Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:6]([CH3:7])=[CH:5][C:4]([CH3:8])=[CH:3][C:2]=1[CH3:9].C[OH:11]>>[CH3:9][C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[C:6]([CH3:7])[N+:1]=1[O-:11]
Reactant: CO
Reactant: Cc1cc(C)nc(C)c1
Product: Cc1cc(C)[n+]([O-])c(C)c1

Procedure:
In a 500 mL round bottom flask equipped with a magnetic stirrer and thermometer were added 36.7 g (164 mmol) of 77% 3-chloroperbenzoic acid (Aldrich) and 200 mL of methylene chloride. This slurry was cooled to 5° C. and a solution of: 16.6 g (137 mmol) of collidine (Aldrich) in 50 mL of methylene chloride was added over 30 min while maintaining the temperature at 5-10° C. The mixture was then allowed to warm to room temperature over 1 hr and then stirred overnight. The crude reaction mixture was transferred slowly to a beaker containing 200 g of basic alumina, which resulted in a slight warming of the mixture. The mixture was stirred and filtered and the alumina was mixed with 300 mL of 2:1 CHCl3:CH3OH. The solvent was removed on a rotary evaporator at room temperature. The alumina was washed with ether and the solvent was removed to yield 24.7 g of a clear liquid, which solidified to give a white, waxy solid. This yield was slightly high due to the presence of some salt. TLC (silica gel developed with methanol) showed a single major spot (Rf=0.45) along with a minor spot (Rf=0.55). The major spot was the desired N-oxide, 1H NMR (CDCl3, 300 MHz) δ (ppm): 6.96 (s), 2.51 9(s) and 2.28 (s). The minor spot corresponded to the starting collidine. 1H NMR (CDCl3, 300 MHz) δ (ppm): 6.78 (s), 2.48 (s) and 2.26 (s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C@H:10]([CH3:12])[C@H:9]([N:13]([CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[C:14](=[O:21])[C:15]([OH:20])([CH3:19])[C:16]([NH2:18])=[O:17])[C:8](=[O:30])[N:7]([CH2:31][CH:32]=[O:33])[C:6]=2[CH:34]=1.[BH4-].[Na+].C(OC(=O)C)C.CCCCCCC>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C@H:10]([CH3:12])[C@H:9]([N:13]([CH2:22][C:23]([F:28])([F:29])[C:24]([F:25])([F:26])[F:27])[C:14](=[O:21])[C:15]([OH:20])([CH3:19])[C:16]([NH2:18])=[O:17])[C:8](=[O:30])[N:7]([CH2:31][CH2:32][OH:33])[C:6]=2[CH:34]=1
Reactant: C[C@H]1Oc2ccc(F)cc2N(CC=O)C(=O)[C@H]1N(CC(F)(F)C(F)(F)F)C(=O)C(C)(O)C(N)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H]1Oc2ccc(F)cc2N(CCO)C(=O)[C@H]1N(CC(F)(F)C(F)(F)F)C(=O)C(C)(O)C(N)=O
Yield: 32.9 %

Procedure:
1.00 g (2.0 mmol N-[(6R,7S)-2-Fluoro-6-methyl-8-oxo-9-(2-oxo-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-2-hydroxy-2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamide in 30 ml tetrahydrofurane were reduced with 0.09 g (2.0 mmol) sodium borohydride. Chromatography on silicagel with ethylacetate/heptane 0:100 to 100:0 yielded 0.33 g (34%) N-[(6R,7S)-2-fluoro-9-(2-hydroxy-ethyl)-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-2-hydroxy-2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamide, MS m/e (%): 502.0 (M+H+, 100).
Reaction SMILES: O.[NH2:2][C:3]1[C:4](=[O:13])[N:5]([CH3:12])[C:6](=[O:11])[N:7]([CH3:10])[C:8]=1[NH2:9].[CH:14]([C:16]1[CH:26]=[CH:25][C:19]([CH:20]=[CH:21][C:22]([OH:24])=[O:23])=[CH:18][CH:17]=1)=O.CO.NC1N(C)C(=O)N(C)C(=O)C=1CC(=CC1C=CC=CC=1)C(O)=O>C(O)(=O)C.[N+](C1C=CC=CC=1)([O-])=O>[CH3:12][N:5]1[C:4](=[O:13])[C:3]2[N:2]=[C:14]([C:16]3[CH:26]=[CH:25][C:19](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])=[CH:18][CH:17]=3)[NH:9][C:8]=2[N:7]([CH3:10])[C:6]1=[O:11]
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Agent: Cn1c(N)c(CC(=Cc2ccccc2)C(=O)O)c(=O)n(C)c1=O
Solvent: O
Solvent: CC(=O)O
Solvent: O=[N+]([O-])c1ccccc1
Product: Cn1c(=O)c2nc(-c3ccc(/C=C/C(=O)O)cc3)[nH]c2n(C)c1=O

