1]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: C=CCBr
Product: C=CCC(CCCCCCCCCCCCCC)C(=O)OCC
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a solution of n-butyl lithium (hexane, 0.048 mol) in 120 mL of anhydrous tetrahydrofuran at 0° C. and under argon atmosphere, diisopropylamine was added (6.8 mL, 0.048 mol). Afterwards, ethyl hexadecanoate (11.3 g, 0.04 mol) in tetrahydrofuran (15 mL) was added dropwise and the homogeneous solution was stirred for 1 h at the same temperature. Next, allyl bromide (4.0 mL, 0.048 mol) was added and the resulting mixture was stirred at room temperature for 12 h. The mixture was poured on water, extracted with ethyl acetate, dried over anhydrous sodium sulfate and the solvent evaporated to afford 11.9 g of an oil. The product was chromatographed (silica gel, hexane: ethyl acetate, 3%) to afford 8.7 g of a colorless oil (67% yield).
Reaction SMILES: C(O)=O.C(N(CC)CC)C.[F:11][C:12]([F:24])([F:23])[C:13]1[C:21]2[O:20][CH2:19][C:18](=[O:22])[C:17]=2[CH:16]=[CH:15][CH:14]=1>ClCCl>[F:24][C:12]([F:11])([F:23])[C:13]1[C:21]2[O:20][CH2:19][C@H:18]([OH:22])[C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: O=C1COc2c1cccc2C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: ClCCl
Product: O[C@H]1COc2c1cccc2C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of formic acid (60 μL, 1.56 mmol) and triethylamine (186 μL, 1.33 mmol), a dichloromethane (2.0 mL) solution of 7-(trifluoromethyl)-1-benzofuran-3-one (90 mg, 0.445 mmol) produced in Example 47 (47E) was added, and chloro[(1S,2S)—N-(p-toluenesulfonyl)-1,2-diphenylethanediamine](mesitylene)ruthenium(II) (8.4 mg, 0.013 mmol) was added thereto at room temperature, and then, the resulting mixture was stirred overnight under a nitrogen atmosphere at room temperature.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7]([C:13](O)=[O:14])=[C:6]2[O:16][CH:17]([CH3:19])[CH3:18].[CH3:20][NH2:21].[OH-].[NH4+]>>[CH3:20][NH:21][C:13]([C:7]1[N:8]([CH3:12])[C:9]2[C:5]([C:6]=1[O:16][CH:17]([CH3:19])[CH3:18])=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)=[O:14]
Reactant: COc1ccc2c(c1)c(OC(C)C)c(C(=O)O)n2C
Reactant: CN
Agent: [NH4+]
Agent: [OH-]
Product: CNC(=O)c1c(OC(C)C)c2cc(OC)ccc2n1C
Yield: 45 %

Procedure:
Prepared from 5-methoxy-1-methyl-3-(1-methylethoxy)-1H-indole-2-carboxylic acid by the procedure of Example 1 with 40% aqueous methylamine solution substituted for ammonium hydroxide. Yield 45% after recrystallization from hexane; mp 85°-86° C.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[S:9])[C:5]([F:8])([F:7])[F:6])[CH3:2].[CH3:10][CH2:11][O:12][C:13](C(CBr)=O)=[O:14]>C1COCC1.O.C(Cl)Cl>[F:6][C:5]([F:8])([F:7])[C:4]1[S:9][CH:2]=[C:1]([C:13]([O:12][CH2:11][CH3:10])=[O:14])[N:3]=1
Reactant: CCNC(=S)C(F)(F)F
Reactant: CCOC(=O)C(=O)CBr
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1csc(C(F)(F)F)n1
Temperature: 95 °C
Yield: 42 %

