Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][CH2:5][C:6]1([CH3:25])[O:10][N:9]=[C:8]([S:11][CH2:12][C:13]2[C:14]([C:21]([F:24])([F:23])[F:22])=[N:15][N:16]([CH2:19][CH3:20])[C:17]=2F)[CH2:7]1.O.C(OCC)(=O)C>CN(C)C=O>[Cl:4][CH2:5][C:6]1([CH3:25])[O:10][N:9]=[C:8]([S:11][CH2:12][C:13]2[C:14]([C:21]([F:24])([F:23])[F:22])=[N:15][N:16]([CH2:19][CH3:20])[C:17]=2[C:1]#[N:2])[CH2:7]1
Reactant: [C-]#N
Reactant: CCn1nc(C(F)(F)F)c(CSC2=NOC(C)(CCl)C2)c1F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(C(F)(F)F)c(CSC2=NOC(C)(CCl)C2)c1C#N
Temperature: 50 °C
Reaction time: 10 h
Yield: 100 %

Procedure:
0.30 g (6.0 mmoles) of sodium cyanide was added, at room temperature, into a solution of 1.08 g (3.0 mmoles) of 5-chloromethyl-3-(1-ethyl-5-fluoro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline dissolved in 10 ml of N,N-dimethylformamide. The mixture was stirred at 50° C. for 10 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water and extraction with ethyl acetate was conducted. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 1.10 g (yield: quantitative) of 5-chloromethyl-3-(5-cyano-1-ethyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline.
Reaction SMILES: O1CCOCC1.[O:7]=[C:8]([CH2:13][C:14](=[O:30])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:17][CH:16]=1)[C:9]([O:11]C)=[O:10].[OH-].[K+]>C(O)C>[O:7]=[C:8]([CH2:13][C:14](=[O:30])[C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:19][CH:20]=1)[C:9]([OH:11])=[O:10]
Reactant: CCCCCCCCCc1ccc(C(=O)CC(=O)C(=O)OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: CCCCCCCCCc1ccc(C(=O)CC(=O)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
There are dissolved in 45 ml of ethanol and 5.4 ml of dioxane 2.92 g (8.9 mMol) of the ester product of Step A above. To this solution 6.75 ml of 2 N potassium hydroxide was added, whereupon a precipitate formed. The reaction mixture was stirred at room temperature for 4 hours, then evaporated to dryness, dissolved in water, and extracted with ether. The aqueous layer was then acidified to pH 1 using 2 N hydrochloric acid; and the product was extracted into ethyl acetate, after which it was dried and evaporated, to yield 1.8 g. The crude product was crystallized from benzene, giving 480 mg in the first crop, m.p. 93°-94° C.; and 320 mg in the second crop, m.p. 90°-91° C. Analysis:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[C:19]([NH:27][C:28]1[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:29]=1[C:30]([O:32]C)=[O:31])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C(=O)C>[C:19]([NH:27][C:28]1[CH:37]=[C:36]([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)[CH:35]=[CH:34][C:29]=1[C:30]([OH:32])=[O:31])(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: OB(O)c1cc2ccccc2s1
Reactant: COC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C(Nc1cc(-c2cc3ccccc3s2)ccc1C(=O)O)c1ccccc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 3.2 %

Procedure:
56 mg of benzothiophene-2-boronic acid, 55 mg of sodium carbonate and 30 mg of polymer supported bis(acetato)triphenylphosphine palladium(II) were added to 2.5 mL of N,N-dimethylacetamide solution containing 70 mg of methyl 2-(benzamido)-4-bromobenzoate, and stirred at 90° C. for 12 hours. After cooled to room temperature 37 mg of benzothiophene-2-boronic acid and 22 mg of sodium carbonate were added and stirred at 90° C. for 12 hours. After the reaction mixture was cooled to room temperature, insoluble were removed by filtration and ethyl acetate and 1.0 mol/L hydrochloric acid were added. The organic layer was separated, and dried over anhydrous magnesium sulfate after washed with 1.0 mol/L hydrochloric acid and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. 1.0 mL of 2.0 mol/L aqueous sodium hydroxide and 2.0 mL of ethanol were added to the obtained residue and stirred at room temperature for 1 hour. 0.6 mol/L hydrochloric acid was added to the reaction mixture and a solid substance was separated by filtration to obtain 2.5 mg of 2-(benzamido)-4-(benzothiophen-2-yl)benzoic acid as white solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].I[C:8]1[CH:9]=[C:10]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=1.[OH:20][C:21]1[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:31]=[C:30]([CH2:38][O:39][C:40]2[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][CH:41]=2)[C:22]=1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].CN(C)C=O>O1CCOCC1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[OH:20][C:21]1[C:33]([C:34]([F:36])([F:37])[F:35])=[CH:32][CH:31]=[C:30]([CH2:38][O:39][C:40]2[CH:45]=[CH:44][C:43]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])[CH:9]=3)=[CH:42][CH:41]=2)[C:22]=1[C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24]
Reactant: CC(C)(C)OC(=O)c1c(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)ccc(C(F)(F)F)c1O
Reactant: CN(c1cccc(I)c1)S(C)(=O)=O
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: O
Product: CN(c1cccc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C(=O)OC(C)(C)C)cc2)c1)S(C)(=O)=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 20.8 %