Procedure:
5,6-Diamino-l,3-dimethyluracil hydrate (1.70 g, 10.0 mmol) and 4-formylcinnamic acid (1.76 g, 10.0 mmol) were refluxed in acetic acid (10 mL)-methanol (100 mL) for 0.5 hour. (E)-4[(6-Amino-l,2,3-4-tetrahydro-1,3-dimethyl-2,4-dioxo-5-pyrimidinyl)iminomethyl]cinnamic acid was precipitated as a yellow powder (1.84 g, 56%); mp 299°-301° C. with effervescence. Analysis for (C16H16N4O4): C,58.53;H,491;N,1707. Found: C,58.36;H,4.93;N,16.90. The structure was confirmed by H-NMR and EI mass spectrum. The (E)-4-[(6-amino-1,2,3,4-tetrahydro-1,3-dimethyl-2,4-dioxo-5-pyrimidinylmethyl]cinnamic acid (500 mg, 1.52 mmol) was then refluxed in nitrobenzene (125 mL) for 2.5 hours with slow distillation to remove water formed. The reaction mixture was cooled and the precipitate washed with ether. Recrystallization from N,N-dimethylformamide-water gave the monohydrate of the title compound as a pale yellow powder; mp>380° C. Analysis for (C16H14N4O4H2O):C, 55.81; H, 4.68; N, 16.27. Found: C, 56.05: H, 4.69; N, 16.27. The structure was confirmed by 1H-NMR and EI mass spectrum.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH:17]([NH:20][CH3:21])[CH:16]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.I[CH2:31][C:32]([NH2:34])=[O:33].CCN(C(C)C)C(C)C>C(#N)C>[F:1][C:2]([F:28])([F:29])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH:17]([N:20]([CH2:31][C:32]([NH2:34])=[O:33])[CH3:21])[CH:16]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: NC(=O)CI
Reactant: CNC1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN(CC(N)=O)C1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Yield: 123.2 %

Procedure:
A solution of 50 mg of amine prepared in Example 11, 33 mg of iodoacetamide and 0.05 mL of DIPEA in 0.5 mL of acetonitrile was heated in a sealed vial at 50° C. for 2 h (or room temperature for 16 h). The volatiles were evaporated under a stream of nitrogen and the residue was purified on a 1 mm preparative silica gel plate eluted with 5% MeOH in methylene chloride to afford 70 mg of title compound. Mass spec (NH3 /CI): 475 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:16]=1)[CH2:9][C:8]2([CH3:28])[CH3:27])=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH3:27][C:8]1([CH3:28])[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)[NH:11][CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:16]=2)[CH2:9]1
Reactant: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(N3CCOCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2ccc(C(=O)O)cc21
Temperature: 70 °C
Reaction time: 6 h
Yield: 90.1 %

Procedure:
To a stirred mixture solution of 4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (380.0 mg, 1.0 mmol) in methanol (10.0 mL) and tetrahydrofuran (10.0 mL) was added 50% sodium hydroxide in water (1.5 mL). The reaction mixture was stirred at 70° C. for 6 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (330.0 mg, 90%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=367.1.
Reaction SMILES: C(C1COC(=O)N1[C:14](=[O:32])[CH:15]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:18])C1C=CC=CC=1.[OH:33]O.[Li+].[OH-]>C1COCC1.O>[CH:26]1([CH2:25][CH:15]([CH2:16][C:17]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)=[O:18])[C:14]([OH:32])=[O:33])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: OO
Reactant: O=C(CC(CC1CCCCC1)C(=O)N1C(=O)OCC1Cc1ccccc1)N1CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(CC(=O)N1CCOCC1)CC1CCCCC1

