Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[SH:7][C:8]1[N:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br.O>CN(C)C=O>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][S:7][C:8]1[N:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: BrCCCCCCCBr
Reactant: Sc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: BrCCCCCCCSc1ncccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
Potassium carbonate (9.95 g) was added to a solution of 2-mercaptopyrimidine (6.73 g) and 1,7-dibromoheptane (15.48 g) in N,N-dimethylformamide (85 ml). The mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), and then the solvent was distilled off under reduced pressure. The residual oil was subjected to column chromatography on silica gel and eluted with ethyl acetate-hexane (1:4, v/v) to obtain 2-(7-bromoheptylthio)pyrimidine (8.5 g) as an oil. This oil was dissolved in N,N-dimethylformamide (45 ml). Potassium phthalimide (5.44 g) was added to the solution, and the mixture was stirred at 100° C. for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4). The solvent was distilled off under reduced pressure to obtain N-[7-(2-pyrimidinylthio)heptyl]phthalimide (10.36 g, 48.6%) as an oil.
Reaction SMILES: N[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])[N:3]=1.S(=O)(=O)(O)[OH:24].N([O-])=O.[Na+]>O>[OH:24][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])[N:3]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1nc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)nc1O
Temperature: 60 °C

Procedure:
14.0 g of 2-amino-3-nitro-6-(2-chloro-4-trifluoromethylphenoxy)pyridine prepared in Preparation Example 2 was poured into 29 ml of concentrated sulfuric acid, and the mixture was heated at 60° C. Thereafter, the resulting mixture was allowed to stand for cooling, and further cooled with ice to 0° to 10° C. An aqueous solution of 4.6 g of sodium nitrite and 14 ml of water was gradually added dropwise thereto at the same temperature while stirring whereby the mixture was allowed to react. After completion of the reaction, the reaction product was poured into water, followed by subjecting to purification in the same manner as in Preparation Example 2 to obtain 10.3 g of a titled compound having a melting point of 87° to 93° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.Cl.[CH2:27]([N:29]([CH2:36][CH3:37])[CH:30]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]1)[CH3:28]>>[CH2:36]([N:29]([CH2:27][CH3:28])[CH:30]1[CH2:35][CH2:34][CH2:33][N:32]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:20])[CH2:31]1)[CH3:37]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CCN(CC)C1CCCNC1
Agent: Cl
Product: CCN(CC)C1CCCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)C1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and N,N-diethylpiperidin-3-amine dihydrochloride. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.26 (br. s., 6H) 1.57 (br. s., 2H) 1.76-2.17 (m, 2H) 2.36-2.90 (m, 9H) 3.02 (br. s., 1H) 3.70 (br. s., 1H) 4.52-4.92 (m, 1H) 7.48-7.60 (m, 3H) 7.63-7.73 (m, 1H) 7.95-8.10 (m, 2H) 8.43 (s, 1H); ESI-MS m/z [M+H]+ 459.3.
Reaction SMILES: S(Cl)([Cl:3])=O.C1C=CC=CC=1.[Cl:11][C:12]1[C:20]([Br:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[CH:17][C:13]=1[C:14](O)=[O:15]>CN(C=O)C>[Cl:11][C:12]1[C:20]([Br:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[CH:17][C:13]=1[C:14]([Cl:3])=[O:15]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(Br)c1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=C(Cl)c1cc([N+](=O)[O-])cc(Br)c1Cl
Yield: 100.4 %

Procedure:
5.1 ml (69.9 mmol) of thionyl chloride and a solvent mixture comprising 50 ml of benzene and 0.2 ml of DMF were added to 14.07 g (50.2 mmol) of 2-chloro-3-bromo-5-nitrobenzoic acid. The obtained mixture was heated under reflux for 2 hours and distilled to remove the solvent. Benzene was added to the residue and the obtained mixture was distilled again to remove the solvent. Thus, 15.07 g of the title compound was obtained (yield: quantitative).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH2:9])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([C:7](=[S:23])[NH2:9])[CH:10]=1
Reactant: Cc1ccc([N+](=O)[O-])c(C(N)=O)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc([N+](=O)[O-])c(C(N)=S)c1
Temperature: 25 °C
Yield: 159.5 %

