Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][CH:6]([CH:12]([CH3:14])[CH3:13])[CH2:7][S:8]([NH2:11])(=[O:10])=[O:9])(=O)C.C[O-].[Na+]>CO>[OH:4][CH2:5][CH:6]([CH:12]([CH3:14])[CH3:13])[CH2:7][S:8]([NH2:11])(=[O:9])=[O:10]
Reactant: CC(=O)OCC(CS(N)(=O)=O)C(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)C(CO)CS(N)(=O)=O
Temperature: 25 °C
Yield: 77.4 %

Procedure:
In 50 ml of methanol was dissolved 7.0 g of 3-acetoxy-2-isopropyl-1-propanesulfonamide and while the solution was stirred at room temperature, 6.5 g of 28 w/w % sodium methoxide was added and reacted for 30 minutes. The reaction mixture was then concentrated to dryness. The residue was subjected to silica gel (100 g) column chromatography and elution was carried out with chloroform-methanol (9:1) to provide 4.4 g of the title compound. m.p. 83°-84° C.
Reaction SMILES: [Cl:1][C:2]1[C:20]([N+:21]([O-])=O)=[CH:19][CH:18]=[C:17]([Cl:24])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.[ClH:25]>[Fe].CO>[ClH:1].[ClH:25].[NH2:21][C:20]1[C:2]([Cl:1])=[C:3]([C:17]([Cl:24])=[CH:18][CH:19]=1)[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc([N+](=O)[O-])c3Cl)c2n1
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N)c3Cl)c2n1
Reaction time: 1 h

Procedure:
To a mixture of 8-(2,6-dichloro-3-nitrobenzyloxy)-2-methylquinoline (1.0 g), concentrated hydrochloric acid (5.2 ml) and methanol (5.2 ml) was added iron powder (666 mg). The mixture was heated under reflux for 2 hours and stirred in an ice-water bath for 1 hour. The precipitate was collected by vacuum filtration and washed with 1N hydrochloric acid and water to give 8-(3-amino-2,6-dichlorobenzyloxy)-2-methylquinoline dihydrochloride (635 mg) as a brownish powder.
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].N1C=CC=CC=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[C:16]([N:4]1[C:5](=[O:6])[C:7]([CH3:8])=[CH:9][NH:1][C:2]1=[O:3])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1c[nH]c(=O)n(C(=O)c2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of thymine (1) in THF was added pyridine and the reaction was cooled to 0° C. Benzoyl chloride was added carefully at 0° C. and the reaction was stirred overnight at room temperature. The reaction mass was evaporated to give the crude solid which was purified by SiO2 flash chromatography to give the N3-benzoyl thymine (4) as a white solid. NMR (600 MHz, CD3OD): δ 7.94 (m, 2H), 7.71 (t, 1H, J=7.3 Hz), 7.57 (m, 2H), 7.38 (s, 1H), 1.90 (s, 3H); Mass (ESI-MS): 231.22 (M+H); m.p: 178-180° C.
Reaction SMILES: CO[C:3]([C@H:5]([C@@H:17]([CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[C:18]([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19])[CH2:6][N:7]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[N:9]([CH3:15])[C:8]1=[O:16])=[O:4].Cl.[CH2:33]([O:40][NH2:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C([Mg]Cl)(C)C.[Cl-].[NH4+]>C1COCC1>[CH2:33]([O:40][NH:41][C:3]([C@H:5]([C@@H:17]([CH2:26][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31]1)[C:18]([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19])[CH2:6][N:7]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[N:9]([CH3:15])[C:8]1=[O:16])=[O:4])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COC(=O)[C@@H](CN1C(=O)N(C)C(C)(C)C1=O)[C@@H](CC1CCCC1)C(=O)N1CCCCC1
Reactant: NOCc1ccccc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CN1C(=O)N(C[C@H](C(=O)NOCc2ccccc2)[C@@H](CC2CCCC2)C(=O)N2CCCCC2)C(=O)C1(C)C

