Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:30])[CH:17]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[C:16](=O)[C:15]3[C:14]([C:25](OCC)=[O:26])=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.O.[NH2:32][NH2:33]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH3:30])[NH:9][C:10]3[C:15]4[C:16](=[N:32][NH:33][C:25](=[O:26])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[CH:17]2[C:18]2[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1C)C(C)(c1ccc(F)cc1)N2
Reactant: NN
Solvent: CO
Solvent: O
Product: Cn1ccnc1C1c2n[nH]c(=O)c3cccc(c23)NC1(C)c1ccc(F)cc1
Temperature: 30 °C
Reaction time: 10 h
Yield: 36 %

Procedure:
To a solution of ethyl 2-(4-fluorophenyl)-2-methyl-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (120 mg, 0.30 mmol) in methanol (4 mL) was added hydrazine monohydrate (0.7 mL) at room temperature, the mixture was stirred under 30° C. for 10 hr. The solvent was evaporated to obtain crude solid, which was washed by 14 mL of mixture of ethyl acetate and methanol (13:1) to obtain the title compound as a green solid (40 mg, yield 36%). LC-MS (ESI) m/z: 376 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.39 (s, 3H), 3.71 (s, 3H), 4.74 (s, 1H), 6.72 (s, 1H), 7.03 (s, 1H), 7.06-7.11 (m, 2H), 7.16-7.19 (d, J=8 Hz, 1H), 7.25-7.28 (d, J=8 Hz, 1H), 7.49 (s, 1H), 7.54-7.58 (m, 3H), 12.05 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:17]1[N:18]=[CH:19][N:20](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:21]=1)([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]=1)[CH3:4].Cl.N1C=CC=CC=1.Cl>CO>[CH3:1][O:2][C:3]([C:17]1[N:18]=[CH:19][NH:20][CH:21]=1)([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]=1)[CH3:4]
Reactant: COc1ccc2cc(C(C)(OC)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc2cc(C(C)(OC)c3c[nH]cn3)ccc2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 40.9 %

Procedure:
4-[1-Methoxy-1-(6-methoxynaphthalen-2-yl)ethyl]-1-trityl-1H-imidazole (1.5 g) and pyridine hydrochloride (500 mg) were dissolved in methanol (8 ml). The solution was stirred at 60° C. for 2 h. After cooling, 1 N-hydrochloric acid was added to the solution, and precipitate was filtered off. The filtrate was washed with ether and neutralized with potassium carbonate. The filtrate was extracted with ethyl acetate, washed with saturated aqueous solution of sodium chloride, dried and concentrated. The residue was purified by silica gel column chromatography (eluent, ethyl acetate:methanol=30:1) to give the titled compound (0.33 g) as a colorless powder.
Reaction SMILES: Cl[O-].[Na+].[OH:4][CH2:5][C:6]1[C:7](OCOC)=[C:8]([CH:16]2[CH2:20][CH2:19][CH2:18][CH:17]2[C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][O:31][CH3:32])=[CH:25][CH:24]=2)=[O:22])[CH:9]=[C:10]([O:12][CH2:13][O:14][CH3:15])[CH:11]=1.C[CH2:38][O:39]C(C)=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:38][O:39][CH:13]([O:14][CH3:15])[O:12][C:10]1[CH:9]=[C:8]([CH:16]2[CH2:20][CH2:19][CH2:18][CH:17]2[C:21](=[O:22])[C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30][O:31][CH3:32])=[CH:27][CH:28]=2)[CH:7]=[C:6]([CH:11]=1)[CH:5]=[O:4]
Reactant: COCOc1ccc(C(=O)C2CCCC2c2cc(OCOC)cc(CO)c2OCOC)cc1
Reactant: CCOC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: COCOc1ccc(C(=O)C2CCCC2c2cc(C=O)cc(OC(OC)OC)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
Add sodium hypochlorite (150 mL) to a solution of (±)-[2-(3-hydroxymethyl-2,5-bis-methoxymethoxy-phenyl)-cyclopentyl]-(4-methoxymethoxy-phenyl)-methanone (1.69 g, 3.66 mmol) and tetrabutylammonium bromide (0.500 g, 1.55 mmol) in EtOAc. Stir the biphasic mixture vigorously for 2 hours at ambient temperature and separate the layers. Extract the aqueous solution with EtOAc (50 mL) and wash the combined organics with H2O (50 mL) and brine (25 mL), then dry (MgSO4), filter and concentrate to obtain the subtitled product (1.88 g, >95%) as an oil that may be used without purification. 1H NMR (CDCl3) δ 1.76-1.81 (m, 1H), 1.97-2.14 (m, 4H), 2.24-2.39 (m, 1H), 3.41 (s, 3H), 3.42 (s, 3H), 3.58 (s, 3H), 3.80-3.86 (m, 1H), 4.28-4.33 (m, 1H), 4.94-5.07 (m, 4H), 5,12 (s, 2H), 6.81 (d, J=8.9 Hz, 2H), 7.00 (d, J=3.1 Hz, 1H), 7.08 (d, J=3.1 Hz, 1H), 7.61 (d, J=8.9 Hz, 2H), 10.00 (s, 1H).
