Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([CH3:24])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.C(N(CC)CC)C.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl>[C:32]([OH:39])(=[O:1])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[OH:1][CH2:2][C@@H:3]([CH3:24])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1
Reactant: O=C(Cl)c1ccccc1
Agent: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (20S)-21-hydroxy-20-methylpregn-4-en-3-one (8.0 g, 24.2 mmole) in dichloromethane (200 mL) was cooled in an ice-water bath and treated sequentially with triethylamine (3.69 mL, 26.6 mmole) and benzoyl chloride (3.09 mL, 26.6 mmole) and stirred for 16 hours at room temperature. After the reaction mixture was diluted with dichloromethane (200 mL), it was extracted with ether, dried over magnesium sulfate and filtered and the filtrate was concentrated to a solid which was purified by flash chromatography to give (20S)-21-hydroxy-20-methylpregn-4-en-3-one benzoate (9.4 g, 89.5%) melting at 193°-195° C. after recrystallization from acetone. IR 1716, 1676, 1614 (m), 1284 cm-1 ; MS (CI) 435 (100%, M+1), 313 (70%, M+1-PhCOOH); 1H NMR (CDC13) δ 0.77 (3H, s, C18 -Me), 1.04 (d, C 22 -Me), 1.19 (s, C19 -Me), 4.05 (1H, dd, 1/2 C21 -CH2), 4.34 (1H, dd, 1/2 C21 -CH2), 5.72 (1H, s, C4 -H), 7.45 (2H, t), 7.56 (1H, t), 8.04 (2H, dd).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][C:9]2=O)([O-:3])=[O:2].C(O)C.Cl.[NH2:19][OH:20]>O>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][C:9]2=[N:19][OH:20])([O-:3])=[O:2]
Reactant: NO
Reactant: O=C1CCCc2c1cccc2[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cccc2c1CCCC2=NO
Yield: 90.3 %

Procedure:
In a 100 mL flask equipped with a reflux condenser were placed 2.26 g of 5-nitro-1-tetralone and 60 mL of ethanol. To the mixture was added a solution of hydroxylamine hydrochloride (1.82 g) in water (4.5 mL). The content of the flask was stirred with a stirring bar at reflux for 8 hours. After evaporating the solvent, the residue was purified by column chromatography (eluent: hexane/ethyl acetate=5/1)′ to give 2.2 g of 5-nitro-1-tetralone oxime.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]=[O:11])[CH2:6][CH2:5]1.C(N(CC)CC)C.[C:19](Cl)(=[O:23])[C:20]([CH3:22])=[CH2:21]>ClCCl.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[CH:10]([N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][C:19](=[O:23])[C:20]([CH3:22])=[CH2:21])[CH2:5][CH2:6]1)=[O:11]
Reactant: C=C(C)C(=O)Cl
Reactant: NCCN1CCN(C=O)CC1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)NCCN1CCN(C=O)CC1
Yield: 43.7 %

