Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([C:10]([C:12]2[N:13]=[CH:14][NH:15][CH:16]=2)=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1.C(OCC)(=O)C>[CH2:17]([N:15]1[CH:16]=[C:12]([C:10]([C:9]2[C:4]([F:3])=[N:5][CH:6]=[CH:7][CH:8]=2)=[O:11])[N:13]=[CH:14]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(c1c[nH]cn1)c1cccnc1F
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(c1cn(Cc2ccccc2)cn1)c1cccnc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
Sodium hydride (60% in mineral oil, 23 mg, 0.58 mmol) was added to a solution of (2-fluoropyridin-3-yl)(1H-imidazol-4-yl)methanone (100 mg, 0.52 mmol) in tetrahydrofuran (3 ml), cooled to 0° C. The reaction mixture was then stirred for 30 minutes. Benzyl bromide (0.062 ml, 0.52 mmol) was added and the mixture was warmed up to room temperature. The reaction mixture was stirred for 18 hours, diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound (100 mg, 68% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[N+:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br)([O-:16])=[O:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([N+:14]([O-:16])=[O:15])[CH:18]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccn(Cc3cccc([N+](=O)[O-])c3)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.8 %

Procedure:
To a solution of 1H-indole-6-carboxylic acid methyl ester (1.0 g, 5.7 mmol) and 3-nitrobenzyl bromide (1.48 g, 6.8 mmol) in DMF (15 mL) was added K2CO3 (1.6 g, 11.4 mmol). After stirring at room temperature for 16 hr, the solution was diluted with ethyl acetate (100 ml) and washed with water (3×50 ml). The organic layer was dried (MgSO4), filtered and concentrated. The remaining residue was recrystallized with ethyl acetate/hexane to provide 1.34 g (76% yield) of 1-(3-nitrobenzyl)-1H-indole-6-carboxylic acid methyl ester as light orange crystals. 1H NMR (300 MHz, DMSO) δ 8.13 (m, 2H), 8.03 (s, 1H), 7.81 (d, 1H, J=3.0 Hz), 7.67-7.54 (m, 4H, J=9.0 Hz), 6.65 (d, 1H, J=3.0 Hz), 5.73 (s, 2H), 3.81 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11](O)=O.C1CCC(N=C=NC2CCCCC2)CC1.[N:29]1[C:33]2[CH:34]=[CH:35][C:36]([C:38]([NH:40][NH2:41])=O)=[CH:37][C:32]=2[NH:31][CH:30]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:51])=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]1[S:51][C:38]([C:36]2[CH:35]=[CH:34][C:33]3[NH:29][CH:30]=[N:31][C:32]=3[CH:37]=2)=[N:40][N:41]=1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccccc1CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: COc1ccccc1CCc1nnc(-c2ccc3[nH]cnc3c2)s1

Procedure:
The compound was synthesized starting from 3-(2-methoxyphenyl)propionic acid (181 mg; 1 mmol), DCC (206 mg; 1 mmol), benzimidazol-5-carbohydrazide (176 mg; 1 mmol) and Lawesson's reagent (606 mg; 1.5 mmol) as described in method 2; yield: 0.012 g (3.6%); MS m/z: 337.4 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 3.06 (t, 2H, 3J=7.5 Hz); 3.39 (t, 2H, 3J=7.5 Hz); 3.79 (s, 3H); 6.84-6.88 (m, 1H); 6.97-6.99 (m, 2H); 7.18-7.20 (m, 1H); 7.80 (d, 1H, 3J=8.7 Hz); 7.88 (dd, 1H, 4J=1.7 Hz, 3J=8.7 Hz); 8.19-8.20 (m, 1H); 8.78 (s, 1H); HPLC (METHOD [A]): rt 12.78 min (92.7%)
Reaction SMILES: [Br:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:3]=1[NH:4][C:5](=[O:16])[C:6]([F:15])([C:11]([F:14])([F:13])[F:12])[C:7]([F:10])([F:9])[F:8].CI.[C:26](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:26][N:4]([C:5](=[O:16])[C:6]([F:15])([C:11]([F:12])([F:13])[F:14])[C:7]([F:8])([F:9])[F:10])[C:3]1[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:2]=1[Br:1]
Reactant: O=C([O-])[O-]
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1Br)C(F)(C(F)(F)F)C(F)(F)F
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CN(C(=O)C(F)(C(F)(F)F)C(F)(F)F)c1ccc([N+](=O)[O-])cc1Br
Yield: 70 %