Procedure:
7.0 g (0.040 mol) of the product from Step A was suspended in toluene (140 mL). Lawesson's reagent (9.4 g, 0.023 mol) was added and the resulting mixture heated at 100° for 3 h (the mixture became homogeneous at 85° C.). After cooling to room temperature, the toluene was removed on the rotary evaporator. The residue was flash chromatographed on silica gel eluting with 20% ethyl acetate/hexane to furnish 7.2 g (95% yield) of the title compound as a yellow semisolid. 1H NMR (400 MHz, CDCl3) δ 7.92-7.94 (d,1H), 7.93 (br s, 1H, overlap with doublet), 7.25-7.32 (m,2H), 7.17 (br s, 1H), 2.45 (s,3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8][CH:9]=[CH:10][C:6]=2[C:5]([C:11]([OH:13])=O)=[CH:4][N:3]=1.[CH2:14]([NH2:18])[CH:15]([CH3:17])[CH3:16]>>[CH2:14]([NH:18][C:11]([C:5]1[C:6]2[CH:10]=[CH:9][NH:8][C:7]=2[C:2]([Cl:1])=[N:3][CH:4]=1)=[O:13])[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)CN
Reactant: O=C(O)c1cnc(Cl)c2[nH]ccc12
Product: CC(C)CNC(=O)c1cnc(Cl)c2[nH]ccc12

Procedure:
Prepared in a similar manner to Example 19 (e) from 7-chloro-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid using isobutylamine (28 mg) instead of tetrahydro-pyran-4-ylmethylamine to give the title compound (38 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7](O)[CH2:6][CH2:5]2.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]=[CH:5]2
Reactant: OC1CCc2cc(Br)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: Brc1ccc2c(c1)C=CC2
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A solution of 5-bromoindan-1-ol (5.00 g, 23.5 mmol) and p-Toluenesulfonic acid monohydrate (100 mg, 0.5 mmol) in benzene (150.00 mL) was heated to reflux for 2 h and water was continuously removed from the reaction mixture with a Dean-Stark trap. After cooling to room temperature, the benzene solution was washed with water, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification of the residue by flash chromatography (hexane) yielded pure 5-bromoindene (4.0 g, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=1)[NH:7][C:6](=[O:20])[CH:5]2SC>O1CCCC1.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11](=[O:19])[C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)[CH:10]=1)[NH:7][C:6](=[O:20])[CH2:5]2
Reactant: CSC1C(=O)Nc2c(C(=O)c3ccc(F)cc3)cc(Cl)cc21
Agent: [Ni]
Solvent: C1CCOC1
Product: O=C1Cc2cc(Cl)cc(C(=O)c3ccc(F)cc3)c2N1
Yield: 76.6 %

