Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][CH2:7][S:8][C@@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[CH:11](/[C:12](=[N:29]/[OH:30])/[CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C:18]2=[O:28])[CH2:10]1)=O.[C:33]([O-:36])([O-:35])=O.[K+].[K+].C[OH:40].O>>[C:18]([OH:28])(=[O:40])/[CH:19]=[CH:21]/[C:33]([OH:36])=[O:35].[NH2:5][CH2:6][CH2:7][S:8][C@@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[CH:11](/[C:12](=[N:29]/[OH:30])/[CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C:18]2=[O:28])[CH2:10]1
Reactant: CO
Reactant: O=C([O-])[O-]
Reactant: C[C@]12CC[C@@H](SCCNC(=O)C(F)(F)F)CC1/C(=N/O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [K+]
Solvent: O
Product: C[C@]12CC[C@@H](SCCN)CC1/C(=N/O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: O=C(O)/C=C/C(=O)O

Procedure:
To a stirred solution of 3α-(2-trifluoroacetamidoethylthio)-6-(E)-hydroxyiminoandrostan-17-one (Prepn. 78, 115 mg) in MeOH/H2O 95/5 (7 mL), K2CO3 (159 mg) was added. The mixture was refluxed for 1.5 hrs and then concentrated, washed with water, extracted with CH2Cl2 and dried with Na2SO4. Fumaric acid (27 mg) was added and the resulting solution evaporated to dryness. The residue was purified by flash chromatography (SiO2, CH2Cl2/MeOH/NH3 9/1/0.1). To the concentrated fractions a stoichiometric amount of fumaric acid in MeOH was added. The solution was concentrated and the resulting mixture centrifugated. The solid was washed with Et2O/EtOH 9/1 (0.8 mL) to give, after centrifugation, the title compound I-dv (53 mg, 50%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 10.45 (1H, s), 8.10 (3H, m), 6.35 (2H, s), 3.29 (1H, dd), 3.22 (1H, m), 2.86 (2H, t), 2.67 (1H, m), 2.60 (2H, t), 2.50-0.80 (20H, m), 0.76 (3H, s), 0.67 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6](O)[CH:7]=1.[OH-:14].[Na+].Cl[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1>CN(C=O)C.CO>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[O:14][CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1
Reactant: COC(=O)Cc1cc(O)cc(F)c1
Reactant: [OH-]
Reactant: ClCc1ccc2ccccc2n1
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(F)c1
Temperature: 100 °C

Procedure:
18.4 g (0.1 mol) of the compound from Example I are dissolved in 50 ml of DMF and 4 g (0.1 mol) of NaOH in 40 ml of methanol are added. 17.8 g (0.1 mol) of 2-chloromethylquinoline in 50 ml of DMF are added dropwise to this mixture with stirring and it is then heated at 100° C. for 5 h. After cooling, the solvent is evaporated in vacuo, the residue is taken up in dichloromethane, and the solution is washed twice with water, dried and concentrated in vacuo to a small volume. Separation is carried out by column chromatography (silica gel 60, eluent: toluene/ethyl acetate=9:1 to 8:2).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[N:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH:18]([C:24](=[O:26])[CH3:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C1COCC1.CO.C(Cl)Cl>[CH2:22]([O:21][C:19](=[O:20])[CH:18]([N:6]1[C:2]([CH3:1])=[N:3][C:4]([C:7]([F:10])([F:9])[F:8])=[N:5]1)[C:24](=[O:26])[CH3:25])[CH3:23]
Reactant: Cc1nc(C(F)(F)F)n[nH]1
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C(C(C)=O)n1nc(C(F)(F)F)nc1C
Temperature: 40 °C
Reaction time: 0.33 h

