Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([NH2:10])=[N:2]1.[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12>O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([N:10]2[C:14](=[O:15])[C:13]3[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11]2=[O:16])=[N:2]1
Reactant: Nc1n[nH]c2ccccc12
Reactant: O=C1OC(=O)c2ccccc21
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1c1n[nH]c2ccccc12
Temperature: 25 °C
Yield: 398.5 %

Procedure:
A 1,4-dioxane (0.5 L) solution of 1H-indazol-3-amine (3.3 g) and phthalic anhydride (14.8 g) was stirred with heating under reflux for 15 hours. After cooled to room temperature, the reaction solution was evaporated under reduced pressure, water (50 mL) was added to the residue, and the precipitated solid was collected through filtration, washed with distilled water and ethyl acetate in that order, and dried to give the title compound as a white solid (26.0 g).
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([CH2:11]N)[OH:10]>O.O.C([O-])(=O)C.[Cd+2].C([O-])(=O)C>[C:2]1([C:1]2[O:10][CH2:9][CH2:11][N:8]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: N#Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [Cd+2]
Solvent: O
Product: c1ccc(C2=NCCO2)cc1
Temperature: 125 °C
Reaction time: 48 h

Procedure:
A mixture of about 104.1 grams (1.0 mole) benzonitrile, about 63.1 grams (1.03 mole) ethanolamine, and about 6.2 grams (0.025 mole) cadmium acetate dihydrate is heated and stirred at about 125 degrees C. to about 130 degrees C. under nitrogen for about two days. The product is distilled under vacuum and the fraction boiling at about 120 degrees C. to about 121 degrees C. at 16 mmHg is collected.
Reaction SMILES: [Cl:1]C1C=CC(O)=CC=1.ClC1C=C(O)C=C(Cl)C=1.[CH3:18][N:19]1[C:24]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][O:34][C:35]3[CH:40]=[C:39]([Cl:41])[CH:38]=[C:37]([Cl:42])[CH:36]=3)[CH2:27][CH2:26]2)=[CH:23][C:22](=[O:43])[N:21]([CH3:44])[C:20]1=[O:45]>>[ClH:1].[CH3:18][N:19]1[C:24]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][O:34][C:35]3[CH:40]=[C:39]([Cl:41])[CH:38]=[C:37]([Cl:42])[CH:36]=3)[CH2:27][CH2:26]2)=[CH:23][C:22](=[O:43])[N:21]([CH3:44])[C:20]1=[O:45]
Reactant: Oc1ccc(Cl)cc1
Agent: Cn1c(N2CCN(CCCOc3cc(Cl)cc(Cl)c3)CC2)cc(=O)n(C)c1=O
Agent: Oc1cc(Cl)cc(Cl)c1
Product: Cl

Procedure:
The same treatment as in Example 3 was effected except that 4-chlorophenol was replaced with 3,5-dichlorophenol, thereby obtaining 12.5 g of the crystals of 1,3-dimethyl-6-[4-(3-[3,5-dichlorophenoxy]propyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].CC1C=CC(S(O[CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH3:53])(=O)=O)=CC=1.O>O1CCCC1>[C:1]1([CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH3:53])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Reactant: OCCOCCOCCOCCOCCOCCOCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COCCOCCOCCOCCOCCOCCOCCOCCOCCOCc1ccccc1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 80.2 %