Procedure:
117.9 g (0.75 mol) of N-2-aminoethyl-N'-formylpiperazine, 85.8 g (0.85 mol) of triethylamine and 100 mg of 2,6-di-tert.-butyl-4-methylphenol were reacted in 230 ml of dichloromethane with 78.4 g (0.75 mol) of methacryloyl chloride as described in Example 1 and the mixture was worked up. 73.9 g (44% of theory) of N-formyl-N'-(methacryloylaminoethyl)piperazine were obtained in this manner as a colorless oil.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=O)=O>Cl.[Zn]>[SH:2][C:5]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(Cl)cc1S(=O)(=O)Cl
Agent: Cl
Agent: [Zn]
Product: COC(=O)c1ccc(Cl)cc1S
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
Over a period of 1.5 hours, 243.5 g (3.7 mol) of zinc powder were added a little at a time to a suspension of 205 g (0.75 mol) of methyl 2-chlorosulfonyl-4-chlorobenzoate in 1 l of concentrated hydrochloric acid and 375 g of ice. Stirring was continued for 3 hours, and the mixture was then slowly heated to 70° C. After 2 hours at this temperature, the mixture was cooled. The reaction mixture was allowed to stand at room temperature for 12 hours and then extracted with ethyl acetate, the combined organic phases [lacuna] and the solvent was removed. This gave 125.4 g (83%) of methyl 2-mercapto-4-chlorobenzoate.
Reaction SMILES: [OH:1][C@:2]12[C@H:11]3[CH2:12][C:13]4[C:18]5[C@@:7]1([CH2:8][CH2:9][NH:10]3)[C@@H:6]([O:19][C:17]=5[C:16]([O:20][CH3:21])=[CH:15][CH:14]=4)[C:5](=[O:22])[CH2:4][CH2:3]2.C([O-])([O-])=O.[K+].[K+].[CH:29]1([CH2:32]Br)[CH2:31][CH2:30]1>CC#N>[CH:29]1([CH2:32][N:10]2[CH2:9][CH2:8][C@@:7]34[C:18]5[C:13]6[CH2:12][C@@H:11]2[C@:2]3([OH:1])[CH2:3][CH2:4][C:5](=[O:22])[C@@H:6]4[O:19][C:17]=5[C:16]([O:20][CH3:21])=[CH:15][CH:14]=6)[CH2:31][CH2:30]1
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)NCC[C@]314
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314

Procedure:
To a suspension of Compound 3 (9.5 g, 31.5 mmol) in 80 mL of CH3CN was added K2CO3 (10.9 g, 79.0 mmol) portionwise followed by cyclopropylmethyl bromide (3.97 mL, 41.0 mmol) dropwise via syringe. The suspension was heated at reflux for 18 h. LC-MS showed a single peak corresponding to the desired product (Tr=0.830 min, M+H=356). The mixture was cooled to ambient temperature and the solid was filtered off and washed with CH3CN. The filtrate was concentrated and the golden yellow residue was diluted with CH2Cl2 and H2O. The layers were separated and the aqueous was further extracted with CH2Cl2. The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated to provide 9.76 g (87%) of Compound 4 as a white foam that turned to a light yellow oily foam overnight. LC/MS, m/z=356.2 [M+H]+ (Calc: 356.43).
Reaction SMILES: CN(C)C=O.Cl[CH2:7][C:8]([C:10]1[N:11]=[CH:12][S:13][CH:14]=1)=O.[C:15]([CH2:17][C:18](=[S:20])[NH2:19])#[N:16].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[S:20]1[CH:7]=[C:8]([C:10]2[N:11]=[CH:12][S:13][CH:14]=2)[N:19]=[C:18]1[CH2:17][C:15]#[N:16]
Reactant: O=C(CCl)c1cscn1
Reactant: N#CCC(N)=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1nc(-c2cscn2)cs1
Temperature: 60 °C
Reaction time: 1 h
Yield: 44.6 %

Procedure:
A N,N-dimethylformamide (49 mL) suspension of 2-chloro-1-(1,3-thiazol-4-yl)ethanone (4.9 g), 2-cyanoethanethioamide (3.3 g) and potassium carbonate (4.6 g) was stirred at 60° C. for 1 hour in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. An organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=3/1). Isopropyl ether was added to the residue, and the solid was collected by filtration to obtain the title compound (2.8 g) as a faint orange solid.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5]([NH:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:11]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:9]=1)=O.[NH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37]2[CH:38]=[N:39][C:40]([N:43]([CH2:45][CH2:46][CH2:47][O:48][CH3:49])[CH3:44])=[CH:41][CH:42]=2)=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>C(OCC)(=O)C>[C:20]([C:10]1[CH:9]=[C:8]([NH:7][C:5]([NH:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]([C:37]3[CH:38]=[N:39][C:40]([N:43]([CH2:45][CH2:46][CH2:47][O:48][CH3:49])[CH3:44])=[CH:41][CH:42]=3)=[CH:29][CH:28]=2)=[O:4])[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:11]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: COCCCN(C)c1ccc(-c2ccc(N)c3ccccc23)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COCCCN(C)c1ccc(-c2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)cn1
Reaction time: 5 h

