Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[OH:11].[Cl-].[Ca+2].[Cl-].O>C(O)C>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([OH:11])[CH:4]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Cl)c(O)c1
Temperature: 90 °C
Yield: 92.4 %

Procedure:
A suspension of 2-chloro-5-nitrophenol (25.0 g, 144 mmol), calcium chloride (40 g, 360 mmol) and reduced iron (40.2 g, 720 mmol) in ethanol (500 mL)/water (50 mL) was stirred with heating at 90° C. for 4 hr. After the reaction mixture was cooled to room temperature, the insoluble material was filtered off through a pad filled with celite, and washed with ethanol. The filtrate and the washing fluid were combined, and concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (400 mL), washed with water (250 mL×2), 5% aqueous sodium hydrogen carbonate solution (250 mL×2) and saturated brine (250 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (19.1 g, 92%) as a brown powder. This was used for the next reaction without further purification.
Reaction SMILES: CN(C)C=O.F[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1.[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.[H-].[Na+]>O>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[CH:8][CH:9]=1)#[N:14]
Reactant: N#Cc1ccc(F)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-n2ccnc2)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
1500 ml of dry dimethylformamide (DMF) are placed in a 1000 ml four-necked flask while passing nitrogen over it and 72.67 g (0.6 mol) of 4-fluorocyanobenzene and 61.2 g (0.9 mol) of imidazole and finally 21.6 g (0.9 mol) of sodium hydride are added. The reaction mixture is heated to 100° C., stirred at this temperature for 4 hours and subsequently overnight at room temperature. The reaction mixture is then poured into water and the resulting mixture is extracted a number of times with dichloromethane. The organic phase is dried, evaporated on a rotary evaporator and finally dried further at 60° C. under reduced pressure. The yield is 94 g (93% of theory).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH3:13])=[N:10][CH:11]=1.BrBr.O>C(O)(=O)C>[CH3:13][O:12][C:9]1[N:10]=[C:11]2[S:1][C:2]([NH2:3])=[N:5][C:6]2=[CH:7][CH:8]=1
Reactant: COc1ccc(N)cn1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2nc(N)sc2n1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Potassium thiocyanate Fluka 60519 (38.8 g, 400 mmol, 8.0 equiv.) and 5-amino-2-methoxypyridine Aldrich A6, 120-9 (6.2 g, 50 mmol, 1.0 equiv.) were added to 100 mL glacial acetic acid precooled to 5° C. (semi solid) with mechanical stirring. Bromine (23.9 g, 150 mmol, 3.0 equiv.) dissolved in 30 mL glacial acetic acid was added dropwise to the reaction mixture over 1.5 hr at 0° C. The thick slurry was stirred 2 hrs at 0° C. and overnight at RT. Then 30 mL water was added to the orange suspension, which was heated to 85° C. and filtered hot. The residue was treated again with acetic acid, heated and filtered like before. The combined filtrates were cooled and neutralized with NH4OH at pH 6. The red precipitate was filtered, dissolved in ethyl acetate and washed with NaHCO3 and brine, dried over Na2SO4, evaporated and crystallized from ethyl acetate-hexane using charcoal to give 5-methoxy-thiazolo[5,4-b]pyridin-2-ylamine m/e 182.0 (MH+).
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[N+:12]([CH3:15])([O-:14])=[O:13].[OH-].[Na+]>CO.O>[CH2:10]1[O:11][C:3]2[CH:2]=[CH:1][C:6]([CH:7]=[CH:15][N+:12]([O-:14])=[O:13])=[CH:5][C:4]=2[O:9]1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])C=Cc1ccc2c(c1)OCO2
Temperature: 4 °C
Reaction time: 0.5 h