Procedure:
To a stirred solution of the product of step (b) (25 g) in tetrahydrofuran (500 mL) at −20° C. was added a solution of potassium tert-butoxide in tetrahydrofuran (1.61M, 50 mL) over 1 hour, maintaining the temperature at about −20° C. The reaction mixture was stirred for a further 15 minutes then a solution of the product of step (a) (29.7 g) in tetrahydrofuran (100 mL) was added over 90 minutes, maintaining the temperature at about −20° C. After stirring at −20° C. for a further 3 hours, the mixture was allowed to warm to 20° C. and stirred for 16 hours. Water (125 mL) was then added and the resultant mixture was concentrated in vacuo to 140 mL. Sodium chloride (12.5 g) was added to the stirred concentrate, which was then washed with diisopropyl ether (4×125 mL). The aqueous phase was diluted with water (50 mL) and extracted with dichloromethane (3×125 mL). The combined dichloromethane extracts were concentrated in vacuo to give the title compound as an orange-brown oil (27.93 g). GC retention time 21.8 mins
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[Cu][C:13]#[N:14].[C-]#N.[Na+]>CN(C=O)C.O>[O:9]=[C:7]1[NH:6][C:5]2[CH:10]=[CH:11][C:2]([C:13]#[N:14])=[CH:3][C:4]=2[O:8]1
Reactant: O=c1[nH]c2ccc(Br)cc2o1
Reactant: N#C[Cu]
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]c(=O)oc2c1
Temperature: 150 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
A mixture of 6-bromo-1,3-benzoxazol-2(3H)-one (2 g; 9.34 mmol) and copper (I) cyanide (1.42 g; 15.86 mmol) in 6 ml DMF is heated at 150° C. under nitrogen atmosphere for 22 hr. After cooling to room temperature, a solution of 1.55 g (31.6 mmol) of sodium cyanide in 32 ml water is added followed by 1 hr stirring. The system is extracted thoroughly with ethyl acetate, washed with brine, dried and concentrated in vacuo to provide 1.5 g (93% yield) of the title compound enough pure as to prosecute the synthesis.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH2:9]=[O:10].[OH-].[Na+]>O>[C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[C:3]=1[CH:9]=[O:10])[OH:2]
Reactant: C=O
Reactant: Oc1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=Cc1c(O)cccc1O

Procedure:
A resorcinol-formaldehyde was prepared by the addition of resorcinol (16.6 parts weight), formaldehyde (5.4 parts weight dry; 14.7 parts weight wet), sodium hydroxide (1.3 parts weight), and soft water (366 parts weight). The total solids content of the resin was approximately 6.0 wt %, and the pH was approximately 9.0.
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([O:15]CC)=[O:14])=[CH:4]2.[OH-].[Na+].Cl>C(O)C.O>[N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([OH:15])=[O:14])=[CH:4]2
Reactant: CCOC(=O)C1=Cc2cnc3cccc(n23)S1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1=Cc2cnc3cccc(n23)S1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 193.69 g of the above ethyl 5-thia-1,8b-diazaacenaphthylene-4-carboxylate in 1 l of ethanol was added a solution of 62.9 g (1.57 mol) of sodium hydroxide in 500 ml of water, and the mixture was stirred at room temperature for 0.5 hour. To this reaction mixture was added about 130 ml of concentrated hydrochloric acid with stirring to bring the pH into the range of 4-5 and the resulting precipitate was recovered by filtration and rinsed with ethanol, acetone, and diethyl ether in that order to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[C:12](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH3:12])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(F)ccc1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
20 g (126 mmol) 5-fluoro-2-nitro-phenol are dissolved in 300 ml acetone. 22.6 g (163 mmol) potassium carbonate are added and the mixture is stirred for 30 min at 20° C. Over a period of 10 min, 9.4 ml (150 mmol) methyl iodide, diluted in 50 ml acetone, is added and the mixture is stirred for a further 18 h at 20° C. Then it is left for another 12 h at 65° C. with stirring. The solvent is eliminated in vacuo, the residue is taken up in water and extracted three times with ethyl acetate. Then the combined organic phases are extracted three times with 10% aqueous sodium carbonate solution. The organic phase is dried over magnesium sulphate. The solvent is eliminated in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[CH:17]=[O:18]>>[CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH:17]=[O:18]
Reactant: CN(C)C=O
Reactant: COc1ccsc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccsc1C=O
Reaction time: 1 h

