Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[N+]#N.[OH2:12]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[OH:12]
Reactant: N#[N+]c1cc(Cl)c(Cl)cc1Cl
Reactant: O
Product: Oc1cc(Cl)c(Cl)cc1Cl

Procedure:
In the fourth stage, the 2,4,5-trichlorobenzenediazonium strong mineral acid salt in solution in water is hydrolytically decomposed at a temperature from the reflux temperature to a temperature of 375° C. At the lower temperatures, the solution is refluxed in the presence of a cupric salt, the 2,4,5-trichlorophenol formed is steam distilled from the reaction and separately recovered. At higher temperatures of 130° C. to 375° C., preferably from 140° C. to 220° C., the aqueous solution is injected into a column packed with a suitable inert material and maintained at the desired temperature, either with or without additional super-heated steam. The 2,4,5-trichlorophenol steam distills from the top of the heated column and the concentrated aqueous strong mineral acid is recovered from the bottom of the column.
Reaction SMILES: C([O-])([O-])OCC.C(OC(=O)C)(=O)C.C(O[CH:17]=[C:18]([C:24](=[O:35])[C:25]1[C:30]([F:31])=[CH:29][C:28]([F:32])=[C:27]([F:33])[C:26]=1[F:34])[C:19]([O:21][CH2:22][CH3:23])=[O:20])C.[CH:36]1([NH2:39])[CH2:38][CH2:37]1>>[CH:36]1([NH:39][CH:17]=[C:18]([C:24](=[O:35])[C:25]2[C:30]([F:31])=[CH:29][C:28]([F:32])=[C:27]([F:33])[C:26]=2[F:34])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:38][CH2:37]1
Reactant: NC1CC1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(F)cc(F)c(F)c1F
Agent: CCOC([O-])[O-]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1c(F)cc(F)c(F)c1F

Procedure:
The resulting compound (28.4 g) was treated with ethyl orthoformate and acetic anhydride to convert it into ethyl 3-ethoxy-2-(2',3',4',6'-tetrafluorobenzoyl)acrylate and this compound was then treated with cyclopropylamine to give 32.8 g of ethyl 3 -cyclopropylamino-2-(2',3',4',6'-tetrafluorobenzoyl)acrylate. m.p. 107°-108° C.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=2)[C:6]([C:16]([OH:18])=O)=[CH:5]1)([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:55][C:56]1[S:57][CH:58]=[CH:59][N:60]=1>C(Cl)Cl>[S:57]1[CH:58]=[CH:59][N:60]=[C:56]1[NH:55][C:16]([C:6]1[C:7]2[C:12](=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[N:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)=[O:18]
Reactant: Nc1nccs1
Reactant: CC(C)n1cc(C(=O)O)c2ccc([N+](=O)[O-])cc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1cc(C(=O)Nc2nccs2)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 4.9 %