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[N:5]=[N:4][N:3]=1.C(N(CCCC)CCCC)CCC.P(Cl)(Cl)(Cl)=O.Cl.[CH3:30][O:31][NH2:32]>C(#N)C.CN(P(N(C)C)(N(C)C)=O)C>[CH3:30][O:31][NH:32][C:8](=[O:10])[CH2:7][N:6]1[C:2]([SH:1])=[N:3][N:4]=[N:5]1
Reactant: CON
Reactant: O=C(O)Cn1nnnc1S
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CONC(=O)Cn1nnnc1S
Temperature: 0 °C
Reaction time: 1.33 h
Yield: 70.9 %

Procedure:
To an ice cold solution of 5-mercapto-1H-tetrazole-1-acetic acid (160 mg) in acetonitrile (3.2 ml) are added tri-n-butylamine (476 μl) and phosphorus oxychloride (183 μl). After 80 minutes' stirring, a solution of methoxyamine hydrochloride (167 mg) and tri-n-butylamine (476 μl) in hexamethylphosphorotriamide is added to the above solution. After another 1 hour's stirring at 0° C., the mixture is extracted with 5% aqueous sodium hydrogen carbonate (40 ml). The extract solution is washed with ethyl acetate, acidified with concentrated hydrochloric acid to pH 2.5, saturated with sodium chloride and extracted with methyl ethyl ketone. The extract is dried over magnesium sulfate and concentrated to give 5-mercapto-1H-tetrazole-1-acetohydroxamic acid methyl ester (134 mg). mp. 165°-167° C. (decomp.).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=[O:12].OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O.[ClH:26]>C(O)(=O)C.O=[Pt]=O>[ClH:26].[NH:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH:2]1[C:11]([OH:13])=[O:12]
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: O=[Pt]=O
Agent: Cl
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CC(=O)O
Product: O=C(O)C1CCC2CCCCC2N1

Procedure:
A mixture of PtO2 (25 wt. %) and 2-quinolinecarboxylic acid (Aldrich) in acetic acid was hydrogenated at RT under 60 Psi overnight. The reaction mixture was stripped to dryness. Concentrated HCl was added and stripped to dryness to give the title compound as a white solid.