Procedure:
To a stirring solution of 5-methyl-3-(trifluoromethyl)-1H-1,2,4-triazole (2 g, 13.24 mmol) in THF (60 ml) is added K2CO3 (3.66 g, 26.5 mmol). The mixture is allowed to stir for 20 minutes at 40° C. before adding ethyl 2-chloro-3-oxobutanoate (2.61 g, 15.88 mmol) and leaving to stir. The reaction mixture is filtered to remove solids, before concentrating under vacuum to yield a dark orange/red oil. The oil is taken up in 2% MeOH in DCM and purified on silica eluting with 2% MeOH in DCM to afford the title compound as a pale yellow oil. MS m/z 280.0 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]=[CH:6][C:7]1[CH:16]=[CH:15][C:14]2[NH:13][C:12](=[O:17])[CH:11]3[CH2:18][CH2:19][CH2:20][CH:10]3[C:9]=2[CH:8]=1)=[O:4].C(O)(=O)C.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[NH:13][C:12](=[O:17])[CH:11]3[CH2:18][CH2:19][CH2:20][CH:10]3[C:9]=2[CH:8]=1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)C=Cc1ccc2c(c1)C1CCCC1C(=O)N2
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccc2c(c1)C1CCCC1C(=O)N2

Procedure:
2.73 g (10.1 mmol) of 8-(methoxycarbonylethenyl)-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one is dissolved in 100 ml of ethyl acetate, and after 273 mg of 10% Pd-C and 0.1 ml of acetic acid are added, it is stirred for 24 hours in a hydrogen atmosphere. After filtration, the filtrate is concentrated by evaporation and purified by column chromatography on silica gel with hexane-ethyl acetate: 2.7 g.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[S:11](Cl)(=[O:13])=[O:12].[NH3:15]>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[S:11]([NH2:15])(=[O:13])=[O:12]
Reactant: O=S(=O)(Cl)c1c(Cl)nc2ccccn12
Reactant: N
Solvent: CC#N
Product: NS(=O)(=O)c1c(Cl)nc2ccccn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4.6 g of 2-chloroimidazo[1,2-a]pyridine- 3-sulfonyl chloride in 60 ml of acetonitrile is added to 60 ml of aqueous ammonia under cooling and the mixture is stirred at room temperature for 2 hours. The acetonitrile is distilled off under reduced pressure and the resulting crystals are collected by filtration and washed with water to give 3.8 g of the title compound. Recrystallization from dilute ethanol gives colorless needles.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=O)[CH2:6][CH2:5]2.[N:13](OCCC(C)C)=O.Cl.O>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[CH2:7][CH:6]([NH2:13])[CH2:5]2
Reactant: CC(C)CCON=O
Reactant: O=C1CCc2cc(F)c(F)cc21
Agent: Cl
Solvent: O
Solvent: CO
Product: NC1Cc2cc(F)c(F)cc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5,6-difluoro-2,3-dihydro-1H-inden-1-one (4.60 g, 27.4 mmol) in MeOH (90 mL) at 40° C. was added isoamyl nitrite (4.17 g, 35.6 mmol) followed by concentrated HCl (2.7 mL). Upon heating for 45 min the solution was cooled to room temperature and water was added. Precipitated solid was collected by filtration and rinsed thoroughly with water affording 3.97 g of a light orange solid. The solid was dissolved in HOAc (100 mL), conc HCl (8 mL) was added, followed by 10% Pd/C (1.07 g). The mixture was hydrogenated under 50 psi H2 for 24 hr using a Parr hydrogenation apparatus, and filtered through a bed of Celite (CHCl3 wash). The filtrate was concentrated in vacuo and the residue was dissolved in water. The aqueous solution was basified with solid K2CO3, extracted with CHCl3 (3×), combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (MeOH/CH2Cl2) affording the title compound as a brown oil. 1H NMR (400 MHz, CDCl3) δ 6.95 (t, 2H, J=8.9 Hz), 3.83 (m, 1H), 3.10 (dd, 2H, J=15.8 & 6.8 Hz), 2.60 (dd, 2H, J=15.8 & 5.0 Hz); (M+H) 170, 0.68 min (LC/MS method A).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:27]3[CH:23]([CH2:24][NH:25][CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([N:25]2[CH2:24][CH:23]3[CH:27]([C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:20][CH2:21][C:22]3=[O:28])[CH2:26]2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccc(F)cc3)CC12
Reaction time: 1 h
Yield: 66.8 %