Procedure:
1.03 ml of 3-methoxythiophene were dissolved in 2.3 ml of dimethylformamide. While cooling in ice, 1.06 ml of phosphoryl chloride were added. After 1 h, the reaction solution was added to ice, and the solution was neutralized with 5 molar sodium hydroxide solution. The aqueous phase was extracted 3 times with 25 ml of diethyl ether each time, and the combined organic phases were then washed with 50 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated. 840 mg of the product with the molecular mass of 142.18 (C6H7O2S) were obtained. MS (ESI): 143.0 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]([C@@H:9]2[CH2:18][C:17]3[C:12](=[C:13]([F:20])[CH:14]=[C:15]([F:19])[CH:16]=3)[O:11][CH2:10]2)[C:7](=[S:21])[NH:6][CH:5]=1.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.ClCCl>CO>[CH2:22]([NH:1][CH2:2][CH2:3][C:4]1[N:8]([C@@H:9]2[CH2:18][C:17]3[C:12](=[C:13]([F:20])[CH:14]=[C:15]([F:19])[CH:16]=3)[O:11][CH2:10]2)[C:7](=[S:21])[NH:6][CH:5]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCCc1c[nH]c(=S)n1[C@H]1COc2c(F)cc(F)cc2C1
Reactant: O=Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: Fc1cc(F)c2c(c1)C[C@@H](n1c(CCNCc3ccccc3)c[nH]c1=S)CO2
Reaction time: 64 h

Procedure:
To (R)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione (2.36 g, 7.58 mmol) and benzaldehyde (0.85 ml, 8.34 mmol) in a mixture of methanol (15 ml), and dichloromethane (15 ml) sodium cyanoborohydride (0.67 g, 10.66 mmol) was added at 20-25° C. in portions. The mixture was stirred for 64 h, quenched with 1N HCl (12 ml) with stirring followed by 3N NaOH (12 ml). The mixture was extracted with DCM (100 ml), the organic phase was washed with brine (50 ml), dried (MgSO4) and evaporated to dryness. The residue was purified on a silica gel column with ethyl acetate and a mixture of ethyl acetate with methanol (9:1) as eluents. Fractions containing the product were collected, evaporated under reduced pressure to approx 20 ml then cooled on ice. The precipitate was collected, washed with ethyl acetate—petroleum ether (1:1) mixture, dried on air. Yield was 1.25 g (41%), the product having a mp 188-90° C. (2-propanol-DCM).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([Br:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CCCCCC.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH2:1][Br:17])[CH:3]=1
Reactant: Cc1cc(C)cc(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: Cc1cc(Br)cc(CBr)c1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
A mixture of 3,5-dimethylbromobenzene (70 g, 0.378 M), NBS (67.3 g, 0.373 M), and benzoyl peroxide (2.27 g, 0.009 M) in carbon tetrachloride (300 mL) was refluxed for 3 hr. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated in vacuo to give a pale brown oil. The crude product was dissolved in hexane and filtered through a short silica gel pad (diameter: 9.5 cm, height: 7 cm). The silica gel pad was washed with hexane until the product eluted completely. The filtrate was evaporated in vacuo to give 94 g of 1-bromo-3-(bromomethyl)-5-methylbenzene (contaminated with starting material and 1-bromo-3,5-bis-bromomethylbenzene) as a pale brown oil, which solidified on standing at room temperature. The mixture was used directly in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:9][C:10]([F:17])([F:16])[C:11](OCC)=[O:12])[C:5]([N+:23]([O-])=O)=[CH:4][N:3]=1.Cl.CCOC(C)=O.CCOCC>CC(O)=O.[Fe]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:23][C:11](=[O:12])[C:10]([F:17])([F:16])[CH2:9][N:8]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:6]=2[N:7]=1
Reactant: CCOC(=O)C(F)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Agent: [Fe]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 65.5 %

