Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[CH:15]=O.[C:17]1([CH2:23][C:24](OC)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CC([O-])(C)C.[Na+].CN(C=O)C>C1(C)C=CC=CC=1>[C:11]([C:9]1[CH:10]=[C:6]2[N:5]=[CH:4][C:3]3[CH:15]=[C:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:24](=[O:25])[NH:1][C:2]=3[N:7]2[N:8]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: COC(=O)Cc1ccccc1
Reactant: CC(C)(C)c1cc2ncc(C=O)c(N)n2n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc2ncc3cc(-c4ccccc4)c(=O)[nH]c3n2n1
Temperature: 105 °C
Reaction time: 48 h
Yield: 45.7 %

Procedure:
A solution of 7-amino-2-tert-butylpyrazolo[1,5-a]pyrimidine-6-carbaldehyde (1.5 g, 6.87 mmol, 1.00 eq.), methyl 2-phenylacetate (4.1 g, 27.30 mmol, 4.00 eq.) and NaOtBu (1.3 g, 13.53 mmol, 2.00 eq.) in toluene (30 mL) was stirred at 105° C. for about 30 min under nitrogen. Then the reaction mixture was added 30 mL of DMF and the mixture was stirred for about 2 days at 105° C. After concentrating under vacuum, the residue was diluted with water and extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:6) to give the resulted product (1 g, 46%) as a yellow solid. LCMS (m/e)=319 (M+H); 1H NMR (300 MHz, DMSO, δ, ppm) 8.82 (s, 1H), 8.42 (s, 1H), 7.72 (d, J=6.9 Hz, 2H), 7.50-7.38 (m, 3H), 6.72 (s, 1H), 1.42 (s, 9H).
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11]N)=[CH:7][CH:6]=1.Cl.[CH3:16][N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1>OS(O)(=O)=O.O1CCOCC1>[CH3:16][N:17]1[CH2:22][CH2:21][C:20]2[NH:11][C:8]3[CH:7]=[CH:6][C:5]([O:4][C:3]([F:14])([F:13])[F:2])=[CH:10][C:9]=3[C:19]=2[CH2:18]1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: CN1CCC(=O)CC1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CN1CCc2[nH]c3ccc(OC(F)(F)F)cc3c2C1
Temperature: 80 °C
Reaction time: 6 h
Yield: 76.2 %

Procedure:
(4-(Trifluoromethoxy)phenyl)hydrazine hydrochloride (1 g, 4.37 mmol) was dissolved in 7% H2SO4 in 1,4-dioxane (50 mL), 1-methylpiperidin-4-one hydrochloride (0.65 g, 4.37 mmol) was added and stirred at 80° C. for 6 h. Reaction was monitored by TLC & LCMS. After completion of the reaction, reaction mixture was concentrated under vacuum and slowly quenched with aq. NaHCO3 solution, extracted with EtOAc. Organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure and purified by column chromatography to afford 0.9 g of 2-methyl-8-(trifluoromethoxy)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, free base) δ (ppm) 7.9 (bs, 1H), 7.3-7.2 (m, 2H), 7.1-6.9 (d, 1H), 3.7 (s, 2H), 2.9-2.8 (m, 4H), 2.6 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH2:16][CH:17]=O)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[CH:7]=1.[Cl-].[Na+].[NH2:21][CH2:22][CH2:23][NH:24][S:25]([C:28]1[C:29]2[CH:30]=[CH:31][N:32]=[C:33]([OH:38])[C:34]=2[CH:35]=[CH:36][CH:37]=1)(=[O:27])=[O:26].[BH4-].[Na+]>CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH2:16][CH2:17][NH:21][CH2:22][CH2:23][NH:24][S:25]([C:28]2[C:29]3[CH:30]=[CH:31][N:32]=[C:33]([OH:38])[C:34]=3[CH:35]=[CH:36][CH:37]=2)(=[O:26])=[O:27])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[CH:7]=1
Reactant: NCCNS(=O)(=O)c1cccc2c(O)nccc12
Reactant: O=CCOc1ccc(Cl)cc1-c1ccccc1Cl
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: Cl
