Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[C:21]([F:29])[CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:33]O.Cl>CO.O>[F:29][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[C:25]([F:28])([F:27])[F:26])[CH2:18][C@H:10]1[CH2:9][C@H:8]([C:6]2[O:7][NH:33][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(C(F)(F)F)c(F)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(C(F)(F)F)c(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 93.6 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluoro-4-(trifluoromethyl)benzyl)piperidine-1-carboxylate (0.781 g, 1.80 mmol) (from example 140, step 1) was dissolved in MeOH (15 mL) and cooled to −40° C. Sodium hydroxide (0.072 g, 1.80 mmol) dissolved in water (1 mL) was added over 1 min and the resulting solution was stirred at −40° C. for 20 min. Then hydroxylamine (50% by weight in water, 0.12 mL, 1.96 mmol) was added over 1 min and stirring continued at −40° C. for 2 h 15 min. The reaction mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (30 mL, 180.00 mmol) and the mixture was continued to be stirred at 80° C. for 1 h. Then cooled to room temperature. Methanol was evaporated, then water was added. Extracted three times with DCM. Combined organic layers dried over MgSO4 and evaporated. Crude trans-methyl 2-(3-fluoro-4-(trifluoromethyl)-benzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (678 mg, 94%) was isolated as an off-white foam. MS m/z 403 (M+H)+
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:26])=O.O>ClCCl>[Cl:26][CH2:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: CCCCCCOc1ccc(/C=C/c2ccc(CO)cc2)cc1
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CCCCCCOc1ccc(/C=C/c2ccc(CCl)cc2)cc1
Yield: 60 %

Procedure:
To a solution of 1.7 g (5.5 mmole) of (E)-4-hydroxymethyl-4′-hexyloxystilbene (21) in 12 ml of dichloromethane cooled in an ice bath under a nitrogen atmosphere were added dropwise 0.5 ml of thionylchloride in 3 ml of dichloromethane. After 1.5 h 16 ml of water were added and the organic layer was separated. It was washed with 12 ml of brine, dried over MgSO4, and the solvent was evaporated. A white solid was obtained which was recrystallized from 80 ml of a 1:1 mixture of hexane and ethanol. 1.1 g of white crystals were obtained (yield 60%).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:14]=1C=O>ClCCl>[Cl:12][C:13]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:14]=1[OH:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cccc(C=O)c1Cl
Solvent: ClCCl
Product: COc1cccc(O)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
3-Chloroperoxybenzoic acid (760 mg, 4.396 mmol) was added portionwise to a solution of 2-Chloro-3-Methoxybenzaldehyde (500 mg, 2.931 mmol) in dichloromethane (12 ml) and the mixture was stirred for 3 hours at room temperature. Further 3-chloroperoxybenzoic acid (760 mg, 4.396 mmol) was added and mixture allowed to stir for 18 hrs. The solution was diluted with 12 ml dichloromethane and washed with saturated sodium sulphite solution (15 ml) and saturated sodium hydrogen carbonate solution (15 ml). The organic layer was dried over sodium sulphate and concentrated in vacuo to a yellow gum. The residue was dissolved in methanol (12 ml), triethylamine (0.05 ml) was added and the mixture stirred for 18 hours at room temperature. The solution was concentrated in vacuo, dissolved in diethyl ether (20 ml) and extracted with 1N sodium hydroxide (20 ml). The aqueous layer was acidified to pH1 by dropwise addition of 2N hydrochloric acid and extracted with diethyl ether (2×25 ml). These combined organic layers were dried over sodium sulphate and concentrated in vacuo to afford the title compound as a brown gum in 70% yield, 325 mg.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:20][CH:21]([CH3:25])[CH2:22][O:23][CH3:24])=[C:12]([N+:17]([O-])=O)[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:26][CH3:27])=[C:5]([CH3:28])[O:4][N:3]=1>C(OCC)(=O)C.CS(C)=O.[Pd]>[CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:20][CH:21]([CH3:25])[CH2:22][O:23][CH3:24])=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:26][CH3:27])=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: COCC(C)Nc1c([N+](=O)[O-])cnc2cc(-c3c(C)noc3C)c(OC)cc12
Agent: [Pd]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COCC(C)Nc1c(N)cnc2cc(-c3c(C)noc3C)c(OC)cc12