Procedure:
In a 45-L cryogenic reactor with a contoured, anchor stirrer was dissolved 5.537 kg (36.9 moles) piperonal in 9 L methanol and 2.252 kg (36.9 moles) nitromethane at 15°-20° C. The jacket temperature was set to -5° C. and the reaction solution cooled to a temperature of +3.5° C. A 21° C. solution of 3.10 kg (38.8 moles) 50% (w:w) aquous sodium hydroxide diluted with 3.7 L water was pumped in. The reaction temperature was maintained between 10°-15° C. When addition was complete, the jacket temperature was reset to 1° C. and stirring continued for 30 minutes. A mixture of 7 kg ice in 19 L water was added to dissolve most of the solid. The reaction mixture was filtered through canvas and then a 27R1OSV Honeycomb filter. The filtered solution was metered into a 21° C. mixture of 7.4 L concentrated hydrochloric acid in 11.1 L deionized water. The final reaction temperature was 26° C. The resulting product was centrifuged and washed until the wash pH rose to at least 6 (by pH indicating paper). The crude product was dissolved in 92 L dichloromethane and the layers separated. The aqueous layer was washed once with 8 L dichloromethane. The combined organics were dried over 1.32 kg magnesium sulfate and filtered through Whatman #1paper. The volume was reduced to 20% and the solution cooled to 4° C. Filtration through Whatman #1paper, followed by ambient temperature drying in vacuo with an air leak afforded 1.584 kg (22%) of a first crop Concentration of the MLS to 25% followed by similar cooling, filtration, and drying afforded 0.262 kg (4%) of a second crop. The yellow product darkened on standing in light and air.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].Cl[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:1]2[CH:5]=[CH:4][CH:3]=[C:2]2[CH:6]=[O:7])=[CH:11][CH:12]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=Cc1ccc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cccc2C=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 110.4 %

Procedure:
To a solution of 1H-pyrrole-2-carbaldehyde (0.58 g, 6.1 mmol) and 1-(chloromethyl)-4-methoxybenzene (1.0 mL, 7.3 mmol) in DMF (15 mL) was added K2CO3 (3.4 g, 24.5 mmol). After stirring 16 hr at room temperature, the mixture was diluted with ethyl acetate (200 mL) and washed with H2O (2×100 mL) then brine (100 mL). The organic layer was dried (MgSO4), filtered and then concentrated to provide 1.45 g (˜100%) of crude 1-(4-methoxybenzyl)-1H-pyrrole-2-carbaldehyde. This material was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>>[CH3:19][S:20]([O:18][CH2:17][CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)(=[O:22])=[O:21]
Reactant: OCCCc1ccc(OCc2ccccc2)cc1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)OCCCc1ccc(OCc2ccccc2)cc1
Yield: 98 %

Procedure:
In substantially the same manner as in Reference Example 12, 3-(4-benzyloxyphenyl)propanol was allowed to react with methanesulfonyl chloride to give 3-(4-benzyloxyphenyl)propyl methanesulfonate. The yield was 98%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 74-75° C.
Reaction SMILES: CC1N=CNC=1.BrCCCC[N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22].C(N(CC)CC)C>CN(C)C=O>[C:16]1(=[O:17])[NH:12][C:13](=[O:22])[C:14]2=[CH:21][CH:20]=[CH:19][CH:18]=[C:15]12
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: Cc1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1NC(=O)c2ccccc21
Temperature: 120 °C
Reaction time: 3 h
Yield: 3.6 %

Procedure:
4-Methylimidazole (5.0 g) and N-(4-bromobutyl)phthalimide (17.2 g) were dissolved in dimethylformamide (250 ml), triethylamine (25.5 ml) was added to the solution, and the resulting mixture was stirred at 120° C. for 3 hours. The reaction mixture was left to cool to room temperature, then ethyl acetate and distilled water were added to the reaction mixture, and the layers were separated. The organic layer was washed with distilled water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate. The reaction mixture was stirred, the deposited solid was removed by filtration, and the resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:methanol=20:1). A mixed solution of ethyl acetate and hexane was added to the resulting roughly purified product, and the resulting mixture was stirred with heating to dissolve the roughly purified product, and then gradually cooled to room temperature to deposit a solid. The deposited solid was collected by filtration to obtain a phthalimide compound (324 mg). (2) By using the compound obtained in (1) mentioned above (324 mg) as a starting material, the title compound (183 mg) was obtained in the same manner as that of Reference Example 9, (2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].N1C=CN=C1.CN(C=O)C>CCOCC>[CH3:13][Si:12]([CH3:14])([C:15]([CH3:18])([CH3:17])[CH3:16])[O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)Oc1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.6 %

