Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH2:32][CH2:33]O)[CH:29]=2)[CH:24]=[CH:23][N:22]=1>CN(C)C=O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:33][CH2:32][O:31][C:28]2[CH:29]=[C:30]3[C:25]([CH:24]=[CH:23][N:22]=[CH:21]3)=[CH:26][CH:27]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: OCCOc1ccc2ccncc2c1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccc3ccncc3c2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 39.4 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (1.267 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.305 g), stirred for 15 minutes and treated with the mesylate prepared from 1.135 g of 2-(7-isoquinolyloxy)ethanol. The mixture was heated under argon at 60° C. for 5 hours. The cooled mixture was treated with glacial acetic acid (2 drops) and the volatiles were removed under vacuum. The residue was partitioned between dichloromethane and dilute cold sodium bicarbonate solution. The dichloromethane layer was washed with water, dried (Na2SO4), filtered, and evaporated to give crude product. The material was purified by HPLC (ethyl acetate) and crystallized from dichloromethane-hexane to provide 0.83 g of 4-[[2-(7-isoquinolyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester as a colorless solid, mp 144°-145° C.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([NH:23][C:24](=O)OC)=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCOCC.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:17])([F:18])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([NH:23][CH3:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Nc1ccc2c(c1)nc(C(C)(C)C)n2CC1CCC(F)(F)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CNc1ccc2c(c1)nc(C(C)(C)C)n2CC1CCC(F)(F)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Methyl {2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}carbamate (115 mg, 0.303 mmol) was dissolved in 10 mL of THF at 0° C. 1M Ha/ether (0.425 mL, 0.424 mmol) was added and the solution was stirred at 0° C. for 15 min. LiAlH4 (57 mg, 1.52 mmol) was added slowly and the solution was stirred at rt overnight. The reaction was quenched at 0° C. by the addition of MeOH (1 mL) and water (2 mL). Anhydrous Na2SO4 (5.0 g) was added and the solution was stirred at rt for 30 min. The solution was filtered and the solvent was evaporated. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. Yield: 95 mg (93%). 1H NMR (400 MHz, CHLOROFORM-D): δ 1.41-1.51 (m, 2H), 1.54 (s, 9H), 1.57-1.67 (m, 2H), 1.68-1.76 (m, 3H), 2.07-2.17 (m, 3H), 2.87 (s, 3H), 4.15 (d, J=7.42 Hz, 2H), 6.61 (dd, J=8.59, 2.34 Hz, 1H), 7.01 (d, J=1.95 Hz, 1H), 7.09 (d, J=8.59 Hz, 1H).
Reaction SMILES: [CH2:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH:2]1[O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([C@:22]1([CH3:28])[CH2:26][O:25]C(=O)[NH:23]1)[CH:16]=[CH:15]2.C(O)C.O.[OH-].[Li+].O>>[NH2:23][C@@:22]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][CH:2]3[CH2:3][CH2:4][CH:5]4[CH:10]([CH2:9][CH2:8][CH2:7][CH2:6]4)[CH2:1]3)[CH:13]=2)[CH:18]=1)([CH3:28])[CH2:26][OH:25]
Reactant: C[C@@]1(c2ccc3cc(OC4CCC5CCCCC5C4)ccc3c2)COC(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@](N)(CO)c1ccc2cc(OC3CCC4CCCCC4C3)ccc2c1
Temperature: 80 °C
Yield: 2.3 %

