Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:38]=[CH:37][C:14]([C:15]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=4)[CH:20]=[CH:19][C:18]=3OS(C(F)(F)F)(=O)=O)=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:39][C:40]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=1B(O)O.N1(CCOC2C=CC(C=O)=CC=2)CCCCC1>>[N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=4)[CH:20]=[CH:19][C:18]=3[C:41]3[CH:42]=[CH:43][C:44]([F:46])=[CH:45][C:40]=3[F:39])=[O:16])=[CH:37][CH:38]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: O=Cc1ccc(OCCN2CCCCC2)cc1
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCCC4)cc3)c(-c3ccc(F)cc3F)ccc2c1
Yield: 85.3 %

Procedure:
Couple trifluoromethanesulfonic acid 1-[4-(2-azepan-1-yl-ethoxy)-benzoyl]-6-methoxynaphthalen-2-yl ester (1.4 g, 2.5 mmol) and 2,4-difluorophenyl boronic acid (1.2 g, 7.6 mmol) by the procedure described for the preparation of 2-(2,4-difluoro-phenyl)-6-methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone to give 1.1 g (85%) of the title compound: mass spectrum (ion spray) m/z=516.3 (M+H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[CH:18]=[C:17]([C:19]#[N:20])[C:12](C(OC)=O)=[C:11]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:23]=2)[N:10]=1.[CH3:32][OH:33]>[Pd].Cl>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:10]=[C:11]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:23]=2)[C:12]2[C:32](=[O:33])[NH:20][CH2:19][C:17]=2[CH:18]=1
Reactant: COC(=O)c1c(C#N)cc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc(S(C)(=O)=O)c1
Reactant: CO
Agent: [Pd]
Agent: Cl
Product: CS(=O)(=O)c1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3N)cc3c2C(=O)NC3)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34 %

Procedure:
A mixture of methyl 6-((1R,2S)-2-aminocyclohexylamino)-4-cyano-2-(3-(methylsulfonyl)phenylamino)nicotinate (117.3 mg, 0.264 mmol) and palladium on carbon (23.6 mg, 0.222 mmol) in MeOH (4 mL) and 1N HCl (4 mL) was stirred at RT for 16 h under a hydrogen atmosphere. The mixture was filtered to remove the catalyst and the filtrate was treated with saturated aq NaHCO3 (20 mL) and stirred at RT for 20 h. The mixture was concentrated under reduced pressure and the residue was extracted with EtOAc/THF (2/1, 2×30 mL). The organic layers were washed with saturated aq NaHCO3 (15 mL), water (15 mL) and brine (15 mL), were dried over anhydrous Na2SO4, and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (DM1020, EtOAc/MeOH=20/1) to give the desired product (37.2 mg, 34%). The product was recrystallized from EtOH to give the title compound as a colorless solid (13.2 mg, 12%). 1H-NMR (DMSO-d6) δ ppm 1.31-1.41 (m, 4H), 1.55-1.68 (m, 6H), 3.05 (s, 1H), 3.21 (s, 3H), 4.08 (s, 1H), 4.23 (s, 2H), 6.17 (s, 1H), 6.78-6.79 (m, 1H), 7.46-7.47 (m, 1H), 7.53-7.56 (m, 1H), 7.96-7.99 (m, 2H), 8.49 (s, 1H), 9.18 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:8]=1)=[O:5].[CH3:32][N:33]([CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1)[C:34]([C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=1)[C:39](O)=[O:40])=[O:35].CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.ClCCl>[CH3:32][N:33]([CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1)[C:34](=[O:35])[C:36]1[CH:44]=[CH:43][CH:42]=[C:38]([C:39]([NH:1][C:2]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:22][C:3]=2[C:4](=[O:5])[NH:6][C:7]2[CH:11]=[CH:10][N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=3)[N:8]=2)=[O:40])[CH:37]=1
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ccn(-c2cccc(C(F)(F)F)c2)n1
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ccn(-c3cccc(C(F)(F)F)c3)n2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.1 %

