Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([C:11]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)=[O:12])=[CH:9][CH:8]=[C:7]([CH3:22])[N:6]=1)=[O:4].C1C=C(Cl)C=C(C(OO)=[O:31])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C([O-])(O)=O.[Na+]>ClCCl>[CH3:22][C:7]1[N+:6]([O-:31])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:10]([C:11]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1nc(C)ccc1C(=O)c1ccc2c(c1)OCO2
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1c(C(=O)c2ccc3c(c2)OCO3)ccc(C)[n+]1[O-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.1 %

Procedure:
To a dichloromethane(20 ml) solution of 6-methyl-3-(3,4-methylenedioxyphenylcarbonyl)pyridine-2-carboxylic acid methyl ester(1.75 g,5.85 mmol) was added mCPBA(1.73 g) under ice-cooling. The mixture was stirred at room temperature for 20 h and an aqueous solution of sodium thiosulfate was added to the mixture to quench the reaction. The mixture was neutralized with a saturated aqueous solution of NaHCO3 and extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4 and concentrated under reduce pressure to give 6-methyl-3-(3,4-methylenedioxyphenylcarbonyl)-2-methoxycarbonylpyridine N-oxide(1.57 g).
Reaction SMILES: [F:1][C:2]1[C:3]([F:27])=[C:4]2[O:9][C:8]3([CH2:12][CH2:11][CH2:10]3)[CH2:7][N:6]3[CH:13]=[C:14]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:15](=[O:21])[C:16]([C:17]=1[N+:18]([O-])=O)=[C:5]23>CN(C=O)C.[Pd]>[NH2:18][C:17]1[C:16]2[C:15](=[O:21])[C:14]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:13][N:6]3[CH2:7][C:8]4([CH2:12][CH2:11][CH2:10]4)[O:9][C:4]([C:5]=23)=[C:3]([F:27])[C:2]=1[F:1]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)c([N+](=O)[O-])c3c1=O)OC1(CCC1)C2
Agent: [Pd]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c3c(c(F)c(F)c(N)c3c1=O)OC1(CCC1)C2
Yield: 67 %

Procedure:
A solution of ethyl 9′,10′-difluoro-8′-nitro-7′-oxo-spiro[cyclobutane-1,2′(3′H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-6′-carboxylate (450 mg, 1.15 mmol) and 10% Pd/C (40.5 mg) in DMF (20 mL) was stirred under hydrogen atmosphere (0.3 MPa) at 50° C. for 3 hours. The catalyst was removed by filtration over Celite and the filtrate was concentrated in vacuo. The resulting solid was dissolved in EtOH—CH2Cl2 (1:5) and filtered. CH2Cl2 was removed, and the resulting precipitate was removed by filtration, washed with EtOH and dried to yield the title compound (270 mg, 67%) as a pale yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 1.27 (3H, t, J=7.3 Hz), 1.74-1.96 (2H, m), 2.02-2.13 (2H, m), 2.14-2.25 (2H, m), 4.20 (2H, q, J=7.3 Hz), 4.33 (2H, s), 7.33 (2H, brs), 8.43 (1H, s). ESIMS (+): 350[M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[NH:9][C:8]2[CH:18]=[CH:19][CH:20]=[N:21][C:7]1=2)=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(O)C>[CH2:28]([NH:35][CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[NH:9][C:8]2[CH:18]=[CH:19][CH:20]=[N:21][C:7]1=2)=[O:5])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C1Nc2cccnc2N(C(=O)CCCl)c2ccccc21
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1Nc2cccnc2N(C(=O)CCNCc2ccccc2)c2ccccc21

Procedure:
6.0 gm of 11-(3-chloropropionyl)-5,11-dihydro-6H-pyrido [2,3-b]-[1,4]benzodiazepin-6-one, 2.3 gm of sodium carbonate and 4.4 gm of benzylamine were refluxed in 80 ml of ethanol for 4 hours. Then the hot mixture was suction-filtered, the alcohol was distilled off, and the residue was purified on a silica gel column. The evaporation residue of the eluate was recrystallized twice from n-propanol.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][C:5]([NH2:9])=[C:4]([O:10][CH3:11])[CH:3]=1.[CH3:12][C:13]1(C)[C:17](C)(C)OB(C(C)=C)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:7]([C:13]([CH3:17])=[CH2:12])=[CH:6][C:5]([NH2:9])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: COc1cc(Cl)c(I)cc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: C=C(C)c1cc(N)c(OC)cc1Cl
Temperature: 25 °C
Yield: 24.8 %