Procedure:
To 4-amino-3-nitrophenol (20 g, 128.9 mmol) was added tert-butyldimethylsilyl chloride (21.5 g, 142.9 mmol), imidazole (13.3 g, 194.8 mmol), and DMF (100 mL). The mixture was stirred at room temperature for 3 h and then diluted with Et2O and washed with H2O. The organics were concentrated under reduced pressure and the resulting solid recrystallized from Et2O—H2O; yielding 26.5 g (76%) product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[C:10](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(F)ccc1Br
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1cc(F)ccc1Br
Temperature: 60 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a suspension of 2-bromo-5-fluorophenol (20.0 g, 104.7 mmol) and potassium carbonate (21.71 g, 157.1 mmol) in acetone (200 mL) was added dimethyl sulphate (10.90 mL, 115.2 mmol). The resulting suspension was allowed to stir at 60° C. for 2 h before being allowed to cool and then concentrated in vacuo. The residue was dissolved in ether (200 mL) and water (100 mL). The organic phase was washed with aqueous hydrochloric acid (2 N, 50 mL), saturated sodium bicarbonate solution (50 mL) with the resulting organic phase being dried (MgSO4) and the solvent evaporated in vacuo to give a pale yellow oil (21.46 g, 100%). δH (300 MHz, CDCl3) 7.45 (1H, dd, Ar), 6.70–6.55 (2H, m, Ar), 3.90 (3H, s, OCH3).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]=1.C(=O)([O-])O.[Na+]>C(O)C.O>[Br:18][C:15]1[CH:16]=[CH:17][C:12]2[N:13]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:11]=2)[CH:14]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Nc1ccc(Br)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Brc1ccc2nc(-c3ccccc3)cn2c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 65.9 %

Procedure:
1.99 g of 2-bromo-1-phenylethanone, 1.73 g of 2-amino-5-bromopyridine and 1 g of sodium hydrogen carbonate in a mixture of 20 ml of ethanol and 5 ml of water are placed in a round-bottomed flask. The mixture is heated at 80° C. for 4 h and left to cool and 40 ml of water are added. The mixture is stirred for 15 min and the precipitate is then recovered by filtration; it is washed with water and then with diisopropyl ether and dried in a desiccator. 1.8 g of compound are obtained. Mp=192-194° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([O:15]CC)=O.[C:18]1([NH:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:12][C:4]1[NH:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[C:2]2[C:3]=1[C:13](=[O:15])[N:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[N:25]=2
Reactant: NNc1ccccc1
Reactant: CCOC(=O)c1c(C)nc2ccccc2c1Cl
Product: Cc1[nH]c2ccccc2c2nn(-c3ccccc3)c(=O)c1-2

Procedure:
The title compound was synthesized following the procedure described in step 3 using 3g and phenyl hydrazine. 1H NMR (DMSO-d6) δ (ppm): 2.77 (3H, s), 7.13 (1H, t, J=7.42 Hz), 7.45 (3H, m), 7.62 (2H, m), 8.20 (3H, m). m/z 276.4 (MH+).
Reaction SMILES: C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.[CH3:24][CH:25]([C:31]([CH3:33])=[O:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>O>[OH:32][CH:31]([CH3:33])[CH:25]([CH3:24])[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)C(C)C(C)=O
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Solvent: O
Product: CCOC(=O)C(C)C(C)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
To a 6 L Erlenmeyer flask containing Baker's yeast (100 g) and sucrose (150 g) was added tap water (1000 mL) and the reaction mixture was mechanically stirred at room temperature for 0.5 h. Ethyl 2-methylacetoacetate (10 g, 0.0694 mol) was added to the reaction mixture and stirring continued for 24 h. Sucrose (50 g) was added and stirring continued for another 24 h. Hyflo super cel (50 g) was added to the reaction mixture and filtered through a sintered glass funnel. The aqueous solution was then extracted with ether (1.5 L), dried over sodium sulfate, and filtered. The solvent ether was removed via simple distillation to obtain ethyl 3-hydroxy-2-methylbutyrate (10 g, 100%) as a mixture of two isomers: 1H NMR (CDCl3) δ 1.18-1.30 (18H, m), 2.47-2.52 (2H, m), 3.85-3.91 (1H, m), 4.05-4.10 (1H, m), 4.13-4.21 (4H, m).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br-].[CH3:13][C:14]([CH3:16])=[O:15].Cl>CCOCC>[OH:15][C:14]([CH3:16])([CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:13]
Reactant: BrCCCc1ccccc1
Reactant: CC(C)=O
Agent: Cl
Agent: [Br-]
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)(O)CCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a mixture of magnesium turnings 13.16 g (0.541 mol) in 200 ml of anhydrous Et2O was added 100.0 g (0.492 mol) of 1-bromo-3-phenyl propane as a solution in 100 ml of Et2O. After of 5-10 ml of the solution had been added, the addition was stopped until the formation of the Grignard reagent was in progress. The remaining bromide was then added over 1 hour. The Grignard reagent was stirred for 20 minutes at 35° C. and then 31.64 g (0.541 mol) of acetone was added over a 45 minute period. The reaction was stirred overnight at room temperature before being cooled to 0° C. and acidified by the careful addition of 20% HCl. The aqueous layer was extracted with Et2O (3×200 ml) and the combined organic layers washed with water, and saturated aqueous NaCl before being dried over MgSO4. Removal of the solvent under reduced pressure and distillation of the residue afforded 63.0 g (72%) of the product as a pale-yellow oil, bp 99°-102° C./0.5 mm Hg. 1H NMR (CDCl3): δ 7.28-7.18 (5H, m), 2.63 (2H, t, J=7.5 Hz), 1.68 (2H, m), 1.52 (2H, m), 1.20 (6H, s).
Reaction SMILES: C(O)C.[NH2:4][C:5]1[CH:14]=[CH:13][C:8]2=[N:9][C:10](=[O:12])[N:11]=[C:7]2[CH:6]=1.[CH2:15]=[C:16]1[O:20][C:18](=[O:19])[CH2:17]1>O>[C:18]([NH:4][C:5]1[CH:14]=[CH:13][C:8]2=[N:9][C:10](=[O:12])[N:11]=[C:7]2[CH:6]=1)(=[O:19])[CH2:17][C:16]([CH3:15])=[O:20]
Reactant: C=C1CC(=O)O1
Reactant: Nc1ccc2c(c1)=NC(=O)N=2
Solvent: O
Solvent: CCO
Product: CC(=O)CC(=O)Nc1ccc2c(c1)=NC(=O)N=2
Yield: 95 %