Procedure:
Compound ethyl 3-((2-chloro-5-nitropyrimidin-4-yl)(cyclopentyl)amino)-2,2-difluoropropanoate (1.0 g, 2.7 mmol) was dissolved in AcOH (10 mL) and then cooled in an ice bath. Iron powder (296 mg, 5.3 mmol) was added followed by the slow addition of HCl (1.5 mL, conc.). After 10 minutes the reaction was transferred to a heat bath and left to stir at 60° C. for 5 hours. The reaction was then cooled, the stir bar and unreacted iron removed by filtration through paper, and the solvent volume reduced by about 75% on a rotovap. The mixture was then diluted with ice water (15 mL) and EtOAc (20 mL), the layers separated, the aqueous layer washed with EtOAc (2×30 mL), the organic extracts combined, washed with sat. NaHCO3 (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated to yield a brown syrup. Trituration with EtOAc (15 mL) and ether (100 mL) was used to coax out a light yellow solid (535 mg, 65% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41-1.96 (m, 8 H) 3.98 (t, J=11.49 Hz, 2 H) 4.87 (q, 1 H) 8.12 (s, 1 H) 11.06 (br. s., 1 H). [M+H] calc'd for C12H13ClF2N4O, 303; found 303.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[O:5][C:6]2=[O:11].C(N(CC)C(C)C)(C)C.[CH3:22][O:23][CH2:24]Cl>CN(C)C=O>[CH3:22][O:23][CH2:24][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[O:5][C:6]2=[O:11]
Reactant: O=C1OC(=O)c2c(O)cccc21
Reactant: COCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cccc2c1C(=O)OC2=O
Temperature: 25 °C
Yield: 95.1 %

Procedure:
To a solution of 4-hydroxy-isobenzofuran-1,3-dione (0.5 g, 3.03 mmol) in anhydrous N,N-dimethylformamide (6 ml) under nitrogen was added N,N-diisopropylethylamine (1.05 ml, 6.06 mmol). The solution was stirred with cooling in an ice bath and chloromethyl methyl ether (0.46 ml, 6.06 mmol) was added. The reaction was allowed to slowly warm to ambient temperature and then stirred for an additional 7 hours. The mixture was concentrated in vacuo to a small volume and diluted with ethyl acetate (75 ml). The organic layer was washed with water (2×40 ml), brine (20 ml), dried (Na2SO4), filtered, and the solvent evaporated in vacuo to give 0.6 g (95%) of 4-methoxymethoxy-isobenzofuran-1,3-dione as a solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10](O)=[O:11].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C(OCC)C>[OH:11][CH2:10][C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: O=C(O)c1cc2ccccc2o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCc1cc2ccccc2o1
Reaction time: 2 h
Yield: 48.6 %

Procedure:
To a stirred solution of benzofuran 2-carboxylic acid (2.50 g) in tetrahydrofuran (50 ml) at 0° C. under nitrogen was added a solution of lithium aluminium hydride (1.0M; 7.7 ml) in tetrahydrofuran. Stirring was continued for 2 h, allowing the temperature to rise to RT. The mixture was diluted with diethyl ether (50 ml) and quenched with water (30 ml). The aqueous layer was separated and extracted with diethyl ether (2×25 ml). The combined extracts were washed with water (30 ml), sodium hydroxide solution (1M; 30 ml), water (30 ml), brine (30 ml) and dried (MgSO4). Filtration and evaporation of solvent under reduced pressure yielded the title compound (1.11 g, 49%) as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[CH2:14]([O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 102.1 %