Procedure:
A mixture of 4-chloro-5-iodo-2-methoxybenzenamine (1.0 g, 3.53 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (889 mg, 5.29 mmol), Pd(PPh3)4 (363 mg, 0.353 mmol), Na2CO3 (1.12 g, 10.6 mmol) in DME (10 mL) and water (3 mL) was stirred at reflux under argon for 6 h. The reaction mixture was allowed to cool to RT and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (5% petroleum ether/ethyl acetate) to afford the desired product (173 mg, 25% yield) as an off-white solid. ESI-MS m/z: 198.5[M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[N:8]1[CH:13]([CH3:15])[S:14][C:7]1=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]2=[O:21].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[N:8]1[CH:13]([CH3:15])[S:14][C:7]1=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]2=[O:21]
Reactant: C1CNCCN1
Reactant: CCOC(=O)c1c2n(c3cc(F)c(F)cc3c1=O)C(C)S2
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2n(c3cc(N4CCNCC4)c(F)cc3c1=O)C(C)S2
Yield: 49.5 %

Procedure:
Ethyl 6,7-difluoro-1-methyl-4-oxo-4H-(1,3)thiazeto(3,2-a)quinoline-3-carboxylate (5.0 g) was suspended in 150 ml of N,N-dimethylformamide and the suspension was stirred with 4.6 g of piperazine at room temperature for 48 hours. N,N-Dimethylformamide was evaporated in vacuo and to the residue was added ice water to collect the crystals by filtration. Purification by a column chromatography (silica gel/chloroform-methanol (1:1)) gave 3.0 g of desired compound, m.p. 224° C. (decompn.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]([F:46])([F:45])[C:9]1[CH:10]=[C:11]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:12][NH:13][CH2:14][C:15]1[C:16]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[CH2:27][CH2:26]2)=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2.Cl[C:48]([O:50][CH2:51][CH3:52])=[O:49].O>C1COCC1>[CH2:51]([O:50][C:48](=[O:49])[N:13]([CH2:12][C:11]1[CH:38]=[C:39]([C:41]([F:44])([F:42])[F:43])[CH:40]=[C:9]([C:8]([F:7])([F:45])[F:46])[CH:10]=1)[CH2:14][C:15]1[C:16]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]3)[CH2:27][CH2:26]2)=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:52]
Reactant: CCOC(=O)Cl
Reactant: FC(F)(F)c1cc(CNCc2cc3ccccc3nc2N2CCN(CC3CCCCC3)CC2)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc2ccccc2nc1N1CCN(CC2CCCCC2)CC1
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
Anhydrous potassium carbonate (0.17 g, 1.23 mmol) was added to a solution of (3,5-bis-trifluoromethyl-benzyl)-[2-(4-cyclohexylmethyl-piperazin-1-yl)-quinolin-3-yl-methyl]-amine (0.23 g, 0.4 mmol) in anhydrous THF (5 mL). After stirring 0.5 h, ethyl chloroformate (0.06 mL, 0.6 mmol) was added slowly under a nitrogen atmosphere. After stirring at RT for overnight, water (25 mL) was added, and the mixture was extracted with ethyl acetate (3×25 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give a colorless liquid. Purification by silica gel chromatography and eluting with 10-30% ethyl acetate/hexane afforded the desired final product as a viscous liquid (0.206 g), yield: 81%.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]([O:23][CH3:24])=[C:8]([O:21][CH3:22])[CH:9]=2)[N:4]=1.[N:25]1[C:33]([NH2:34])=[C:32]2[C:28]([N:29]=[CH:30][NH:31]2)=[N:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:34][C:33]1[N:25]=[CH:26][N:27]=[C:28]2[C:32]=1[N:31]=[CH:30][N:29]2[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]([O:23][CH3:24])=[C:8]([O:21][CH3:22])[CH:9]=2)[N:4]=1
Reactant: Nc1ncnc2nc[nH]c12
Reactant: COc1cc2nc(CCl)n(-c3ccccc3Cl)c(=O)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2nc(Cn3cnc4c(N)ncnc43)n(-c3ccccc3Cl)c(=O)c2cc1OC
Yield: 64.8 %