Procedure:
A solution of 1.10 g of methyl ester from Example 10 and 568 mg of O-benzylhydroxylamine hydrochloride in 7 ml of THF was treated at -20° with 3.5 ml of a 2M i-PrMgCl solution in THF and, after 1 hr. at -20°, treated with a further 1.7 ml of the Grignard reagent. After a further 21/2 hrs. at -20° the mixture was treated with ammonium chloride solution and extracted with methylene chloride. The extracts were dried and concentrated. The residue was crystallized from t-butyl methyl ether/hexane and the crystallizate was dried, there being obtained 1-[2(R)-[1(R)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl)piperidine VII, m.p. 135-137°.
Reaction SMILES: [F:1][CH:2]([F:33])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.[Cl:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]1O.Cl.C(N=C=NCCCN(C)C)C.O>ClCCl.CN(C)C1C=CN=CC=1>[F:33][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]([O:32][CH:36]5[CH2:37][CH2:38][CH2:39][CH2:40][CH:35]5[Cl:34])=[O:31])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1
Reactant: OC1CCCCC1Cl
Reactant: O=C(O)C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(OC1CCCCC1Cl)C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Reaction time: 8 h

Procedure:
To a solution of 3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazole-5-carboxylic acid (E, 160 mg) in dichloromethane (5 ml) are added, at room temperature, 2-chlorocyclohexanol (57 mg), 4-dimethylaminopyridine (4 mg) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (94 mg). The mixture is stirred overnight, and water is then added. The aqueous phase is removed and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate. The solids are filtered off and the solvent is distilled off. The residue is purified by chromatography. This gives 2-chlorocyclohexyl 3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazole-5-carboxylate (100 mg, 50%).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:33]=[CH:34][C:35]=1[CH2:36][O:37][Si](C(C)(C)C)(C)C)[CH2:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]([OH:31])[CH:28]([CH3:30])[CH3:29])=[CH:23][C:22]=2[CH3:32])[CH:18]=[CH:19][CH:20]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:33]=[CH:34][C:35]=1[CH2:36][OH:37])[CH2:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]([OH:31])[CH:28]([CH3:29])[CH3:30])=[CH:23][C:22]=2[CH3:32])[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cc(C(O)C(C)C)ccc1-c1cccc(OCc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: Cc1cc(C(O)C(C)C)ccc1-c1cccc(OCc2ccc(CO)c(CO)c2)c1

Procedure:
In a manner similar to that of Example 27(g), by reaction of 1.1 g (1.7 mmol) of 1-{3′-[3,4-bis-(tert-butyldimethylsilanyloxymethyl)benzyloxy]-2-methylbiphenyl-4-yl}-2-methyl-1-propanol with 3.8 mL (3.8 mmol) of 1.0M tetrabutylammonium fluoride, the desired product is obtained in the form of a colourless oil (m=460 mg; Y=65%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][C:10](=[S:22])[C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:12]=1[F:21].[H-].[Na+]>CN1CCCC1=O.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[S:22][C:10]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:12]=3[F:21])=[N:9][C:3]=2[CH:4]=1
Reactant: CS(=O)(=O)c1ccc(C(=S)Nc2cc(Br)ccc2Br)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(-c2nc3cc(Br)ccc3s2)c(F)c1
Temperature: 140 °C
Reaction time: 3 h
Yield: 65.4 %

Procedure:
Intermediate 37 (0.48 g, 1.03 mmol) dissolved in N-Methylpyrrolidinone (0.97 ml) and added NaH (52 mg, 2.2 mmol). This mixture was stirred at 140° C. for 3 h. Reaction mixture cooled to rt and diluted with water to obtain the solid. Solid was filtered and dried to obtain the crude. Crude was purified on column chromatography using 60-120 mesh silicagel and DCM as eluent to afford the titled compound (260 mg) as a white solid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.71-8.66 (m, 1H), 8.32 (d, J 1.7, 1H), 7.92-7.83 (m, 3H), 7.59 (dd, J 1.8, 8.6, 1H), 3.13 (s, 3H).
Reaction SMILES: I[C:2]1[CH:28]=[CH:27][C:5]2[N:6]([CH2:9][C:10]3[CH:26]=[CH:25][C:13]4[N:14]=[C:15]([NH:17][C@@H:18]5[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]5[OH:24])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[C:29]([N:36]1[CH2:41][CH2:40][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][CH2:37]1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.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]>[OH:24][C@@H:19]1[CH2:20][CH2:21][CH2:22][CH2:23][C@H:18]1[NH:17][C:15]1[S:16][C:12]2[CH:11]=[C:10]([CH2:9][N:6]3[C:5]4[CH:27]=[CH:28][C:2]([C:39]5[CH2:40][CH2:41][N:36]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:37][CH:38]=5)=[CH:3][C:4]=4[N:8]=[CH:7]3)[CH:26]=[CH:25][C:13]=2[N:14]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(I)ccc43)cc2s1
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)ncn3Cc2ccc3nc(N[C@@H]4CCCC[C@H]4O)sc3c2)CC1
Temperature: 80 °C
Yield: 31.3 %