Procedure:
3-Fluoro-4-nitrophenol (10 g, 63.65 mmol) was dissolved in N,N-dimethylformamide (120 ml), and then sodium hydride (2.68 g, 67.00 mmol, 60% in oil) was added and the mixture was stirred for 15 minutes at room temperature under a nitrogen atmosphere. After adding benzyl bromide (7.6 ml, 63.65 mmol), the mixture was stirred overnight at room temperature under a nitrogen atmosphere. Water was added to the reaction solution, and the precipitated crystals were filtered out, washed with water and dried by aspiration to obtain the title compound (16.06 g, quant.) as crude light yellow crystals. These were used without further purification for the following reaction.
Reaction SMILES: [Li]CCCC.[C:6]([O:10][C:11](=[O:20])[NH:12][C:13]1[CH:14]=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=1)([CH3:9])([CH3:8])[CH3:7].CN(CCN(C)C)C.[I:29]I>CCOCC>[C:6]([O:10][C:11](=[O:20])[NH:12][C:13]1[CH:14]=[N:15][C:16]([Cl:19])=[CH:17][C:18]=1[I:29])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)nc1
Reactant: II
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1I
Temperature: -10 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
n-BuLi (52.4 mL, 0.12 mol, 2.5 M soln in hexanes) was added dropwise over 30 mins to a cooled −78° C. solution of (6-chloro-pyridin-3-yl)-carbamic acid tert-butyl ester (10.0 g, 43.7 mmol) and TMEDA (19.8 mL, 0.13 mol) dissolved in ether. The solution was warmed to −10° C., stirred for 2 hours and then recooled to −78° C. A solution of iodine (22.75 g, 90 mmol) in ether (100 mL) was added via an addition funnel and the reaction was warmed to room temperature and stirred for 16 hours. The reaction was quenched with sat NH4Cl and sodium thiosulfite was added. The mixture was stirred for 30 mins and then extracted with ether. The organic extracts were washed with sodium thiosulfite, dried over MgSO4, filtered and concentrated. Purification by silica gel chromatography (0% to 15% EtOAc in hexanes) gave the product (8.6 g, 56%). 1H NMR (300 MHz, CDCl3): δ 1.52 (s, 9H), 6.58 (s, 1H), 7.26 (d, J=8.6 Hz, 1H), 7.96 (m, 1H), 8.23 (d, J=2.8 Hz, 1H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[CH:3][C:2]=1[OH:12].[CH:13]1[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=1.C1CCN2C(=NCCC2)CC1>CC(O)C>[CH2:19]([O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[C:2]([OH:12])[CH:3]=[CH:4]2)[C:16]1[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc2cccc(O)c2n1
Solvent: CC(C)O
Solvent: C1CCC2=NCCCN2CC1
Product: Oc1ccc2cccc(OCc3ccccc3)c2n1
Temperature: 80 °C
Reaction time: 16 h
Yield: 84.5 %

Procedure:
To a solution of quinoline-2,8-diol (5.0 g, 31.1 mmol) in i-PrOH (50 mL) was added BnBr (5.31 g, 31.1 mmol) and DBU (2.02 g, 5.32 mmol). The mixture was stirred at 80° C. for 16 h. The mixture was evaporated and to the residue was added DCM (100 mL), and this solution was washed with 0.5 N NaOH (50 mL), 10% HCl (50 mL), and H2O (50 mL). The organic layer was evaporated to give the desired compound (6.6 g, yield 85%). 1HNMR (CDCl3, 400 MHz) δ: 9.16 (br. s., 1H), 7.74 (d, J=9.8 Hz, 1H), 7.49-7.36 (m, 5H), 7.20-7.10 (m, 2H), 7.09-7.03 (m, 1H), 6.67 (d, J=9.5 Hz, 1H), 5.19 (s, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])=[CH:12][CH:11]=[CH:10][C:9]=2[O:23][CH2:24][CH2:25][S:26][CH3:27])(=[O:4])[CH2:2][CH3:3].C([O-])(O)=[O:29].[Na+].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl.O>[C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])=[CH:12][CH:11]=[CH:10][C:9]=2[O:23][CH2:24][CH2:25][S:26]([CH3:27])=[O:29])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccccc1C
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCC(=O)c1cnc2c(OCCS(C)=O)cccc2c1Nc1ccccc1C
Temperature: 4 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
3-Propanoyl-4-(2-methylphenylamino)-8-(2-methylthioethyloxy)quinoline (0.10 g, 0.26 mmol) was dissolved in methylene chloride (5 ml). NaHCO3 (45 mg) in H2O (5 ml) was added. The mixture was cooled to 4° C. A solution of 71% m-CPBA (0.062 g, 0.25 mmol) in methylene chloride (5 ml) was added dropwise. After stirring for 1 h at 2°-4° C., the organic layer was washed with a saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and evaporated. Chromatography (SiO2 ; CH2Cl2 :EtOH 90:10) gave 50 mg (48%) of the desired product.
Reaction SMILES: [CH:1]1([C:11]2[CH:12]=[C:13]([C:17](=[O:19])[CH3:18])[CH:14]=[CH:15][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:20](OCC)(=[O:26])[C:21]([O:23]CC)=[O:22].[O-]CC.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[O:26]=[C:20]([CH2:18][C:17](=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)[CH:12]=1)[C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1cccc(C2CCCc3ccccc32)c1
Agent: CC[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Product: O=C(O)C(=O)CC(=O)c1cccc(C2CCCc3ccccc32)c1
Reaction time: 1.5 h