Procedure:
Prepared according to Procedure C using Intermediate 2a (200 mg, 0.546 mmol), adenine (81 mg, 0.601 mmol), K2CO3 (83 mg, 0.601 mmol), and DMF (4 mL). The crude product was recrystallized from ethanol (EtOH) to provide 164 mg of a beige solid (65%), mp 281.5-282.7° C. (decomposes). 1H NMR (DMSOd6) δ: 8.06 (s, 1H); 8.04 (s, 1H); 7.76-7.81 (m, 1H); 7.70-7.76 (m, 1H); 7.60-7.67 (m, 2H); 7.45 (s, 1H); 7.22 (s, 2H); 6.90 (s, 1H); 5.08 (d, J=17 Hz, 1H); 4.91 (d, J=17 Hz, 1H); 3.87 (s, 3H); 3.87 (s, 3H). 13C NMR (DMSO-d6) ppm: 159.9, 156.2, 155.4, 152.9, 150.0, 149.7, 149.4, 143.0, 141.9, 133.7, 132.1, 131.9, 131.2, 130.8, 129.3, 118.4, 113.6, 108.4, 105.8, 56.5, 56.1, 44.7. MS (ES): m/z 464.1 (M+). Anal. calcd. for C22H18ClN7O3.0.1C2H6O.0.05KCl: C, 56.47; H, 3.97; Cl, 7.88; N, 20.76. Found: C, 56.54; H, 4.05; Cl, 7.77; N, 20.55.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:13])[O:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=O)[C:10]=2[CH:11]=1.[OH:14][CH2:15][CH2:16][NH2:17]>>[OH:14][CH2:15][CH2:16][N:17]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:4])[C:10]=2[CH:11]=[C:2]([CH3:1])[C:3]1=[O:13]
Reactant: NCCO
Reactant: Cc1cc2c(oc1=O)CCCC2=O
Product: Cc1cc2c(n(CCO)c1=O)CCCC2=O

Procedure:
Prepared analogously to Example 5(b) from 3-methyl- 5,6,7,8-tetrahydro-cumarin-5-one and 2-hydroxy- ethylamine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12].C(=O)([O-])[O-].[Na+].[Na+].[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>CC(C)=O>[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([NH:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12])=[O:28]
Reactant: COc1cc(N)c2nccc(C)c2c1
Reactant: O=C(Cl)CCCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc(NC(=O)CCCCCBr)c2nccc(C)c2c1
Yield: 61 %

Procedure:
To a mixture of 9.4 g (0.05 mol) of 8-amino-6-methoxy-4-methylquinoline and 8.7 g (0.082 mol) of anhydrous sodium carbonate in 60 ml of acetone was added dropwise a solution of 6-bromohexanoylchloride in 35 ml of acetone. The mixture was heated under reflux for 4 hours, cooled and filtered. The filter cake was washed with with chloroform and the filtrate and wash were combined and concentrated in vacuo to dryness. The residual solid was recrystallized first from ethanol and then from 85% aqueous ethanol to give 10.8 g (61%) of product, mp 111°-113°.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1O.CCN=C=NCCCN(C)C.CS(O)(=O)=O>O.C(Cl)(Cl)Cl>[F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:5]([C:6]2[O:8][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=2)=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: Nc1ccccc1O
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)c(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CS(=O)(=O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)cc(C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
4-Fluoro-3-nitro-5-trifluoromethyl benzoic acid (1.00 g, 4.0 mmol), 2-aminophenol (0.47 g, 4.4 mmol), CHCl3 (20 mL), and WSC (0.83 g, 4.4 mmol) were added together and stirred at room temperature for 1 hour. Water was added, and this was extracted with chloroform/acetone (3:1). After the organic layer obtained was dried over anhydrous sodium sulfate, it was filtered and concentrated. To a dioxane (20 mL) solution of the solid obtained was added methanesulfonic acid (2.28 g, 24 mmol), and this was heated to reflux for 18 hours. After the reaction solution was cooled, water was added, and the precipitated crystals were filtered, and after being washed with water were dried to yield the title compound (0.70 g, 54% yield) as yellowish-brown crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][CH2:16][CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:21]1[C:22]2[O:29][N:28]=[C:27]([C:30]3[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=3)[C:23]=2[N:24]=[CH:25][N:26]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][N:15]([CH2:16][CH3:17])[C:21]2[C:22]3[O:29][N:28]=[C:27]([C:30]4[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=4)[C:23]=3[N:24]=[CH:25][N:26]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(-c2noc3c(Cl)ncnc23)cc1
Reactant: CCNCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC1CCN(C(=O)OC(C)(C)C)CC1)c1ncnc2c(-c3ccc(S(C)(=O)=O)cc3)noc12
Reaction time: 0.17 h
Yield: 324.6 %