Procedure:
A solution of 5-(2,2,2-trichloroethoxycarbonyl)amino-3-t-butyl-1-p-tolylpyrazole (26 mmol), 1-amino-4-{6-[(3-methoxypropyl)methylamino]pyridin-3-yl }naphthalene (26 mmol), diisopropylethylamine (25 mmol) and DMSO (75 mL) is heated to 55-90° C. and held for 2-8 h. To this solution, ethyl acetate (100 mL) is added. The organic layer is washed with brine (4×50 mL), and dried over MgSO4. The solvent is removed under reduced pressure, and residue is crystallized from a suitable solvent such as acetonitrile (50 mL) at 0° C. The product is collected by filtration and recrystallized from a suitable solvent such as isopropanol and dried in vacuum to constant weight.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](Cl)=[O:5].[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.CCCCCC>O1CCCC1>[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:4](=[O:5])[CH:3]=[C:2]([CH3:7])[CH3:1])=[CH:11][CH:10]=1
Reactant: CC(C)=CC(=O)Cl
Reactant: Nc1ccc(Br)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)=CC(=O)Nc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 9.48 g (80 mmol) of 3,3-dimethylacryloyl chloride in 200 ml of dry tetrahydrofuran (THF) was added with vigorous shaking a solution of 13.76 g (80 mmol) of 4-bromoaniline in 300 ml of dry THF. The mixture stood at room temperature for 2 hours and was then treated with 80 g of ice followed by 200 ml of hexane. The organic layer was separated and the aqueous layer was extracted with 2×50 ml of hexanes. The organic layers were combined and washed successively with 30 ml of water and 2×ml of saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by recrystallization from an ethyl acetate and hexanes mixture to give the title compound as colorless crystals.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C(N(CC)CC)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH:23]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[NH:22][C:21]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=3[O:39][CH:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)=[N:20]2)=[CH:15][CH:14]=1.[NH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.C(=O)(O)[O-].[Na+]>C1COCC1.C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH:23]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[N:22]([C:1]([N:45]3[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]3)=[O:2])[C:21]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=3[O:39][CH:40]3[CH2:41][CH2:42][CH2:43][CH2:44]3)=[N:20]2)=[CH:17][CH:18]=1
Reactant: COc1ccc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2)c(OC2CCCC2)c1
Reactant: C1CNCCN1
Reactant: O=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)N2CCNCC2)c(OC2CCCC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Phosgene (0.48 mL, 0.925 mmol, 1.93 M in toluene) was added dropwise to a mixture of triethylamine (0.14 mL, 1.0 mmol) and 4,5-bis-(4-chloro-phenyl)-2-(2-cyclopentyloxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (89 mg in THF (2 mL) at 0° C. The reaction mixture was stirred for 1 h at 0° C. and evaporated. The residue was kept under high vacuum for 30 min. Methylene chloride (2 mL) was added to the residue and the solution was added dropwise to a solution of piperazine (0.24 g, 2.78 mmol) in methylene chloride (2 mL) at 0° C. After 1 h, the reaction was worked up with aqueous sodium bicarbonate. The mixture was extracted with methylene chloride and washed with water and brine. The organic layer was extracted with 0.5 N HCl (2×50 mL). The combined aqueous layers were cooled to 0° C. and basified using 2 N NaOH. The mixture was extracted with methylene chloride (3×50 mL). The organic extracts were dried over sodium sulfate and evaporated. Flash chromatography of the residue over silica gel using 3-6% methanol in methylene chloride gave [4,5-Bis-(4-chloro-phenyl)-2-(2-cyclopentyloxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-piperazin-1-yl-methanone (89 mg, 81%). HR-MS (ES, m/z) calculated for C32H35N4O3Cl2[(M+H)+]593.2081, observed 593.2084.
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][NH:27]2.C1(C)C=CC=CC=1>C(O)(=O)C>[F:16][C:13]([F:14])([F:15])[C:10]([CH:11]=[N:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][NH:27]2)([OH:17])[CH2:9][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[O:20][CH3:21])([CH3:18])[CH3:19]
Reactant: Nc1cccc2[nH]ncc12
Reactant: COc1c(F)cccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1c(F)cccc1C(C)(C)CC(O)(C=Nc1cccc2[nH]ncc12)C(F)(F)F
Yield: 73.2 %