Reaction SMILES: [Li].[CH3:2][Si:3]([CH3:6])([CH3:5])Cl.[N:7]1[CH:12]=[C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][N:14]2[CH3:15])[CH:10]=[CH:9][CH:8]=1>C1COCC1>[CH3:15][N:14]1[CH2:16][CH2:17][CH2:18][CH:13]1[C:11]1[CH:10]([Si:3]([CH3:6])([CH3:5])[CH3:2])[CH:9]=[CH:8][N:7]([Si:3]([CH3:6])([CH3:5])[CH3:2])[CH:12]=1
Reactant: C[Si](C)(C)Cl
Reactant: CN1CCC[C@H]1c1cccnc1
Agent: [Li]
Solvent: C1CCOC1
Product: CN1CCCC1C1=CN([Si](C)(C)C)C=CC1[Si](C)(C)C
Temperature: -10 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a suspension of lithium powder (0.42 g, 60 mmol) in freshly distilled THF (20 mmol) cooled at −10° C. was added freshly distilled trimethylchlorosilane (7.6 mL, 60 mmol). A solution of (S)-nicotine (3.2 mL, 20 mmol) in THF (20 mL) was injected dropwise over 20 min. The reaction mixture was stirred at 0° C. for 1 h. The precipitate formed was decanted over 2 h and the liquid portion was canulated into a 2 neck flask mounted with a distillation apparatus under Ar. After removal of the THF by distillation at atmospheric pressure, the product was distilled under vacuum (1.5 mm Hg, bp=130–135° C.) to give 71% (4.36 g) of 3-(1-methylpyrrolidin-2-yl)-1,4-bis-trimethylsilanyl-1,4-dihydropyridine i as a yellow oil (95% pure by NMR). 1H NMR (400 MHz, CDCl3): δ 8.24 (s, 1 H), 5.78–5.72 (m, 1 H), 4.37–4.29 (m, 1 H), 3.06–2.93 (m, 1 H), 2.4–1.4 (m, 10 H), 0.08 (s, 9 H), −0.05 (s, 9 H). 13C NMR (100 MHz, CDCl3) δ 127.49, 126.41, 121.14, 102.08, 101.00, 66.67, 57.21, 41.05, 32.52, 26.41, 21.84, −0.83, −0.90, −2.43, −2.64. HRMS Calcd for C16H32N2Si2: 309.2182 [M+H]+. Found: 309.2166 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].N1CCCCC1.Cl>O.N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[CH:13][C:14]([OH:16])=[O:15])([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
30 g. 3-Nitrobenzaldehyde and 30 g. malonic acid were heated in 60 ml. pyridine at a maximum temperature of 50° C. until a clear solution was obtained. Subsequently, 3 ml. piperidine were added thereto and the solution was heated for 1 hour at 80° C. Thereafter, it was heated under reflux for 3 hours. The solution was then poured into 400 ml. water which contained 50 ml. concentrated hydrochloric acid. The precipitated solid material was filtered off and washed with water. It was subsequently dissolved in 400 ml. water in which 8 g. sodium hydroxide had been dissolved. Insoluble materials were then filtered off and the 3-nitrocinnamic acid obtained was again precipitated out by acidification with hydrochloric acid. The compound was recrystallised from ethanol, the yield being 17 g.; m.p. 204° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:5]([N+:22]([O-])=O)=[C:4]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.C1(C)C=CC=CC=1>[Pt].C(O)(C)C>[NH2:22][C:5]1[C:4]([O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[N:3][C:2]([CH3:1])=[C:7]([CH3:8])[C:6]=1[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCCNC(=O)OC(C)(C)C)c1C
Agent: [Pt]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: Cc1nc(Oc2ccccc2)c(N)c(NCCCCNC(=O)OC(C)(C)C)c1C
Yield: 87.6 %

Procedure:
Tert-butyl 4-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]butylcarbamate (9.17 g, 21.3 mmol), toluene (50 mL), isopropanol (5 mL) and 5% platinum on carbon (7.0 g) were combined and maintained under hydrogen pressure (50 psi, 3.5 Kg/cm2) overnight on a Parr apparatus. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting brown oil was dried under high vacuum to provide 7.47 g of tert-butyl 4-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]butylcarbamate.