Procedure:
(R)-4-[6-(Decahydro-naphthalen-2-yloxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (200 mg, 0.0005 mol) was dissolved in ethanol (2.2 g, 0.049 mol) and treated with 4.2 M lithium hydroxide, monohydrate in water (2.1 mL, 0.0090 mol). The mixture was then heated to 80° C. overnight. The reaction was then cooled to room temperature and quenched with 1 N HCl. The reaction was then diluted with water and white solid formed. Solid was removed via filtration and dried overnight on filter to give 4 mg the desired product as a white solid (2%). ESI-MS: 337 (M−16)+. 1H NMR (400 MHz, DMSO-d6) δ=7.11-6.92 (m, 3H), 6.75-6.64 (m, 1H), 6.48-6.29 (m, 2H), 3.74-3.58 (m, 1H), 3.20-2.95 (m, 2 H), 1.21-0.96 (s, 22H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1[N:7]=[CH:8][S:9][C:10]=1[CH:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH3:5][C:6]1[N:7]=[CH:8][S:9][C:10]=1[CH:11]([NH:18][C:1](=[O:3])[CH3:2])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)Cl
Reactant: Cc1ncsc1C(N)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC(c1ccccc1)c1scnc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetyl chloride was added to a solution of the product from Example 56 and triethylamine in dry dichloromethane. The mixture was stirred at room temperature overnight and then washed with aqueous sodium hydrogen carbonate solution. The organic phase was separated, dried and evaporated and the residue was purified by flash chromatography to give the title compound.
Reaction SMILES: [CH2:1](I)[CH3:2].C(=O)(O)[O-].[Na+].[CH3:9][O:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][S:16][C@@H:17]2[CH2:21][NH:20][C@H:19]([C:22](=[O:25])[NH:23][CH3:24])[CH2:18]2)=[CH:13][CH:12]=1.[Cl-].[Na+]>CN(C)C=O>[CH2:1]([N:20]1[CH2:21][C@@H:17]([S:16][CH2:15][C:14]2[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:27][CH:26]=2)[CH2:18][C@H:19]1[C:22](=[O:25])[NH:23][CH3:24])[CH3:2]
Reactant: CNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1
Reactant: CCI
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C[C@@H](SCc2ccc(OC)cc2)C[C@H]1C(=O)NC
Reaction time: 1 h

Procedure:
0.71 ml of ethyl iodide and 742 mg of sodium bicarbonate were added to a solution of 2.25 g of (2S, 4S)-4-(4-methoxybenzylthio)-2-methylcarbamoylpyrrolidine dissolved in 20 ml of dry dimethylformamide, and the mixture was stirred at 0° to 5° C. for 1 hour and then at room temperature for 5 hours. At the end of this time, the reaction mixture was poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluted with ethyl acetate), to afford 1.87 g of the title compound as colorless crystals, melting at 68°-70° C.
Reaction SMILES: O.NN.[CH2:4]([O:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2C(=O)C3=CC=CC=C3C2=O)=[CH:12][C:11]=1[N+:27]([O-:29])=[O:28])=[O:8])[CH3:5]>COCCOC>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([O:6][CH2:4][CH3:5])=[O:8])=[C:11]([N+:27]([O-:29])=[O:28])[CH:12]=1
Reactant: CCOC(=O)Nc1ccc(N2C(=O)c3ccccc3C2=O)cc1[N+](=O)[O-]
Agent: NN
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)Nc1ccc(N)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 93.7 %

Procedure:
21.0 g (0.42 mol) hydrazine hydrate is added dropwise with stirring under reflux to a suspension of 142.1 g (0.4 mol) 2-ethoxycarbonylamino-5-phthalimido-nitrobenzene in 700 ml 1,2-dimethoxyethane and the mixture is allowed to react for a further 2 hours. After cooling to room temperature, precipitated phthalyl hydrazide is filtered off and the dark red filtrate in the vacuum is evaporated to dryness. The remaining solid residue is recrystallized from about 150 ml toluene. 84.4 g 5-amino-2-ethoxycarbonylaminonitrobenzene are obtained as dark red crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7]2)([O-:3])=[O:2].ClCl.C(Cl)(Cl)[Cl:16]>CC(O)=O>[Cl:16][C:11]1[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]2[C:10]=1[NH:9][CH2:8][CH2:7]2
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2
Reactant: ClC(Cl)Cl
Agent: ClCl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Cl)c2c(c1)CCN2