Procedure:
1.46 g (4.746 mmol) of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal is stirred with 632 mg (4.746 mmol) of 4-aminoindazole in 6.78 ml of glacial acetic acid for two days at room temperature. The reaction mixture is drawn off three times with toluene in a rotary evaporator, and the residue is chromatographed on silica gel (mobile solvent ethyl acetate/hexane). 1.47 g (73.5%) of the desired compound is isolated.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[N:11][C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[N:9]2)[CH:5]=[CH:4][N:3]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH2:34][C@H:33]([NH2:37])[CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].S(C1C=CC(NC2N=CN(C3C=CN=C(N[C@H]4CCCNC4)C=3)N=2)=CC=1)(=O)(=O)N.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.CN1C(=O)CCC1.ClCCl>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH2:34][C@H:33]([NH:37][C:2]2[CH:7]=[C:6]([N:8]3[CH:12]=[N:11][C:10]([NH:13][C:14]4[CH:19]=[CH:18][C:17]([S:20](=[O:22])(=[O:21])[NH2:23])=[CH:16][CH:15]=4)=[N:9]3)[CH:5]=[CH:4][N:3]=2)[CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: NS(=O)(=O)c1ccc(Nc2ncn(-c3ccnc(Cl)c3)n2)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: NS(=O)(=O)c1ccc(Nc2ncn(-c3ccnc(N[C@H]4CCCNC4)c3)n2)cc1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H](Nc2cc(-n3cnc(Nc4ccc(S(N)(=O)=O)cc4)n3)ccn2)C1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
A microwave reaction vessel was charged with 50 mg of 4-[1-(2-Chloro-pyridin-4-yl)-1H-[1,2,4]triazol-3-ylamino]-benzenesulfonamide (0.14 mmol, 1 equiv), 110 mg (S)-3-amino-piperidine-1-carboxylic acid tert-butyl ester (0.57 mmol, 4 equiv) and 17.0 mg DMAP (0.014 mmol, 0.1 equiv) in NMP (1.5 mL). The resulting solution was warmed to 130° C. via microwave irradiation for 20 min and then heated at 180° C. for an additional 70 min via microwave irradiation. The reaction mixture was cooled and concentrated in vacuo and the residue purified by preparative HPLC. To a solution of 12.0 mg of this product, 3-(S)-{4-[3-(4-sulfamoyl-phenylamino)-[1,2,4]triazol-1-yl]-pyridin-2-ylamino}-piperidine (0.029 mmol, 1 equiv) in dichloromethane (5 mL), di-tert-butyl dicarbonate (9.5 mg, 0.043 mmol, 1.5 equiv) and 6 μL triethylamine (0.058 mmol, 2 equiv) were added and the resulting solution stirred at rt for 1 h. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography on silica gel eluting with 50% EtOAc: petroleum ether moving to EtOAc (4.2 mg, 29%); MS (ES+) m/e 515.55, (ES−) m/e 513.70
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[N:20]1[C:29]2[C:24](=[CH:25][C:26]([C:30](O)=[O:31])=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:30]([C:26]3[CH:25]=[C:24]4[C:29](=[CH:28][CH:27]=3)[N:20]=[CH:21][CH:22]=[CH:23]4)=[O:31])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1ccc2ncccc2c1
Yield: 9.9 %