Procedure:
Into a 50-mL round bottom flask, was placed 2-amino-5-(piperidin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)benzamide 8d (100 mg, 0.23 mmol, 1.00 equiv), 3-(methyl(2-morpholinoethyl)carbamoyl)benzoic acid (130 mg, 0.45 mmol, 1.91 equiv), EDC.HCl (67 mg, 0.35 mmol, 1.50 equiv), 4-dimethylaminopyridine (43 mg, 0.35 mmol, 1.51 equiv), and dichloromethane (5 mL). The resulting solution was stirred for 4 h at 25° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting mixture was washed with 3×10 mL of water and 3×10 mL of aqueous NH4Cl. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 108.6 mg (66%) of a white solid. 1H-NMR (400 MHz, CD3OD, ppm): δ 8.66-8.64 (d, J=8.8 Hz, 1H), 8.39 (s, 1H), 8.16 (s, 3H), 8.07-8.05 (d, J=7.6 Hz, 1H), 7.99 (s, 1H), 7.79 (s, 1H), 7.16-7.68 (m, 3H), 7.61 (s, 1H), 7.07 (s, 1H), 4.11-4.10 (d, J=3.2 Hz, 2H), 3.98 (s, 3H), 3.80-3.77 (m, 4H), 3.59-3.54 (m, 6H), 3.14 (m, 4H), 1.99-1.79 (m, 6H). MS (ES, m/z): 704 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([NH2:9])[N:3]=1.[C:10]([O:14][C:15]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C([O-])([O-])=O.[Na+].[Na+]>>[NH2:9][C:4]1[N:3]=[C:2]([C:20]2[CH:21]=[CH:22][C:17]([C:15]([O:14][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:16])=[CH:18][CH:19]=2)[C:7]([CH3:8])=[CH:6][N:5]=1
Reactant: Cc1cnc(N)nc1Cl
Reactant: CC(C)(C)OC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cnc(N)nc1-c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 120 °C
Yield: 50.2 %

Procedure:
To 4-chloro-5-methylpyrimidin-2-amine (150 mg, 1.04 mmol), tetrakistriphenylphosphine Palladium (0) (60 mg, 0.052 mmol) and 4-(tert-butoxycarbonyl)phenylboronic acid (347 mg, 1.56 mmol), 1,2-DME (3 mL) and Na2CO3 (1.04 mL, 2 M, 2.08 mmol) were added and heated to 120° C. in a microwave reactor for 30 minutes. The reaction mixture was filtered using EtOAc and the filtrate was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to yield tert-butyl 4-(2-amino-5-methylpyrimidin-4-yl)benzoate (149 mg, 50%). ESI-MS m/z calc. 285.1, found 286.3 (M+1)+. Retention time 1.36 minutes.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N+:15]([O-])=[CH:14][CH:13]=[CH:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(OC(=O)C)(=O)C.[N+:27]([CH:30]([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])([O-:29])=[O:28]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([C:30]([N+:27]([O-:29])=[O:28])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:13]=[CH:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc2c(ccc[n+]2[O-])c1
Reactant: CCOC(=O)C(C)[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCOc1ccc2nc(C(C)(C(=O)OCC)[N+](=O)[O-])ccc2c1
Temperature: 23 °C
Reaction time: 12 h
Yield: 69.8 %