Procedure:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-N-(1-methoxypropan-2-yl)-3-nitroquinolin-4-amine (for a preparation see Intermediate 1)(25.8 g, 66.8 mmol) was dissolved in a mixture of ethyl acetate (1000 ml) and DMSO (50 ml) and the solution was hydrogenated using a flow-hydrogenation apparatus (H-cube™) (settings: 20° C., 1 bar, 1 ml/min flow rate) and a 10% Pd/C CatCart 70 catalyst cartridge. The catalyst cartridge was changed whenever it became blocked. The reaction mixture was evaporated under reduced pressure and partitioned between ethyl acetate (750 ml) and water (3×750 ml). The aqueous layers were combined and extracted with ethyl acetate (750 ml). The organic layers were were combined, dried (hydrophobic frit) and evaporated under reduced pressure. The residue was dissolved in DCM and applied to a silica cartridge (100 g). The cartridge was eluted with a 2M ammonia in methanol/DCM gradient (0-4%). The appropriate fractions were combined and evaporated under reduced pressure to give 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4-(1-methoxypropan-2-yl)quinoline-3,4-diamine and recovered 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N-(1-methoxypropan-2-yl)-3-nitroquinolin-4-amine (6.5 g)
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1.[C:13]([N:16]1[CH2:21][CH2:20][CH:19]([C:22](Cl)=[O:23])[CH2:18][CH2:17]1)(=[O:15])[CH3:14]>CCCCC>[F:5][C:6]1[CH:7]=[C:8]([F:12])[CH:9]=[CH:10][C:11]=1[C:22]([CH:19]1[CH2:18][CH2:17][N:16]([C:13](=[O:15])[CH3:14])[CH2:21][CH2:20]1)=[O:23]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: Fc1cccc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCC
Product: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Temperature: 100 °C
Yield: 47 %

Procedure:
To a rapidly stirred slurry of aluminum chloride (3.3 g, 24.7 mmol) and 1,3-difluorobenzene (10 mL) at ambient temperature was added 1-acetylpiperidine-4-carbonyl chloride (2.5 g, 13.2 mmol). The reaction mixture was heated at reflux (100° C.) for 1.5 hours and then poured into 30 mL of ice water, the mixture was extracted with DCM (50 ml) and the organic layer was washed with water and dried over Na2SO4. The solvent was removed in vacuo to give an oil. Trituration of the oil with pentane gave the title product (1.75 g, 6.22 mmol, 47%) as a white solid. MS (ESI) m/z 268.3 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 1.04 min.
Reaction SMILES: [C:1]([N:8]1[C:17]2[CH:12]([CH2:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH:9]1[CH:18]=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[H][H]>C(O)C.[Pd]>[C:1]([N:8]1[C:17]2[CH:12]([CH2:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH:9]1[CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: [H][H]
Reactant: CCOC(=O)C=CC1CCC2CC=CC=C2N1C(=O)C(=O)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCC1CCC2CC=CC=C2N1C(=O)C(=O)OCC
Yield: 94.4 %

Procedure:
N-Ethoxalyl-2-ethoxycarbonylethenyltetrahydroquinoline (4 g, 12.1 mmol) in ethanol (100 mL) was hydrogenated over 10% palladium on carbon (500 mL) under atmospheric pressure of hydrogen for 1.5 h at room temperature. The mixture was filtered through celite and the filtrate was concentrated to give 3.83 g of N-ethoxalyl-2-ethoxycarbonylethyltetrahydroquinoline (95%): 1H NMR (270 MHz, CDCl3) δ7.03~7.19 (m, 4H), 4.78 (m, 1H), 4.11(q, 4H, J 7 Hz), 2.73 (t, 2H, J=6 Hz), 2.47 (m, 1H), 1.69 (m, 1H), 1.25 (t, 3H, J=7 Hz), 1.11 (t, 3H, J=7Hz).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([Cl:18])[CH:12]=1>CC(C)=O>[Cl:18][C:13]1[CH:12]=[C:11]([NH:10][C:2]2[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=2)[CH:16]=[CH:15][C:14]=1[OH:17]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Nc1ccc(O)c(Cl)c1
Solvent: CC(C)=O
Product: Oc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1Cl
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Cyanuric chloride (12.95 g, 70.0 mmol) was dissolved in acetone (200 mL), the solution was cooled to 0-5° C. with an ice bath, and 4-amino-2-chlorophenol (10.09 g, 70.0 mmol) in acetone (100 mL) was added. The mixture was stirred at 0-5° C. for 1 hour under nitrogen. The reaction mixture was extracted three times using dichloromethane; the combined organic layer were washed with brine and dried over sodium sulfate. The sample was concentrated in vacuo, and the resulting solid was dried overnight under vacuum to yield E6 (20.2 g, 99%); mp 180° C.; HPLC: Inertsil ODS 3V C18, 40:30:30 v:v:v [KH2PO4 (0.01 M, pH 3.2):CH3OH:CH3CN], 264 nm, Rt 11.6 min, 99.4% purity; MS (TOF ES+) m/z 293 (97.5), 291 (M+H, 100).
Reaction SMILES: I[C:2]1[CH:11]=[N:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[C:18]1([CH3:27])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:7][NH:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][N:10]=[CH:11][C:2]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH3:27]
Reactant: Cc1ccccc1B(O)O
Reactant: CNC(=O)c1ccncc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CNC(=O)c1ccncc1-c1ccccc1C
Temperature: 80 °C
Yield: 88.6 %