Reaction SMILES: C(O[CH:4]1[NH:9][C:7](=[O:8])[CH2:6][CH2:5]1)C.S(=O)(=O)(O)O.[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)(=O)C>[OH:21][C:15]1[CH:20]=[CH:19][C:18]([CH:4]2[NH:9][C:7](=[O:8])[CH2:6][CH2:5]2)=[CH:17][CH:16]=1
Reactant: CCOC1CCC(=O)N1
Reactant: Oc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C1CCC(c2ccc(O)cc2)N1
Temperature: 25 °C
Reaction time: 48 h
Yield: 18.9 %

Procedure:
At 0° C., 12.9 g of γ-ethoxy-γ-butyrolactam, 10 ml of conc. sulphuric acid and 90 ml of glacial acetic acid were initially charged and admixed, a little at a time, with a total of 18.8 g of phenol. After thawing, the mixture was stirred at room temperature for 2 days. For work-up, the mixture was poured onto ice and extracted three times with ethyl acetate, and the combined extracts were washed once each with water and saturated sodium chloride solution, dried and concentrated. After some time, γ-2-hydroxyphenyl-y-butyrolactam (XI-2b) of melting point 220° C. (6.4 g, 36% of theory) crystallized from the aqueous phase. The residue obtained after concentration was stirred with a 1:1 mixture of cyclohexane/ethyl acetate and gave, after filtration with suction, 4.65 g of γ-4-hydroxyphenyl-γ-butyrolactam (XI-2a) of melting point 183° C. The filtrate was concentrated. A further 3.35 g (total: 45% of theory) of γ-4-hydroxyphenyl-γ-butyrolactam were obtained by recrystallization from dichloromethane/hexane.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[C:7]([Cl:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[N:11]([O-])=O.[Na+]>O.Cl>[Cl:1][C:2]1[C:8]([Cl:9])=[C:7]([Cl:10])[CH:6]=[CH:5][C:3]=1[NH:4][NH2:11]
Reactant: Nc1ccc(Cl)c(Cl)c1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(Cl)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
Fifty grams of 2,3,4-trichloroaniline was added portionwise to a solution of 200 ml of concentrated hydrochloric acid at approximately 0° C. To the reaction mixture was added 17.6 g of sodium nitrite dissolved in 100 ml of water dropwise over 1 hour. Next, 94.8 g of stannous chloride dissolved in 100 ml of concentrated hydrochloric acid was added dropwise to the reaction mixture over a 1 hour period while maintaining the temperature at approximately 0° C. The reaction mixture was stirred for approximately 1 hour at this temperature and then warmed to room temperature and stirred for 20 additional hours. The precipitated solid was collected by filtration and dried. The collected solid was added to a cold solution of 300 ml of 25% aqueous sodium hydroxide and this solution was stirred at approximately 5° C. for 1 hour. This aqueous solution was then extracted with ether and the organic phase was washed with water and saturated sodium chloride, and finally dried over anhydrous magnesium sulfate. The organic phase was evaporated under reduced pressure and the residue was recrystallized from ethanol to afford 35 g of 2,3,4-trichlorophenylhydrazine. Yield 66%. mp=138°-140° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:25][C:24]([CH3:26])=[C:23]([CH3:27])[N:19]3[C:20](=[O:22])[CH:21]=2)[CH2:3][CH2:2]1.[I:28]N1C(=O)CCC1=O.C1(COC2C(OC)=CC=CC=2/C=C/C2N=C3SC=CN3C(=O)C=2I)CC1>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:25][C:24]([CH3:26])=[C:23]([CH3:27])[N:19]3[C:20](=[O:22])[C:21]=2[I:28])[CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1cccc(/C=C/c2cc(=O)n3c(C)c(C)sc3n2)c1OCC1CC1
Agent: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC1CC1
Solvent: CC#N
Product: COc1cccc(/C=C/c2nc3sc(C)c(C)n3c(=O)c2I)c1OCC1CC1

Procedure:
To a solution of Step 3 intermediate (500 mg, 1.568 mmol) in acetonitrile (10 ml) was added N-iodosuccinimide (494 mg, 2.195 mmol) and reacted according to the procedure described in Step 4, Intermediate 2 to afford 600 mg of the desired compound; 1H NMR (300 MHz, CDCl3) δ 0.32-0.34 (m, 2H), 0.54-0.56 (m, 2H), 1.17-1.20 (m, 1H), 2.29 (s, 3H), 2.58 (s, 3H), 3.75-3.77 (m, 2H), 3.80 (s, 3H), 7.04-7.13 (m, 2H), 7.25-7.27 (m, 1H), 7.47 (d, J=15.9 Hz, 1H), 8.12 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 509.01 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:13]O)[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[CH2:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)C(CO)c1ccc(Cl)cc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C(=O)OC)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
Methyl 2-(4-chlorophenyl)-3-hydroxypropanoate (16.2 g, 75.5 mmol) was dissolved in DCM (200 mL). Triethylamine (26.3 mL, 188.7 mmol) was then added, and the solution was cooled to 0° C. The solution was then treated with methanesulfonyl chloride (5.84 mL, 75.5 mmol), and the mixture was stirred at 0° C. for 30 minutes. The cold solution was acidified to a pH of 1, and extracted with methylene chloride. The combined organic layers were washed with 1N HCl, water, 6% NaHCO3, dried over Na2SO4 and concentrated. The crude oil was filter chromatographed on SiO2 (with gypsum, Aldrich 28,852-7, 350 g) and eluted with 20:1 hexane:EtOAc to give methyl 2-(4-chlorophenyl)acrylate (10.9 g, 73%).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.[Cl-].S(Cl)([Cl:16])=O>>[CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:16])=[O:8])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CN(C)c1ccc(C(=O)O)cc1
Agent: [Cl-]
Product: CN(C)c1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Firstly, 4-dimethylamino benzoylchloride was prepared. The reaction was accomplished by placing 4-dimethylamino benzoic acid (ex. Lancaster) (4.0 g, 24.22 mmol) in a 25 ml round bottom flask, to which was added thoinyl chloride (ex. Aldrich) (3.0 ml). This reaction mixture became orange immediately upon the addition of the thionyl chloride. The reaction mixture was stirred for 1 hour at ambient temperature, after which time the remaining thionyl chloride was removed under reduced pressure. The last trace of the thionyl chloride was removed by azeotroping with dry benzene (2×20 ml).