Procedure:
N,N'-Carbonyldiimidazole (1.13 g) is added to a solution of 2-(4-fluorophenyl)acetic acid (1.08 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 1 hour at +5° C. and a solution of 7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.3 g) and triethylamine (0.98 cc) in dichloromethane (40 cc) is then added. The reaction mixture is stirred for 1 hour at +5° C. and then for 16 hours at 20° C. The reaction mixture is washed with distilled water (3×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized form acetonitrile (5 cc). The crystals are drained, washed with isopropyl ether (10 cc) and dried. (3aRS,7aRS)-2-[(4-fluorophenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolone (2 g) melting at 210° C. is obtained.
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:7]=[C:8]([CH2:13][NH:14][O:15][CH3:16])[CH:9]=[N:10][C:11]=1[Cl:12].[CH2:17]1[C:22](=[O:23])[O:21][CH2:20][C:18]1=O.O>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:7]=[C:8]([CH2:13][N:14]([O:15][CH3:16])[C:18]2[CH2:20][O:21][C:22](=[O:23])[CH:17]=2)[CH:9]=[N:10][C:11]=1[Cl:12]
Reactant: CONCc1cnc(Cl)c(Cl)c1
Reactant: O=C1COC(=O)C1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CON(Cc1cnc(Cl)c(Cl)c1)C1=CC(=O)OC1
Yield: 61 %

Procedure:
120 μl (2.04 mmol) of acetic acid and 422 mg (2.04 mmol) of 1-(5,6-dichloropyridin-3-yl)-N-methoxymethanamine (III-3) are added to 224 mg (2.24 mmol) of tetronic acid in 50 ml of toluene, and the mixture is heated under reflux on a water separator for 3 hours. The reaction mixture is concentrated under reduced pressure, the residue is taken up in ethyl acetate and the mixture is washed successively twice with 1 N aqueous hydrochloric acid, twice with 1 N aqueous sodium hydroxide solution and saturated sodium chloride solution and dried over sodium sulphate. Concentration of the organic phase under reduced pressure and purification of the residue by recrystallization from ethyl acetate gives 360 mg (59% of theory) of 4-[[(5,6-dichloropyridin-3-yl)methyl](methoxy)amino]furan-2(5H)-one.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](C(O)=O)[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].[NH2:18][C:19](=[N:31][OH:32])[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([F:30])[CH:21]=1.Cl.[CH2:34](N=C=NCCCN(C)C)C.N#N.C(N(C(C)C)C(C)C)C>C1COCC1.CC#N>[CH3:17][C:12]1[CH:13]=[C:14]([C:19]2([C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([F:30])[CH:21]=3)[N:18]=[CH:34][O:32][NH:31]2)[CH:15]=[CH:16][C:11]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: CCN=C=NCCCN(C)C
Reactant: COC(=O)c1ccc(C(N)=NO)cc1F
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1C
Agent: Cl
Agent: N#N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1ccc(C2(c3ccc(-c4ccccc4C)c(C)c3)N=CON2)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Intermediate 3 (814 mg; 3.60 mmol; 1.20 eq.), Intermediate 1 (637 mg; 3 mmol; 1 eq.) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (690 mg; 3.60 mmol; 1.20 eq.) were dissolved in THF (10 mL) and CH3CN (10 mL) in a 20 mL microwave vial under N2. The reaction mixture was stirred overnight at RT. Then n-ethyldiisopropylamine (DIEA) (1.22 mL; 7.20 mmol; 2.40 eq.) was added and the mixture was heated in the microwave at 150° C. for 30 min. The reaction mixture was evaporated to dryness. EtOAc (50 mL) was added and the mixture was washed with HCl 0.1 N (2×25 mL), a saturated aqueous solution of NaHCO3 (25 mL) and dried over MgSO4. After evaporation of the solvents, the resulting crude product was purified by flash chromatography (c-hex/EtOAc: 9.5/0.5), affording the title compound as a white powder. 1H NMR (DMSO-d6, 300 MHz) δ 8.17-8.16 (m, 1H), 8.12 (d, J=7.2 Hz, 1H), 8.29-8.04 (m, 2H), 7.98 (dd, J=11.1, 2.5 Hz, 1H), 7.39-7.27 (m, 4H), 7.14-7.11 (m, 1H), 3.91 (s, 3H), 2.13 (s, 3H), 2.03 (s, 3H). LC/MS (Method A): 403.0 (M+H)+. HPLC (Method A) Rt 6.23 min (Purity: 93.5%).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH:15]([CH3:31])[CH2:16][CH2:17][CH2:18][C:19]1[N:20]=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:22][C:23]=1[CH3:24].Cl>O1CCCC1>[CH3:24][C:23]1[O:22][C:21]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[N:20][C:19]=1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:31][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: Cc1oc(-c2ccccc2)nc1CCCC(C)Br
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCCCCc1nc(-c2ccccc2)oc1C)C(=O)OCC
Reaction time: 0.17 h
Yield: 87.5 %