Procedure:
A solution of 1-isopropyl-6-nitro-1H-indole-3-carboxylic acid (200 mg, 0.81 mmol) in methylene chloride (4 mL) and N,N-diisopropylethylamine (0.32 mL, 1.85 mmol) at 25° C. was treated with benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluoro-phosphate (463 mg, 1.05 mmol). The reaction was stirred at 25° C. for 20 min. At this time, the reaction was treated with 2-aminothiazole (186 mg, 1.85 mmol) and was stirred at 25° C. for 24 h. At this time, the reaction mixture was partitioned between water (50 mL) and ethyl acetate (50 mL) and was treated with a 1N aqueous hydrochloric acid solution (25 mL). The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was dissolved in a hot solution of 1/1 hexanes/ethyl acetate and then filtered. The filtrate was cooled in the freezer for 1 h. At this time, the resulting solid was collected by filtration. The filtrate was concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded 1-isopropyl-6-nitro-1H-indole-3-carboxylic acid thiazol-2-ylamide (13 mg, 4.9%) as a yellow solid: mp 236-239° C.; EI-HRMS m/e calcd for C15H14N4O3S (M+) 330.0786, found 330.0792.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[NH2:45][C:46]([CH3:50])([CH3:49])[CH2:47][OH:48].[Cl-].[Na+]>C1COCC1>[OH:48][CH2:47][C:46]([NH:45][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:23])([CH3:50])[CH3:49]
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)O)n(C)n1
Reactant: CC(C)(N)CO
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)NC(C)(C)CO)n(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
To a solution of 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.3 mmol) in THF (2.7 mL) was added 1-hydroxybenzotriazole hydrate (47.2 mg, 0.3 mmol), N-ethyldiisopropylamine (131.9 μL, 0.76 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidazole hydrochloride (59.1 mg, 0.3 mmol) and 2-amino-2-methyl-1-propanol (27.8 mg, 0.3 mmol) and the resulting mixture stirred overnight at room temperature. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and saturated sodium hydrogen carbonate solution and then dried over sodium sulfate, filtered and evaporated. Concentration and purification by chromatography (silica, dichloromethane:methanol=99:1 to 95:5) afforded the title compound (115 mg, 94%) as a white solid. MS: m/e=403.2 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=2[C:13](=[O:16])[CH2:14][CH3:15])[CH2:3][CH2:2]1.[C:17](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH:1]1([C:4]2[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:17])=[O:9])=[CH:6][C:5]=2[C:13](=[O:16])[CH2:14][CH3:15])[CH2:2][CH2:3]1
Reactant: CCC(=O)c1cc(C(=O)O)ccc1C1CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCC(=O)c1cc(C(=O)OC)ccc1C1CC1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 4-cyclopropyl-3-propanoylbenzoic acid (compound 10.6, 500 mg, 2.29 mmol) in N,N-dimethylformamide (20 mL) and potassium carbonate (633 mg, 4.55 mmol). The mixture was cooled to 0-5° C. then iodomethane (157 μL, 2.52 mmol) was added drop-wise. The resulting mixture was stirred for 1 h at 5-10° C., then quenched with water/ice (80 mL). The aqueous phase was extracted with ethyl acetate (2×150 mL) and the combined organic layers were washed with brine (20 mL), sodium carbonate (sat., 20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. Obtained 400 mg (75%) of the title compound as a light brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](=O)[CH:7]=[CH:6][NH:5][C:4]=1[CH3:10].P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:10])[C:3]=1[O:2][CH3:1]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1c(C)[nH]ccc1=O
Product: COc1c(Cl)ccnc1C

Procedure:
3-Methoxy-2-methyl-4(1H)-pyridone (5.6 g) was suspended in phosphorus oxychloride (50 ml), refluxed for 10 hours, and concentrated. To the resultant residue was added toluene and the residual phosphorus oxychloride was evaporated under reduced pressure. To the resultant oily substance were added chloroform and water and the chloroform layer was separated. The aqueous layer was made alkaline with potassium carbonate and extracted with chloroform. The chloroform solutions thus obtained were combined, washed with water, dried, and evaporated. The residue was purified by column chromatography on silica gel, to give 4-chloro-3-methoxy-2-methylpyridine (4.8 g) as a light brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]=[C:10]2[C:13]#[N:14])=[CH:5][CH:4]=1>CC1C=CC(C(C)C)=CC=1.CCCCCC.[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[C:13]#[N:14])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(C#N)=CCC2
Agent: [Pd]
Solvent: CCCCCC
Solvent: Cc1ccc(C(C)C)cc1
Product: COc1ccc2cccc(C#N)c2c1
Temperature: 150 °C
Yield: 44.2 %

Procedure:
To a mixture of 7-methoxy-3, 4-dihydronaphthalene-1-carbonitrile (9.95 g, 53.1 mmol) in p-cymene (1600 mLs) was added 10% Pd/C (5 g), the reaction mixture was stirred and heated to 150° C. overnight. The mixture was cooled and the catalyst removed by filtering through filter aid. The p-cymene was removed on the rotovap with the vacuum pump, giving a liquid which solidified on standing. The solid was slurried in hexane, filtered and dried to afford a-white solid (4.3 g, 44%). A portion was purified further by silica gel (10% ethyl acetate-hexanes) to produce a white solid: mp 77–78° C.; 1H NMR (DMSO-d6): δ 3.97 (3H, s), 7.36 (1H, s), 7.39 (1H, d, J=2.5 Hz), 7.52 (1H, t, J=7.4 Hz), 8.04–8.13 (2H, m), 8.24 (1H, d, J=8.2 Hz).
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([O:16]C)=[O:15])=[CH:8][CH:7]=1.Cl>[OH-].[Na+]>[C:14]([CH2:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:18])=[O:2])=[CH:7][CH:8]=1)([OH:16])=[O:15]
Reactant: COC(=O)COc1ccc(OCC(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)COc1ccc(OCC(=O)O)cc1
Temperature: 70 °C
Yield: 67.3 %