Procedure:
To a stirring solution of ethyl 2,2,2-trifluoroethanethioamide (0.35 g, 2.71 mmol) in THF (12 ml) was added ethyl bromo pyruvate (0.375 ml, 2.98 mmol) at RT. Reaction mixture was heated at 90-100° C. for 16 h. Reaction mixture was diluted with water and DCM. The organic layer was separated and distilled out to get crude product which was column purified using 0-2% EtOAC in hexane to get titled compound in 42% yield.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[N:16]3[C:11]([C:12]([NH2:17])=[N:13][CH:14]=[N:15]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:18]N1C(C)(C)C(=O)N(Br)C1=O>C1COCC1>[Br:18][C:10]1[CH:9]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:16]2[C:11]=1[C:12]([NH2:17])=[N:13][CH:14]=[N:15]2
Reactant: Nc1ncnn2c(CN3CCOCC3)ccc12
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: C1CCOC1
Product: Nc1ncnn2c(CN3CCOCC3)cc(Br)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 160.2 %

Procedure:
To a solution of 7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (562 mg, 2.40 mmol) in THF (19 ml) at −20 C was added 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (344 mg, 1.2 mmol) in three portions. The reaction was stirred at −20 C for 3 h. Upon the completion, the reaction was quenched with aqueous saturated Na2SO3 and allowed to warm up to rt. The crude was extracted with ethyl acetate. The organic was washed with brine, dried over Na2SO4 and concentrated. The resulting crude was purified via column chromatography (95:5 v/v CH2Cl2—CH3OH) to afford 600 mg of the title compound as yellow solid (yield 79%). 1H-NMR (DMSO-d6) δ 7.84 (s, 1H), 6.71 (s, 1H), 3.74 (s, 2H), 3.51 (t, J=4 Hz, 4H), 2.37(t, J=4 Hz, 4H); MS [M+H]+=312; LCMS RT=1.04 min.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].[C:15]1(=[O:21])[O:20][C:18](=[O:19])[CH2:17][CH2:16]1.ClC(Cl)C(Cl)Cl>Cl>[C:5]([C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:21])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)(C)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)C(Cl)Cl
Product: CC(C)(C)c1ccc(C(=O)CCC(=O)O)cc1
Temperature: 0 °C

Procedure:
Aluminum chloride powder (80.0 g, 600 mmol) was added in portions to a stirred mixture of tert-butylbenzene (40.0 g, 300 mmol) and succinic anhydride (26.7 g, 267 mmol) and 1,1,2,2-tetrachloroethane (100 mL). After all the aluminum chloride had been added, the mixture was poured into a mixture of ice (500 mL) and concentrated hydrochloric acid (100 mL). The organic layer was separated, washed with water (500 mL) and the solvent distilled off. Solid residue was dissolved in hot 15% aqueous solution of sodium carbonate (1000 mL), filtered, cooled and the acid was precipitated with hydrochloric acid (acidified to pH=1). The crude acid was filtered, dried on air and recrystalised from benzene (500 mL) to give 4-(4-tert-butyl-phenyl)-4-oxo-butyric acid as colorless crystals.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:25]12[CH2:33][C:29]([CH2:34]O)([CH2:30][CH2:31][CH2:32]1)[CH2:28][CH2:27][CH2:26]2.C([Li])CCC.CCCCCC>O1CCCC1>[N:25]12[CH2:33][C:29]([CH2:34][O:11][C:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)=[O:12])([CH2:30][CH2:31][CH2:32]1)[CH2:28][CH2:27][CH2:26]2
Reactant: OCC12CCCN(CCC1)C2
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(OCC12CCCN(CCC1)C2)c1c[nH]c2ccccc12
Reaction time: 1 h
Yield: 60 %