Procedure:
To 35 ml of dry tetrahydrofuran, 650 mg of 60% sodium hydride was added, and 3.9 g of diethyl malonate was added dropwise with stirring under ice-cooling. After the stirring was continued for 10 minutes, 4-(4-bromopentyl)-5-methyl-2-phenyloxazol (2.5 g) was added. The mixture was stirred for 10 minutes at room temperature and then heated to reflux for 12 hours. The reaction solution was poured into ice-cold water, neutralized with dilute hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane: ethyl acetate=10:1) to provide 2.75 g of the objective compound as colorless oil.
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:11][C:10]([CH:12]2[O:16][CH2:15][CH2:14][O:13]2)=[CH:9][CH:8]=1.[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Br.O>O1CCCC1.C(OCC)(=O)C>[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][C:7]1[S:11][C:10]([CH:12]2[O:16][CH2:15][CH2:14][O:13]2)=[CH:9][CH:8]=1
Reactant: Fc1cccc(CBr)c1
Reactant: Brc1ccc(C2OCCO2)s1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Fc1cccc(Cc2ccc(C3OCCO3)s2)c1
Reaction time: 0.28 h
Yield: 13.9 %

Procedure:
n-Butyl lithium (2.44N hexane solution, 6.4 mL, 16.9 mmol) was added dropwise to a solution of 2-(5-bromo-thiophen-2-yl)-[1,3]dioxolane (3.0 g, 13 mmol) in tetrahydrofuran (30 mL) at from −75° C. to −69° C., and the solution was stirred for 17 minutes. 3-Fluorobenzyl bromide (1.7 mL, 14.3 mmol) was added dropwise to this reaction solution at from −75° C. to −69° C. After dropwise addition was completed, the reaction solution was gradually allowed to room temperature. Water and ethyl acetate were added to the reaction solution, which was then partitioned, the organic layer was concentrated in vacuo, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1), and the title compound (478 mg, 1.81 mmol, 13.9%) was obtained as a brown oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[CH2:11](Br)[C:12]#[CH:13]>>[CH2:13]([O:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1)[C:12]#[CH:11]
Reactant: C#CCBr
Reactant: OCc1ccc(CO)cc1
Product: C#CCOCc1ccc(CO)cc1

Procedure:
In an analogous manner to that described in Example 1, from 4-(hydroxymethyl)benzyl alcohol and propargyl bromide there is obtained 4-[(2-propynyloxy)methyl]benzyl alcohol. This alcohol is reacted in an analogous manner to that described in Example 2 with cyclopropane carboxylic acid chloride to give cyclopropane carboxylic acid p-[(2-propynyloxy)methyl]benzyl ester.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]1[O:15][C:14]2[CH:13]=[CH:12][C:9]([CH2:10]O)=[CH:8][C:7]=2[O:6]1>>[CH2:5]1[O:15][C:14]2[CH:13]=[CH:12][C:9]([CH2:10][Cl:3])=[CH:8][C:7]=2[O:6]1
Reactant: OCc1ccc2c(c1)OCO2
Reactant: O=S(Cl)Cl
Product: ClCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
153.9 g (1.29 mols) of thionyl chloride are poured onto 65.6 g (0.431 mol) of 3,4-methylenedioxybenzyl alcohol. The mixture is stirred for 90 minutes at ambient temperature (15°-25° C.) and the excess thionyl chloride is then evaporated. The residue is taken up in dimethylformainde (DMF) and the latter is then evaporated. Finally, the residue is taken up in 500 ml of DMF (it is not necessary to isolate the 3,4-methylenedioxybenzyl chloride thus obtained).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[CH:8][N:7]=1)=[O:5])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:25])C=1>>[CH2:1]([NH+:3]([O-:25])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[CH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1ccc(C(=O)NCC)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCNC(=O)c1ccc(C(=O)[NH+]([O-])CC)nc1