Procedure:
After [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)-dichloromethane adduct (82 mg, 0.1 mmol), 1,1′-bis(diphenylphosphino)ferrocene (166 mg, 0.3 mmol) and cesium carbonate (460 mg, 3 mmol) were added to a solution of N-(3-iodophenyl)-N-methylmethanesulfonamide (310 mg, 1 mmol) and tert-butyl 2-hydroxy-6-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}-3-(trifluoromethyl)benzoate (494 mg, 1 mmol) obtained in Example (22-4) in 1,4-dioxane (5 ml) and the mixture was stirred under heating at 60° C. for 4 hours, the mixture was left to stand at room temperature overnight. N,N-dimethylformamide (5 ml) was added to the reaction mixture and the mixture was stirred under heating at 70° C. for 9 hour and left to stand at room temperature for one week. The reaction mixture was poured into water and extracted with ethyl acetate (twice). The organic layer was successively washed with water and a saturated aqueous NaCl solution (twice) and dried with anhydrous magnesium sulfate. After the residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=3/1), recrystallization was carried out using tetrahydrofuran and diisopropyl ether to give the title compound as a grayish white crystal (115 mg, yield: 21%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6](Cl)=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[OH:21].[OH-].[K+]>>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([O:21][C:15]3[C:16]([CH3:20])=[CH:17][CH:18]=[CH:19][C:14]=3[CH3:13])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cccc(C)c1O
Reactant: Nc1ccc2ccc(Cl)nc2n1
Agent: [K+]
Agent: [OH-]
Product: Cc1cccc(C)c1Oc1ccc2ccc(N)nc2n1
Yield: 80 %

Procedure:
The procedure is similar to that described in Example 4, but starting with 2-amino-7-chloro-1,8-naphthyridine (17.95 g), 2,6-dimethylphenol (48.6 g) and potassium hydroxide pellets (13.2 g; 85% purity). After treatment with caustic soda and washing, the product produced (24.8 g; m.p. 204° C.) is purified by chromatography on a column 45 mm in diameter containing silica (360 g; 0.040-0.063 mm), eluting with pure methylene chloride and collecting 100-cc fractions. After concentration to dryness of fractions 1 to 48 at 40° C. under reduced pressure (4 kPa), 2-amino-7-(2,6-dimethylphenoxy)-1,8 naphthyridine (21.2 g) is produced, m.p. 218° C.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:25])[CH2:6][C@@H:5]1[CH3:26])(=[O:3])[CH3:2].Cl[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][N:29]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.O.CCOC(C)=O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:25][C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][N:29]=2)[CH2:6][C@@H:5]1[CH3:26])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2ccc3c(c2)[C@H](N)C[C@H](C)N3C(C)=O)cc1
Reactant: N#Cc1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2ccc(C#N)cn2)C[C@H](C)N3C(C)=O)cc1
Temperature: 200 °C

Procedure:
Ethyl 4-((2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (for a preparation, see Intermediate 16) (300 mg, 0.851 mmol) and 6-chloronicotinonitrile (236 mg, 1.702 mmol) in anhydrous NMP (5 mL) were treated with DIPEA (0.445 mL, 2.55 mmol). The reaction vial was sealed and heated under microwave irradiation to 200° C. for 2 h. The cooled solution was diluted with water to −20 mL, stirred and the resulting sticky solid isolated by decantation. The solid was dissolved in EtOAc, the solution washed with brine and dried by passing through a hydrophobic frit. The solution was concentrated in vacuo and the residue purified by MDAP (Formate) to give crude ethyl 4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (120 mg) as a beige gum which was used directly in the next step without further purification. LCMS: (Formate, 2 min), Rt=1.12 min, MH+455.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH2:16](O)[CH3:17]>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5]([O:7][CH2:16][CH3:17])=[O:6]
Reactant: Nc1cc(C(=O)O)cc(Cl)n1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(N)nc(Cl)c1
Yield: 88 %