Procedure:
A solution of indole-3-carboxylic acid (1.62 g, 10 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.70 g, 10.5 mmol), stirred for one hour, and degassed with a stream of nitrogen for 10 minutes giving a suspension. Meanwhile, a cooled (-10° C.) solution of 1-azabicyclo[3.3.1]nonane-5-methanol (1.71 g, 11 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated (via syringe) with 2.5N n-butyllithium/hexane (10.7 mmol), stirred for 30 minutes, concentrated in vacuo, and taken up in anhydrous tetrahydrofuran (10 mL) under nitrogen. The 1,1'-carbonyldiimidazole adduct suspension was transferred into this solution, and the mixture was stirred overnight (18 hours) and concentrated in vacuo. The residue was partitioned between methylene chloride (100 mL) containing a little isopropanol and saturated sodium carbonate (50 mL), and the organic layer was separated. The aqueous solution was dried (Na2SO4), concentrated in vacuo, and filtered through alumina (eluted with 7% methanol/methylene chloride). The filtrated was concentrated in vacuo and the residue was triturated from cold ether and recrystallized from acetonitrile (2 crops) to afford 1.79 g (60%) of colorless crystals; m.p. 207°-209° C.
Reaction SMILES: CS(O[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[CH2:18][C:19]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=3)([C:22]([F:25])([F:24])[F:23])[CH2:20][N:21]=2)=[CH:9][CH:8]=1)(=O)=O.O.[NH3:35]>C1COCC1.CO>[Cl:32][C:30]1[CH:31]=[C:26]([C:19]2([C:22]([F:25])([F:24])[F:23])[CH2:18][C:17]([C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:7]([CH2:6][NH2:35])=[CH:8][CH:9]=3)=[N:21][CH2:20]2)[CH:27]=[C:28]([Cl:33])[CH:29]=1
Reactant: CS(=O)(=O)OCc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Reaction time: 12 h

Procedure:
{4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]naphthalen-1-yl}methyl methanesulfonate (0.7 g) was dissolved in a mixed solvent of THF (20 ml) and methanol (20 ml), and aqueous ammonia solution (28%, 20 ml) was added thereto. The mixture was stirred for 12 hour, and then added water. The mixture was extracted with ethyl acetate, and the organic layer was dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, to obtain the desired compound as crude product (0.48 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12](O)([CH3:14])[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.S(=O)(=O)(O)O.O.C([O-])([O-])=[O:23].[Na+].[Na+].[C:28](#[N:30])[CH3:29]>>[NH2:1][C:2]1[CH:3]=[C:4]([C:12]([NH:30][C:28](=[O:23])[CH3:29])([CH3:14])[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(O)c1cc(N)cc(C(F)(F)F)c1
Reactant: CC#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(=O)NC(C)(C)c1cc(N)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 44 %

Procedure:
To a solution of 2-[3-amino-5-(trifluoromethyl)phenyl]propan-2-ol (2.05 g, 9.35 mmol) in acetonitrile (110 mL), was added concentrated sulfuric acid (1.99 mL, 37.4 mol).The reaction was allowed to stir at rt for 72 h. Water was added and the pH was adjusted to 8 by the addition of saturated aq. Na2CO3. The mixture was extracted with EtOAc (2×) and the combined organic solutions were washed with water then brine, dried over Na2SO4, filtered and evaporated. The residue was triturated with DCM and the solid was collected. The filtrate was evaporated and further purified by column chromatography. The solid and column fractions were combined to give N-{1-[3-amino-5-(trifluoromethyl)phenyl]-1-methylethyl}acetamide (1.07 g, 44.0%). LCMS: (FA) ES+ 261.1.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]#[N:10].[Cl-:11].[NH4+:12]>CO>[ClH:11].[CH3:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]([NH2:12])=[NH:10]
Reactant: [NH4+]
Reactant: [Cl-]
Reactant: Cn1ccnc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: Cl
Product: Cn1ccnc1C(=N)N
Temperature: 25 °C
Yield: 90.6 %