Procedure:
A 0.05 M solution of 1-(4-benzyl-2-oxo-oxazolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-butane-1,4-dione (1 g) in 3:1 —THF/H2O was treated at 0° C. with 8 equivalents of 30% H2O2 followed by 2.0 equivalents of LiOH. The resulting mixture was stirred at 0–25° C. until the substrate had been consumed (approximately 1 hour). The excess peroxide was quenched at 0° C. with a 10% excess of 1.5 N aqueous Na2SO3. After buffering to pH 9–10 with aqueous NaHCO3 and evaporation of the THF, the oxazolidone chiral auxiliary was recovered by MeCl2 extraction. The carboxylic acid was isolated by EtOAc extraction of the acidified (pH 1–2) aqueous phase, then recrystallized from EtOAc and hexane to yield 0.58 g of 2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid; H1NMR (DMSO-δ): 12(1H, s, COOH), 3.6–3.3(8H, m), 2.8–2.3(3H, m), 1.8–1.1(l 1H, m), 0.9–0.7(2H, m); MS: 282.2(M−1), 284.1 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1.[N:11]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.CC(=O)CC>[CH2:20]([O:19][C:17]([N:11]1[CH2:12][CH2:13][N:14]([CH2:2][CH2:3][CH2:4][C:5]2[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=2)[CH2:15][CH2:16]1)=[O:18])[CH3:21]
Reactant: ClCCCc1cccnc1
Reactant: CCOC(=O)N1CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCC(C)=O
Solvent: O
Product: CCOC(=O)N1CCN(CCCc2cccnc2)CC1

Procedure:
A mixed solution of 3-(3-chloropropyl)pyridine 1.92 g, ethyl 1-piperazinecarboxylate 1.6 g, anhydrous potassium carbonate 3.0 g, potassium iodide 1 g, tetra-n-butylammonium bromide 0.1 g and 2-butanone 50 ml was refluxed for 24 hours. To the reaction mixture was added water 50 ml, and the product was extracted with ethyl acetate. The extract was washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to yield 1-ethoxycarbonyl-4-[3-(3-pyridyl)propyl]piperazine. This was dissolved in a mixture of 20% sodium hydroxide 25 ml and ethanol 25 ml and the solution refluxed for 2 days. The reaction mixture was concentrated under reduced pressure and to the residue was added ethyl acetate 100 ml and anhydrous magnessium sulfate. After stirring the resultant mixture, the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure to yield 1.56 g of oily 1-[3-(3-pyridyl)propyl]piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=O)=[C:4]2[N:3]=1.[S:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23].N1CCCCC1.C(O)(C)C>CCO>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:10][CH2:11]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[C:21]3[S:17][C:18](=[O:23])[NH:19][C:20]3=[O:22])=[C:4]2[N:3]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1cnn2c(NC3CC3)cc(Cl)nc12
Solvent: C1CCNCC1
Solvent: CCO
Solvent: CC(C)O
Product: O=C1NC(=O)C(=Cc2cnn3c(NC4CC4)cc(Cl)nc23)S1
Temperature: 80 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
To 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (440 mg, 1.86 mmol) in EtOH was added thiazolidine-2,4-dione (458 mg, 3.91 mmol) and piperidine (208 μl, 2.05 mmol). The reaction was heated at 80° C. overnight. To the reaction mixture, isopropanol (3 mL) was added in the along with 218 mg thiazolidine-2,4-dione and 94 μL of piperidine. The temperature was increased to 90° C. and the reaction was stirred at that temperature overnight. The precipitate was filtered while hot and dissolved in MeOH. To the reaction mixture, 1M HCl (1 mL) was added and the mixture sonicated. The precipitate was filtered and washed with MeOH to yield 340 mg (54% yield) 5-((5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)thiazolidine-2,4-dione as a yellow powder. LCMS (M+1=336)
Reaction SMILES: [I-].[Na+].[In].Br[CH2:5][CH:6]=[C:7]([CH3:9])[CH3:8].[CH3:10][O:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=2[F:28])=[C:16]([CH:29]=[O:30])[CH:15]=1)=[O:13]>CN(C=O)C.CCOC(C)=O.O>[CH3:10][O:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=2[F:28])=[C:16]([CH:29]([OH:30])[C:7]([CH3:9])([CH3:8])[CH:6]=[CH2:5])[CH:15]=1)=[O:13]
Reactant: CC(C)=CCBr
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C=O)c1
Agent: [I-]
Agent: [In]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=CC(C)(C)C(O)c1cc(C(=O)OC)ccc1-c1cc(OC)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a mixed solution of sodium iodide (2080 mg, 13876 μmol), indium (2000 mg, 6938 μmol, commercially available from Sigma-Aldrich, St. Louis, Mo., USA) and 1-bromo-3-methylbut-2-ene (1616 μL, 13876 μmol, commercially available from Sigma-Aldrich, St. Louis, Mo., USA) in DMF (30 mL), was added 21.3 (1593 mg, 13876 μmol). The mixture was stirred at room temperature for 1 hour and then diluted with EtOAc and water. The organic phase was washed with water and brine and then dried over anhydrous sodium sulfate. After filtration, the organic solvent was removed in vacuo to give a residue which was purified by CombiFlash® chromatography to give the product as an oil (2.30 g, 92%). MS ESI m/e: 376.1 (M+18)+.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[OH-].[Na+]>CCOCC.O>[CH3:12][N:9]1[CH2:10][CH2:11][CH:6]([CH2:4][OH:3])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C1CCN(C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CN1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.2 %