Procedure:
The mother liquor obtained is re-used in four further reaction cycles by using it at 80° C. to replace fresh ethanol containing 50% by weight of water for dissolving 2.86 kg per hour of 5-amino-2-benzimidazolone at such a rate that 26.86 kg per hour of amine solution can be reacted as described above with 2.06 kg per hour of diketene. Workup gives 4.25 to 4.34 kg per hour of 5-acetoacetylamino-2-benzimidazolone of consistent quality, corresponding to a yield of 95 to 97% based on amine.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11].[H][H]>CC(O)C>[CH3:3][O:4][C@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[OH:11]
Reactant: [H][H]
Reactant: COC1CCCCC1=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CO[C@H]1CCCC[C@H]1O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
In a 100 ml autoclave were charged 3.4 ml of a 0.1M solution of potassium hydroxide (0.34 mmol) in 2-propanol, 4.2 mg (0.02 mmol) of (1S,2S)-diphenylethylenediamine, 1.28 g (10.0 mmol) of 2-methoxycyclohexanone, 8.4 mg (0.005 mmol) of Ru2Cl4 [(S)-BINAP]2NEt3, and 6.5 ml of 2-propanol in a nitrogen atmosphere, and hydrogen was introduced therein to 50 atm. The mixture was stirred at 50° C. for 60 minutes and cooled to room temperature. The disappearance of the starting material was confirmed by gas chromatography. The solvent was evaporated under reduced pressure, and the residue was distilled under reduced pressure to obtain (1R,2S)-2-methoxycyclohexanol. The optical purity of the product was found to be 97% d.e. and 92% e.e. by gas chromatography.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:9]=1[C:10]([O:12]C)=O)(=[O:7])=[O:6].[CH3:21][NH:22][CH3:23].CC(C)([O-])C.[K+]>C(O)(C)(C)C.CO>[CH3:21][N:22]([CH3:23])[C:10](=[O:12])[C:9]1[C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=[CH:17][C:8]=1[S:5]([NH:4][CH2:3][CH2:2][OH:1])(=[O:6])=[O:7]
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCO
Reactant: CNC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)(C)O
Product: CN(C)C(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCO
Reaction time: 96 h
Yield: 87.7 %

Procedure:
A solution of methyl 2-[N-(2-hydroxyethyl)aminosulfonyl]-6-nitrobenzoate (4.58 g, 15.1 mmol) in absolute MeoH (50 ml) was added to a solution of dimethylamine (6.8 g, 0.15 mol) and potassium tertbutoxide (0.68 ml of a 0.262 M solution in tertbutanol) in absolute MeOH (100 ml). After stirring at 20°-25° for 4 days, solvents were removed under reduced pressure. The residue was dissolved in EtOAc and washed with 0.5 N HCl followed by a saturated aqueous NaCl solution. The EtOAc extract was dried (Na2SO4), filtered and concentrated to give 4.2 g (88%) of product.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[F-:12].[K+].C1S(=O)(=O)CCC1>>[F:12][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: [F-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: O=[N+]([O-])c1ccc(F)c(F)c1
Temperature: 110 °C
Yield: 10.3 %