Product: O=S(=O)(NCCNCCOc1ccc(Cl)cc1-c1ccccc1Cl)c1cccc2c(O)nccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 6.0 mL of the (5,2′-dichloro-biphenyl-2-yloxy)-acetaldehyde stock solution (1.88 mmol) is added to a stirred mixture of 1-hydroxy-isoquinoline-5-sulfonic acid (2-amino-ethyl)-amide sodium chloride (438 mg, 1.34 mmol) and 4 Å molecular sieve (400 mg) in anhydrous CH3OH (8 mL) at ambient temperature under nitrogen. The resultant mixture is stirred for 16 hours. After being cooled to 0° C., the mixture is treated with powdered sodium borohydride (112 mg, 2.95 mmol), then stirred at 0° C. for 1 hour and at ambient temperature for another 1 hour. After filtration and subsequent concentration in vacuo, the crude product is chromatographed on silica (gradient 5-15% CH3OH in EtOAc) to give the desired product as a gum. It is dissolved in EtOAc (15 mL), filtered and concentrated to give 493 mg (0.926 mmol, 69% yield) of the free amine as a white solid. The free amine is dissolved in EtOAc (3,0 mL) and subsequently treated dropwise with 1N HCl/Et2O (8 mL) to give a white suspension. After filtration and vacuum drying at 50° C., 470 mg (0.8.26 mmol, 89% yield) of the title compound is obtained as a white powder. ESIMS: m/z 532 [(M+H)+, 35Cl, 35Cl], 534 [(M+H)+, 35Cl, 37Cl], 536 [(M+H)+, 37Cl, 37Cl].
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]([C:17]1[CH:57]=[CH:56][C:20]([O:21][C@H:22]2[CH2:27][CH2:26][C@H:25]([N:28]3[C:33](=[O:34])[C:32]([CH2:35][C:36]4[CH:41]=[CH:40][C:39]([C:42]5[C:43]([C:48]#[N:49])=[CH:44][CH:45]=[CH:46][CH:47]=5)=[CH:38][CH:37]=4)=[C:31]([CH2:50][CH2:51][CH3:52])[N:30]4[N:53]=[CH:54][N:55]=[C:29]34)[CH2:24][CH2:23]2)=[CH:19][CH:18]=1)([CH3:16])[CH3:15]>O.C(OCC)(=O)C>[OH:13][C:14]([C:17]1[CH:57]=[CH:56][C:20]([O:21][C@H:22]2[CH2:27][CH2:26][C@H:25]([N:28]3[C:33](=[O:34])[C:32]([CH2:35][C:36]4[CH:41]=[CH:40][C:39]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=5[C:48]5[NH:3][C:4](=[O:7])[O:5][N:49]=5)=[CH:38][CH:37]=4)=[C:31]([CH2:50][CH2:51][CH3:52])[N:30]4[N:53]=[CH:54][N:55]=[C:29]34)[CH2:24][CH2:23]2)=[CH:19][CH:18]=1)([CH3:16])[CH3:15]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](Oc3ccc(C(C)(C)O)cc3)CC2)c2ncnn12
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](Oc3ccc(C(C)(C)O)cc3)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.29 g), sodium hydrogen carbonate (0.47 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C. for 30 min, 4′-[(4-{trans-4-[4-(1-hydroxy-1-methylethyl)phenoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.17 g) was added, and the mixture was stirred at 90° C. for 16 hr. Hydroxylammonium chloride (0.097 g) and sodium hydrogen carbonate (0.15 g) were further added, and the mixture was stirred at 90° C. for 4 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (1 mL). N,N′-Carbonyldiimidazole (0.050 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.046 mL) were added, and the mixture was stirred at room temperature for 2 hr. N,N′-Carbonyldiimidazole (0.050 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.046 mL) were further added, and the mixture was stirred at room temperature for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was acidified with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography and recrystallized (ethyl acetate-hexane) to give the title compound as a colorless solid (0.087 g, 47%).