Procedure:
4-Ethylaminomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.12 g, 0.49 mmol) was dissolved in anhydrous THF (5 mL) and treated with NaH, 60% oil dispersion (20 mg, 0.49 mmol) at ambient temperature. After stirring for 10 min, 7-chloro-3-(4-methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidine (0.15 g, 0.49 mmol) was added. The reaction was stirred for 3 h and concentrated under vacuum. The residue was subjected to SiO2 with ethyl acetate and hexane (1/1) to afford Compound D2 (0.82 g, 61%). 1H NMR (400Mz, DMSO-d6) δ 8.49 (s, 1H), 8.41 (d, J=7.1, 2H), 8.34 (d, J=7.1, 2H), 4.10˜3.74 (m, 7H), 3.52 (m, 1H), 3.25 (t, 3H), 1.41˜1.22 (m, 4H). LCMS 516.3[M+H].
Reaction SMILES: [CH3:1][C@H:2]1[C@@:6]([CH2:8]CC)([OH:7])[CH2:5][CH2:4][NH:3]1.[Cl:11][C:12]1[CH:19]=[C:18](F)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15].C(=O)([O-])[O-].[Li+].[Li+]>>[Cl:11][C:12]1[CH:19]=[C:18]([N:3]2[CH2:4][CH2:5][C@@:6]([OH:7])([CH3:8])[C@@H:2]2[CH3:1])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: CCC[C@]1(O)CCN[C@H]1C
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@@H]1N(c2ccc(C#N)c(Cl)c2)CC[C@]1(C)O

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2,3-dimethylpyrrolidin-3-ol 0.5 oxalate (1.50 g), 2-chloro-4-fluorobenzonitrile (3.04 g) and lithium carbonate (1.04 g), the title compound was obtained as a colorless solid (yield: 1.70 g, yield: 72%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][C:5]([CH2:11][CH2:12][CH2:13][CH3:14])=[N:6]2.[C:15]([O:19][C:20]([C:22]1[C:23]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34]Br)=[CH:30][CH:29]=2)=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[CH2:11]([C:5]1[N:6]([CH2:34][C:31]2[CH:32]=[CH:33][C:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])=[CH:29][CH:30]=2)[C:7]2[C:3]([N:4]=1)=[C:2]([Cl:1])[N:10]=[CH:9][N:8]=2)[CH2:12][CH2:13][CH3:14]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc2ncnc(Cl)c2[nH]1
Product: CCCCc1nc2c(Cl)ncnc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
The titled compound was prepared by the alkylation of 6-chloro-8-butyl purine (0.063 g, 0.3 mmol) with t-Butyl-4-bromomethylbiphenyl-2'-carboxylate (0.104 g, 0.3 mmol) according to the procedure described in Step 3 of Example 12. After flash-chromatographic purification of the crude product using ethyl acetate-hexane (1:1), the product was obtained as a foam (0.085 g, 60%).
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16].CO>C(Cl)Cl>[CH3:14][N:15]([CH:17]=[C:11]1[CH2:1][CH2:2][C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:9]1=[O:10])[CH3:16]
Reactant: O=C1CCCc2ccccc21
Reactant: COC(OC)N(C)C
Solvent: CO
Solvent: ClCCl
Product: CN(C)C=C1CCc2ccccc2C1=O
Temperature: 25 °C