Procedure:
(4-Methoxycarbonylmethoxy-phenoxy)-acetic acid methyl ester 82 (100 grams, 394 mmol) was added to 3.25 M-sodium hydroxide solution (600 mL) and heated to 70° C. for 20 hours and poured onto ice cold water (1 lit) and the pH adjusted to 1 with concentrated hydrochloric acid. Crude 83 was filtered, dried, and recrystallized from DMF by precipitating with water to give pure 83 (60 grams, 67.4%) as a white powder. M.p: 254-256.5° C. IH NMR (CDCl3+DMSO, d6) 4.44 (s, 2H, OCH2), 6.72 (s, 2H, Ar).
Reaction SMILES: [N:1]([C@@H:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:14][CH3:15])[CH2:6][C@H:5]1[OH:16])=[N+]=[N-].[H][H]>[Pd].C(O)C>[NH2:1][C@@H:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:14][CH3:15])[CH2:6][C@H:5]1[OH:16]
Reactant: COc1cccc2c1C[C@@H](N=[N+]=[N-])[C@H](O)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1cccc2c1C[C@@H](N)[C@H](O)C2
Reaction time: 0.83 h

Procedure:
4.0 g of palladium on charcoal (10%) are coated with 100 ml of ethanol. 8.76 g (0.040M) of trans-3-azido-1,2,3,4-tetrahydro-5-methoxy-2-naphthalinol are dissolved in 100 ml of ethanol, and the solution is added to the catalyst suspension. The mixture is subsequently hydrogenated at 20° at 1.2 bar hydrogen pressure. Every 10 minutes for 50 minutes, the reaction vessel is emptied and rinsed with hydrogen. The reaction mixture is then filtered through a G 4 Hyflo suction filter. The catalyst is washed with methylene chloride and the filtrate concentrated by evaporation. Trans-3-amino-1,2,3,4-tetrahydro-5-methoxy-2-naphthalinol is obtained (m.p. 130°-132° after purification by column chromatography, silica gel, methylene chloride and 10% methanol).
Reaction SMILES: Cl.C([N:9]1[CH2:18][CH2:17][C:16]2[N:15]=[C:14]([Cl:19])[C:13]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:12][C:11]=2[CH2:10]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCl.CO>[ClH:19].[Cl:19][C:14]1[C:13]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:12][C:11]2[CH2:10][NH:9][CH2:18][CH2:17][C:16]=2[N:15]=1
Reactant: CCOC(=O)c1cc2c(nc1Cl)CCN(Cc1ccccc1)C2
Agent: CC(Cl)OC(=O)Cl
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(nc1Cl)CCNC2
Temperature: 40 °C