Procedure:
2'-Bromo-4'-nitro-2,3,3,3-tetrafluoro-2-(trifluoromethyl)propionanilide was reacted with methyl iodide, in acetone and in the presence of potassium carbonate, yielding N-methyl-2'-bromo-4'-nitro-2,3,3,3-tetrafluoro-2-(trifluoromethyl)propionanilide, an oil, yield 70% (>99% branched isomer).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[CH:4][N:3]=1.[CH:15]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([CH3:17])[CH3:16]>>[ClH:1].[ClH:1].[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([N:21]2[CH2:22][CH2:23][N:18]([CH:15]([CH3:17])[CH3:16])[CH2:19][CH2:20]2)=[N:3][CH:4]=1
Reactant: CC(C)N1CCNCC1
Reactant: Fc1ccccc1-c1ccc(Cl)nc1
Product: CC(C)N1CCN(c2ccc(-c3ccccc3F)cn2)CC1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 2-chloro-5-(2-fluorophenyl)pyridine and 1-isopropylpiperazine.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[NH:8][CH2:9][CH2:10][C:4]2=[N:3][N:2]=1.C(N(CC)CC)C.[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23]>ClCCl>[N+:22]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([N:8]2[C:7]3[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=3[N:5]3[CH:1]=[N:2][N:3]=[C:4]3[CH2:10][CH2:9]2)=[O:30])=[CH:32][CH:33]=1)([O-:24])=[O:23]
Reactant: c1ccc2c(c1)NCCc1nncn1-2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCc2nncn2-c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 3 mmol of 5,6-dihydro-4H-[1,2,4]-triazolo[4,3-a][1,5]benzodiazepine in 10 ml of dichloromethane under argon is added 5 mmol of triethylamine. To the mixture is added dropwise 3.3 mmol of 4-nitrobenzoyl chloride in 3 ml of dichloromethane. The mixture is stirred at room temperature 3 hours and then washed with water, aqueous NaHCO3 and brine. The organic layer is dried (Na2SO4) and the solvent removed under vacuum. The residue is purified by chromatography on silica gel to give the desired product as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][NH:12][C@H:11]([CH3:15])[CH2:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br:16][C:17]1[C:22]2[NH:23][C:24](Cl)=[N:25][C:21]=2[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=1>O1CCOCC1>[Br:16][C:17]1[C:22]2[N:23]=[C:24]([N:12]3[CH2:13][CH2:14][N:9]([C:3]4[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=4)[CH2:10][C@H:11]3[CH3:15])[NH:25][C:21]=2[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=1
Reactant: C[C@@H]1CN(c2ncc(Cl)cc2Cl)CCN1
Reactant: FC(F)(F)c1cc(Br)c2[nH]c(Cl)nc2c1
Solvent: C1COCCO1
Product: C[C@@H]1CN(c2ncc(Cl)cc2Cl)CCN1c1nc2c(Br)cc(C(F)(F)F)cc2[nH]1

Procedure:
A mixture of the piperazine from step (a) above (148 mg, 0.6 mmol) and 7-bromo-2-chloro-5-trifluoromethyl-1H-benzoimidazole (150 mg, 0.5 mmmol, Example 6b) in dioxane (2 mL) reacted under the conditions of Example 3c to give the title compound. Mp: 135-137° C. MS (ESI, pos. ion) m/z: 510 (M+1)
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH3:12])[C:8]([CH3:11])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH2:13].[Mn]([O-])(=O)(=O)=[O:15].[K+]>N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:15])=[O:13])=[C:7]([CH3:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1ccc(C(C)(C)C)cc1C
Reactant: O
Agent: [K+]
Solvent: c1ccncc1
Product: Cc1cc(C(C)(C)C)ccc1C(=O)O
Temperature: 80 °C
Reaction time: 1 h
Yield: 8.5 %