Procedure:
To a suspension of 450 mg (1.7 mmol) 3-iodo-N-methyl-isonicotinamide in 10 ml toluene were added successively 60 mg (0.05 mmol) tetrakis(triphenylphosphine)palladium(0), 2.5 ml 2 M sodium carbonate solution in water and 342 mg (2.5 mmol) o-tolylboronic acid. The mixture was heated under argon at 80° C. for 20 h. The aqueous layer was separated and washed twice with toluene. The combined organic layers were washed with brine, dried (magnesium sulfate) and evaporated. Chromatography of the residue afforded 341 mg (87%) of the title compound as a light yellow solid. M.p. 90-92° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[C:15]([CH3:17])[CH:16]=[C:12]3[NH:11][C:10](=O)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.O=P(Cl)(Cl)[Cl:27]>>[Cl:27][C:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[N:13]2[N:14]=[C:15]([CH3:17])[CH:16]=[C:12]2[N:11]=1
Reactant: Cc1cccc(-c2cc(=O)[nH]c3cc(C)nn23)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Cc1cccc(-c2cc(Cl)nc3cc(C)nn23)c1
Temperature: 25 °C

Procedure:
7-(3-Methylphenyl)-2-methylpyrazolo[1,5-a]pyrimidin-5(4H)-one (673 mg) is dissolved in POCl3 (15 mL) and pyridine (0.2 mL) and stirred overnight while heating. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with 1 M NaHCO3 aqueous solution and brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and purified by column chromatography to yield the target compound (381 mg). 1H NMR (CDCl3, 300 MHz): δ 7.79 (m, 2H), 7.45 (m, 3H), 6.77 (m, 1H), 6.46 (s, 1H), 2.50 (s, 3H), 2.46 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1)=[O:2].[BH4-].[Na+].C(OCC)(=O)C>C(O)C>[OH:2][CH2:1][C:3]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)C1(C=O)CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)C1(CO)CCCC1
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
To a solution of methyl 1-formylcyclopentanecarboxylate (954 mg, 6.11 mmol, Synthesis 1997, 32-34) in ethanol (10 mL) was added sodium tetrahydroborate (104 mg, 2.75 mmol) at ambient temperature. After being stirred for 30 min, the mixture was concentrated in vacuo to give an oil. The residual oil was dissolved with ethyl acetate, and the solution was washed with brine. The extract was dried over magnesium sulfate and concentrated in vacuo to afford 806 mg (83%) of the title compound as a colorless oil. The crude product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[S:21][C:13]3=[N:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[N:12]3[CH:11]=2)[C:5]=1[CH3:22])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:28]>C(Cl)Cl>[CH2:1]([S:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[S:21](=[O:28])[C:13]3=[N:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[N:12]3[CH:11]=2)[C:5]=1[CH3:22])[CH3:2]
Reactant: CCSc1ccnc(-c2cn3c(nc4ccccc43)s2)c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCSc1ccnc(C2=Cn3c(nc4ccccc43)S2=O)c1C

Procedure:
A solution of 2-(4-ethylthio-3-methylpyrid-2-yl)-thiazolo[3,2-a]benzimidazole (0.01 mole) is dissolved in CH2Cl2 solution (100 ml) at 0° C. and treated with m-chloroperoxybenzoic acid (0.01 mole) for 0.5 hours. The solution is then washed with sodium carbonate solution and dried (MgSO4). Purification by chromatography on silica gives the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([CH3:14])=[N:9]2)([O-:3])=[O:2].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:33]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[Br:33][CH2:14][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[N:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c([N+](=O)[O-])cccc2n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc2nc(CBr)ccc12