Procedure:
A solution of the product from Step A above (0.095 mg, 0.287 mmol) in 10 mL of dichloromethane was treated with 1-chloroethyl chloroformate (0.050 g; 0.344 mmol), and the mixture was warmed at reflux temperature overnight. The reaction was concentrated under reduced pressure to afford a yellow oil, which was dissolved in 10 mL of methanol. The solution was heated at 40° C. for 2 h, cooled to room temperature and concentrated in vacuo. To the yellow solid was added diisopropyl ether. The pale yellow crystals were collected by filtration and recrystallized from ethanol to afford the title compound. LC/MS: 240.0 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:69]=[C:68]([O:70][CH3:71])[CH:67]=[C:66]([O:72][CH3:73])[C:4]=1/[CH:5]=[CH:6]/[CH:7]([S:28]([CH:31](/[CH:52]=[CH:53]/[C:54]1[C:59]([O:60][CH3:61])=[CH:58][C:57]([O:62][CH3:63])=[CH:56][C:55]=1[O:64][CH3:65])[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([NH:40][C:41](=[O:51])[C:42]2[CH:47]=[CH:46][C:45]([N+:48]([O-])=O)=[CH:44][CH:43]=2)[CH:33]=1)(=[O:30])=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)[CH:9]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].O>O.CC(C)=O>[CH3:73][O:72][C:66]1[CH:67]=[C:68]([O:70][CH3:71])[CH:69]=[C:3]([O:2][CH3:1])[C:4]=1/[CH:5]=[CH:6]/[CH:7]([S:28]([CH:31](/[CH:52]=[CH:53]/[C:54]1[C:59]([O:60][CH3:61])=[CH:58][C:57]([O:62][CH3:63])=[CH:56][C:55]=1[O:64][CH3:65])[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([NH:40][C:41](=[O:51])[C:42]2[CH:43]=[CH:44][C:45]([NH2:48])=[CH:46][CH:47]=2)[CH:33]=1)(=[O:29])=[O:30])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([NH:16][C:17](=[O:27])[C:18]2[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=2)[CH:9]=1
Reactant: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)c3ccc([N+](=O)[O-])cc3)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)c3ccc([N+](=O)[O-])cc3)c2)c(OC)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)c3ccc(N)cc3)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)c3ccc(N)cc3)c2)c(OC)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of 2,4,6-trimethoxystyryl-3-(4-nitrobenzamido)-4-methoxybenzylsulfone (example 10) (1.3 mmol) in acetone water (10:5) was heated to 50° C. After 30 min, sodiumhydrosulfite (Na2S2O4) (26.3 mmol) was added slowly, and the mixture was heated at reflux (50° C., 1 h.), cooled to room temperature and water was added. The product was rinsed with NaHCO3, and then isolated by extraction with ethyl acetate. The organic layer was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the crude product was recrystallized from 2-propanol to give pure (E)-2,4,6-Trimethoxystyryl-3-(4-aminobenzamido)-4-methoxybenzylsulfone. m.p. 137-140° C. NMR (DMSO-d6) δ 3.82 (s, 3H), 3.83(s, 6H), 3.86(s, 3H), 4.22(s, 2H), 6.14(s, 2H), 6.80-8.16(m, aromatic), 8.60 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[NH:14][N:13]=[C:12]([CH:15]3[CH2:17][CH2:16]3)[CH:11]=2)[N:3]=1.[OH:18][C@@H:19]1[CH2:23][NH:22][C@H:21]([C:24]([NH:26][C:27]2[CH:32]=[N:31][CH:30]=[CH:29][N:28]=2)=[O:25])[CH2:20]1.ClC1N=C(NC2NN=C(C3CC3)C=2)N=C(N2CCC[C@@]2(C)C(NC2C=NC(F)=CC=2)=O)N=1>>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][C:10]2[NH:14][N:13]=[C:12]([CH:15]3[CH2:17][CH2:16]3)[CH:11]=2)[N:3]=[C:2]([N:22]2[CH2:23][C@@H:19]([OH:18])[CH2:20][C@H:21]2[C:24]([NH:26][C:27]2[CH:32]=[N:31][CH:30]=[CH:29][N:28]=2)=[O:25])[N:7]=1
Reactant: Clc1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Reactant: O=C(Nc1cnccn1)[C@@H]1C[C@H](O)CN1
Agent: C[C@@]1(C(=O)Nc2ccc(F)nc2)CCCN1c1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Product: O=C(Nc1cnccn1)[C@@H]1C[C@H](O)CN1c1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1

Procedure:
Compound 85B was prepared from 1A and 85A as described for 1C. LC/MS [M+H]+: 443/445; Ret time (Method F): 2.18 min.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].Cl[S:36]([NH2:39])(=[O:38])=[O:37].O>CN(C)C(=O)C>[S:36]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:38])(=[O:37])[NH2:39]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: NS(=O)(=O)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(N)(=O)=O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.8 %