Procedure:
From 1 g of N,N'-diethylpyridine-2,5-dicarboxamide and 1.8 g of MCPBA.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][NH:10][CH2:9]1.S(=O)(=O)(O)O.[N+:24]([O-])([OH:26])=[O:25]>C(OCC)(=O)C>[N+:24]([C:16]1[CH:17]=[CH:18][C:13]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][C:14]=2[CH:15]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2c(c1)CCNCC2
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
To a cooled (0° C.) solution of trifluoroacetic acid (67.2 ml, =869.38 mmol), 2,3,4,5-Tetrahydro-1H-benzo[d]azepine (18 g, 122.44 mmol) was added drop-wise over a period of 20 min. To this, concentrated sulphuric acid (23.4 ml, 440.78 mmol) was added over a period of 45 min at 0° C., and the mixture was stirred for an additional 30 minutes. To this reaction mixture, concentrated nitric acid (8.1 ml, 192.23 mmol) was added drop-wise at 0° C. over a period of 1 h, followed by stirring at room temperature for 2 h. To the reaction mixture, ethyl acetate (250 ml) was added drop-wise at 0° C. The resulting precipitate was filtered and washed with ethyl acetate (100 ml). The crude solid product was added to chloroform (250 ml), washed with 10% sodium hydroxide solution (150 ml), dried over Na2SO4, and concentrated to give the sub-title compound as a light yellow solid (17.4 g). 1H NMR (300 MHz, DMSO-d6) δ 7.99-7.93 (m, 2H); 7.38 (d, J=8.1 Hz, 1H); 2.98-2.94 (m, 4H); 2.79-2.76 (m, 4H); MS: ESI (positive): 193 (M+H).
Reaction SMILES: [C:1]([C:4]1[N:8]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:7]=[C:6]([C:21]([F:24])([F:23])[F:22])[C:5]=1[C:25]#[N:26])(=O)[NH2:2].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[Cl:20][C:10]1[CH:11]=[C:12]([C:16]([F:17])([F:19])[F:18])[CH:13]=[C:14]([Cl:15])[C:9]=1[N:8]1[C:4]([C:1]#[N:2])=[C:5]([C:25]#[N:26])[C:6]([C:21]([F:23])([F:24])[F:22])=[N:7]1
Reactant: N#Cc1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C(N)=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: N#Cc1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C#N
Reaction time: 3 h