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][CH:11]([OH:18])[CH2:12][C:13]([CH3:17])([O:15][OH:16])[CH3:14]>C(N(CC)CC)C.CCOCC>[CH:1]1([NH:7][C:8](=[O:9])[O:18][CH:11]([CH3:10])[CH2:12][C:13]([CH3:17])([O:15][O:16][C:8](=[O:9])[NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(O)CC(C)(C)OO
Reactant: O=C=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(CC(C)(C)OOC(=O)NC1CCCCC1)OC(=O)NC1CCCCC1
Reaction time: 48 h
Yield: 39 %

Procedure:
A mixture of 18.7 g. (0.15 mole) of cyclohexyl isocyanate, 6.7 g. (0.05 mole) of 1,3-dimethyl-3-hydroperoxybutyl alcohol and 3 drops of triethylamine was stirred for five days at ambient temperature. The reaction vessel was protected with a calcium chloride tube to keep out moisture. Within two days, a solid began to appear, and after the five day stirring period the reaction mixture was stripped in vacuo. The residue was slurried in 100 ml of ether and filtered. The filter cake was washed with an additional 30 ml of ether and air dried. A total of 7.5 grams of a colorless solid was obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[C:8](N1C=CN=C1)([N:10]1[CH:14]=[CH:13]N=C1)=[S:9].COC(OC)CN>C1(C)C=CC=CC=1>[S:4]1[CH:5]=[CH:6][CH:7]=[C:3]1[CH2:2][N:1]1[CH:13]=[CH:14][NH:10][C:8]1=[S:9]
Reactant: NCc1cccs1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: COC(CN)OC
Solvent: Cc1ccccc1
Product: S=c1[nH]ccn1Cc1cccs1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Under a blanket of nitrogen, 11.3 g (0.1 mol) 2-aminomethylthiophene is added to 19.6 g (0.11 mol) 1,1'-thiocarbonyldiimidazole in 200 ml anhydrous toluene at 0° C. The reaction is held at 0° C. for 4 hours. Then 10.5 g (0.1 mol) aminoacetaldehyde dimethyl acetal is added and the reaction is warmed at 80° C. for 2 hours. The toluene is removed and the residue dissolved in 100 ml ethanol, 15 ml water and 15 ml concentrated HCl. The mixture is refluxed 5 hours, cooled and poured onto 1 liter of ice. After recrystallization (1/1 EtOH/H2O) the desired product is obtained as white shiny crystals, mp 128°-130° C.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:7]=[C:6]([C:8](Cl)=[O:9])[NH:5][C:4]=1[C:11]([O:13][CH3:14])=[O:12]>C1COCC1>[NH2:1][C:8]([C:6]1[NH:5][C:4]([C:11]([O:13][CH3:14])=[O:12])=[C:3]([Cl:2])[CH:7]=1)=[O:9]
Reactant: N
Reactant: COC(=O)c1[nH]c(C(=O)Cl)cc1Cl
Solvent: C1CCOC1
Product: COC(=O)c1[nH]c(C(N)=O)cc1Cl
Yield: 51.1 %

Procedure:
Ammonia (5.8 mL, 2.9 mmol) was added to a solution of methyl 3-chloro-5-(chlorocarbonyl)-1H-pyrrole-2-carboxylate (0.15 g, 0.58 mmol) in THF and the resulting solution stirred until no starting material was evident by TLC. The solvent was evaporated and purification was accomplished by silica gel column chromatography (30 to 100% EtOAc/hexanes) to afford the title compound (0.060 g, 51%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.29 (br. s., 1H), 7.82 (br. s., 1H), 7.47 (br. s., 1H), 6.80 (s, 1H), 3.77 (s, 3H). LCMS: m/z 201.4 (M−1).