Procedure:
To a solution of 5-nitroindoline (0.5 g, 3.1 mmol) in 15 mL of AcOH was added a solution of Cl2 in AcOH dropwise until 30% of starting material was consumed. The reaction mixture was concentrated in vacuo, yielding an oil which was subjected to column chromatography (CHCl3, neat) to provide 0.23 g (1.2 mmol) of the desired product.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[C:13]([CH3:14])=[N:12][N:11]=[C:10]([C:15]2[CH:16]=[CH:17][C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=2)[C:9]2[CH:8]=[C:7]([O:25][CH3:26])[C:6]([O:27][CH3:28])=[CH:5][C:4]1=2>CCCCCC.CC(O)C>[CH3:1][CH2:2][CH:3]1[C:13]([CH3:14])=[N:12][N:11]=[C:10]([C:15]2[CH:16]=[CH:17][C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=2)[C:9]2[CH:8]=[C:7]([O:25][CH3:26])[C:6]([O:27][CH3:28])=[CH:5][C:4]1=2
Reactant: CC[C@H]1C(C)=NN=C(c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc21
Solvent: CC(C)O
Solvent: CCCCCC
Product: CCC1C(C)=NN=C(c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc21

Procedure:
Analytical evaluations of the starting material, and final preparations of R- and S-tofisopam were performed by using Chiral Tech OD GH060 columns (Daicel) (Hexane/IPA 90/10, 25° C., detection at 310 nm). See FIG. 3a and 3b. The final preparation of R-tofisopam was 98%+ pure by analytical chromatography. The final preparation of S-tofisopam was 95%+ pure by analytical chromotography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=3)=[C:16]([O:27][CH2:28][CH2:29][OH:30])[N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>C(O)(=O)C.Cl.O1CCOCC1.[C].[Pd]>[ClH:1].[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]2[C:12]([NH:11][S:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)(=[O:10])=[O:9])=[N:13][CH:14]=[N:15][C:16]=2[O:27][CH2:28][CH2:29][OH:30])=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(-c2c(NS(=O)(=O)c3ccc(Cl)cc3)ncnc2OCCO)cc1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Nc1ccc(-c2c(NS(=O)(=O)c3ccc(Cl)cc3)ncnc2OCCO)cc1
Reaction time: 16 h

Procedure:
200 mg of p-chloro-N-[6-(2-hydroxyethoxy)-5-(p-nitrophenyl)-4-pyrimidinyl]benzenesulfonamide in 15 ml of glacial acetic acid and 2 ml of 4N HCl in dioxane were hydrogenated over 50 mg of palladium-carbon (10%) at room temperature and normal pressure. After filtering the catalyst under suction, the solution was evaporated under reduced pressure. The residue was dissolved in 30 ml of methanol and the solution was treated with 1 ml of dioxane-HCl. After 16 hours, the solution was evaporated under reduced pressure and the residue was recrystallized from methanol and acetonitrile. There was obtained N-[5-(p-aminophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl]-p-chlorobenzenesulfonamide hydrochloride, melting point 206° C. (with decompositon).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:22][C@@H:23]([CH2:32]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>CN(C=O)C>[CH3:22][C@@H:23]([CH2:32][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=3)[CH2:14][CH2:13]2)=[CH:16][CH:17]=1)[CH2:24][C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](C)CC(=O)OC(C)(C)C)cc1
Reactant: Oc1ccc(N2CCN(c3ccncc3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](COc1ccc(N2CCN(c3ccncc3)CC2)cc1)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 42.4 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 2.44 g) was added to a stirred suspension of 4-[4-(4-pyridyl)piperazin-1-yl]phenol (15.5 g) in dry DMF (120 ml) and the mixture was stirred for 45 minutes at room temperature. tert-Butyl (3R)-3-methyl-4-(p-toluene-sulphonyloxy)butyrate (20 g) was added and the mixture was stirred at room temperature for 20 hours. The mixture was evaporated and the residue was partitioned between dichloromethane and water. The organic layer was washed with water, filtered through phase separating paper (Whatman IPS) and evaporated. The residue was triturated under diethyl ether. The solid so obtained was recrystallised from ethyl acetate to give tert-butyl (3R)-3-methyl-4-[4-[4-(4-pyridyl)piperazin-1-yl]phenoxy]butyrate (10.6 g), m.p. 112°-113° C.; [alpha]D =-5.5° (conc.=1g/100 ml of methanol; 20° C.); NMR (CDCl3) δ 8.3(2H,d), 6.89(4H,m), 6.7(2H,m), 3.79(2H,d), 3.46(4H,m), 3.28(4H,m), 2.31-2.53(2H,m), 2.08-2.21(1H,m), 1.44(9H,s), 1.07(3H,d).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][C:13]([NH:23][C:24](=[O:41])[C:25]2[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][C:28]([C:35]([F:38])([F:37])[F:36])=[CH:27][C:26]=2[O:39][CH3:40])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[CH3:40][O:39][C:26]1[CH:27]=[C:28]([C:35]([F:36])([F:37])[F:38])[CH:29]=[C:30]([C:31]([F:34])([F:32])[F:33])[C:25]=1[C:24]([NH:23][C:13]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:14][CH2:15][CH2:16][NH:11][CH2:12]1)=[O:41]
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC1(c2ccccc2)CCCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC1(c2ccccc2)CCCNC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.4 %