Procedure:
5-Carbamoyl-4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethylpyrazole (3.57 g) was heated to 200° C. with phosphorus pentoxide (2.82 g) with stirring. After 3 hours, the cooled product was treated with ice, and extracted with dichloromethane (3×50 ml). The organic solution was washed with water, dried over anhydrous magnesium sulphate, and evaporated in vacuo to give a solid. Recrystallization from hexane gave 1-(2,6-dichloro-4-trifluoromethylphenyl)-4,5-dicyano-3-trifluoromethylpyrazole in the form of white crystals (1.8 g), m.p. 80° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[CH2:6][C@@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:9][CH2:8]1.[H-].[Na+].Br[C:26]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][N:27]=1.O>CN(C)C=O>[CH3:35][S:32]([C:29]1[CH:30]=[CH:31][C:26]([O:1][CH2:2][CH2:3][C@@H:4]2[CH2:6][C@@H:5]2[CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:14])[CH2:9][CH2:8]2)=[N:27][CH:28]=1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Reactant: O=C(OCc1ccccc1)N1CCC([C@H]2C[C@H]2CCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OCc3ccccc3)CC2)nc1
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
To a solution of 860 mg (2.83 mmol) benzyl 4-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carboxylate in 14.5 ml anhydrous N,N-dimethylformamide at ambient temperature was added 147 mg (3.68 mmol) sodium hydride. The solution was stirred for 20 minutes. 669 mg (2.83 mmol) 2-bromo-5-(methylsulfonyl)pyridine was added into the solution. It was heated to 50° C., and stirred for 3 hours. 100 ml water was added into the mixture, and it was extracted with 50 ml ethyl acetate three times. The crude product was dried and purified using a Biotage Horizon® system (0-50% ethyl acetate/hexanes mixture) to give the title compound as colorless oil. 1H NMR (CDCl3): δ 8.71 (d, J=2.4 Hz, 1H), δ 8.03 (dd, J=8.8 Hz, 2.5 Hz, 1H), δ 7.30-7.37 (m, 5H), δ 6.84 (d, J=8.7 Hz, 1H), δ 5.13 (s, 2H), δ 4.49 (t, J=7.1 Hz, 2H), δ 4.10-4.16 (m, 2H), δ 3.07 (s, 2H), δ 2.75-2.76 (m, 2H), δ 2.08-2.12 (m, 1H), δ 1.74-1.75 (m, 2H), δ 1.50-1.56 (m, 2H), δ 1.29-1.40 (m, 2H), δ 0.88-0.99 (m, 2H), δ 0.56-0.70 (m, 2H). LC/MS 459.2 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH2:7].[C:8]([O:12][C:13]([O:15]N=C(C1C=CC=CC=1)C#N)=O)([CH3:11])([CH3:10])[CH3:9]>O1CCCC1>[C:8]([O:12][C:13]([NH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][C:13]([O:12][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:15])=[O:15])([CH3:11])([CH3:10])[CH3:9]
Reactant: NCCNCCN
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCNCCNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
A solution of diethylenetriamine (0.42 g; 4.1 mmol) in tetrahydrofuran (THF; 5 ml) is stirred at 0° C. under nitrogen for 20 minutes. A solution of 2-(tert-butoxycarbonyloximino)-2-phenylacetonitrile (Boc-ON; 2.04 g; 8.2 mmol) in THF (5 ml) is then added dropwise and the reaction mixture is stirred at 0° C. for 1 hour. The solvent is eliminated at reduced pressure and the resulting residue is purified by silica gel column chromatography with methanol-ammonium hydroxide 100:3. 1.2 g (yield 96%) of an oil having the following characteristics is thus obtained:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([C@@H:15]2[CH2:24][C:23]3[C:22]([OH:25])=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:17][C@H:16]2[OH:26])[CH2:11][CH2:10]1.[N+](=[CH2:29])=[N-]>CO>[CH3:29][O:25][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:23]=1[CH2:24][C@@H:15]([N:12]1[CH2:11][CH2:10][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:14][CH2:13]1)[C@H:16]([OH:26])[CH2:17]2
Reactant: C=[N+]=[N-]
Reactant: COc1ccccc1N1CCN([C@@H]2Cc3c(O)cccc3C[C@H]2O)CC1
Solvent: CO
Product: COc1ccccc1N1CCN([C@@H]2Cc3c(cccc3OC)C[C@H]2O)CC1
Reaction time: 48 h

Procedure:
A solution of 2.0 g of trans-5,6,7,8-tetrahydro-7-[4-(2-methoxyphenyl)-1-piperazinyl]-1,6-naphthalenediol in methanol is treated with about 2 equivalents of freshly prepared diazomethane. The solution is stored at 0° C for 48 hours. The solvent is removed in vacuo, the residue is dissolved in ethyl acetate and washed with dilute sodium hydroxide solution. After drying and removal of solvent in vacuo, an oil remains which crystallizes on trituration with a very small amount of ether. The crystalline material is washed with a small amount of isopropyl ether and recrystallized from etherisopropyl ether to give 1.13 g of the title compound, melting point 138°-141° C.