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9](N)[C:4]=2[CH2:3][O:2]1.N([O-])=O.[Na+].[S:15](=[O:17])=[O:16].[ClH:18]>C(O)(=O)C.O.O.O.[Cu](Cl)Cl>[CH2:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([S:15]([Cl:18])(=[O:17])=[O:16])[C:4]=2[CH2:3][O:2]1
Reactant: Nc1cccc2c1COC2
Reactant: O=S=O
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=S(=O)(Cl)c1cccc2c1COC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 22.1 g of the crude hydrochloride salt prepared in Example 2 in a mixture of 30 ml of concentrated hydrochloric acid and 30 ml acetic acid was cooled to 0°-5°. A solution of 6.2 g of sodium nitrite in 15 ml water was added dropwise at 0°-5°. The thick suspension was diluted with 19 ml of concentrated hydrochloric acid to facilitate stirring and 1.0 g of sodium nitrite was added; stirring was continued for 1 hour. The suspension of the diazonium salt was added portionwise at 0°-5° to a stirred mixture of 80 ml of acetic acid, 25 ml of sulfur dioxide and 1.6 g of copper (II) chloride dihydrate. The resulting pale green suspension was allowed to warm to ambient temperature and stirred for 4.5 hours. The yellow-green solution was poured into 1000 ml of cold water and the aqueous mixture extracted three times with 1-chlorobutane. The combined organic solution was washed three times with water and saturated sodium bicarbonate solution, then dried over magnesium sulfate, and filtered. Evaporation of the solvent in vacuo gave 9.8 g of 1,3-dihydrobenzo[c]furan-4-sulfonyl chloride as a yellow oil which crystallized on cooling and scratching, m.p. 40°-43°.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:21]1([CH2:24][NH:25][CH2:26][CH:27]2[CH2:29][CH2:28]2)[CH2:23][CH2:22]1>CN(C=O)C>[CH:21]1([CH2:24][N:25]([CH2:26][CH:27]2[CH2:29][CH2:28]2)[C:2]2[C:11]([CH:12]=[O:13])=[CH:10][C:9]3[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:23][CH2:22]1
Reactant: C1CC1CNCC1CC1
Reactant: Cc1cccc2cc(C=O)c(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2cc(C=O)c(N(CC3CC3)CC3CC3)nc12
Temperature: 25 °C
Yield: 49.2 %

Procedure:
2-Chloro-8-methyl-quinoline-3-carbaldehyde (0.115 g, 0.559 mmol), and potassium carbonate (0.231 g, 1.67 mmol) were put in a 25 mL two necked RB flask. To this, 3 mL of DMF was added followed by dropwise addition of bis-cyclopropylmethyl amine (0.083 g, 0.67 mmol). The reaction mixture was refluxed for 2 h and was cooled to RT. It was then poured on crushed ice (10 mL) and extracted with EtOAc (3×10 mL). The organic layer was washed with brine and dried over sodium sulphate. The solvent was evaporated under vacuum to give a yellow colored oil (0.081 g, 50%).
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].[Li].[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][C:18]1=[O:22].C(Br)CC.C(O)(=O)C>C1COCC1>[CH2:2]([CH:19]1[CH2:20][CH2:21][N:17]([CH2:16][CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=2)[C:18]1=[O:22])[CH2:1][CH3:3]
Reactant: O=C1CCCN1CCc1ccccn1
Reactant: CC(C)NC(C)C
Agent: [Li]
Solvent: CC(=O)O
Solvent: CCCBr
Solvent: C1CCOC1
Product: CCCC1CCN(CCc2ccccn2)C1=O
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a 2 M lithium diisopropylamine solution in THF of −78° C. is added 1-(2-(pyridin-2-yl)-ethyl)pyrrolidin-2-one and the mixture is stirred for 1.5 h at −78° C. Then 1-propyl bromide is added and the reaction is stirred for another 1.5 h at −78° C. The reaction mixture is allowed to warm up to 0° C. before ice-cold water with acetic acid is added and subsequently extracted 3 times with dichloromethane. The dichloromethane is concentrated in vacuo and the residue is dissolved in dichloromethane, washed with saturated NaHCO3 and brine. Crude 3-propyl-1-(2-(pyridin-2-yl)ethyl)pyrrolidin-2-one is obtained after removal of the solvents in vacuo. The product is purified by column chromatography.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH3:10])[C:5]([CH2:11][S@@:12]([C:14]2[NH:18][C:17]3[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:16]=3[N:15]=2)=[O:13])=[N:4][CH:3]=1.[CH:25]1([C@H:31]([NH2:33])[CH3:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C(#N)C>[CH:25]1([C@H:31]([NH3+:33])[CH3:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:16]2[NH:15][C:14]([S@:12]([CH2:11][C:5]3[C:6]([CH3:10])=[C:7]([O:8][CH3:9])[C:2]([CH3:1])=[CH:3][N:4]=3)=[O:13])=[N:18][C:17]=2[CH:19]=1