Procedure:
A solution that consists of 800 mg (4.25 mmol) of 5-nitro-2-methylquinoline in 20 ml of tetrachloromethane is mixed with 11 mg (0.04 mmol) of benzoyl peroxide and 794 mg (4.46 mmol) of N-bromosuccinimide. The reaction mixture is allowed to reflux for 8 hours in the presence of UV light. Insoluble components are filtered off, and the filtrate is concentrated by evaporation. After purification on silica gel with hexane-ethyl acetate (0–100%), 320 mg (28% of theory) of the product is obtained.
Reaction SMILES: [O:1]=[C:2]([NH:22][CH:23]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1)[C:24]([F:27])([F:26])[F:25])/[CH:3]=[CH:4]/[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH:10]([NH:14]C(=O)OC(C)(C)C)[CH2:9][CH2:8]2.Cl.O>O1CCOCC1>[NH2:14][CH:10]1[C:11]2[C:7](=[CH:6][C:5](/[CH:4]=[CH:3]/[C:2]([NH:22][CH:23]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=3)[C:24]([F:25])([F:26])[F:27])=[O:1])=[CH:13][CH:12]=2)[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCc2cc(/C=C/C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)ccc21
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: NC1CCc2cc(/C=C/C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.2 g of tert-butyl {5-[(1E)-3-oxo-3-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-amino)prop-1-en-1-yl]-2,3-dihydro-1H-inden-1-yl}carbamate were dissolved in 40 ml of dioxane and admixed with 10 ml of semisaturated hydrochloric acid, and stirred at room temperature overnight. The reaction mixture was admixed with water and extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated. This gave 1.5 g of (2E)-3-(1-amino-2,3-dihydro-1H-inden-5-yl)-N-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]-ethyl}-acrylamide (82%).
Reaction SMILES: CO[C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]=1.[N+:9]([CH3:12])([O-:11])=[O:10]>>[N+:9]([CH:12]=[C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]1)([O-:11])=[O:10]
Reactant: C[N+](=O)[O-]
Reactant: COC1=NCCCC1
Product: O=[N+]([O-])C=C1CCCCN1

Procedure:
A solution of 33.9 g of (1A) and 36.6 g of nitromethane was refluxed for 3 days, cooled and quenched in one liter of cold ether. Filtration gave a solid crude product, m.p. 79° - 81°. Evaporation of the filtrate and trituration of the residue with cold ether give additional crude product. The crude product was continuously extracted from a Soxhlet thimble with ether for 18 hours, after which time only a small amount of dark oil remained. The solvent pot (not containing crystallized product) was cooled and the solid product was filtered, giving 2-(nitromethylene)piperidine (1B), as a pale yellow solid, m.p.: 80.5°-81°.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:7]([OH:9])=O)[CH3:6])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:16]([O:19][CH2:20][CH3:21])(=[O:18])C>C1COCC1.CN(C)C1C=CN=CC=1>[C:1]([NH:4][CH:5]([CH3:6])[C:7](=[O:9])[C:16]([O:19][CH2:20][CH3:21])=[O:18])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H](C)C(=O)O
Reactant: CCOC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C(C)NC(C)=O
Temperature: 0 °C

Procedure:
52 g (396 mmol) of acetylalanine were dissolved in 800 ml of THF, and 45 mg (0.4 mmol) of 4-dimethylaminopyridine and 96 ml (1188 mmol) of pyridine were added. The mixture was heated to reflux, and 88 ml (792 mmol) of ethyl oxalyl chloride were added dropwise over a period of 45 min. The mixture was stirred at reflux for a further 3 h. The reaction mixture was added to ice-water, ethyl acetate was added and the mixture was extracted. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. The crude mixture was reacted further without any further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:13][CH2:14][CH3:15])[C:7]([NH2:9])=[O:8])([O-])=O.[C:16](OC(=O)C)(=O)[CH3:17].C(O)(=O)C>[Ni]>[CH2:14]([N:13]1[C:12]2[CH:11]=[CH:10][C:6]([C:7](=[O:8])[NH2:9])=[CH:5][C:4]=2[N:1]=[C:16]1[CH3:17])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CCNc1ccc(C(N)=O)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CC(=O)O
Product: CCn1c(C)nc2cc(C(N)=O)ccc21
Reaction time: 5 h
Yield: 88 %

Procedure:
A mixture of 125 g (0.6 mole) of compound III, 214 g (2.1 moles) of acetic anhydride, 1.2 ml of Raney nickel and 36 g (0.6 mole) of acetic acid was hydrogenated at 80° C and a pressure of 100 to 30 kg/sq.cm for 5 h. After cooling, the catalyst was filtered, and the filtrate was concentrated by normal pressure until 135 ml of distillate were collected. Then 150 ml of 6N sulphuric acid were added to the residue. The reaction was very exothermic. The solution was refluxed with active carbon for 15 min and filtered. The filtrate was mixed with 1.2 kg of ice and exactly neutralized with 2N sodium hydroxide. The precipitate was washed with water and dried at 100° C. Melting point: 251° C. Yield: 88% (108 g).
Reaction SMILES: [C:1]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:14]([O-])([OH:16])=[O:15]>>[N+:14]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:1]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[O:8])([O-:16])=[O:15]
Reactant: O=C(O)C=CC(=O)c1ccccc1
Reactant: O=[N+]([O-])O
Product: O=C(O)C=CC(=O)c1cccc([N+](=O)[O-])c1