Procedure:
An amount of 10.0 g (61.62 mmol) of 4-tert-butyl-o-xylene is added to 100 mL solution of 20% water in pyridine and stirred at 80° C. for one hour. 25 g (154.05 mmol) of potassium permanganate is also added and continued to stir at 80° C. for three hours more. After cooling to room temperature, the mixture is filtered through a thick pack of celite and washed many times with water. The water layer is acidify to pH ˜2, and the precipitate is filtered and crystallized out of water: methanol to give 2.4 g (8.5% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) □ 1.282 (S, 9H), 2.530 (S, 3H), 7.295 (d, J=6.9 Hz 2H), 7.821 (d, J=2.1 Hz 1H). Ref: JACS, 66, 154-5(1944)
Reaction SMILES: O=[C:2]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([Si](C(C)C)(C(C)C)C(C)C)[CH:10]=[CH:9]2)[CH2:3][C:4]#[N:5].O.NN.NC1C=C[NH:31][N:30]=1>CCO>[NH:11]1[C:12]2[C:8](=[CH:7][C:6]([C:2]3[CH:3]=[C:4]([NH2:5])[NH:30][N:31]=3)=[CH:14][CH:13]=2)[CH:9]=[CH:10]1
Reactant: Nc1cc[nH]n1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(C(=O)CC#N)ccc21
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1cc(-c2ccc3[nH]ccc3c2)n[nH]1
Yield: 41 %

Procedure:
To a solution of 3-Oxo-3-(1-triisopropylsilanyl-1H-indol-5-yl)-propionitrile (490 mg, 1.44 mmol) in 15 mL of absolute EtOH, 720 μL of hydrazine monohydrate (14.4 mmol) were added and the reaction refluxed for 18 hours. LC-MS showed complete conversion to the aminopyrazole and also silyl deprotection. The mixture was concentrated under reduced pressure, and purified with SiO2 column (eluent gradient from 100% DCM to DCM:MeOH 9:1) to afford the title compounds (120mg, yield: 41%)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[CH:22]1([NH2:25])[CH2:24][CH2:23]1>>[CH:22]1([NH:25][C:4](=[O:6])[C:3]2[CH:8]=[CH:9][C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[CH:11][C:2]=2[OH:1])[CH2:24][CH2:23]1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(OCc2ccc(OC)cc2)cc1O
Product: COc1ccc(COc2ccc(C(=O)NC3CC3)c(O)c2)cc1

Procedure:
Methyl 2-hydroxy-4-[(4-methoxybenzyl)oxy]benzoate (Percec, V; Tomazos, D. J. Mater. Chem. 1993, 3, 643-650) (530 mg, 1.83 mmol) was dissolved in cyclopropyl amine (3 mL) and left at room temperature for a week. The volatiles were removed in vacuo and the residue was purified by silica gel flash chromatography (040% ethyl acetate in petroleum ether) to give the subtitled compound (407 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN([C:22]([O:26][N:27]1N=NC2C=CC=C[C:28]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CNOC.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([N:27]([O:26][CH3:22])[CH3:28])=[O:18])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (4-benzyloxy-phenyl)-acetic acid (61.9 mmol, 15.0 g), HBTU (74.3 mmol, 28.1 g), and N,O-dimethylhydroxylamine hydrochloride (92.9 mmol, 9.0 g) in DMF (100 mL) at 0° C. was added DIEA (136.3 mmol, 17.5 g) drop-wise. The reaction mixture was warmed to room temperature and stirred for 30 min. The mixture was diluted with ethyl acetate, washed with water, and 1.0 N HCl, followed by brine. The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure to provide 2-(4-benzyloxy-phenyl)-N-methoxy-N-methyl-acetamide.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[NH:16][CH:15]=[CH:14][C:13]=3[NH:12][C:11]([CH3:20])=[C:10]2[C:21]([O:23][CH2:24][CH2:25][C:26]#[N:27])=[O:22])=[C:5]([O:28][CH3:29])[CH:4]=1)#[N:2].C(OCC)(OCC)O[CH2:32][CH3:33]>S(=O)(=O)(O)O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[N:16][C:17]=3[O:19][CH2:32][CH3:33])[NH:12][C:11]([CH3:20])=[C:10]2[C:21]([O:23][CH2:24][CH2:25][C:26]#[N:27])=[O:22])=[C:5]([O:28][CH3:29])[CH:4]=1)#[N:2]
Reactant: CCOC(OCC)OCC
Reactant: COc1cc(C#N)ccc1C1C(C(=O)OCCC#N)=C(C)Nc2cc[nH]c(=O)c21
Agent: O=S(=O)(O)O
Product: CCOc1nccc2c1C(c1ccc(C#N)cc1OC)C(C(=O)OCCC#N)=C(C)N2
Temperature: 130 °C
Reaction time: 8 h