Procedure:
To a stirred solution of (1R,2R)-2-((6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (100 mg, 0.20 mmol) from Step 5 of Example 183 in DMF (2 mL) were added N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (93 mg, 0.30 mmol), potassium carbonate (55 mg 0.40 mmol), bis-triphenylphosphine palladium (II) chloride (6.3 mg, 0.009 mmol), and 1,1′-bis(diphenylphosphino)ferrocene (5 mg, 0.009 mmol). The mixture was flushed with argon and heated in a sealed vessel at 80° C. for 15 h. The reaction mixture was purified directly by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford tert-butyl 4-(1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate as a solid (35 mg, 31%). 1H NMR (500 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.97 (d, J=7.9 Hz, 1H), 7.66 (s, 1H), 7.63 (s, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.33 (m, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.18 (dd, J=1.2, 8.1 Hz, 1H), 6.09 (br s, 1H), 5.45 (s, 2H), 4.75 (d, J=3.9 Hz, 1H), 3.98 (br s, 2H), 3.46-3.59 (m, 4H), 3.36-3.42 (m, 2H), 2.02 (m, 1H), 1.87 (m, 1H), 1.56-1.67 (m, 2H), 1.38-1.48 (m, 9H), 1.13-1.32 (m, 4H); LCMS (ESI) m/z 560 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[C:32](=[O:33])[C:11]2=[CH:12][N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[CH:30][CH:29]=[N:28]4)=[CH:23][CH:22]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1.C(N(C(C)C)CC)(C)C.CC1C(C)=NC=CC=1N.[C:52](Cl)(=[O:54])[CH3:53]>ClCCl.O>[C:52]([O:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[C:32](=[O:33])[C:11]2=[CH:12][N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[CH:30][CH:29]=[N:28]4)=[CH:23][CH:22]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1)(=[O:54])[CH3:53]
Reactant: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1[C@@H]1CCCC[C@H]1O
Reactant: CC(=O)Cl
Agent: Cc1nccc(N)c1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(=O)OC1CCCCC1n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Reaction time: 0.33 h

Procedure:
(±)-2-(trans-2-Hydroxycyclohexyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 508, 50 mg, 0.11 mmol) was dissolved in dichloromethane (2 ml) and treated sequentially with diisopropylethylamine (0.028 ml, 0.16 mmol, 1.4 equiv), dimethyl-4-aminopyridine (1.4 mg, 0.011 mmol, 0.1 equiv) and acetyl chloride (0.014 ml, 0.19 mmol, 1.7 equiv). After stirring for 20 minutes, additional acetyl chloride (0.014 ml, 0.19 mmol, 1.7 equiv) was added and the mixture was stirred for an additional 20 minutes. The mixture was poured into water (15 mL) and extracted with dichloromethane (2×15 mL). The organic extracts were washed once with hydrochloric acid (10 mL, 1 N aqueous) and sodium bicarbonate (10 mL, aqueous saturated), dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 80:20; dichloromethane:methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.38 (1H, dd, J=6.1, 3.4 Hz), 8.36 (1H, s), 7.90 (1H, d, J=2.4 Hz), 7.72-7.70 (3H, m), 7.46-7.42 (2H, m), 7.39-7.36 (1H, m), 7.29-7.26, (2H, m), 6.47 (1H, dd, J=2.2, 1.9 Hz), 5.47 (1H, d, J=16.7 Hz), 5.42 (1H, d, J=16.2 Hz), 5.32-5.26 (1H, m), 4.56-4.49 (1H, m), 216-2.19 (2H, m), 2.13-1.99 (2H, m), 1.87 (3H, s), 1.89-1.81 (2H, m), 1.54-1.47 (2H, m) ppm; high resolution mass spectrometry (ES+) m/z 482.2202 [(M+H)+; calculated for C28H28N5O3: 482.2187].
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:8][CH2:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=3)[NH:11][CH:10]=2)=[CH:5][CH2:4]1.I.CS[C:23]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)=[NH:24]>C(O)C>[CH3:1][N:2]([CH3:19])[CH:3]1[CH2:8][CH2:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:23]([C:25]4[S:26][CH:27]=[CH:28][CH:29]=4)=[NH:24])[CH:16]=3)[NH:11][CH:10]=2)=[CH:5][CH2:4]1
Reactant: CSC(=N)c1cccs1
Reactant: CN(C)C1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Agent: I
Solvent: CCO
Product: CN(C)C1CC=C(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)CC1
Reaction time: 24 h
Yield: 93.5 %