Procedure:
1-Methyl-4-piperdine carboxylic acid ethyl ester (8.95 g, 53 mmol) was dissolved in ether (100 ml) and a 1N solution of lithium aluminium hydride in tetrahydrofuran (57 ml, 57.5 mmol) added at 0° C. and the reaction mixture allowed to warm to ambient temperature and stirred for 3 hours. Water (2 ml), 2N sodium hydroxide (4 ml) and a further portion of water (2 ml) was added and the precipitate collected by suction filtration. The filtrate was evaporated to afford the title compound (4.6 g, 68% yield) as a colourless oil:
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[C:26]([O:25][C:23]([N:17]1[CH2:22][CH2:21][N:20]([C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][N:2]=[CH:7][CH:6]=3)=[CH:16][CH:15]=2)[CH2:19][CH2:18]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(-c3ccncc3)cc2)CC1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
In N,N-dimethylformamide (40 ml), 4-(4-pyridyl)benzoic acid hydrochloride (654 mg) and tert-butyl 1-piperazinecarboxylate (569 mg) were suspended. To the resulting suspension, 1-hydroxybenzotriazole (374 mg) and N-methylmorpholine (336 μl) were added. The resulting mixture was ice cooled, followed by the addition of 1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (796 mg). After stirring at room temperature for 7 hours, the solvent was distilled off. The residue was purified by chromatography on a silica gel column (2% methanol—dichloromethane), followed by washing with hexane, whereby the title compound (905 mg, 89%) was obtained.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([S:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23](C(=O)C)[CH2:22][CH2:21]4)(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1>O1CCOCC1>[F:30][C:2]([F:1])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([S:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[NH:23][CH2:22][CH2:21]4)(=[O:16])=[O:17])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: CC(=O)N1CCc2cc(S(=O)(=O)N3CCN(c4ccc(C(F)(F)F)cc4)CC3)ccc21
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc2c(c1)CCN2)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Yield: 75 %

Procedure:
1-{5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-2,3-dihydro-indol-1-yl}-ethanone was refluxed in 1,4-dioxane (5 mL) and concentrate HCl (2.5 mL) for 2 h. The reaction was then diluted with dichloromethane and washed with 1N HCl, saturated sodium bicarbonate, dried (Na2SO4), filtered and concentrated to provide 5-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-2,3-dihydro-1H-indole (1.03 g, 75%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.48-7.20 (m, 4H). 6.88 (d, 2H), 6.60 (d, 1H), 3.70 (t, 2H), 3.36-3.33 (m, 4H), 3.15-3.12 (m, 4H), 3.10 (t, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][NH:5]2.Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18].C(N1C2C(=CC(Br)=CC=2)N(C(OC(C)C)=O)C[C@@H]1C)(=O)C>>[C:12]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[N:5]([C:17]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])[CH2:6][C@@H:7]1[CH3:15])(=[O:14])[CH3:13]
Reactant: CC(=O)N1c2ccc(Br)cc2NC[C@@H]1C
Reactant: O=C(Cl)Oc1ccccc1
Agent: CC(=O)N1c2ccc(Br)cc2N(C(=O)OC(C)C)C[C@@H]1C
Product: CC(=O)N1c2ccc(Br)cc2N(C(=O)Oc2ccccc2)C[C@@H]1C

Procedure:
Phenyl (S)-4-acetyl-7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate was prepared from (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone and phenyl chloroformate according to the procedure outlined above for (S)-isopropyl 4-acetyl-7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate. MS (ESI, pos. ion) m/z 389, 391 [M+1]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.O>N1C=CC=CC=1>[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Nc1ccc(Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccccc1Nc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 51.3 %