Procedure:
A solution of 6-Heptyloxy-quinoline 1-oxide (500 mg, 0.002 mol) and acetic anhydride (0.255 mL, 0.00270 mol) in N,N-dimethylformamide (5 mL, 0.06 mol) was added to a solution of ethyl 2-nitropropionate (284 mg, 0.00193 mol) in DMF (2 mL) at at 23° C. dropwise. The reaction mixture was then stirred at 23° C. for 12 hours. The reaction mixture was then heated at 50° C. for 6 hours. Solvent was removed under vacuum, and the residue was treated with Na2CO3 (sat), and DCM. Organic layer was collected, and dried over Na2SO4. The mixture was then purified via chromatography (SiO2, 24 g, ethyl acetate/hexanes 0-35%) to give a pure product 523 mg (70%). 1H NMR (CHLOROFORM-d) δ: 8.09 (d, J=8.5 Hz, 1H), 7.95 (d, J=9.0 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.39 (dd, J=9.3, 2.5 Hz, 1H), 7.08 (d, J=2.5 Hz, 1H), 4.40 (q, J=7.0 Hz, 2H), 4.09 (t, J=6.5 Hz, 2H), 2.40 (s, 3H), 1.82-1.93 (m, 2H), 1.45-1.56 (m, 2H), 1.26-1.44 (m, 9H), 0.92 (t, J=6.7 Hz, 3H). MS (M+1): 389.30.
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][CH2:11][O:12][C:13]1[CH:17]=[CH:16][O:15][N:14]=1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[NH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:17]=[CH:16][O:15][N:14]=1
Reactant: CC(C)(C)OC(=O)NCCOc1ccon1
Agent: Cl
Solvent: C1COCCO1
Product: NCCOc1ccon1
Temperature: 25 °C
Reaction time: 72 h
Yield: 83 %

Procedure:
4M Hydrogen chloride in dioxane (10 ml) was added to a solution of 3-[2-(t-butoxycarbonylamino)ethoxy]isoxazole (Method 79; 500 mg, 2.2 mmol) in dioxane (10 ml) and the mixture was stirred at ambient temperature for 3 days. The resulting solid was collected by filtration, washed with ether and dried to give the title compound (298 mg, 83%) as a white solid NMR 3.20 (m, 2H), 4.39 (t, 2H), 6.13 (s, 1H), 8.30 (s, 3H), 8.69 (s, 1H); m/z 129.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH2:11])[CH:10]=1)[NH:7][C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:5]2.C[O:19][C:20]([CH:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)=[O:21]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:25]3[CH2:26][CH2:27][CH:22]([C:20]([OH:21])=[O:19])[CH2:23][CH2:24]3)[CH:10]=1)[NH:7][C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:5]2
Reactant: COC(=O)C1CCC(=O)CC1
Reactant: Nc1cc(Cl)cc2cc(-c3ccccc3)[nH]c12
Product: O=C(O)C1CCC(Nc2cc(Cl)cc3cc(-c4ccccc4)[nH]c23)CC1

Procedure:
7-Amino-5-chloro-2-phenyl-1H-indole prepared in Example 3 and 4-oxo-cyclohexane-1-carboxylic acid methyl ester were reacted according to the same procedures as Step B of Example 1 and Example 30 sequentially to give the title compound.
Reaction SMILES: [OH:1][C:2]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[C:4](=[O:19])[C:3]=1[C:20](OCC)=[O:21].Cl.[NH2:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C(N(C(C)C)C(C)C)C>O1CCOCC1>[OH:1][C:2]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:5]2([CH2:6][CH2:7][O:8][CH2:9][CH2:10]2)[C:4](=[O:19])[C:3]=1[C:20]([NH:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:21]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2ccc(OC)cc2C2(CCOCC2)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)C1(CCOCC1)C(=O)C(C(=O)NCC(=O)OC(C)(C)C)=C2O
Temperature: 86 °C
Reaction time: 4 h
Yield: 52.4 %

Procedure:
A mixture of ethyl 4-hydroxy-7-methoxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (0.52 g, 1.6 mmol), tert-butyl 2-aminoacetate hydrochloride (0.39 g, 2.3 mmol) in 5 mL dioxane was treated with N-ethyl-N-isopropylpropan-2-amine (0.61 g, 4.7 mmol). The mixture was warmed to 86° C. and stirred for 4 hours, M+1=418. The mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-30% EtOAc/hexane to give 0.35 g of the title compound as a pale yellow solid. MS (m/z)=418 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:15]=2[F:24])(=[O:13])=[O:12])=[CH:6][CH:5]=1)[CH3:3].[CH3:25][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>C1COCC1>[CH3:3][N:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:25])[S:11]([C:14]2[C:15]([F:24])=[C:16]([F:23])[C:17]([F:22])=[C:18]([F:21])[C:19]=2[F:20])(=[O:13])=[O:12])=[CH:6][CH:5]=1)[CH3:1]
Reactant: CN(C)c1ccc(NS(=O)(=O)c2c(F)c(F)c(F)c(F)c2F)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(C)c1ccc(N(C)S(=O)(=O)c2c(F)c(F)c(F)c(F)c2F)cc1
Reaction time: 0.17 h
Yield: 60 %