Procedure:
2-Amino-6-chloroisonicotinic acid (500 mg, 2.90 mmol) was dissolved in ethanol (29.0 mL), and the solution was stirred under heat and reflux for 3 hours after adding thionyl chloride (1.06 mL, 14.5 mmol). The solvent was then evaporated under reduced pressure. The residue was extracted with chloroform after adding a sodium hydrogen carbonate aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give ethyl 2-amino-6-chloroisonicotinate (510 mg, yield 88%).
Reaction SMILES: [H-].[Na+].CS(C)=O.[I-].C[S+](C)(C)=O.[CH2:13]([C@:15]12[CH2:39][CH2:38][C:37](=[O:40])[CH2:36][C@H:16]1[CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[C:22]3[C:26](=[CH:27][C:28]=12)[CH:25]=[N:24][N:23]3[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)[CH3:14].[CH2:41]([C@@]12CCC(=O)C[C@@H]1CCCC1C=C3C(=CC=12)C=NN3C1C=CC(F)=CC=1)C>C1COCC1>[CH2:13]([C:15]12[CH2:39][CH2:38][C:37]3([CH2:41][O:40]3)[CH2:36][CH:16]1[CH2:17][CH2:18][CH2:19][C:20]1[C:28]2=[CH:27][C:26]2[CH:25]=[N:24][N:23]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[C:22]=2[CH:21]=1)[CH3:14]
Reactant: CC[C@@]12CCC(=O)C[C@@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Reactant: CC[C@]12CCC(=O)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Agent: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCC12CCC3(CO3)CC1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Temperature: 65 °C
Yield: 89.1 %

Procedure:
A flask with stir bar and nitrogen line was charged with sodium hydride (60% in oil 0.106 g, 2.66 mmol) and DMSO (7 mL). The mixture was warmed in an oil bath heated to about 65° C. for about 45 min. The mixture was cooled to rt, diluted with THF (7 mL) then cooled to about 0° C. Trimethylsulfoxonium iodide (0.585 g, 2.66 mmol) was added and the mixture was stirred for about 15 min. (4aR,12bR)-12b-Ethyl-9-(4-fluoro-phenyl)-1,2,4a,5,6,7,9,12b-octahydro-4H-9,10-diaza-benzo[3,4]cyclohepta[1,2-f]inden-3-one; compound with (4aS,12bS)-12b-ethyl-9-(4-fluoro-phenyl)-1,2,4a,5,6,7,9,12b-octahydro-4H-9,10-diaza-benzo[3,4]cyclohepta[1,2-f]inden-3-one (9, R1=4-Fluorophenyl, R2=Ethyl) (0.500 g, 1.328 mmol) suspended in THF (9 mL) was added to the reaction mixture. After about 15 min the ice bath was removed and the mixture was allowed to warm to rt for about 6 h. The mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc (100 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (25 mL). The combined organic layers were washed with water (2×50 mL) and brine (30 mL). The organic solution was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (25 g) using a gradient of 0-20% EtOAc in DCM. Product fractions were combined and concentrated under reduced pressure to yield rac-(2′R,4aS,12bS)-12b-ethyl-9-(4-fluorophenyl)-2,4,4a,5,6,7,9,12b-octahydro-1H-spiro[benzo[6,7]cyclohepta[1,2-f]indazole-3,2′-oxirane] (14, R1=4-Fluorophenyl, R2=Ethyl) (0.462 g, 1.183 mmol, 89% yield); LC/MS, method 3, Rt=3.14 min, MS m/z 391 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.27 (d, J=0.8 Hz, 1H), 7.93 (s, 1H), 7.85-7.78 (m, 2H), 7.56 (s, 1H), 7.45-7.37 (m, 2H), 3.26-3.19 (m, 1H), 2.97-2.92 (m, 1H), 2.67 (d, J=4.7 Hz, 1H), 2.62 (d, J=4.7 Hz, 1H), 2.36-2.32 (m, 1H), 2.23-2.14 (m, 1H), 2.12-1.91 (m, 4H), 1.91-1.68 (m, 3H), 1.62-1.54 (m, 1H), 1.32-1.28 (m, 1H), 1.26-1.16 (m, 1H), 1.07-0.94 (m, 1H), 0.40 (t, J=7.3 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1[C:14](=O)[NH:13][C:12]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[N:11][C:5]=1[NH:6]2.O=P(Cl)(Cl)[Cl:25].C(Cl)(Cl)Cl.CO>C(Cl)(Cl)Cl.CO>[Cl:25][C:14]1[C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])[NH:6][C:5]=2[N:11]=[C:12]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[N:13]=1
Reactant: CC(C)(C)C(=O)Nc1nc2[nH]c3cccc(Cl)c3c2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)Nc1nc(Cl)c2c(n1)[nH]c1cccc(Cl)c12
Temperature: 115 °C
Yield: 70 %