Procedure:
To a solution of 445 mg (0.767 mmol) rac-3-(2-methoxy-4,6-bis-trifluoromethyl-benzoylamino)-3-phenyl-piperidine-1-carboxylic acid benzyl ester in methanol (4.5 ml) were added 44 mg Pd/C 10%. The mixture was stirred under a hydrogen atmosphere at room temperature for 1.5 hour. The apparatus was purged with argon. The catalyst was filtered and the filtrate was concentrated in vacuo to provide 330 mg (96%) of the title compound as a white foam. MS (m/e): 447.3 (M+H).
Reaction SMILES: [Na].Cl[C:3]1[N:4]=[N:5][C:6]([S:9][CH2:10][CH:11]=[CH2:12])=[CH:7][CH:8]=1.[CH:13]1[C:18]([OH:19])=[CH:17][CH:16]=[C:15]([CH3:20])[CH:14]=1>>[CH3:20][C:15]1[CH:14]=[CH:13][C:18]([O:19][C:3]2[N:4]=[N:5][C:6]([S:9][CH2:10][CH:11]=[CH2:12])=[CH:7][CH:8]=2)=[CH:17][CH:16]=1
Reactant: Cc1ccc(O)cc1
Reactant: C=CCSc1ccc(Cl)nn1
Agent: [Na]
Product: C=CCSc1ccc(Oc2ccc(C)cc2)nn1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
0.23 g(0.01 mol) of metallic sodium was dissolved in 30 ml of dry p-cresol. To the resulting solution was added 1.87 g(0.01 mol) of 3-chloro-6-allylthiopyridazine and then the reaction solution was stirred for 5 hours at 100±5° C. After the reaction was allowed to stop, the reaction solution was cooled and adjusted to alkaline (pH 14) with 150 ml of 2N--NaOH, thereby precipitating the crystals. The precipitated crystal was extracted with diethyl ether, washed twice with purified water, dried over anhydrous magnesium sulfate and then concentrated to remove diethyl ether. The resulting oily residue was slowly cooled to obtain the title compound as a pale white amorphous crystal.
Reaction SMILES: [C:1]12([NH:11][C:12](=[O:31])[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21]C(=O)C(F)(F)F)=[C:17]([N+:28]([O-:30])=[O:29])[CH:16]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH-].[Na+]>CO>[C:1]12([NH:11][C:12](=[O:31])[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([N+:28]([O-:30])=[O:29])[CH:16]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: O=C(CCc1ccc(NC(=O)C(F)(F)F)c([N+](=O)[O-])c1)NC12CC3CC(CC(C3)C1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccc(CCC(=O)NC23CC4CC(CC(C4)C2)C3)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.5 g of N-(1-Adamantyl)-3-(3-nitro-4-trifluoroacetamidophenyl)propionamide (prepared as described in Example 20) was dissolved in 10 ml of methanol. 10 ml of a 2N aqueous solution of sodium hydroxide were then added to the solution, which was then stirred for 3 hours at room temperature. At the end of this time, the methanol was removed by distillation under reduced pressure. Extraction of the residue with ethyl acetate afforded the title compound as an oily substance.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10]C(=O)OC(C)(C)C)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[ClH:18]>>[ClH:18].[NH2:10][C@@H:7]1[CH2:8][CH2:9][C@H:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]1
Reactant: CC(=O)[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)CC1
Agent: Cl
Product: CC(=O)[C@H]1CC[C@@H](N)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of tert-butyl cis-4-acetylcyclohexylcarbamate (1.8 g, 7.46 mmol) in HCl (4M in dioxane) (93 mL, 373 mmol) was stirred at RT for 16 hours. The resulting mixture was concentrated to dryness to afford 1-(cis-4-aminocyclohexyl)ethanone hydrochloride as a white solid (1.33 g, 100% yield).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:23][CH2:24][CH3:25])[CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:9]=[C:8]1[CH2:20][CH2:21][CH3:22])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:34])C=1>>[CH2:24]([O:23][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N+:12]([O-:34])=[CH:11][C:10]=2[N:9]=[C:8]1[CH2:20][CH2:21][CH3:22])[CH3:25]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCC(OCC)OCC
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCCc1nc2c[n+]([O-])c3ccccc3c2n1CCC(OCC)OCC