Reactant: COc1ccc2nc([S@@](=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Reactant: C[C@@H](N)C1CCCCC1
Solvent: CC#N
Product: COc1ccc2[nH]c([S@@](=O)Cc3ncc(C)c(OC)c3C)nc2c1
Product: C[C@@H]([NH3+])C1CCCCC1
Reaction time: 0.75 h
Yield: 36.4 %

Procedure:
(S)-omeprazole (1.0 g, 2.9 mmol) was dissolved in acetonitrile (10 ml). (R)-1-cyclohexyl ethyl amine (0.83 ml, 5.7 mmol) was added to the solution whereupon a white solid precipitated. After 45 minutes acetonitril (10 ml) was added to the thick reaction mass and stirring was continued for 45 minutes. The precipitate was filtered off, washed with acetonitrile, and dried. 0.5 g of the title compound was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][N:2]=1.C[Si]([C:11]#[N:12])(C)C.[Cl-].[Al+3].[Cl-].[Cl-].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)Cl.CCO>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:1]2[CH:6]([C:11]#[N:12])[CH:5]=[CH:4][CH:3]=[N:2]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccnnc1
Reactant: C[Si](C)(C)C#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N2N=CC=CC2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of pyridazine (3.63 mL, 49.9 mmol) in DCM (60 mL) was added trimethylsilyl cyanide (11.99 mL, 90 mmol) and aluminum chloride (20 mg, 0.150 mmol). After stirring the reaction mixture at room temperature for 10 minutes, a solution of para-toluene sulfonyl chloride (16.38 mL, 86 mmol) in DCM (100 mL) was added dropwise via an addition funnel over 30 minutes. The resulting light orange solution was left stirring at room temperature overnight. The reaction mixture was concentrated to give a light brown solid. To this material was added EtOH (100 mL). A white precipitate formed which was filtered through a sintered funnel. The precipitate was washed with ethanol and collected. m/z=262 (M+H).
Reaction SMILES: [CH:1]1([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:14]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:23]([CH2:26][C:27](=[O:29])[CH3:28])(=[O:25])[CH3:24]>C(O)(=O)C.Cl.O.C(O)C>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH:11][N:14]=[C:26]([C:27](=[O:29])[CH3:28])[C:23](=[O:25])[CH3:24])=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(C2CCCCC2)cc1
Reactant: CC(=O)CC(C)=O
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=O)C(=NNc1ccc(C2CCCCC2)cc1)C(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
To a solution of 4-cyclohexylaniline (500 mg, 2.86 mmol) in 10 mL of acetic acid and 2 mL of concentrated hydrochloride solution, sodium nitrite (237 mg, 3.43 mmol) in 4 mL of water was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 h. Then to the reaction mixture was added dropwise a solution of sodium acetate (703 mg, 8.58 mmol) and acetylacetone (372 mg, 3.72 mmol) in 10 mL of ethanol and 6 mL of water. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH/H2O (1:1) and hexane, and dried to give 3-[(4-cyclohexylphenyl)hydrazono]pentane-2,4-dione (420 mg, 51%).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[CH:9]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[CH:21][CH:20]=[C:19]2[S:23](Cl)(=[O:25])=[O:24])=[CH:14][CH:13]=1)([CH3:11])[CH3:10].C(C1C=CC(N2C=CC(S(Cl)(=O)=O)=C2)=CC=1)(C)C.C(O)(C(F)(F)F)=O.[Br:52][C:53]1[C:54]([CH3:76])=[N:55][O:56][C:57]=1[NH:58][S:59]([C:62]1[CH:66]=[CH:65][N:64]([C:67]2[CH:72]=[CH:71][C:70]([CH:73]([CH3:75])[CH3:74])=[CH:69][CH:68]=2)[CH:63]=1)(=[O:61])=[O:60]>O.C(#N)C>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:23]([C:19]1[N:18]([C:15]2[CH:16]=[CH:17][C:12]([CH:9]([CH3:11])[CH3:10])=[CH:13][CH:14]=2)[CH:22]=[CH:21][CH:20]=1)(=[O:24])=[O:25].[Br:52][C:53]1[C:54]([CH3:76])=[N:55][O:56][C:57]=1[NH:58][S:59]([C:62]1[CH:66]=[CH:65][N:64]([C:67]2[CH:72]=[CH:71][C:70]([CH:73]([CH3:74])[CH3:75])=[CH:69][CH:68]=2)[CH:63]=1)(=[O:61])=[O:60]