Procedure:
To 9 (2 g, 6.274 mmol) was added 30 mL of POCl3 in a 250 mL round bottom flask. The reaction mixture was refluxed at 110-120° C. for 4 hours. After this the POCl3 was evaporated and the mixture was neutralized using NH4OH. The aqueous mixture was filtered (the precipitate being the compound). The filtrate also contained some compound. Therefore, it was extracted using chloroform and ethyl acetate. The precipitate obtained was dissolved in chloroform and methanol. Both the dissolved precipitate and extracted filtrate were dried using sodium sulfate overnight. To the solution was added silica, and solvent was removed under reduced pressure to provide a silica gel plug. The plug was transferred on top of a column packed with silica gel, twenty times the weight of plug, eluted with chloroform, 1% methanol in chloroform and 5% methanol in chloroform. Fractions containing the product 10 (TLC) were pooled and evaporated to give a solid. The overall yield was 70%. TLC Rf 0.86 (chloroform-methanol 5:1), m.p. 245.6-246.1° C., 1H NMR: δ 1.24 (s, 9H, pivaloyl); 7.37-7.63 (m, 3H, phenyl); 10.32 (s, 1H, 9-NH, exch); 12.96 (s, 1H, 2-NH, exch).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>CO>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([N:6]=[CH:14][N:15]([CH3:17])[CH3:16])=[O:5]
Reactant: NC(=O)c1cc(F)ccc1Br
Reactant: COC(OC)N(C)C
Solvent: CO
Product: CN(C)C=NC(=O)c1cc(F)ccc1Br
Temperature: 120 °C
Yield: 72 %

Procedure:
A mixture of 2-bromo-5-fluorobenzamide (9.50 g, 43.57 mmol) and N,N-dimethylformamide dimethyl acetal (20 ml) was heated under argon at 120° C. for 1.5 h. The methanol formed during the reaction was collected through a reflux condenser. The reaction mixture was allowed to cool and the excess N,N-dimethylformamide dimethyl acetal was removed under reduced pressure. The residual oil was crystallized from a mixture of ether (75 ml) and hexane (50 ml) to give 8.55 g (72% yield) of the title material as white crystals. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.21 (3H, s, CH3), 3.24 (3H, s, CH3), 7.0 (1H, m, aromatic), 7.58 (1H, dd, J=5.0 Hz and J=8.5 Hz, aromatic), 7.64 (1H, dd, J=3.0 Hz and J=9.1 Hz, aromatic), 8.64 (1H, s, CH).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[C:8]([O:12][C:13]([NH:15][CH2:16][CH2:17]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:14])([CH3:11])([CH3:10])[CH3:9]>CN(C=O)C>[C:8]([O:12][C:13](=[O:14])[NH:15][CH2:16][CH2:17][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)([CH3:11])([CH3:10])[CH3:9]
Reactant: Cc1ccc(S(=O)(=O)OCCNC(=O)OC(C)(C)C)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCn1ccnc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 28.5 %