Reaction SMILES: C([Li])(C)(C)C.[Cl:6][C:7]1[N:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][CH:8]=1.CN(C)[CH:17]=[O:18].C(O)(=O)C>C1COCC1.CCOCC>[Cl:6][C:7]1[N:12]=[C:11]([O:13][CH3:14])[C:10]([CH:17]=[O:18])=[CH:9][CH:8]=1
Reactant: CN(C)C=O
Reactant: COc1cccc(Cl)n1
Agent: [Li]C(C)(C)C
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1nc(Cl)ccc1C=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a solution of tert-butyllithium (1.7M in pentane, 48.5 mL, 83.0 mmol) in 150 mL of THF at -78° C. was added 6-chloro-2-methoxypyridine (8.94 mL, 75.0 mmol) over 5 min. The reaction mixture was stirred at -78° C. for 1 h, then dimethylformamide (7.55 mL, 97 mmol) was added and the mixture was stirred at this temperature for 1.5 h. After the addition of glacial acetic acid (8.6 mL, 150 mmol), the reaction mixture was allowed to warm to room temperature over a 30- min period, then diluted with ether (200 mL). The organic phase was washed with saturated aqueous NaHCO3 (100 mL) and brine (100 mL), and was dried over MgSO4. Concentration afforded the crude product as a light yellow solid which was recrystallized from hexanes to give 9.6 g (75%) of 6-chloro-2-methoxy-3-pyridinecarboxaldehyde as a white solid: mp 80°-81° C. (mp 62°-64° C.)(See Dainter, R. S.; Suschitzky, H.; Wakefield, B. J. Tetrahedron Lett. 1984, 25, 5693.). 1H NMR (300 MHz, CDCl3) δ10.31 (s, 1H), 8.07 (d, 1H, J=9 Hz), 7.03 (d, 1H, J=9 Hz), 4.09 (s, 3H); IR (nujol) 1685, 1580, 1565, 1270, 1140, 1090, 1005, 905, 820, 755 cm-1.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10]([NH:12][NH:13][C:14]([NH2:16])=[S:15])=N.CN1C([N+]([O-])=O)=CN=C1C(=NNC(N)=S)OCC>>[NH2:16][C:14]1[S:15][C:10]([C:3]2[N:2]([CH3:1])[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=2)=[N:12][N:13]=1
Reactant: Cn1c([N+](=O)[O-])cnc1C(=N)NNC(N)=S
Agent: CCOC(=NNC(N)=S)c1ncc([N+](=O)[O-])n1C
Product: Cn1c([N+](=O)[O-])cnc1-c1nnc(N)s1

Procedure:
In a similar manner, acid treatment of the mixture of 1-(1-methyl-5-nitro-2-imidazolecarboximidoyl)-3-thiosemicarbazide and ethyl 1-methyl-5-nitro-2-imidazolecarboxylate thiosemicarbazone, gives the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([NH2:17])=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:19][CH2:20][S:21](Cl)(=[O:23])=[O:22].O>CN(C)C(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3=[N:17][S:21](=[O:23])(=[O:22])[CH2:20][CH2:19][N:13]3[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)(C)c1ccc(-c2cccnc2N)cc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)c1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
A solution of 3-(4-tert-butylphenyl)pyridin-2-amine (301 mg) in N,N-dimethylacetoamide (4 mL) was added dropwise to 2-chloroethanesulfonyl chloride (437 mg) and additional N,N-dimethylacetoamide (1 mL) was used to complete the addition of above solution. After being stirred at 60° C. for 3 hr, the mixture was cooled to room temperature. Water (10 mL) was added dropwise to the reaction mixture and the whole was stirred at room temperature for 0.5 hr. The precipitate was collected by filtration, washed with water (10 mL) and diisopropyl ether (3 mL), and dried in vacuo at 60° C. to give the title compound (366 mg) as an off-white powder.