Procedure:
10.00 g (25.62 mmol) of the compound from Example 20A are suspended in 250 ml of triethyl orthoformate and heated to 130° C. Then, over a total period of 8 hours, 15 drops of concentrated sulfuric acid are added each hour to the reaction mixture. It is then stirred at the same temperature overnight. After cooling, excess orthoester is removed in a rotary evaporator, and the crude product is purified by column chromatography (silica gel; mobile phase: cyclohexane/ethyl acetate 1:1). 7.20 g (65% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=1)[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CC(C)=O>[CH2:34]([O:27][C:23]1[CH:22]=[C:21]([CH2:20][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:26]=[CH:25][CH:24]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(Cc1cccc(O)c1)C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NC(Cc1cccc(OCc2ccccc2)c1)C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 71 %

Procedure:
171 (580 mg, 1 equivalent) was dissolved in 15 ml of acetone, then potassium carbonate (238 mg, 1.1 equivalent) and benzylbromide (1.1 equivalent, 206 μl) were added successively. The reaction mixture was let overnight at room temperature. The reaction mixture is concentrated and 50 ml of AcOEt are added. The organic phase are washed with 10% citric acid, saturated NaHCO3 and brine then dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (AcOEt/Hexane 2/8) to afford 172 as white solid (513 mg, 71%). 1H NMR (CDCl3): δ 1.46 (s, 9H), 2.64 (s, 1H), 3.05 (m, 1H), 3.18 (m, 1H), 4.39 (m, 1H), 5.20 (s, 1H), 5.25 (s, 4H), 6.95 (d, 1H, J=7.1 Hz), 7.00 (d, 1H, J=7.9 Hz), 7.07 (s, 1H), 7.20 (m, 2H), 7.27 (d, 2H, J=7.4 Hz), 7.32 (t, 1H, J=7.9 Hz), 7.50 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]2[N:6]([CH3:39])[C:7](=[O:38])[CH:8]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17]CC4C=CC(OC)=CC=4)=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:41]=[CH:40][C:5]2[N:6]([CH3:39])[C:7](=[O:38])[CH:8]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(COc2ccc(C3=NC(Cc4ccc(C(F)(F)F)cc4)C(=O)N(C)c4ccc(Cl)cc43)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CN1C(=O)C(Cc2ccc(C(F)(F)F)cc2)N=C(c2ccc(O)cc2)c2cc(Cl)ccc21
Reaction time: 3 h

Procedure:
(Z)-7-chloro-5-(4-(4-methoxybenzyloxy)phenyl)-1-methyl-3-(4-(trifluoromethyl)benzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (50 mg, 0.086 mmol) was dissolved in 4 N HCl in dioxane (3 mL) and stirred for 3 h. The solution was then concentrated, and sonicated in 5 mL of diethyl ether. The product was collected by filtration as a bright yellow solid (24.2 mg, 61%). 1H NMR (300 MHz, DMSO-d6) δ 3.30 (s, 3H), 3.32-3.43 (m, 3H), 6.80 (d, 2H), 7.22 (d, 1H), 7.30-7.40 (m, 2H), 7.50-7.78 (m, 6H); ESI m/z measured 459.1078 [M+H+], calculated 459.1087.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[N:8]([CH3:17])[C:7]2[CH:18]=[CH:19][CH:20]=[N:21][C:6]1=2)=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[CH2:28]([N:30]1[CH2:34][CH2:33][CH2:32][C:31]1([CH3:36])N)[CH3:29].C1(N)C(F)=C(F)C(F)=C([NH2:46])C=1F.Cl.Cl>C(O)C>[CH2:28]([N:30]1[CH2:34][CH2:33][CH2:32][CH:31]1[CH2:36][NH:46][CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[N:8]([CH3:17])[C:7]2[CH:18]=[CH:19][CH:20]=[N:21][C:6]1=2)=[O:4])[CH3:29]
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Reactant: CCN1CCCC1(C)N
Reactant: CN1C(=O)c2ccccc2N(C(=O)CCl)c2ncccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCN1CCCC1CNCC(=O)N1c2ccccc2C(=O)N(C)c2cccnc21