Procedure:
4-(N,N-Dimethylamino)-1-(pentafluorophenylsulfonamido)benzene (100 mg, 0.273 mmol) was dissolved in dry THF (2.5 mL) and to the system was added under N2 at room temperature a 1M solution of lithium bis(trimethylsilyl)amide (0.274 mL). The reaction mixture was stirred for 10 min followed by addition of MeI (65 mg, 0.028 mL). The reaction mixture was stirred overnight, the solvent was evaporated under reduced pressure and the crude product purified by HPLC using silica as the stationary phase and eluting with 20% EtOAc/Hex (v/v) to afford the product as a white solid in 60% yield (62 mg). EI m/z: 380(35, M+), 149(100). 1H NMR (CD3OD) 7.05(d, J=8 Hz, 2H), 6.68(d, J=8 Hz, 2H), 3.33(s, 3H) 2.93(s, 6H). Anal. calcd. for C15H13F5SO2N2: C 47.37, H 3.45, N 7.37. Found: C 47.37, H 3.49, N 7.32.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.Br[CH2:13][C:14]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:15].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH:16]1([C:14]([C:13]2[O:11][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=3[C:8]=2[CH3:9])=[O:15])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(CBr)C1CCCCC1
Reactant: CC(=O)c1cc(F)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)C2CCCCC2)oc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
To a mixture of 5′-fluoro-2′-hydroxyacetophenone (5.00 g), 2-bromo-1-cyclohexylethanone (7.98 g) synthesized above and N,N-dimethylformamide (50 mL) was added potassium carbonate (13.4 g), and the mixture was stirred at room temperature overnight. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% ethyl acetate/hexane) to give the title object compound (5.38 g, 64%) as a pale-yellow solid.
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([S:10][CH2:11][CH2:12][OH:13])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>C(Cl)(Cl)Cl>[C:1]([C:5]1[N:9]=[C:8]([S:10][CH2:11][CH2:12][O:13][C:30](=[O:31])[NH:29][C:26]2[CH:27]=[CH:28][C:23]([C:22]([F:21])([F:33])[F:32])=[CH:24][CH:25]=2)[NH:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)c1n[nH]c(SCCO)n1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1n[nH]c(SCCOC(=O)Nc2ccc(C(F)(F)F)cc2)n1

Procedure:
To 5 g (20 mmole) of 3-t-butyl-5-(2-hydroxyethylthio)-1H-1,2,4-triazole in 50 ml of chloroform was added 0.1 g of triethylamine and 3.8 g (20 mmole) of 4-trifluoromethylphenylisocyanate. After refluxing for three hours, the mixture was concentrated in vacuo and crystallized from ether/hexane to give 3-t-butyl-5-(2-(4-trifluoromethylphenylcarbamoyloxy)-ethylthio)-1H-1,2,4-triazole.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[N+:12]2[O-])=[CH:7][CH:6]=1)=[O:4].[F:16][C:17]([F:21])([F:20])[CH2:18][NH2:19].CC1C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1>ClCCl>[F:16][C:17]([F:21])([F:20])[CH2:18][NH:19][C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[CH:14][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)[N:12]=1
Reactant: NCC(F)(F)F
Reactant: COC(=O)c1ccc2ccc[n+]([O-])c2c1
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc2ccc(NCC(F)(F)F)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 205.1 %