Procedure:
2-Fluoronitrobenzene (3.0 g) and 4-chloroaniline (2.5 g) were dissolved in pyridine (30 ml) and stirred at 80° C. for 18 hours. The resultant solution was allowed to cool, and thereafter, water (100 ml) was added thereto and the mixture was extracted with ethyl acetate (50 ml×3). The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was re-crystallized from ethyl acetate-hexane, to thereby yield the target compound (2.5 g) as pale-brown crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:17]=2[CH3:26])=[CH:11][C:10]=1[S:27](Cl)(=[O:29])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.[CH2:38]([NH2:43])[C:39]([CH3:42])([CH3:41])[CH3:40]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:17]=2[CH3:26])=[CH:11][C:10]=1[S:27]([NH:43][CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])(=[O:29])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)CN
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(OCc2ccccc2)c(S(=O)(=O)Cl)c1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(OCc2ccccc2)c(S(=O)(=O)NCC(C)(C)C)c1
Reaction time: 6 h

Procedure:
A solution of the title E compound, 2-benzyloxy-5-(2,6-dimethyl-4-nitrophenoxy)benzenesulfonyl chloride (1.12 g, 2.5 mmol) in 20 mL of CH2Cl2 is treated sequentially with N-methylmorpholine (NMM; 550 mL, 5 mmol) and neopentylamine (442 mL, 3.75 mmol) at RT. After 6 h, the mixture is partitioned between water and EtOAc, and the organic solution is washed with aqueous 1N HCl and brine, dried over anhydrous Na2SO4 and concentrated to afford 2-benzyloxy-5-(2,6-dimethyl-4-nitrophenoxy)-N-(2,2-dimethylpropyl)benzenesulfonamide: NMR (CDCl3) 0.78 (s, 9H), 2.22 (s, 6H), 2.58 (d, 2H, J=7.5), 4.82 (t, 1H, J=7.5), 5.18 (s, 2H), 6.88 (dd, 1H, J=9, 3.7), 7.03, (d, 1H, J=9), 7.33-7.51 (m, 6H), 8.04 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([OH:14])=O)=[CH:6]2.[CH3:15][C:16]([OH:25])([CH3:24])[CH2:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([N:21]1[CH2:22][CH2:23][CH:18]([CH2:17][C:16]([CH3:24])([OH:25])[CH3:15])[CH2:19][CH2:20]1)=[O:14])=[CH:6]2
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: CC(C)(O)CC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c(C(=O)N3CCC(CC(C)(C)O)CC3)cc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.7 %

Procedure:
To a solution of 478 mg of 5-methoxyindole-2-carboxylic acid and 432 mg of 2-methyl-1-(piperidin-4-yl)-2-propanol in 8 mL of DMF were added 575 mg of 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride and 169 mg of 1-hydroxybenzotriazole, followed by stirring at room temperature for 1 day. 0.2M aqueous hydrochloric acid was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with 0.2M aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform:methanol=1:0-24:1], and then crystallized from a mixture of ethyl acetate/diisopropyl ether to obtain 683 mg of 1-{1-[(5-methoxy-1H-indol-2-yl)carbonyl]piperidin-4-yl}-2-methylpropan-2-ol as a white crystal.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:19]1([C:24](Cl)=[O:25])[S:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[C:19]1([C:24]([NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)=[O:25])[S:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1cccs1
Reactant: NCCCOc1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCOc1ccncc1)c1cccs1
Yield: 70.4 %

Procedure:
To a solution of 700 mg (4.60 mmol) of 4-(3-aminopropyloxy)pyridine and 0.77 ml (5.52 mmol) of triethylamine in 30 ml of methylene chloride, 0.50 ml (4.68 mmol) of thenoyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was washed successively with a saturated aqueous solution of sodium bicarbonate and brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 850 mg of the desired compound (yield: 70.0%, colorless crystals).
Reaction SMILES: [C:1]([C:3]1[CH:7]=[N:6][N:5]2[CH:8]=[CH:9][NH:10][C:4]=12)#[N:2].S(=O)(=O)(O)[OH:12].[OH-].[NH4+]>>[C:1]([C:3]1[CH:7]=[N:6][N:5]2[CH:8]=[CH:9][NH:10][C:4]=12)(=[O:12])[NH2:2]
Reactant: N#Cc1cnn2cc[nH]c12
Reactant: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: NC(=O)c1cnn2cc[nH]c12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
7-Cyano-1H-imidazo[1,2-b]pyrazole (3 g) was added to conc. sulfuric acid under ice-cooling. The mixture was stirred at room temperature for 45 minutes. The reaction mixture was cooled at 0°-5° C. and carefully poured into ice water (30 ml). The aqueous solution was neutralized with conc. ammonium hydroxide solution and stirred for 1 hour under ice-cooling. The precipitate was collected, washed with cold water and dried over phosphorus pentoxide in vacuo to give 7-carbamoyl-1H-imidazo[1,2-b]pyrazole (3.45 g).