Procedure:
4-Hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.145 g, 0.314 mmol) was dissolved in N,N-dimethylacetoamide (1.5 mL), and the solution was added with chlorosulfonamide (0.0440 mL, 0.377 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture was added with water and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography (chloroform/methanol=85/15) to obtain 4-sulfamoyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0914 g, yield 54%).
Reaction SMILES: CN(C)C=O.[C:6]([CH2:9][N:10]1[C:14](=[O:15])[C:13](=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:12][C:11]1=[S:23])([OH:8])=[O:7].[OH-].C[N+](C)(C)C.[CH2:30](Br)[CH3:31]>CO>[C:6]([CH2:9][N:10]1[C:14](=[O:15])[C:13](=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:12][C:11]1=[S:23])([O:8][CH2:30][CH3:31])=[O:7]
Reactant: CCBr
Reactant: O=C(O)CN1C(=O)C(=Cc2ccccc2)SC1=S
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)C(=Cc2ccccc2)SC1=S
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Under an atmosphere of nitrogen, 4.2 ml of anhydrous N,N-dimethylformamide was added dropwise to 0.279 g of 3-carboxymethyl-5-benzylidenerhodanine (prepared as described in Example 1) at room temperature, and then 1.14 ml of methanol solution of 91.15 mg of tetramethylammonium hydroxide was added dropwise. After the mixture was stirred at room temperature for 20-30 minutes, 0.075 ml of ethyl bromide was added dropwise to the reaction mixture. The mixture was stirred at the same temperature for about 2 hours, and then concentrated under reduced pressure. The residue was diluted with 15 ml of water and extracted with ethyl acetate. The extract was washed with 50 ml of aqueous solution of sodium bicarbonate, 50 ml of water and 50 ml of aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from a mixture of ethyl acetate and n-hexane (1:3) to obtain 14 mg of the titled compound.
Reaction SMILES: N1NC(=O)C=CC=1.BrC1C=C2C(=CC=1)C=C(OS(C(F)(F)F)(=O)=O)C=C2.[Br:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH:38]=[CH2:39])[CH:34]=2)[CH:29]=1.[CH3:40][CH:41]1[CH2:45][CH2:44][CH2:43][NH:42]1.C([Li])CCC>>[Br:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH:34]=[C:33]([CH2:38][CH2:39][N:42]1[CH2:43][CH2:44][CH2:45][CH:41]1[CH3:40])[CH:32]=[CH:31]2
Reactant: C=Cc1ccc2cc(Br)ccc2c1
Reactant: CC1CCCN1
Agent: O=S(=O)(Oc1ccc2cc(Br)ccc2c1)C(F)(F)F
Agent: O=c1cccn[nH]1
Agent: [Li]CCCC
Product: CC1CCCN1CCc1ccc2cc(Br)ccc2c1

Procedure:
Another aspect of the invention, relates to the preparation of 2-(6-{2-methyl-1-pyrrolidin-1-yl]-ethyl}-2-naphthalen-2-yl)-2H-pyridazin-3-one active agent. The process comprises the steps of converting a trifluoro-methanesulfonic acid 6-bromo-naphthalen-2-yl ester to 2-bromo-6-vinyl-naphthalene; and reacting 2-bromo-6-vinyl-naphthalene with a 2-methylpyrrolidine anion generated with n-butyllithium to provide a 1-[2-(6-bromo-naphthalen-2-yl)-ethyl]-2-methyl-pyrrolidine compound, which is reacted with 2H-pyridazin-3-one in the presence of a copper catalyst and ligand to provide a 2-(6-{2-methyl-1-pyrrolidin-1-yl]-ethyl}-2-naphthalen-2-yl)-2H-pyridazin-3-one active agent.
Reaction SMILES: C1(C)CCC(C(C)C)[CH:3]([C:10]([CH:20]2C(C(C)C)CCC(C)C2)([CH3:19])[C:11](=[O:18])[CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)C1.[Br:31]Br>>[Br:31][CH:12]([N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[C:11](=[O:18])[C:10]([CH3:20])([CH3:19])[CH3:3]
Reactant: CC1CCC(C(C)C)C(C(C)(C(=O)Cn2cncn2)C2CC(C)CCC2C(C)C)C1
Reactant: BrBr
Product: CC(C)(C)C(=O)C(Br)n1cncn1