Procedure:
To 10 mL of methyl alcohol in a sealed tube is added sodium hydride (440 mg, 11 mmol) with stirring. 1-Methyl-2-imidazole carbonitrile (1.18 g, 11 mmol) is added. The mixture is stirred at room temperature for 20 h, and ammonium chloride (588 mg, 11 mmol) is added. The bottle is then sealed and stirred at 80° C. for 8 h, and cooled to room temperature. The mixture is filtered, and the filtrate is concentrated. The residue is treated with 1% methyl alcohol in diethyl ether, and the precipitates are collected by filtration and dried to give 1-methyl-2-imidazole carboxamidine hydrochloride as a gray solid (1.6 g). MS: m/z 125.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10](=[O:14])[CH:11]=[CH:12][CH3:13])[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH:7]=1.C(O)(=[O:17])C>C(OC(=O)C)(=O)C>[CH3:1][C:2]1[CH:3]([C:10](=[O:14])[CH:11]=[CH:12][CH3:13])[C:4]([CH3:8])([CH3:9])[CH2:5][C:6](=[O:17])[CH:7]=1
Reactant: CC(=O)O
Reactant: CC=CC(=O)C1C(C)=CCCC1(C)C
Solvent: CC(=O)OC(C)=O
Product: CC=CC(=O)C1C(C)=CC(=O)CC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10 ml of acetic anhydride were first added to a solution kept at 10° of 3.5 g of Na2Cr2O7 .2H2O in 10 ml of acetic acid and the obtained mixture was stirred for one hour. A solution of 2.1 g of 2,6,6-trimethyl-1-(but-2-enoyl)-cyclohex-2-ene [prepared according to the method described in Helv. Chim. Acta 53, 541 (1970)], in 10 ml of acetic anhydride was then added to the above mixture. After having been stirred overnight at room temperature, the reaction mixture was then poured onto crushed ice and extracted with ether. After the usual treatments of washing, drying and evaporation, there was obtained 2.0 g of crude material containing 80 % of the desired keto compound.
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[NH:12][C:11](=[O:14])[CH:10]=[CH:9][C:8]=2[CH:7]=[CH:6][C:5]1=[O:15])[CH:2]=[CH2:3].[CH3:16]C(C)([O-])C.[K+].C1COCC1.CI>CN(C=O)C>[CH3:16][O:14][C:11]1[N:12]=[C:13]2[C:8]([CH:7]=[CH:6][C:5](=[O:15])[N:4]2[CH2:1][CH:2]=[CH2:3])=[CH:9][CH:10]=1
Reactant: C=CCn1c(=O)ccc2ccc(=O)[nH]c21
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CI
Product: C=CCn1c(=O)ccc2ccc(OC)nc21

Procedure:
A solution of 1-(2-propen-1-yl)-1,8-naphthyridine-2,7(1H,8H)-dione (123 mg, 0.61 mmol) in DMF (2 ml) was treated under argon with a solution of potassium t-butoxide in THF (1M; 0.7 ml, 0.7 mmol) then methyl iodide (0.06 ml, 142 mg, 1 mmol) was added. After 30 minutes the mixture was evaporated and the residue chromatographed eluting with 0-100% ethyl acetate in hexane affording an oil (120 mg, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.CN(CCN(C)C)C.[Li]CCCC.[CH3:24][S:25]SC.S(=O)(=O)(O)O>CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[S:25][CH3:24]
Reactant: CSSC
Reactant: COc1cccc(OC)c1
Agent: CN(C)CCN(C)C
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cccc(OC)c1SC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,3-dimethoxybenzene (1.94 mL, 15 mmol) and TMEDA (2.35 mL, 15.75 mmol) in ether (40 mL) a under nitrogen atmosphere at 0° C. is added dropwise n-BuLi (9.84 mL, 1.6M in hexane, 15.75 mmol). The mixture is stirred at 0° C. for 30 min then dimethyl disulfide (1.33 mL, 15 mmol) is added and stirring is continued at RT for 30 min. The mixture is poured into dilute sulfuric acid and the ether layer is separated. The aqueous is extracted with ether. The ether solutions are combined and washed with water and brine then dried over sodium sulfate. The solvent is removed under reduced pressure to give the title compound as a white solid.