Procedure:
To a solution of 7-(methoxycarbonyl)quinoline 1-oxide (200 mg, 0.984 mmol) and 2,2,2-trifluoroethylamine (292 mg, 0.295 mmol) at 0° C. was added 4-methylbenzenesulphonic anhydride (964 mg, 2.95 mmol) portionwise over a period of 45 minutes. The reaction was allowed to warm up to room temperature and stirred overnight. The reaction was diluted with dichloromethane and washed with a saturated solution of ammonium chloride. The aqueous layer was extracted into dichloromethane (1×). The organics were combined and washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography gave the title compound (172 mg, 62%). +ESI (M+H) 285.1
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]3[CH2:18][NH:17][CH2:16][CH2:15][C:13]3=2)[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[CH:19]([O:22][C:23]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:24]=1[C:25](O)=[O:26])([CH3:21])[CH3:20]>>[CH:19]([O:22][C:23]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:24]=1[C:25]([N:17]1[CH2:16][CH2:15][C:13]2=[C:14]3[C:9](=[CH:10][CH:11]=[C:12]2[CH2:18]1)[C:8]1[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=1)[N:2]3[CH3:1])=[O:26])([CH3:21])[CH3:20]
Reactant: Cn1c2ccccc2c2ccc3c(c21)CCNC3
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2c(ccc3c4ccccc4n(C)c23)C1

Procedure:
Prepared in analogy to example 1.1 from 11-methyl-2,3,4,11-tetrahydro-1H-pyrido[4,3-a] carbazole and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=2)=[CH:4][CH:3]=1.[Br:18]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:18][C:10]1[O:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:12][C:11]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1coc(-c2ccc(F)cc2)n1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1nc(-c2ccc(F)cc2)oc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 2-(4-fluorophenyl)oxazole-4-carboxylate (7.44 g) in chloroform (100 ml) was added dropwise bromine (8.1 ml) at room temperature, and the resulting mixture was stirred at room temperature for 30 minutes and then refluxed for 8 hours. After cooling the reaction mixture, 10% aqueous sodium thiosulfate solution was added to the mixture and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (solvent: ethyl acetate:n-hexane=1:9) to obtain ethyl 5-bromo-2-(4-fluorophenyl)-oxazol-4-carboxylate (9.21 g) as pale yellowish powder.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Br)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][N:15]([CH2:13][CH3:14])[CH2:16][CH2:17]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CCN1CCNCC1
Reactant: Nc1cc2ccccc2c(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCN(c2nc(N)cc3ccccc23)CC1
Yield: 38 %

Procedure:
3-Amino-1-bromoisoquinoline (10.3 g) and 1-ethylpiperazine (10.5 g) were reacted in the presence of potassium carbonate (13.8 g) in N,N-dimethylformamide (80 ml) at room temperature for 3 days. The reaction solution was concentrated, followed by the addition of purified water (500 ml), and the resulting mixture was stirred under ice-cooling for 1 hr. The resulting ocherous precipitates were collected by filtration, washed with a small amount of ice-water and hexane, and then dried at 50° C. under reduced pressure, to give 3-amino-1-(4-ethylpiperazin-1-yl)isoquinoline (4.5 g).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.I[CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:13]([N:9]1[CH2:8][CH2:7][CH:6]([C:4]([OH:3])=[O:5])[CH2:11][CH2:10]1)[CH3:14]
Reactant: CCI
Reactant: CCOC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCN1CCC(C(=O)O)CC1
Temperature: 25 °C