Procedure:
A slurry of 30.5 g (0.091 mol) of 5-chloro-7-(4-fluorobenzoyl)-3-methylthioindolin-2-one in 2.5 l of tetrahydrofuran was stirred vigorously and treated with 285 g of wet Raney nickel for 6 minutes. The mixture was filtered and the filter cake obtained was washed with 200 ml of tetrahydrofuran. The resulting filtrate was evaporated to leave 20.2 g of residue. This residue was recrystallized from acetone to give 16.8 g (64%) of the titled compound as white, fluffy needles, mp. 222°-225° C.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:16]=3[C:26]([F:29])([F:28])[F:27])[O:12][N:11]=2)=[CH:6][CH:5]=1.[OH:30][CH:31]1[CH2:36][NH:35][CH2:34][CH:33]([C:37]([OH:39])=[O:38])[CH2:32]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(O)C.CS(C)=O>[OH:30][CH:31]1[CH2:36][N:35]([CH2:3][CH:2]([OH:1])[C:4]2[CH:5]=[CH:6][C:7]([C:10]3[N:14]=[C:13]([C:15]4[O:19][N:18]=[C:17]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:16]=4[C:26]([F:27])([F:28])[F:29])[O:12][N:11]=3)=[CH:8][CH:9]=2)[CH2:34][CH:33]([C:37]([OH:39])=[O:38])[CH2:32]1
Reactant: FC(F)(F)c1c(-c2ccccc2)noc1-c1nc(-c2ccc(C3CO3)cc2)no1
Reactant: O=C(O)C1CNCC(O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CC(C)O
Product: O=C(O)C1CC(O)CN(CC(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a mixture of 3-(4-(oxiran-2-yl)phenyl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole, Preparation 28C (30 mg, 0.075 mmol) and 5-hydroxypiperidine-3-carboxylic acid (21.81 mg, 0.150 mmol) in 2-propanol (2 mL) and DMSO (2.000 mL) was added cesium carbonate (122 mg, 0.376 mmol). The reaction mixture was heated at 80° C. Next, 5-hydroxypiperidine-3-carboxylic acid (21.81 mg, 0.150 mmol) was added and the reaction was checked after 4 hr. Product peak was observed but starting material remained. The reaction mixture was heated overnight. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the desired product was 5.6 mg, and its purity was 99%. 1H NMR (400 MHz, MeOD) δ ppm 8.21 (2H, d, J=7.78 Hz), 7.69 (4H, d, J=6.78 Hz), 7.53-7.65 (3H, m), 5.19 (1H, dt, J=10.10, 3.61 Hz), 4.16 (1H, br. s.), 3.08-3.26 (5H, m), 2.86-3.06 (2H, m), 1.87-2.06 (3H, m). MS (m+1)=545.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]=[CH:11][C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=2.[Si:23]([O:30][CH2:31][CH2:32][CH2:33]Br)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C.O>[Si:23]([O:30][CH2:31][CH2:32][CH2:33][N:13]1[C:14]2[C:19](=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=2)[CH:20]=[C:12]1[CH:11]=[CH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[Cl:3])([C:26]([CH3:27])([CH3:28])[CH3:29])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: COc1ccc2[nH]c(C=Cc3ccccc3Cl)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)cc(C=Cc1ccccc1Cl)n2CCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (1.05 g of a 50% dispersion in mineral oil, 0.022 mol) was added to a solution of the 2-[2-(2-Chlorophenyl)ethenyl]-5-methoxy-1H-indole prepared according to example 37 (4.13 g, 0.014 mol) in DMF (30 mL) and the solution was stirred at room temperature for 5 min. 3-Bromopropyl tert-butyl(dimethyl)silyl ether (4.04 g, 0.016 mol) was added and stirring was continued for 2 h. The solution was diluted with water, extracted with EtOAc which was washed well with brine and the organic phase was dried, the drying agent was removed and the solution was concentrated to dryness to give 1-(3-{[tert-Butyl(dimethyl)silyl]oxy}propyl)-2-[2-(2-chlorophenyl)ethenyl]-5-methoxy-1H-indole (28) as an oily solid (4.98 g) (as a mixture of E/Z isomers) which was used without further purification.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:11]=[CH:10][O:9][CH:8]=1.[CH3:12][C:13]1[C:17]2[CH2:18][CH2:19][CH2:20][C:21](=[O:22])[C:16]=2[O:15][N:14]=1.[Cl-].[NH4+]>CCCCCC.CCOCC>[O:9]1[CH:10]=[CH:11][C:7]([C:21]2([OH:22])[C:16]3[O:15][N:14]=[C:13]([CH3:12])[C:17]=3[CH2:18][CH2:19][CH2:20]2)=[CH:8]1
Reactant: Cc1noc2c1CCCC2=O
Reactant: Brc1ccoc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1noc2c1CCCC2(O)c1ccoc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.3 %