Procedure:
Thus, for example, 3,3-dimethyl-1-(4-methoximinomethyl-phenoxy)-1-(1,2,4-triazol-1-yl)-butan-2-one of the formula ##STR11## can be prepared by reacting 3,3-dimenthyl-1-(1,2,4-triazol-1-yl)-butan-2-one initially with bromine to form 1-bromo-(1,2,4-triazol-1-yl)-3,3-dimethyl-butan-2-one, and subsequently reaching this with 4-hydroxybenzaldehyde O-methyl oxime ether in the presence of a base. This synthesis can be illustrated by means of formulae as follows:
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:21])[N:4]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:5]([CH3:15])=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>>[CH3:15][C:5]1[N:4]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:3](=[O:21])[C:2]([NH:1][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])=[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=1
Reactant: COC(=O)Cn1c(C)cc(Oc2ccccc2)c(N)c1=O
Reactant: O=C(Cl)OCc1ccccc1
Product: COC(=O)Cn1c(C)cc(Oc2ccccc2)c(NC(=O)OCc2ccccc2)c1=O

Procedure:
2.5 g (7.9 mmol) of methyl 3-amino-6-methyl-2-oxo-4-phenoxy-1,2-dihydropyridine-1-acetate are treated with 1.7 ml (11.9 mmol) of phenylmethyl chloroformate under the conditions of Example 3.
Reaction SMILES: Br[C@@H:2]([CH2:6][CH3:7])[C:3]([NH2:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:15][O:16][C:17](=[O:22])[CH2:18][CH2:19][CH2:20][NH2:21]>C(#N)C>[CH3:15][O:16][C:17](=[O:22])[CH2:18][CH2:19][CH2:20][NH:21][C@@H:2]([C:3](=[O:4])[NH2:5])[CH2:6][CH3:7]
Reactant: COC(=O)CCCN
Reactant: CC[C@H](Br)C(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC[C@@H](NCCCC(=O)OC)C(N)=O
Temperature: 60 °C
Reaction time: 43 h

Procedure:
A mixture of (S)-2-bromobutyramide (IIh) (optical purity>98.4%; 0.25 g, 1.5 mmol), potassium carbonate (1.1 g, 8.0 mmol, 5 equiv.) and methyl-4-aminobutyrate hydrochloride (0.46 g, 3.0 mmol, 2 equiv.) is diluted in 5 ml (15 vol.) of acetonitrile and heated at 60° C. for until complete conversion. After 43 hours (GC: >90% conversion), the mixture is cooled to room temperature and filtered. The cake is rinsed with acetonitrile (20 ml) and the combined filtrates are concentrated to dryness under reduce pressure. The crude product is used directly in the subsequent step.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:15](Br)=[C:14]([C:17]([F:20])([F:19])[F:18])[N:13]=[C:12]([O:21][CH3:22])[C:11]=1[Br:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1([Li])C=CC=CC=1.C1CCCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(OCC)C>[Br:23][C:11]1[C:12]([O:21][CH3:22])=[N:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][C:10]=1[CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1nc(C(F)(F)F)c(Br)c(CO[Si](C)(C)C(C)(C)C)c1Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: CCOCC
Product: COc1nc(C(F)(F)F)cc(CO[Si](C)(C)C(C)(C)C)c1Br
Reaction time: 0.08 h

Procedure:
To a solution of the compound from Step E above (2.68 g, 3.41 mmol) in tetrahydrofuran (50 mL) at −78° C. was added 2.0M phenyllithium in cyclohexane (1.70 mL, 3.41 mmol). After the reaction was stirred for 5 min, 10% citric acid in THF was added. The mixture was diluted with ethyl ether, washed sequentially with water and saturated brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (silica gel; 10 to 15% ethyl acetate/hexanes gradient elution) to yield the title compound. 1H NMR (400 MHz, CDCl3) δ 7.52 (s, 1H), 4.74 (s, 2H), 4.08 (s, 3H), 0.99 (s, 9H), 0.17 (s, 6H). LC/MS: 400/402 (M+H and M+H+2).