Procedure:
Using the general method of Example 18, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.5 g, 1.96 mmol) was coupled with 6-quinolinecarboxylic acid (0.34 g, 1.96 mmol) to provide 0.08 g of N6-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-6-quinolinecarboxamide as a tan powder, m.p. 122-127° C. (foaming). 1H NMR (300 MHz, DMSO-d6) δ8.98 (m, 1H), 8.73 (t, J=5.4 Hz, 1H), 8.43 (m, 2H), 8.23 (s, 1H), 8.13-8.03 (m, 3H), 7.60 (m, 2H), 7.40 (m, 1H), 7.20 (m, 1H), 6.58 (broad s, 2H), 4.66 (t, J=6.7 Hz, 2H), 3.37 (m, 2H), 1.96 (m, 2H), 1.64 (m, 2H); MS (EI) m/e 410.1847 (410.1855 calcd for C24H22N6O).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:16][C:17](=[O:19])[CH3:18])=[C:9]([O:12][C:13](=[O:15])[CH3:14])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:20]([C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25])#[CH:21]>>[ClH:1].[C:20]([C:22]1[CH:23]=[C:24]([NH:25][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:16][C:17](=[O:19])[CH3:18])=[C:9]([O:12][C:13](=[O:15])[CH3:14])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:26]=[CH:27][CH:28]=1)#[CH:21]
Reactant: C#Cc1cccc(N)c1
Reactant: CC(=O)Oc1cc2ncnc(Cl)c2cc1OC(C)=O
Product: C#Cc1cccc(Nc2ncnc3cc(OC(C)=O)c(OC(C)=O)cc23)c1
Product: Cl
Temperature: 27.5 °C
Yield: 76.3 %

Procedure:
Into a 2.0 L four necked round-bottomed flask, equipped with a mechanical stirrer; reflux condenser and thermometer socket are charged the above organic layer containing 4-chloro-6,7-diacetoxy-quinazoline and 3-ethynylaniline (12 g). The reaction mass was slowly heated to reach reflux condition and maintained at reflux for 14 hours and the reaction was found to be over by HPLC. Then the reaction was cooled to 25-30° C. and filtered the mass, washed the cake with chloroform, and dried to get 29 g (76.3% by theory) of N-(3-ethynylphenyl)-6,7-diacetoxy-4-quinazolinamine hydrochloride as yellow solid.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5]C=CC=1.[N+:7]([C:10]1[C:11](C=O)=[CH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)([O-:9])=[O:8].CCCCCC.[C:28]([O:31][CH2:32][CH3:33])(=[O:30])C>>[CH2:32]([O:31][C:28](=[O:30])[C:6]([CH3:5])=[CH:1][C:15]1[CH:14]=[C:13]2[CH:12]=[CH:11][C:10]([N+:7]([O-:9])=[O:8])=[CH:19][C:18]2=[CH:17][CH:16]=1)[CH3:33]
Reactant: CCOC(C)=O
Reactant: c1ccccc1
Reactant: O=Cc1cc2ccccc2cc1[N+](=O)[O-]
Solvent: CCCCCC
Product: CCOC(=O)C(C)=Cc1ccc2cc([N+](=O)[O-])ccc2c1
Temperature: 25 °C

Procedure:
To 200 ml of benzene, 9.3 g (46 mmol) of 3-nitro-2-naphtaldehyde and 17.6 g (48.5 mmol) of Wittig reagent (carbethoxy ethylidene triphenylphosphorane) (manufactured by Aldrich Chemical Co., Inc.) were added, and the resulting mixture was stirred at room temperature for one night. The completion of the reaction was verified by TLC, and the reaction liquid was concentrated, whereby a crude product was obtained. This crude product was refined by a column chromatography (aminopropyl-modified silica gel (Fuji Silysia Chem. Co., NH-DM); developing solvent: hexane/ethyl acetate=1/1), whereby 13.0 g of the aimed compound were obtained as a crystal (yield: 96%).
Reaction SMILES: C(OC([N:11]1[CH2:15][CH:14]([O:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13][N:12]1[C:23](=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)=O)C1C=CC=CC=1>CO>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][C:23]([N:12]2[CH2:13][CH:14]([O:16][C:17](=[O:22])[C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:15][NH:11]2)=[O:32])=[CH:26][CH:27]=1
Reactant: CC(C)(C)C(=O)OC1CN(C(=O)Cc2ccc(F)cc2)N(C(=O)OCc2ccccc2)C1
Solvent: CO
Product: CC(C)(C)C(=O)OC1CNN(C(=O)Cc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98 %