Procedure:
A solution of compound 113 (0.18 g, 0.704 mmol) in dry ethanol (10 mL) was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.4 g, 1.409 mmol) at room temperature and stirred for 24 h. Solvent was evaporated and crude was diluted with sat. NaHCO3 solution (20 mL) and product was extracted into CH2Cl2 (2×25 mL). The combined CH2Cl2 layer was washed with brine (20 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 1:9) to obtain compound 114 (0.24 g, 90%) as a solid. mp 113-115° C.; 1H NMR (DMSO-d6) δ 1.42-1.53 (m, 1H), 1.97-2.02 (m, 1H), 2.08-2.22 (m, 8H), 2.31-2.60 (m, 3H), 6.03 (s, 1H), 6.21 (brs, 2H), 6.65 (dd, 1H, J=1.2, 8.4 Hz), 7.09 (t, 1H, J=4.2 Hz), 7.20 (s, 1H), 7.28-7.31 (m, 2H), 7.58 (d, 1H, J=4.5 Hz), 7.71 (d, 1H, J=2.7 Hz), 10.88 (s, 1H); ESI-MS m/z (%): 365 (MH+, 39), 320 (38), 183 (76), 160 (100); ESI-HRMS calculated for C21H25N4S (MH+), Calculated: 365.1813; Observed: 365.1794.
Reaction SMILES: [CH:1](=[C:8]1/[C:9]([O:11][C:12](=[O:14])[CH2:13]/1)=[O:10])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]1[C@@H:23]2[C@@H:18]([CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:17][NH:16]1>ClCCl>[CH:1](=[C:8](/[CH2:13][C:12]([N:16]1[CH2:17][C@H:18]2[C@H:23]([CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:15]1)=[O:14])\[C:9]([OH:11])=[O:10])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C/C(=C\c2ccccc2)C(=O)O1
Reactant: C1CC[C@H]2CNC[C@H]2C1
Solvent: ClCCl
Product: O=C(O)/C(=C/c1ccccc1)CC(=O)N1C[C@H]2CCCC[C@H]2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
To a suspension of (E)-benzylidenesuccinic anhydride (13.9 g) in dichloromethane (120 ml) was added cis-hexahydroisoindoline (12.0 g) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed successively with 1N hydrochloric acid and brine and dried over MgSO4. After the solvent was evaporated under reduced pressure, the residue was crystallized from ethyl acetate to give 19.5 g of (E)-2-benzylidene-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionic acid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[C:11]1[CH2:24][CH2:25][O:26][CH3:27].C(N(CC)CC)C.[C:35]1([S:41](Cl)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl>[NH2:23][C:14]1[C:13]2[N:12]=[C:11]([CH2:24][CH2:25][O:26][CH3:27])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:41]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[O:43])=[O:42])[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCNS(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 42.9 %

Procedure:
Under a nitrogen atmosphere a solution of 1-(8-aminooctyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 2.7 mmol) in dichloromethane (50 mL) was cooled to 0° C. Triethylamine (415 μL, 2.98 mmol) was added followed by benzenesulfonyl chloride (345 μL, 2.71 mmol). The reaction mixture was allowed to warm slowly to ambient temperature and then it was maintained overnight. The reaction mixture was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography (50 g of silica gel eluting with 7.5% methanol in dichloromethane). The purified material was recrystallized from propyl acetate, triturated with hexanes, and then dried in a vacuum oven to provide 590 mg of N-{8-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]octyl}benzenesulfonamide as a yellow powder, m.p. 146-149° C. Analysis: Calculated for C27H35N5O3S: % C, 63.63; % H, 6.92; % N, 13.74; Found: % C, 62.96; % H, 7.03; % N, 13.09. Karl Fisher showed 0.16% or 0.045 mole water.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]5[O:27][CH2:28][O:29][C:23]=5[CH:22]=4)=[CH:17][C:15]=3[N:16]=2)[C:5]([NH:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:7]=1.[CH:30]1[C:35]([C:36]([OH:38])=[O:37])=[CH:34][C:33]2[C:39]([O:41][C:42](=O)[C:32]=2[CH:31]=1)=[O:40]>>[CH2:9]([NH:8][C:5]1[C:4]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]5[O:27][CH2:28][O:29][C:23]=5[CH:22]=4)=[CH:17][C:15]=3[N:16]=2)=[CH:3][C:2]([N:1]2[C:39](=[O:40])[C:33]3[C:32](=[CH:31][CH:30]=[C:35]([C:36]([OH:38])=[O:37])[CH:34]=3)[C:42]2=[O:41])=[CH:7][CH:6]=1)[CH2:10][CH3:11]
Reactant: CCCNc1ccc(N)cc1-c1nc2cc(-c3ccc4c(c3)OCO4)ccc2o1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: CCCNc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3ccc4c(c3)OCO4)ccc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-propylaminophenyl)-5-(3,4-methylenedioxyphenyl)benzoxazole (157 mg, 0.40 mmol) and 1,2,4-benzenetricarboxylic anhydride (76 mg, 0.40 mmol) the title compound was obtained (82 mg, 36%). 1H NMR (DMSO) δ 13.78(s, 1H), 8.49(t, 1H), 8.42(dd, 1H), 8.30(s, 1H), 8.12(d, 1H), 8.07(d, 1H), 8.00(d, 1H), 7.78(d, 1H), 7.64(dd, 1H), 7.47(dd, 1H), 7.35(d, 1H), 7.24(dd, 1H), 7.04(d, 1H), 7.01(d, 1H), 6.08(s, 2H), 3.35(m, 2H), 1.76(m, 2H), 1.07(t, 3H). MS 562.2 m/z (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)[CH:2]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH2:44][CH2:45][CH:46]([OH:58])[CH2:47][N:48]1[CH2:57][CH2:56][C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH2:49]1>C(Cl)Cl>[CH2:49]1[C:50]2[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:56][CH2:57][N:48]1[CH2:47][CH:46]([OH:58])[CH2:45][NH:44][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:8]=1
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: O=C(O)c1cccc(-c2cccnc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.9 %