Procedure:
To ethylpiperidine-4-carboxylate (1 eq) in ethanol was added iodoethane (1.1 eq) and potassium carbonate (2 eq) and the resulting mixture was refluxed for 16 h. The mixture was then cooled to room temperature and filtered. Ethanol was concentrated and partitioned between methylene chloride and water. The organic layer was then washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated. To it was then added concentrated hydrochloric acid and water (2:1) and the mixture was refluxed for 5 h. The resulting 1-(ethyl)piperidine-4-carboxylic acid was then azeotroped with toluene. MS: MH+=158.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[CH:8]=[N:7][CH:6]=1.CC(C)([O-])C.[K+].C(O)(=O)C>O1CCCC1.CC(C)=O.Cl>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([C:10]2([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:9]3[CH:8]=[N:7][CH:6]=[C:5]3[CH2:4][CH2:3][CH2:2]2)=[CH:12][CH:13]=1)#[N:18]
Reactant: CCOC(=O)C(c1ccc(C#N)cc1)n1cncc1CCCCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: CCOC(=O)C1(c2ccc(C#N)cc2)CCCc2cncn21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 8.1 g of 5-(3-chloropropyl)-1-(α-ethoxycarbonyl-p-cyanobenzyl)-1H-imidazole in 50 ml of tetrahydrofuran is cooled to 0° in an ice bath. To this is added 8.0 g of potassium-t-butoxide as a solid in portions. The mixture is stirred at room temperature for 2 h, neutralized with 10% acetic acid and partitioned between methylene chloride and water. The organic layer is washed with water, dried over magnesium sulfate and evaporated to yield an oil which is dissolved in a small volume of acetone and neutralized with ethereal hydrogen chloride. The solid is collected to yield 5-(p-cyanophenyl)-5-ethoxycarbonyl-5,6,7,8-tetrahydroimidazo[1,5-a]-pyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:22])[S:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[NH2:23][C:24]1[CH:25]=[C:26]([CH:30]([OH:32])[CH3:31])[CH:27]=[CH:28][CH:29]=1>>[OH:32][CH:30]([C:26]1[CH:25]=[C:24]([NH:23][C:17](=[O:19])[C:16]2[CH:15]=[CH:14][C:13]([S:10](=[O:12])(=[O:11])[N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH3:22])=[CH:21][CH:20]=2)[CH:29]=[CH:28][CH:27]=1)[CH3:31]
Reactant: CC(O)c1cccc(N)c1
Reactant: COc1ccc(N(C)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Product: COc1ccc(N(C)S(=O)(=O)c2ccc(C(=O)Nc3cccc(C(C)O)c3)cc2)cc1

Procedure:
4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzoic acid (7) (100 mg, 0.31 mmol) was treated with 1-(3-aminophenyl)ethanol (36 mg, 0.26 mmol) using method C. The residue was purified using flash chromatography eluting with 0-40% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give N-(3-(1-hydroxyethyl)phenyl)-4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzamide as an off white solid. Yield: 52 mg (46%). 1H-NMR: 10.45 (s, 1H), 8.12 (d, J=8.5 Hz, 2H), 7.75-7.74 (m, 1H), 7.68-7.64 (m, 3H), 7.30 (t, J=8.0 Hz, 1H), 7.10 (d, J=8.0 Hz, 1H), 7.01 (d, J=8.0 Hz, 2H), 6.90 (d, J=8.0 Hz, 2H), 5.19 (d, J=4.5 Hz, 1H), 4.75-4.68 (m, 1H), 3.75 (s, 3H), 3.15 (s, 3H), 1.33 (d, J=6.5 Hz, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[OH-:18].[K+]>C(O)(C)(C)C>[N+:15]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:9][C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)=[CH:7][C:2]=1[OH:18])([O-:17])=[O:16]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1ccc(OCc2ccsc2)cc1F
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=[N+]([O-])c1ccc(OCc2ccsc2)cc1O

Procedure:
A mixture of 2-fluoro-4-(3-thienylmethoxy)nitrobenzene (4.21 g), aqueous potassium hydroxide solution (50 mL; 50% w/v) and t-butanol (20 mL) is heated at reflux for 4 hours. It is then evaporated to dryness and the residue is partitioned between ethyl acetate (100 mL) and hydrochloric acid (100 mL; 1 N). The organic phase is washed with water (3×100 mL), dried over magnesium sulphate, filtered and evaporated, to give 2-nitro-5-(3-thienylmethoxy)phenol, in the form of a yellow solid.