Procedure:
22 g of finely powdered 3-benzoylacrylic acid was added in 1-gram portions to 11° g of stirred fuming (90%) nitric acid at -5° over a 30-minute period, the mixture being allowed to heat to 0°. Then the temperature of the mixture was allowed to rise to 2° and held until a clear solution was obtained. The mixture then was poured on ice, and the solid which formed was filtered, washed with water, dried (MgS04) and recrystallized from ethanol to give 3-(3-nitrobenzoyl)acrylic acid (8A), m.p.: 199°-201°.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1C.[CH3:12][O:13][C:14](=[O:21])[C@H:15]([CH2:17][CH2:18][S:19][CH3:20])[NH2:16].C(N(CC)CC)C>CN1CCCC1=O>[CH3:12][O:13][C:14](=[O:21])[CH:15]([NH:16][C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1)[CH2:17][CH2:18][S:19][CH3:20]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: COC(=O)[C@@H](N)CCSC
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COC(=O)C(CCSC)Nc1ccc([N+](=O)[O-])cc1
Temperature: 90 °C

Procedure:
1 g of 4-fluoro-3-methylnitrobenzene, 0.694 g of L-methionine methyl ester and 1.09 ml of triethylamine were added to a solution of 5 ml of N-methylpyrrolidinone. The reaction medium was heated at 90° C. for 7 hours and, after cooling to room temperature, was poured into an ice water mixture. The reaction medium was then extracted with ethyl acetate and the organic phase was dried and concentrated to dryness. After purification by chromatography on a column of silica, 4-methylsulfanyl-2-(4-nitrophenylamino)butyric acid methyl ester (28) was obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([C:11]1[O:15][N:14]=[C:13]([NH:16][C:17]([C@@H:19]2[CH2:23][C@@H:22]([OH:24])[CH2:21][N:20]2[C:25]2[CH:30]=[CH:29][N:28]=[C:27](Cl)[N:26]=2)=[O:18])[CH:12]=1)([CH3:10])([CH3:9])[CH3:8].C(N(C(C)C)CC)(C)C>O>[C:7]([C:11]1[O:15][N:14]=[C:13]([NH:16][C:17]([C@@H:19]2[CH2:23][C@@H:22]([OH:24])[CH2:21][N:20]2[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:26]=2)=[O:18])[CH:12]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2C[C@@H](O)CN2c2ccnc(Cl)n2)no1
Reactant: C1COCCN1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2C[C@@H](O)CN2c2ccnc(N3CCOCC3)n2)no1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Morpholine (0.01 mL, 0.115 mmol) is added to a solution of (2S,4R)-1-(2-chloro-pyrimidin-4-yl)-4-hydroxy-pyrrolidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide (42 mg, 0.115 mmol) and diisopropylethylamine (0.02 mL, 0.115 mol). The reaction is stirred at 60° C. overnight. More morpholine (0.01 mL, 0.115 mmol) is added and the reaction is stirred at 80° C. for 3.5 hours. The reaction is diluted with water and extracted with ethyl acetate twice. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by chromatography on silica eluting with methanol/dichloromethane provides the title compound. ESI m/z 417 [M+H+].
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9](#[N:12])[CH:10]=[CH2:11]>>[C:9]([CH2:10][CH2:11][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)#[N:12]
Reactant: C=CC#N
Reactant: CNc1ccccc1
Product: CN(CCC#N)c1ccccc1
Temperature: 120 °C

Procedure:
1071.5 Parts by weight (10 mol) of N-methylaniline and 15.0 parts by weight of Tonsil® K 10 are placed in a 3-neck stirred flask fitted with a reflux condenser and inlet tube. The mixture is heated to 120° C. and 265.3 parts by weight (5 mol) of acrylonitrile are added at this temperature via the inlet tube. The reaction mixture is subsequently stirred for 18 hours at from 120° to 130° C. and then cooled to 60° C. The catalyst is filtered off and the liquid phase is subjected to fractional distillation. 47.7 parts by weight of acrylonitrile and 620.9 parts by weight of N-methylaniline are recovered and can be used again as starting material. The yield of N-β-cyanoethyl-N-methylaniline is 605.0 parts by weight ~75.5% conversion. The purity is 99.5% N-β-cyanoethyl-N-methylaniline.