Reactant: Cc1noc(N)c1Br
Reactant: CC(C)c1ccc(-n2cccc2S(=O)(=O)Cl)cc1
Agent: CC(C)c1ccc(-n2ccc(S(=O)(=O)Cl)c2)cc1
Agent: Cc1noc(NS(=O)(=O)c2ccn(-c3ccc(C(C)C)cc3)c2)c1Br
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1noc(NS(=O)(=O)c2cccn2-c2ccc(C(C)C)cc2)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl) 1-(4'-isopropylphenyl)pyrrole-2-sulfonamide and N-(4-bromo-3-methyl-5-isoxazolyl) 1-(4'-isopropylphenyl)pyrrole-3-sulfonamide were prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and a mixture of 1-(4'-isopropylphenyl)pyrrole-2-sulfonyl chloride and 1-(4'-isopropylphenyl)pyrrole-3-sulfonyl chloride in 65% combined yield. The 22.85 min, 5% to 95% acetonitrile in water with 0.1 % TFA over 30 min period, C18 analytical column) and N-(4-bromo-3-methyl-5-isoxazolyl) 1-(4'-isopropylphenyl)pyrrole-3-sulfonamide (retention time 24.56 min, 5% to 95% acetonitrile in water with 0.1% TFA over 30 min period, C18 analytical column) as oils.
Reaction SMILES: [O:1]1[C:9]2[CH2:8][CH2:7][N:6]([C:10](=[O:27])[CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:14]=3)[CH2:5][C:4]=2[CH:3]=[CH:2]1.[CH3:28][NH:29][CH3:30].[CH2:31]=O>C(O)(=O)C>[CH3:28][N:29]([CH2:31][C:2]1[O:1][C:9]2[CH2:8][CH2:7][N:6]([C:10](=[O:27])[CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:14]=3)[CH2:5][C:4]=2[CH:3]=1)[CH3:30]
Reactant: O=C(CCc1cccc(CCc2ccccc2)c1)N1CCc2occc2C1
Reactant: CNC
Reactant: C=O
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CCN(C(=O)CCc1cccc(CCc3ccccc3)c1)C2
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.331 g (0.921 mmol) of 1-(6,7-dihydro-4H-furo[3,2-c]pyridin-5-yl)-3-(3-phenethylphenyl) propan-1-one in 20 ml of acetic acid, 0.10 g (1.1 mmol) of 50% aqueous dimethylamine and 0.09 g (1.1 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 15 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[Br:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][NH:26][CH2:27]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Br:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][N:26]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([NH2:17])[C:10]=1[F:16])[CH2:27]2
Reactant: Brc1cccc2c1CNC2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Nc1c(F)c(N2Cc3cccc(Br)c3C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 34.3 %

Procedure:
268 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 198 mg of 4-bromoisoindoline, 274 mg of DBU, and 2 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 147 mg of the target compound.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[I:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[S:23])=[CH:17][CH:16]=1>>[CH2:12]([O:11][C:9]([C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[S:23][C:22]=1[NH:21][C:18]1[CH:19]=[CH:20][C:15]([I:14])=[CH:16][CH:17]=1)=[O:10])[CH3:13]
Reactant: S=C=Nc1ccc(I)cc1
Reactant: CCOC(=O)Cc1cccnc1Cl
Product: CCOC(=O)c1c(Nc2ccc(I)cc2)sc2ncccc12

Procedure:
Prepared from ethyl (2-chloropyridin-3-yl)acetate (D. H. Bremner et al., Synthesis, 1997, 949) (750 mg, 3.8 mmol) and 4-iodophenyl isothiocyanate (1.0 g, 3.8 mmol) by the method of Example 1. Title compound obtained as an off-white solid (800 mg, 50%). δH (DMSO-d6) 10.34 (1H, br s), 8.33-8.30 (2H, m), 7.79 (2H, dt, J 2.0, 6.7 Hz), 7.43-7.31 (3H, m), 4.40 (2H, q, J=7.1 Hz), 1.40 (3H, t, J=7.1 Hz). LCMS (ES+) RT 4.31 minutes, 425 (M+H)+.