Procedure:
9.0 gm of 11-chloroacetyl-5,11-dihydro-5-methyl-6H-pyrido[2,3-b]-[1,4]benzodiazepin-6-one, 3.5 gm of sodium carbonate and 4 gm of 1-ethyl-2-amino-methyl-pyrrolidine were refluxed in 100 ml of ethanol for 1.5 hours. Then the hot mixture was suction-filtered, the filtrate was evaporated in vacuo to dryness, and the residue was recrystallized from acetonitrile and subsequently from ethyl acetate, yielding 48% of theory of the compound of the formula ##STR6## which had a melting point of 169°-171° C. Its dihydrochloride had a melting point of 196°-198° C. (from ethanol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:21][CH3:22])[C:12]1[N:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH2:19][OH:20])[N:13]=1.[H-].[Na+].I[CH3:26].O>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:9])[CH3:10])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:21][CH3:22])[C:12]1[N:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH2:19][O:20][CH3:26])[N:13]=1
Reactant: CCN(c1nc(C)cc(CO)n1)c1ccc(C(C)C)cc1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCN(c1nc(C)cc(COC)n1)c1ccc(C(C)C)cc1Br

Procedure:
To the product of Example 24 and sodium hydride (1.1 eq.) in dry THF under nitrogen was added iodomethane (1.1 eq.) and after four hours the reaction was poured into H2O and extracted three times with CHCl3. The combined extracts were dried over MgSO4, filtered, and evaporated under vacuum. The material was purified by chromatography on silica gel using 10% EtOAc in hexanes to give a light yellow oil. (Rf =0.37)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([N:16]([CH2:20]C=C)[CH2:17][CH:18]=[CH2:19])=[CH:12][CH:11]=2)[OH:9])=[CH:4][C:3]=1[S:23]([NH2:26])(=[O:25])=[O:24]>C(Cl)(Cl)Cl.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:17][CH:18]=[CH:19][CH2:20]3)=[CH:12][CH:11]=2)[OH:9])=[CH:4][C:3]=1[S:23]([NH2:26])(=[O:24])=[O:25]
Reactant: C=CCN(CC=C)c1ccc(C(O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(C(O)c2ccc(N3CC=CC3)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
A solution of 100 mg of 2-chloro-5-((4-diallylamino-phenyl)-hydroxy-methyl)-benzenesulfonamide (0.25 mmol, 1 equivalent) in 5 mL of chloroform is degassed with argon for 5 minutes, then 5 mg of Grubb's catalyst (0.005 mmol, 2% mmol) is added. The reaction mixture is stirred at room temperature for 1 h, then diluted with dichloromethane, filtered through Celite, and a pad of silica gel, then concentrated in vacuo to give 70 mg of the title compound which is carried forward without further purification.
Reaction SMILES: I.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11](SC)=[NH:12])[CH:6]=[CH:7][C:8]=1[Cl:9].[O:15]=[C:16]1[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH2:27][C:28]([NH:30][NH2:31])=O)[CH:22]=2)[NH:17]1.O>CS(C)=O>[Cl:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[Cl:9])[CH2:10][C:11]1[NH:12][C:28]([CH2:27][O:26][C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:15])[CH2:25][CH2:24]3)=[N:30][N:31]=1
Reactant: CSC(=N)Cc1ccc(Cl)c(Cl)c1
Reactant: NNC(=O)COc1ccc2c(c1)CCC(=O)N2
Agent: I
Solvent: O
Solvent: CS(C)=O
Product: O=C1CCc2cc(OCc3nnc(Cc4ccc(Cl)c(Cl)c4)[nH]3)ccc2N1
Temperature: 115 °C