Procedure:
2-[2-(4-Fluorophenyl)acetyl]-4-(2,2-dimethylpropionyloxy)-pyrazolidine 1-carboxylic acid 1-benzyl ester, 31, (1.71 g, 3.86 mmol) is dissolved in methanol (40 mL). The flask is flushed with nitrogen and charged with 10% palladium on carbon (300 mg). The reaction flask is stirred vigorously at room temperature under 1 atmosphere of hydrogen gas for 6 hours. The flask is flushed with nitrogen and the reaction mixture filtered through a pad of Celite, rinsing with ethyl acetate (100 mL). The filtrate is concentrated in vacuo afford 1.18 g (98% yield) of the desired product as a tan solid.
Reaction SMILES: F[C:2]1C=C(C=CC=1)N.C(C1C=CC(C(O)=O)=CC=1)(=O)C1C=CC=CC=1.C(NCC)C.[F:31][C:32]1[CH:33]=[C:34]([NH:38][C:39](=[O:54])[C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46](=[O:53])[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH:41]=2)[CH:35]=[CH:36][CH:37]=1.[H-].[Na+]>C1COCC1>[F:31][C:32]1[CH:33]=[C:34]([N:38]([CH3:2])[C:39](=[O:54])[C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46](=[O:53])[C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[CH:41]=2)[CH:35]=[CH:36][CH:37]=1
Reactant: O=C(Nc1cccc(F)c1)c1cccc(C(=O)c2ccccc2)c1
Reactant: Nc1cccc(F)c1
Agent: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCNCC
Solvent: C1CCOC1
Product: CN(C(=O)c1cccc(C(=O)c2ccccc2)c1)c1cccc(F)c1
Reaction time: 0.08 h

Procedure:
Following Procedure A with the substitution of 20 g (88 mmol) 3-benzoylbenzoic acid [579-18-0] and 8.5 mL (88 mmol) 3-fluoroaniline for 4-benzoylbenzoic acid and diethyl amine, the product N-(3-fluorophenyl)-3-benzoylbenzamide was generated (28 g, 88 mmol) as a clear oil. The oil was dissolved in 50 mL dry THF to which a 10 mL THF slurry of 2.1 g (90 mmol) NaH was slowly added. The mixture was allowed to stir for 5 min then 5.6 mL (90 mmol) of Mel was added and continued stirring for 16 h. The reaction was carefully quenched with water and partitioned between water and CH2Cl2. The organic layer was washed with brine, dried over K2CO3, filtered, and concentrated to yield 29.3 g (88 mmol) product. MS m/z (MH+) 334.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[OH:26][CH:27]([C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH2:40])(=[O:39])=[O:38])=[CH:33][CH:32]=1)[CH2:28][NH:29][CH3:30].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[NH2:40][S:37]([C:34]1[CH:33]=[CH:32][C:31]([CH:27]([OH:26])[CH2:28][N:29]([CH2:20][C:18]2[S:19][C:12]3[C:11](=[O:23])[C:10]([C:8]([NH:7][CH2:6][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:25][CH:24]=4)=[O:9])=[CH:15][N:14]([CH3:16])[C:13]=3[C:17]=2[CH3:22])[CH3:30])=[CH:36][CH:35]=1)(=[O:38])=[O:39]
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: CNCC(O)c1ccc(S(N)(=O)=O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(CN(C)CC(O)c2ccc(S(N)(=O)=O)cc2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 72 h
Yield: 46.8 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), 4-[1-hydroxy-2-(methylamino)ethyl]benzenesulfonamide (Preparation 48)(60 mg, 0.26 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5.0 mL) was stirred for 72 hours at room temperature. The solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (5 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (69 mg) as a white solid.