Procedure:
The 3,4-dihydro-2-(dimethylaminomethylene)-1(2H)-naphthalenone starting material was prepared by heating a mixture of α-tetralone (5.85 g, 40 mmol) and N,N-dimethylformamide dimethyl acetal (32 ml, 240 mmol) at 110° for 3 h. The reaction was allowed to cool to room temperature and excess reagent removed in vacuo to give a thick oil. This crude material was subjected to column chromatography (silica, 5% methanol in CH2Cl2) to afford the desired product as a thick orange oil (3.50 g). δH (CDCl3) 8.02 (1 H, dd, J 7.7, 1.5 Hz), 7.72 (1 H, s), 7.36 (1 H, td, J 7.3, 1.6 Hz), 7.28 (1H, td, J 7.6, 1.5 Hz), 7.15 (1H, dm, J 7.3 Hz), 3.12 (6H, s) and 2.98-2.80 (4H, m). MS (ES+) 202 (MH+, 90%), 175 (MH+−HCN, 100%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:7]=[CH:6][O:5][CH:4]=1.C([O-])(O)=O.[Na+].[C:13](Cl)(Cl)=[S:14]>C(Cl)(Cl)Cl>[N:1]([CH2:2][C:3]1[CH:7]=[CH:6][O:5][CH:4]=1)=[C:13]=[S:14]
Reactant: NCc1ccoc1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: S=C=NCc1ccoc1
Reaction time: 0.75 h
Yield: 81 %

Procedure:
To a solution of 3-(aminomethyl)furan (0.565 g, 5.818 mmol) in 10 mL of CHCl3 at 0° C. was added 10 mL of a saturated NaHCO3 solution and thiophosgene (0.66 mL, 8.66 mmol). The reaction mixture was stirred vigorously for 45 min while maintaining the temperature at between 0°-5° C. The phases were then separated and the aqueous layer extracted with CHCl3 (10 mL). The combined organic solutions were dried (MgSO4), filtered, and the volatiles removed by blowing a gentle stream of nitrogen over the solution. Traces of residual solvent and thiophosgene were then evaporated off under high vacuum (20° C./0.05 mm Hg) to afford 0.659 g,(81 percent of theoretical) of 3-(isothiocyanatomethyl)furan as a dark orange liquid which was found to be pure by NMR and suitable for use in the Diels-Alder step: 1H NMR (300 MHz, CDCl3) d 7.45 (s, 1H), 7.42 (s, 1H), 6.42 (s, 1H), 4.54 (s, 2H); 13C NMR (75 MHz, CDCl3) d 144.0, 139.9, 132.7, 119.5, 109.4, 40.2 ; IR (neat) 2090, 1595 cm-1; MS m/e 139, 81 (base).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]OCCCCC1C=CC([N+]([O-])=O)=CC=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][OH:33])=[CH:27][CH:26]=1)([O-:24])=[O:23]>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:33][CH2:32][CH2:31][C:28]1[CH:27]=[CH:26][C:25]([N+:22]([O-:24])=[O:23])=[CH:30][CH:29]=1
Reactant: O=[N+]([O-])c1ccc(CCO)cc1
Reactant: O=[N+]([O-])c1ccc(CCCCOCCCCCCBr)cc1
Product: O=[N+]([O-])c1ccc(CCOCCCCCCBr)cc1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 52, using 2-(4-nitrophenyl)ethanol in place of 4-(4-nitrophenyl)butan-1-ol. ES/MS calcd. for C14H21BrNO3+ 330.1. Found m/z=330.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH2:12].[Cl:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>ClCCCl.ClCCl>[Cl:13][CH2:14][CH2:15][C:16]([NH:12][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[Cl:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:17]
Reactant: O=C(Cl)CCCl
Reactant: Nc1cnc2ccccc2c1Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(CCCl)Nc1cnc2ccccc2c1Cl
Temperature: 50 °C
Yield: 78.8 %