Procedure:
To the stirred solution of methyl 2-(3,4-dichlorophenyl)ethanimidothioate hydroiodide (0.184 g, 0.51 mmol) in dry DMSO (1 mL) were added 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetohydrazide (0.120 g, 0.51 mmol) and TEA (0.103 g, 1.02 mmol) and heated at 115° C. in a seal tube overnight. Water was added to the reaction mixture. The solid precipate was filtered, dried and purified by preparative HPLC on a Kromasil C4 column (250×20 mm) using a gradient of ACN in 0.1% TFA (0-100%) to give 6-((5-(3,4-dichlorobenzyl)-4H-1,2,4-triazol-3-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one as an off white solid (0.070 g; 34%). 1HNMR 400 MHz, DMSO-d6: δ 2.40 (t, J=7.20 Hz, 2H), 2.82 (t, J=8.00 Hz, 2H), 4.09 (s, 2H), 5.01 (s, 2H), 6.75-6.76 (m, 2H), 6.88 (s, 1H), 7.28 (d, J=8.40 Hz, 1H), 7.59 (d, J=8.00 Hz, 2H), 9.91 (s, 1H), 13.87 (bs, 1H). LCMS: RT 1.71 min; LCMS (ES-API), m/z 403.0.
Reaction SMILES: [Si]([O:8][C@H:9]([C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[C:37]([CH2:42][OH:43])[CH:36]=1)[CH2:10][NH:11][C@H:12]([CH3:34])[CH2:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([CH3:33])[CH:27]=2)=[O:23])[CH:17]=[CH:18][CH:19]=1)(C(C)(C)C)(C)C.CO.O.ClCCl>CO>[NH3:11].[CH3:33][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][C:29]=1[CH3:32])[CH2:25][NH:24][C:22](=[O:23])[CH2:21][CH2:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH2:13][C@H:12]([NH:11][CH2:10][C@H:9]([OH:8])[C:35]2[CH:40]=[CH:39][C:38]([OH:41])=[C:37]([CH2:42][OH:43])[CH:36]=2)[CH3:34])[CH:15]=1
Reactant: Cc1ccc(CNC(=O)CCc2cccc(C[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(CO)c3)c2)cc1C
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Cc1ccc(CNC(=O)CCc2cccc(C[C@@H](C)NC[C@H](O)c3ccc(O)c(CO)c3)c2)cc1C
Product: N

Procedure:
Prepared from 3-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(3,4-dimethylbenzyl)propanamide (Preparation 48) according to the method for example 1 using methanol:water (2.4:1 v/v) instead of acetic acid as solvent and using dichloromethane:methanol: 880 ammonia (94:6:0.6 by volume) as the column eluent to give the title compound as a white solid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([O:27][C:28]([N:30]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]([NH2:37])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(C(C)C)CC)(C)C>CC(O)C>[C:23]([O:27][C:28]([N:30]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]([NH:37][C:18]2[C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=[C:14]3[N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:11]=[CH:12][C:13]=23)[CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCCCC(N)C1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCCC(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Temperature: 120 °C
Yield: 83.2 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (0.6981 g, 2.067 mmol), 3-Amino-azepane-1-carboxylic acid tert-butyl ester (0.4752 g, 2.217 mmol), and diisopropylethylamine (0.50 mL, 2.9 mmol) in propan-2-ol (12 mL) was heated in a microwave reactor at 120° C. for 20 minutes. The solvent was evaporated in vacuo and then purified by column chromatography on silica gel (gradient: 0 to 30% ethyl acetate in heptanes) affording 0.8869 g (83%) of 3-(1-Benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-azepane-1-carboxylic acid tert-butyl ester. LCMS (Method E, ESI): RT=2.07 min, m+H=516.2.