Procedure:
The general method described in Steps 9 and 10 of Example 1 was used to aminate 1-(3,3-diethoxyproyl)-2-propyl-1H-imidazo[4,5-c]quinoline (4.50 g, 13.2 mmol) by reaction with m-CPBA (5.3 g) to provide 1-(3,3-diethoxypropyl)-5-oxido-2-propyl-1H-imidazo[4,5-c]quinoline followed by reaction with p-toluenesulfonyl chloride (4.89 g, 25.7 mmol) and ammonium hydroxide solution (40 mL) to provide 1-(3,3-diethoxypropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as grey needles after recrystallization from methanol, mp 148-150° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=O.[OH:11][CH2:12][C@@H:13]([C@H:15]([C@@H:17]([C@@H:19]([CH2:21][OH:22])[OH:20])[OH:18])[OH:16])[OH:14]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=[C:21]([C@@H:19]([C@H:17]([C@@H:15]([C@@H:13]([CH2:12][OH:11])[OH:14])[OH:16])[OH:18])[OH:20])[OH:22]
Reactant: Cc1ccc(C=O)cc1C
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Product: Cc1ccc(C=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)cc1C

Procedure:
The ionic fluids prepared are used for carrying out the dehydration reaction at room temperature, for example 3,4 dimethyl benzaldehyde is reacted with sorbitol to form 3,4-dimethylbenzylidene sorbitol.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[N+:15]([O-:17])=[O:16].[C:18]([O:22][C:23](=[O:26])[CH2:24]Cl)([CH3:21])([CH3:20])[CH3:19]>CN1C(=O)CCC1>[F:7][C:8]1[CH:13]=[C:12]([CH2:24][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:26])[CH:11]=[C:10]([F:14])[C:9]=1[N+:15]([O-:17])=[O:16]
Reactant: CC(C)(C)OC(=O)CCl
Reactant: O=[N+]([O-])c1c(F)cccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)Cc1cc(F)c([N+](=O)[O-])c(F)c1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 50.5 %