Procedure:
A solution of imidazole (253 mg, 3.72 mmol) in DMF (2 mL) was added to a suspension of NaH (60% in mineral oil, 164 mg, 4.10 mmol) in DMF (8 mL), and the mixture was stirred at room temperature for 45 minutes. A solution of toluene-4-sulfonic acid 2-tert-butoxycarbonylamino-ethyl ester (1.29 g, 4.09 mmol) in DMF (6 mL) was added, and the mixture was stirred at room temperature for 16 h then concentrated in vacuo. The residue was partitioned between H2O (25 mL) and EtOAc (25 mL), and the aqueous phase was extracted with EtOAc (25 mL). The combined organic phases were dried (MgSO4) and concentrated in vacuo. Purification of the crude material by column chromatography on silica gel (200:5:1-100:5:1 CH2Cl2/MeOH/NH4OH) gave a colourless oil (224 mg, 29%). 1H NMR (CDCl3) δ 1.44 (s, 9H), 3.43 (m, 2H), 4.08 (m, 2H), 4.64 (br s, 1H), 6.92 (s, 1H), 7.09 (s, 1H), 7.46 (s, 1H).
Reaction SMILES: NS(N)(=O)=O.Cl[CH2:7][CH2:8][CH2:9][S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:33]([NH2:35])=[O:34])[CH:24]=[C:25]([C:28]4[S:29][CH:30]=[CH:31][CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11].[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C([O-])([O-])=O.[K+].[K+]>>[N:36]1([CH2:7][CH2:8][CH2:9][S:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[C:27]4[C:22](=[C:23]([C:33]([NH2:35])=[O:34])[CH:24]=[C:25]([C:28]5[S:29][CH:30]=[CH:31][CH:32]=5)[CH:26]=4)[NH:21][CH:20]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: C1COCCN1
Reactant: NC(=O)c1cc(-c2cccs2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Agent: NS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)c1cc(-c2cccs2)cc2c(C3CCN(S(=O)(=O)CCCN4CCOCC4)CC3)c[nH]c12
Yield: 55.5 %

Procedure:
Following the general procedure for aminosulfonamide formation outlined in example 2, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(2-thienyl)-1H-indole-7-carboxamide (40 mg, 0.13 mmol) and morpholine (0.069 mL, 0.65 mmol) were allowed to react in the presence of K2CO3 (74 mg, 0.65 mmol). The resulting residue was purified by reverse phase HPLC eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give the title compound (37.3 mg, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][NH:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:34][CH:33]=2)[CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.O>[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][N:30]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:34][CH:33]=2)[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])[CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(OCc3ccccc3)c2)cc1
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: CC(C)(C)c1ccc(CN(CCc2cccc(OCc3ccccc3)c2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To a solution of 951 mg (4.86 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 1.997 g (5.35 mmol) [2-(3-benzyloxy-phenyl)-ethyl]-(4-tert-butyl-benzyl)-amine in 50 ml DMF, were added 1.6 ml (14.58 mmol) N-methylmorpholine and 2.77 g TBTU (7.29 mmol) at rt. After stirring for 16 h at rt, the reaction mixture was diluted with 300 ml water and extracted with EtOAc (2×). The combined organic phases were washed with twice 200 ml water and 100 ml brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (90 g silica gel; heptane/EtOAc 9:1 then 4:1) to give 2.41 g of 5-chloro-1H-indole-7-carboxylic acid [2-(3-benzyloxy-phenyl)-ethyl]-(4-tert-butyl-benzyl)-amide as a light yellow solid (88%). MS (ISP) 551.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([C:9](=[S:11])[NH2:10])[CH:6]=[CH:7][CH:8]=1.Cl[CH:15]([CH:18]=O)[CH:16]=[O:17]>C(O)C>[F:13][C:2]([F:12])([F:1])[C:3]1[CH:4]=[C:5]([C:9]2[S:11][C:15]([CH:16]=[O:17])=[CH:18][N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: NC(=S)c1cccc(C(F)(F)F)c1
Reactant: O=CC(Cl)C=O
Solvent: CCO
Product: O=Cc1cnc(-c2cccc(C(F)(F)F)c2)s1
Yield: 25.8 %

Procedure:
To a solution of 3-(trifluoromethyl)benzenecarbothioamide (1.31 g, 6.37 mmol) in ethanol (15 mL) was added 2-chloropropane-1,3-dial (2.04 g, 19.1 mmol), and the mixture was heated under reflux overnight. The reaction mixture was extracted with ethyl acetate, washed successively with diluted aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give 2-[3-(trifluoromethyl)phenyl]-1,3-thiazole-5-carbaldehyde (423 mg) as colorless crystals. The present compound was dissolved in ethanol (5 mL), sodium borohydride (91 mg, 2.47 mmol) was added under ice-cooling, and the mixture was stirred at room temperature overnight. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (334 mg, 78%) as a colorless oil.