Procedure:
A solution of 4-chloroquinolin-3-amine (6.00 g, 33.59 mmol) and 3-chloropropionyl chloride (4.8 mL, 50.39 mmol) dissolved in 200 mL of 1,2-dichloroethane was heated to 50° C. in an oil bath. After 20 hrs the temperature of the oil bath was increased to 90° C. After an additional 26 hours the reaction was cooled to room temperature, diluted with dichloromethane, washed with saturated aqueous K2CO3, H2O, and brine, dried over Na2SO4, and concentrated under reduced pressure to give 7.12 g of 3-chloro-N-(4-chloroquinolin-3-yl)propanamide as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:29])[C:10]([C:12]1[S:21][C:20]2[C:19]3[CH:22]=[C:23]([C:26](O)=[O:27])[CH:24]=[CH:25][C:18]=3[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=1)=[O:11].[CH3:30][CH:31]1[CH2:36][NH:35][CH2:34][CH:33]([CH3:37])[NH:32]1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:29])[C:10]([C:12]1[S:21][C:20]2[C:19]3[CH:22]=[C:23]([C:26]([N:35]4[CH2:34][C@@H:33]([CH3:37])[NH:32][C@@H:31]([CH3:30])[CH2:36]4)=[O:27])[CH:24]=[CH:25][C:18]=3[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=1)=[O:11]
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)O)ccc1OCC2)c1ccc(Cl)cc1Cl
Reactant: CC1CNCC(C)N1
Product: C[C@@H]1CN(C(=O)c2ccc3c(c2)-c2sc(C(=O)N(C)c4ccc(Cl)cc4Cl)cc2CCO3)C[C@H](C)N1

Procedure:
2-[(2,4-Dichloro-phenyl)-methyl-carbamoyl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid and 2,6-dimethylpiperazine were reacted by General Procedure B to give 360. NMR: (CDCl3): 1.01-1.20 (6H, br m, Me), 2.40-2.62 (2H, br, m), 2.73 (2H, s), 2.82-2.87 (1H, br, m), 2.98-3.00 (2H, m), 3.29 (3H, s, Me), 3.52-3.60 (1H, br m), 4.18-4.21 (2H, m), 4.45-4.55 (1H, br, s, NH), 6.76 (1H, s, Ar), 6.94 (1H, d, J 8.3, Ar), 7.15 (1H, dd, J 8.3 and 1.9, Ar), 7.23 (1H, d, J 8.4, Ar), 7.28 (1H, dd, J 8.5 and 2.2, Ar) and 7.44-7.48 (2H, m, Ar). MS: (ESI+) MH+=544.11
Reaction SMILES: [CH:1]([NH:5][C:6]1[C:7]([NH2:16])=[CH:8][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:11]=1)([CH2:3][CH3:4])[CH3:2].O[CH:18]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)S([O-])(=O)=O.[Na+].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH:1]([N:5]1[C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:14])([F:15])[F:13])=[CH:8][C:7]=2[N:16]=[C:18]1[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: O=S(=O)([O-])C(O)c1ccncc1
Reactant: CCC(C)Nc1ccc(C(F)(F)F)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C)n1c(-c2ccncc2)nc2cc(C(F)(F)F)ccc21
Temperature: 120 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
A mixture of 0.76 g of N1-sec-butyl-4-trifluoromethylbenzene-1,2-diamine, 0.84 g of sodium hydroxy-pyridin-4-yl-methanesulfonate and 17 ml of DMF was stirred for 1 hour at 120° C. The reaction mixture was cooled down to room temperature. Into the reaction mixture was poured a saturated sodium hydrogen carbonate aqueous solution, and the mixture was extracted three times with ethyl acetate. The organic layer was dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, to obtain 0.91 g of 1-sec-butyl-2-pyridin-4-yl-5-trifluoromethyl-1H-benzimidazole (hereinafter, referred to as present active compound 201).
Reaction SMILES: NN.[CH:3]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:8][CH2:7]1)([CH3:5])[CH3:4].ClCCl>C(O)C>[CH:3]([N:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][NH2:15])[CH2:10][CH2:11]1)([CH3:5])[CH3:4]
Reactant: CC(C)N1CCN(CCCN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: ClCCl
Solvent: CCO
Product: CC(C)N1CCN(CCCN)CC1
Reaction time: 0.17 h

Procedure:
Hydrazine (8.63 g, 270 mmol) is added to a stirred suspension of 2-[3-(4-isopropylpiperazin-1-yl)-propyl]-isoindole-1,3-dione (17.0 g, 53.9 mmol) in anhydrous ethanol (400 mL). The resultant mixture is heated in an oil bath at 75° C. for 16 hours. At ambient temperature, dichloromethane (300 mL) is added to the mixture and the suspension is allowed to stir for 10 minutes. After filtration and concentration, the title compound is obtained as a tan oil (8.12 g, 81% yield).