Procedure:
Isomer A: Into 1 mL distilled tetrahydrofuran was placed 0.046 g (0.18 mmol) of 1-[3-(1,2,3,4-tetrahydronaphthalen-1-yl)-phenyl]-ethanone (isomer A), 0.054 g (0.37 mmol) diethyl oxalate, and 0.025 g (0.37 mmol) sodium ethoxide. After stirring for 1.5 hr, excess 10% citric acid solution was added and the THF removed in vacuo. The residue was partitioned between water and ethyl acetate and extracted. The combined organic extracts were washed with water, brine, dried over anhydrous sodium sulphate, filtered, and the solvent removed in vacuo to afford the title compound which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:11]([O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[OH:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccc(OCc2ccccc2)c(O)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 50.4 %

Procedure:
A mixture of 3,4-dihydroxybenzaldehyde (1.38 g, 10 mmol), benzyl bromide (1.71 g, 10 mmol), and K2CO3 (1.24 g, 9 mmol) in 20 mL acetone was stirred at rt for 15 h under Ar atmosphere. Solid was filtered off and the filtrated was diluted with EtOAc (100 mL) and washed with NaH2PO4 (sat. 100 mL), and dried over MgSO4 and concentrated. The residue was chromatographed (hexane/EtOAc) to afford 4-(benzyloxy)-3-hydroxybenzaldehyde as a white solid (1.15 g, 50%). 1H NMR (400 MHz, CDCl3) δ 9.84 (s, 1H), 7.46 (d, J=2.0 Hz, 1H), 7.44-7.40 (m, 6H), 7.04 (d, J=8.0 Hz, 1H), 5.80 (s, 1H), 5.21 (s, 2H); MS (ESI) m/z 229 (M+H+).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C(Cl)Cl.C(OCC)(=O)C>[CH2:22]([O:21][C:19]([N:15]1[CH2:16][CH2:17][CH:12]([CH2:11][OH:10])[CH2:13][CH2:14]1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 95.4 %

Procedure:
DIPEA (4.6 mL, 3.4 g, 26 mmol) was added to a solution of 4-(hydroxymethyl)piperidine (2.00 g, 17.4 mmol) dissolved in methylene chloride (20 mL). The solution was cooled in an ice bath and benzyl chloroformate (2.5 mL, 3.0 g, 18 mmol) was added dropwise over 10 min. After warming to rt and stirring for 96 h, the mixture was diluted with ethyl acetate (50 mL) and washed in succession with 25 mL each of saturated aq. sodium bicarbonate, 2N aq. HCl, saturated aq. sodium bicarbonate, and saturated aq. brine. The organic layer was dried (sodium sulfate), decanted, and evaporated to give 4.14 g of 1-(benzyloxycarbonyl)-4-(hydroxymethyl)piperidine.