Reaction SMILES: C[Al](C)C.[C:5](C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.[CH3:21][C@:22]12[CH2:39][CH2:38][C@H:37]3[C@@H:27]([CH2:28][CH2:29][C:30]4[C@:35]3([CH3:36])[CH:34]=[CH:33][C:32](=[O:40])[CH:31]=4)[C@@H:26]1[CH2:25][CH2:24][C:23]2=[O:41].O>CCCCCC.C(OCC)(=O)C.[Ni+2].C/C(/[O-])=C/C(C)=O>[CH3:5][C:34]1[C@@:35]2([CH3:36])[C:30]([CH2:29][CH2:28][C@@H:27]3[C@@H:37]2[CH2:38][CH2:39][C@@:22]2([CH3:21])[C@H:26]3[CH2:25][CH2:24][C:23]2=[O:41])=[CH:31][C:32](=[O:40])[CH:33]=1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Ni+2]
Agent: CC(=O)/C=C(/C)[O-]
Agent: C[Al](C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC1=CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]12C
Temperature: 58 °C
Yield: 20.1 %

Procedure:
12 ml (12 mmol) of trimethylaluminum of a 10% solution in hexane is introduced at room temperature under nitrogen atmosphere. With stirring, 2.64 g of 2,6-di-tert-butyl-4-methylphenol is added in portions. The solution is stirred for 30 more minutes and 2.84 g (10 mmol) of androsta-1,4-diene-3,17-dione in 20 ml of ethyl acetate is added at 25° C. The solution is heated to 58° C. At 58° C., 143 mg of nickel(II)-acetylacetonate is added. The solution is stirred for 2.5 more hours at a temperature of 60° C. After cooling, 1.1 ml of water is added for hydrolysis and stirred for 15 minutes. The inorganic solid is filtered off and rewashed twice with 50 ml of ethyl acetate. After concentration by evaporation of the ethyl acetate phases, a crude product is obtained, which is chromatographed on silica gel with hexane/ethyl acetate as eluent with increasing ethyl acetate portion. 1.5 g of initial material is recovered. 0.60 g of 1-methyl-androsta-1,4-diene-3,17-dione of melting point 168°-170° C. is obtained. The yield is 20% of theory or 42% taking into consideration the initial material recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][NH:5][C:4](=[O:8])[C:3]=1[Cl:9].C([O-])([O-])=O.[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1NC(=O)C=CC=1>CN(C=O)C>[CH2:16]([N:5]1[C:4](=[O:8])[C:3]([Cl:9])=[C:2]([Cl:1])[CH:7]=[N:6]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=c1[nH]ncc(Cl)c1Cl
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=c1cccn[nH]1
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c(Cl)c(Cl)cnn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.6 %

Procedure:
To a solution of dichloropyridazinone (50.0 g, 303.0 mmol) in DMF (200 mL) was added K2CO3 (50.3 g, 364.0 mmol) at RT under vigorous stirring. Benzylbromide (40.0 mL, 336.0 mmol) was added in rapid drops via a syringe. The resulting suspension was stirred at 50° C. for 1 h until all the pyridazinone was consumed as judged by HPLC. The reaction mixture was then poured into water (400 mL). The resultant suspension was stirred for 15 min at RT, and then filtered. The collected solid was rinsed thoroughly with water until no color was apparent in the filtrate. The solid was dried in a vacuum oven at 50° C. overnight to give the title compound, 2-benzyl-4,5-dichloropyridazin-3(2H)-one, (73.1 g, 95%) as pale yellow solid. HPLC: 3.17 min; MS, M+H=255.