Procedure:
To a solution of 4 ml (0.04 mol) of 10M n-butyllithium in hexane cooled to -78° C. was added 3.59 ml (0.04 mol) of 3-bromofuran in 100 ml of ether and the mixture was stirred for 10 min. To the above cooled solution was added 5.49 g (0.036 mol) 4,5,6,7-tetrahydro-3-methyl-benzisoxazol-7-one and the mixture was allowed to warm to room temperature, and then stirred for 1 h. To the mixture was added saturated ammonium chloride solution and the resulting mixture was extracted with ethyl acetate (3×100 ml), and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to afford 7.6 g (96%) of 7-(3-furyl)-3-methyl-4,5,6,7-tetrahydrobenzisoxazol-7-ol, as a brown oil.
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:13][S:12][C:11]=1[N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32])=[O:9])C.Cl>O>[O:32]=[C:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:30](=[O:31])[N:22]1[C:11]1[S:12][CH:13]=[C:14]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:10]=1[C:8]([OH:9])=[O:7]
Reactant: CCOC(=O)c1c(-c2ccc(C)cc2)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2csc(N3C(=O)c4ccccc4C3=O)c2C(=O)O)cc1

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-4-(4-methylphenyl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 11, Part C). The mixture is heated to reflux for 90 minutes, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.
Reaction SMILES: [F:1][C:2]([F:12])([CH:6]([OH:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[C:3]([OH:5])=[O:4].[CH3:13][O:14][CH2:15][CH2:16]O.C1C=CC=CC=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[F:1][C:2]([F:12])([CH:6]([OH:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH2:16][CH2:15][O:14][CH3:13])=[O:4]
Reactant: COCCO
Reactant: CC(C)CC(O)C(F)(F)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COCCOC(=O)C(F)(F)C(O)CC(C)C
Yield: 72.5 %

Procedure:
To a mixture of 25.0 g of Intermediate 1 (Example 1), 25 g of 2-methoxyethanol and 200 g of benzene was added 0.15 g of p-toluenesulfonic acid monohydrate. With stirring in a nitrogen atmosphere, the mixture was heated for 8 hours while water of reaction was sequentially removed out of the system. After cooling, the reaction mixture was poured into ice water and extracted with ether. The ether solution was washed, dried, and concentrated, obtaining 23.9 g (yield 73%) of crude 2-methoxyethyl 2,2-difluoro-3-hydroxy-5-methylhexanoate. This crude product had a sufficient purity as an intermediate and was ready for use in the subsequent step.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.CCN(CC)CC.[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12>C1(C)C=CC=CC=1>[O:24]=[C:23]1[C:22]2[C:21](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20](=[O:25])[N:1]1[CH:2]1[CH2:3][CH2:4][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CCOC(=O)C1CCC(N)CC1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCC(N2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.1 %

Procedure:
A solution of ethyl 4-aminocyclohexanecarboxylate (0.50 g, 2.92 mmol) in toluene (10 mL) was added Et3N (1.02 mL, 7.30 mmol) and phthalic anhydride (0.56 g, 3.80 mmol) and the mixture refluxed for 6-8 h using dean-stark apparatus to remove water. After completion of the reaction (by TLC), the solvent was evaporated under reduced pressure, water (50 mL) added and stirred for 30 min at rt. The solid material thus obtained was collected by filtration under vacuum and dried to obtain the desired product as off-white solid (0.30 g, 34%). 1H NMR (DMSO-d6): δ 7.84 (s, 4H), 4.19 (q, J=7.20 Hz, 2H), 3.71 (m, 1H), 2.71 (m, 1H), 2.06 (m, 2H), 1.90 (m, 2H), 1.69 (m, 2H), 1.60 (m, 2H), and 1.23 (t, J=7.20 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]([C:14]1[N:15]=[N:16][N:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]=4)[CH:21]=3)[N:18]=1)=[CH:6]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:45][CH2:46][CH2:47][Cl:48]>CN(C=O)C>[Cl:48][CH2:47][CH2:46][CH2:45][N:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[C:7]([C:14]2[N:15]=[N:16][N:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]=4)[CH:21]=3)[N:18]=2)[C:8]1=[O:13]
Reactant: ClCCCBr
Reactant: COc1ccc2[nH]c(=O)c(-c3nnn(Cc4cccc(OCc5ccc6ccccc6n5)c4)n3)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)cc(-c1nnn(Cc3cccc(OCc4ccc5ccccc5n4)c3)n1)c(=O)n2CCCCl
Temperature: 60 °C
Reaction time: 4 h
Yield: 47.2 %