Procedure:
1,500 parts of 3-chloro-4-fluoronitrobenzene and 1,000 parts of potassium fluoride are heated in 1,500 parts of tetramethylenesulfone for 16 hours at 230° C. The solution is cooled to 110° C. and filtered, the solid residue is washed with 500 parts of methylene chloride and the filtrates are combined and distilled. 139 parts (10.3% of theory) of 3,4-difluoronitrobenzene of boiling point 54° C./1 mbar are obtained.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[C:12]([C:18]#[N:19])[C:13](=[O:17])[NH:14][C:15]=1[CH3:16].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C=O)C>[C:22]([CH2:21][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[C:12]([C:18]#[N:19])[C:13](=[O:17])[NH:14][C:15]=1[CH3:16])([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)CBr
Reactant: Cc1[nH]c(=O)c(C#N)cc1-c1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccccc1-c1cc(C#N)c(=O)[nH]c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.9 %

Procedure:
A dispersion of 530 mg of 60% sodium hydride in mineral oil and 10 ml of DMF is treated, dropwise, with a solution of 1.50 g (6.6 mmol) of 5-(2-hydroxyphenyl)-6-methyl-2-oxo1,2-dihydro-3-pyridinecarbonitrile in 20 ml of DMF. The reaction is stirred 30 min at RT, then cooled in an ice bath and 1.11 g (6.6 mmol) of ethyl bromoacetate in 30 ml of DMF is added dropwise. The reaction is allowed to slowly come to RT and stirred overnight under N2. The mixture is concentrated under vacuum, the residue taken up in 80 ml of water and extracted with EtOAc. The aqueous phase is acidified to pH=5 with 10% HCl and extracted with EtOAc (4×80 ml). The combined EtOAc extracts are dried (MgSO4) and the solvent removed to leave an orange solid. This solid is recrystallized from EtOAc to give 740 mg of 5-(2-carboethoxymethoxyphenyl)-6-methyl-2-oxo-1,2 -dihydro-3-pyridinecarbonitrile as a yellow solid, m.p. 188°-190° C. Yield, 37%. 1H-NMR (d6 -DMSO): δ1.20 (t,3H): 2.18 (s,3H); 4.15 (q,2H); 4.80 (s,2H); 7.0 (q,2H); 7.20 (d,1H); 7.35 (t,1H); 8.00 (s,1H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1>N1C=CC=CC=1>[Br:1][C:2]1[N:7]=[C:6]([CH:8]=[CH:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cccc(Br)n1
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cccc(Br)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
6-Bromo-pyridin-2-carbaldehyde (5.0 g, 26.9 mmol), malonic acid (6.3 g, 60.5 mmol), and piperidine (2.2 mL, 22.4 mmol) were added to pyridine (16.3 mL). The reaction mixture was stirred at 100° C. for 1 hour, concentrated under reduced pressure, and then distilled water was added thereto. The mixture was filtered and then the resulting solid was dried under reduced pressure to give 4.5 g of the titled compound as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Br:12][CH2:13][CH2:14][CH2:15]Br>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:15][CH2:14][CH2:13][Br:12])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: BrCCCBr
Product: COC(=O)c1ccc(OCCCBr)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure A starting from 4-hydroxy-benzoic acid methyl ester and 1,3-dibromo-propane. MS (ES+) 272.9
Reaction SMILES: O.[N:2](=[CH:4][C:5](=[O:17])[CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[OH:3].[CH2:18](O)[CH2:19][OH:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:19]1[O:20][C:5]([CH:4]=[N:2][OH:3])([CH2:6][C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[O:17][CH2:18]1
Reactant: OCCO
Reactant: O=C(C=NO)CC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=C(CC1(C=NO)OCCO1)OCc1ccccc1
Yield: 94 %

Procedure:
In a two liter flask fitted with a Dean Stark water separator and a condenser were placed 186.5 g. (0.85 mole) of benzyl oximino-acetoacetate [1.1], 62 g. (1 mole) of ethylene glycol, 800 ml. of benzene (reagent grade) and 2 g. (10.5 mmole) of p-toluenesulfonic acid monohydrate. The reaction mixture was boiled at reflux until 15 ml. of water was removed (3 hours). The benzene solution was washed once with saturated sodium bicarbonate solution and once with brine. After drying over anhyrous sodium sulfate, the benzene solution was evaporated, leaving 212 g. (94% yield) of benzyl oximino-acetoacetate ethylene ketal [2.1] as a light yellow oil ! Its NMR spectrum was consistent with the assigned structure. Generally, the product was used as such in subsequent reactions but one of the isomers can be crystallized2 from toluene-petroleum either (b.p. 30°-60° C.); m.p. 52° C.