Procedure:
To a solution of 3-(pyridin-3-yl)benzoic acid (150 mg, 0.75 mmol) in DCM (6 mL) was added EDCI (215 mg, 1.10 mmol), HOBt (148 mg, 1.10 mmol), Et3N (228 mg, 2.25 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (185 mg, 0.90 mmol). The mixture was stirred at room temperature for 16 h. The reaction solution was then washed with water and extracted with DCM. The organic layer was concentrated, dried and the residue purified by prep-HPLC to give the desired title product (110 mg, Yield 34%). 1H NMR (400 MHz, MeOD) δ 8.80 (d, J=2.0 Hz, 1H), 8.52 (dd, J1=4.8 Hz, J2=3.6 Hz, 1H), 8.10 (s, 1H), 8.09 (dd, J1=8.8 Hz, J2=1.6 Hz, 1H), 7.83 (d, J=7.6 Hz, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.51-7.46 (m, 2H), 7.06-6.95 (m, 4H), 4.15-4.10 (m, 1H), 3.69 (s, 2H), 3.60-3.47 (m, 2H), 2.85-2.79 (m, 4H), 2.69-2.59 (m, 2H). LCMS (m/z): 388.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH2:21]([N:23]([CH2:37][CH3:38])[CH2:24][CH2:25][NH:26][C:27]([C:29]1[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=1[CH:35]=O)=[O:28])[CH3:22]>C(O)C.N1CCCCC1>[CH2:37]([N:23]([CH2:21][CH3:22])[CH2:24][CH2:25][NH:26][C:27]([C:29]1[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=1[CH:35]=[C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[CH:17][C:9]=2[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=2)[NH:13][C:12]1=[O:18])=[O:28])[CH3:38]
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Reactant: CCN(CC)CCNC(=O)c1cc(C)[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1cc(C)[nH]c1C=C1C(=O)Nc2cccc(-c3cccc(C(F)(F)F)c3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 21.9 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (28 mg, 22%).
Reaction SMILES: [OH:1][CH:2]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:3]#[C:4][C:5]1([OH:15])[CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][CH2:6]1>ClCCl.[O-2].[O-2].[Mn+4]>[OH:15][C:5]1([C:4]#[C:3][C:2]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[O:1])[CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][CH2:6]1
Reactant: COc1ccc(C(O)C#CC2(O)CCC3(CC2)OCCO3)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ccc(C(=O)C#CC2(O)CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.1 %

Procedure:
To a solution of 8-(3-hydroxy-3-(4-methoxyphenyl)propyn-1-yl)-1,4-dioxaspiro[4.5]decan-8-ol (Reference Example 4) (7.10 g, 22.3 mmol) in dichloromethane (100 mL), manganese dioxide (9.69 g, 112 mmol) was added, and the obtained solution was stirred at room temperature for 18 hours. The reaction solution was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (5.45 g, 17.2 mmol, 77%) as an oily product.