Procedure:
A mixture of 6-methoxy-3-{2-[3-(2-quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-one (1.00 g, 2.04 mmol), potassium carbonate (564 mg, 4.08 mmol), 1-bromo-3-chloropropane (962 mg, 6.12 mmol), and DMF (100 ml) was stirred for four hours at a bath temperature of 60° C. The solvent of the reaction mixture was removed under reduced pressure. Water was then added to the mixture, and the mixture was extracted with chloroform-methanol (10:1). The thus-obtained organic phase was dried over magnesium sulfate anhydrate, and the solvent was removed under reduced pressure. The organic phase was then subjected to silica gel column chromatography (developer: chloroform-methanol (100:1)), purified, and crystallized from a chloroform-diethylether mixture, to thereby obtain the title compound (546 mg, 0.963 mmol, 47.2%) as pale yellow powder.
Reaction SMILES: [C:1]([C@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([NH:10][C:11]2[C:16]([C:17]([O:19]CC3C=CC=CC=3)=[O:18])=[CH:15][N:14]=[C:13]3[NH:27][CH:28]=[CH:29][C:12]=23)[CH2:5]1)(=[O:3])[NH2:2]>O1CCOCC1.CO.[Pd]>[C:1]([C@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([NH:10][C:11]2[C:16]([C:17]([OH:19])=[O:18])=[CH:15][N:14]=[C:13]3[NH:27][CH:28]=[CH:29][C:12]=23)[CH2:5]1)(=[O:3])[NH2:2]
Reactant: NC(=O)[C@H]1CCC[C@H](Nc2c(C(=O)OCc3ccccc3)cnc3[nH]ccc23)C1
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: NC(=O)[C@H]1CCC[C@H](Nc2c(C(=O)O)cnc3[nH]ccc23)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101 %

Procedure:
To a solution of benzyl 4-{[trans-3-carbamoylcyclohexyl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (36 mg) in dioxane (7 ml) and methanol (7 ml) was added 10% Pd—C (50% wet) (10 mg) and stirred at ambient temperature for 3 hours under hydrogen atmosphere. After filtration the filtrate was evaporated in vacuo to give 4-{[trans-3-carbamoylcyclohexyl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (28 mg).
Reaction SMILES: [S:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:18]=[C:17]([CH3:19])[N:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])[C:15]=2[CH3:30])=[O:13])=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].C([O-])([O-])=O.[K+].[K+].[CH2:37](I)[CH3:38]>CN(C=O)C>[CH2:37]([NH:2][S:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:18]=[C:17]([CH3:19])[N:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:28])([F:27])[F:29])[C:15]=2[CH3:30])=[O:13])=[CH:7][CH:6]=1)(=[O:3])=[O:4])[CH3:38]
Reactant: Cc1cc(C(=O)Nc2ccc(S(N)(=O)=O)cc2)c(C)n1-c1ccccc1C(F)(F)F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCNS(=O)(=O)c1ccc(NC(=O)c2cc(C)n(-c3ccccc3C(F)(F)F)c2C)cc1
Reaction time: 23 h
Yield: 19.2 %