Procedure:
A mixture of potassium tert-butoxide (12.3 g, 111.0 mmol) in NMP (100 ml) was cooled to −20° C. under N2. A mixture of 2,6-difluoronitrobenzene (5.0 g, 31.43 mmol) and tert-butylchloroacetate (7.6 ml, 53.11 mmol) in NMP (100 ml) was added slowly at −10° C. to -20° C. over 1.5 hours. After 1.5 hours the reaction was quenched by pouring into 2M HCl (120 ml) and ice, then heptane (300 ml) was added. The mixture was stirred for 10 minutes, separated and the aqueous extracted with heptane (2×400 ml). The organic layer was washed with brine (×2), dried (MgSO4), filtered and washed with heptane. The solution was concentrated in vacuo and the residue purified by column chromatography (3-4% EtOAc/Heptane) to provide the title compound as an orange oil (4.34 g, 53% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][OH:19])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[N-]=[C:21]=[S:22]>>[OH:19][CH2:18][CH2:17][CH2:16][N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:8]=[CH:9][C:4]([N:1]=[C:21]=[S:22])=[CH:5][CH:6]=2)[CH2:11][CH2:12]1
Reactant: [N-]=C=S
Reactant: O=[N+]([O-])c1ccc(N2CCN(CCCO)CC2)cc1
Product: OCCCN1CCN(c2ccc(N=C=S)cc2)CC1

Procedure:
This compound was prepared from 4-(4-nitrophenyl)-1-piperazinepropanol (which can be prepared according to the procedure of Loewe and Mieth Arzneim.-Forsch. 1966, 16, 1306–1310) using the hydrogenation and isothiocyanate-forming reactions used in Example 4. MS (ES) MH+=277.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O[CH:10]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:10]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccccc3)CC2)c1
Reactant: Oc1ccc(F)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(Oc3ccc(F)cc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-fluorophenol and N-{3-[1-(5-hydroxy-5-phenylpentyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 503.2 (M+H)+.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C@@H:12]1[CH2:16][CH2:15][C@@H:14]([C:17]([N:19]2[CH2:26][CH2:25][C@:24]3([CH3:30])[C:27]([CH3:29])([CH3:28])[C@H:20]2[CH2:21][C:22]2[C:34]([OH:35])=[CH:33][CH:32]=[CH:31][C:23]=23)=[O:18])[CH2:13]1.C(N(CC)CC)C>ClCCl>[OH:35][C:34]1[C:22]2[CH2:21][C@@H:20]3[C:27]([CH3:29])([CH3:28])[C@:24]([CH3:30])([C:23]=2[CH:31]=[CH:32][CH:33]=1)[CH2:25][CH2:26][N:19]3[C:17]([C@@H:14]1[CH2:15][CH2:16][C@@H:12]([NH:11][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH2:13]1)=[O:18]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC1(C)[C@H]2Cc3c(O)cccc3[C@]1(C)CCN2C(=O)[C@@H]1CC[C@@H](N)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)[C@H]2Cc3c(O)cccc3[C@]1(C)CCN2C(=O)[C@@H]1CC[C@@H](NS(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzenesulfonyl chloride (41 mg) is added to a solution of [(1R,3R)-3-amino-cyclopentyl]-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone (80 mg) and triethylamine (120 μL) in dichloromethane (1 mL). The resulting solution is stirred at room temperature overnight and then concentrated under reduced pressure. The residue is purified by HPLC on reversed phase (MeCN/H2O/F3CCO2H) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH2:8]Cl.[O:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23].CN(C)C(N(C)C)=N>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:19]1[C:20](=[O:22])[CH2:21][O:17][C:18]1=[O:23]
Reactant: Fc1ccc(-c2ccc(CCl)c(Cl)c2)cc1
Reactant: O=C1COC(=O)N1
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: O=C1COC(=O)N1Cc1ccc(-c2ccc(F)cc2)cc1Cl

Procedure:
A solution of 0.5 g (1.96 mmol) of 3-chloro-4-(chloromethyl)-4′-fluoro-1,1′-biphenyl, prepared in step 5.3., 0.240 g (2.35 mmol) of 1,3-oxazolidine-2,4-dione and 0.45 g (3.92 mmol) of 1,1,3,3-tetramethylguanidine in 10 ml of tetrahydrofuran is refluxed for 18 hours.