Procedure:
To a suspension of 2,5-dimethyl-1-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylic acid (4-sulfamoyl-phenyl)-amide (83 mg, 0.19 mmol) and K2CO3 (34 mg) in anhyd DMF (0.5 mL) was added ethyl iodide (15 μL, 0.19 mmol). After 19 h additional ethyl iodide (10 μL) was added. After 23 h total the reaction mixture was concentrated to dryness in vacuo. The residue was purified by reverse-phase HPLC to yield 2,5-dimethyl-1-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylic acid (4-ethylsulfamoyl-phenyl)-amide (17 mg, 19%) as a colorless powder; 1H NMR (DMSO-d6): δ 9.7 (s, 1H), 7.90 (d, J=8 Hz, 1H), 7.85 (d, J=8 Hz, 2H), 7.81 (t, J=8 Hz, 1H), 7.70 (t, J=8 Hz, 1H), 7.60 (d, J=8 Hz, 2H), 7.39 (d, J=8 Hz, 1H), 7.28 (d, J=8 Hz, 1H), 6.54 (s, 1H), 2.66 (quintet, J=7 Hz, 2H), 2.03 (s, 3H), 1.77 (s, 3H), 0.86 (t, J=7 Hz, 3H); MS (ESI) m/z 466 [M+H]+. Also recovered from the reaction was dimethyl-1-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylic acid (4-diethylsulfamoyl-phenyl)-amide (12 mg, 13%) as a colorless solid; 1H NMR (DMSO-d6): δ 9.9 (s, 1H), 8.11 (d, J=8 Hz, 1H), 8.08 (d, J=7 Hz, 2H), J=8 Hz, 1H), 7.92 (t, J=8 Hz, 1H), 7.82 (d, J=7 Hz, 2H), 7.60 (d, J=8 Hz, 1H), 6.77 (s, 1H), 3.25 (q, J=7 Hz, 4H), 2.24 (s, 3H), 1.99 (s, 3H), 1.45 (t, J=7 Hz, 6H); MS (ESI) m/z 494 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH2:3][CH2:4]CC(=O)C([O-])=O.CC(CCC=C(C)C)[CH2:19][CH2:20][CH:21]([CH3:27])[C:22](=[O:26])[C:23]([O-:25])=[O:24]>>[CH3:27][CH:21]([CH2:20][CH3:19])[C:22](=[O:26])[C:23]([O:25][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:15])[CH3:16])=[O:24]
Reactant: CC(C)=CCCC(C)CCCC(=O)C(=O)[O-]
Reactant: CC(C)=CCCC(C)CCC(C)C(=O)C(=O)[O-]
Product: CCC(C)C(=O)C(=O)OCCC(C)CCC=C(C)C

Procedure:
MS (EI): 268 (M+, 1); 250 (1); 240 (1); 207 (1); 183 (2); 155 (2); 138 (10); 123 (14); 109 (7); 95 (18); 85 (32); 81 (26); 69 (51); 57 (100); 41 (53); 29 (18).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].N[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18].[OH-].[Na+]>O>[CH:8](=[O:9])[C:12]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:18]
Reactant: Nc1ccccc1O
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1ccccc1O
Temperature: 15 °C
Reaction time: 1 h

Procedure:
3.3 g of 3-aminophenol, 7.0 g of 2-ethylhexyl bromide and 2.0 g of calcium carbonate powder were mixed together with 10 g of dimethylformamide and reacted in a nitrogen atmosphere at 120° C. for 2 hours. Then, 6.4 g of n-octyl bromide was added to the reaction system, and the reaction was further continued for 5 hours under the above conditions. After the reaction, the reaction mixture was returned to room temperature and extracted with toluene to obtain 3-(N-octyl-N-2-ethylhexyl)aminophenol. Then, 11 g of phosphorus oxychloride was added to 13 g of dimethylformamide and stirred for one hour at a temperature of not higher than 15° C., and then the above aminophenol derivative was dropwise added and mixed thereto, and the reaction was carried out at a reaction temperature of 70° C. for 1.5 hours. The reaction product was returned to room temperature, and then put into water containing 8.6 g of sodium hydroxide to obtain a corresponding salicylaldehyde derivative. Then, into 20 g of ethanol, 4.0 g of 2-benzothiazolylacetic acid ethyl ester, 7.7 g of the above salicylaldehyde derivative and 0.5 g of piperidine were mixed and dissolved and reacted at 80° C. for one hour to obtain the desired product as yellowish orange crystals.