Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[NH:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:7][C:6]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=O)[CH3:2].B.[ClH:24].C(=O)([O-])O.[Na+]>O1CCCC1>[ClH:24].[CH2:1]([NH:4][C:5]1[NH:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:7][C:6]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:2]
Reactant: CC(=O)Nc1[nH]c(-c2ccc(F)cc2)nc1-c1ccccc1
Agent: B
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CCNc1[nH]c(-c2ccc(F)cc2)nc1-c1ccccc1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-acetylamino-2-(4-fluorophenyl)-4-phenyl-imidazole (142 mg) in tetrahydrofuran (7 ml) was added 10M borane.tetrahydrofuran complex (12 ml, tetrahydrofuran solution), and the mixture was stirred under argon atmosphere at room temperature for 2 days. To the reaction mixture was slowly added 10% hydrochloric acid, and the mixture was stirred at 60° C. for 10 minutes. After cooling, the mixture was neutralized by adding a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel flush column chromatography (solvent: hexane:ethyl acetate=1:2), and then, treated with hydrogen chloride-methanol solution to obtain 5-ethylamino-2-(4-fluorophenyl)-4-phenyl-imidazole hydrochloride (89 mg) as colorless powder.
Reaction SMILES: F[B-](F)(F)F.[C:6]([N+:10]1[O:11][C:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:13]2[CH:18]=[C:17]([Cl:19])[C:16]([CH3:20])=[CH:15][C:14]=12)([CH3:9])([CH3:8])[CH3:7].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[C:6]([N:10]1[C:14]2[CH:15]=[C:16]([CH3:20])[C:17]([Cl:19])=[CH:18][C:13]=2[C:12]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[O:11]1)([CH3:9])([CH3:7])[CH3:8]
Reactant: C1COCCN1
Reactant: Cc1cc2c(cc1Cl)c(-c1ccccc1)o[n+]2C(C)(C)C
Agent: F[B-](F)(F)F
Product: Cc1cc2c(cc1Cl)C(c1ccccc1)(N1CCOCC1)ON2C(C)(C)C

Procedure:
To a flask containing 6 g. of 1-tert.-butyl-5-chloro-6-methyl-3-phenyl-2,1-benzisoxazolium tetrafluoroborate is added 9 ml. of morpholine and the mixture heated at 80°C. for 1 hour. The reaction mixture is washed in diethyl ether and water and the ether layer separated, dried, evaporated in vacuo to dryness and the residue recrystallized from ether/methylene chloride to obtain 1-tert.-butyl-5-chloro-6-methyl-3-morpholino-3-phenyl-2,1-benzisoxazoline, m.p. 131°-133°C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH:12][C:13](=O)[CH:14]([CH3:16])[CH3:15].Cl.[CH:19]([O:22][NH2:23])([CH3:21])[CH3:20].Cl.CON>C(O)C>[CH:19]([O:22][N:23]1[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:12]=[C:13]1[CH:14]([CH3:16])[CH3:15])([CH3:21])[CH3:20]
Reactant: CC(C)ON
Reactant: CC(C)C(=O)Nc1cnc2ccccc2c1Cl
Agent: CON
Agent: Cl
Solvent: CCO
Product: CC(C)On1c(C(C)C)nc2cnc3ccccc3c21
Yield: 56.3 %

Procedure:
The method of Part B of Example 25 was followed using N-(4-chloroquinolin-3-yl)-2-methylpropanamide (3.6 g, 14.5 mmol), O-isopropylhydroxylamine hydrochloride (1.8 g, 16 mmol) in lieu of O-methylhydroxylamine hydrochloride, and ethanol (60 mL). 1-Isopropoxy-2-isopropyl-1H-imidazo[4,5-c]quinoline (2.2 g) was obtained as a dark oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C[N:8](C)[CH:9]=[O:10].[CH3:12][O:13][C:14]([C:16]1[C:20]([N+:21]([O-:23])=[O:22])=[C:19](C(O)=O)[N:18]([CH2:27][CH2:28][O:29][CH2:30][CH3:31])[N:17]=1)=[O:15]>ClCCl>[C:9]([C:19]1[N:18]([CH2:27][CH2:28][O:29][CH2:30][CH3:31])[N:17]=[C:16]([C:14]([O:13][CH3:12])=[O:15])[C:20]=1[N+:21]([O-:23])=[O:22])(=[O:10])[NH2:8]
Reactant: CCOCCn1nc(C(=O)OC)c([N+](=O)[O-])c1C(=O)O
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCOCCn1nc(C(=O)OC)c([N+](=O)[O-])c1C(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (1.2 mL, 13.76 mmol) and N,N-dimethylformamide (39 μL) were added to a solution of the carboxylic acid of step 2 (1.33 g, 4.63 mmol) in dichloromethane (20 mL) and the reaction mixture stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and azeotroped from dichloromethane (3×50 mL). The product was dissolved in tetrahydrofuran (50 mL), cooled in an ice bath, treated with 0.88 ammonia solution (10 mL) and stirred for 18 hours at room temperature. The mixture was concentrated in vacuo and the residue partitioned between dichloromethane (200 mL) and water (50 mL). The organics phase was dried over magnesium sulphate and concentrated in vacuo to yield the nitro product. 1H NMR (DMSO-D6, 400 MHz) δ: 1.06 (t, 3H), 3.40 (m, 2H), 3.77 (m, 2H), 3.84 (s, 3H), 4.38 (m, 2H), 8.35 (m, 1H), 8.46 (m, 1H). MS APCI+m/z 287 [MH]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1.I[CH2:17][CH3:18].[H-].[Na+]>CN(C=O)C>[CH2:17]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=2)[C:2]([CH3:15])([CH3:1])[CH2:3][CH2:4]1)[CH3:18]
Reactant: CC1(C)CCNc2cc([N+](=O)[O-])ccc21
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCC(C)(C)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of 4,4-dimethyl-7-nitro-1,2,3,4-tetrahydro-quinoline (0.48 g, 2.33 mmol), iodoethane (0.21 ml, 2.56 mmol), and NaH (60%, 0.10 g, 2.5 mmol) in 10 ml of DMF was stirred at RT overnight, and partitioned between EtOAc and H2O. The combined organic portions were washed with brine, dried with MgSO4, filtered, and condensed. The crude compound was purified by flash column chromatography (5 to 10% of CH2Cl2 in hexanes). The titled compound was obtained as a yellow oil. MS (ES+): 235.3 (M+H)+. Calc'd for C13H18N2O2—234.29.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9]C)=O.C(O)(=O)C.[O-:19][C:20]#[N:21].[K+]>O>[OH:1][CH2:2][CH2:3][N:4]1[C:5]2[C:6](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:7](=[O:9])[NH:21][C:20]1=[O:19]
Reactant: COC(=O)c1ccccc1NCCO
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c(=O)n(CCO)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To a stirred mixture of 10 parts of methyl 2-[(2-hydroxyethyl)amino]benzoate and 100 parts of acetic acid is added dropwise a solution of 4.5 parts of potassium cyanate in 25 parts of water. Upon completion, stirring at room temperature is continued overnight. The reaction mixture is evaporated. The solid residue is stirred with water. The product is filtered off, washed with water and ethanol, and dried, yielding 5 parts (48%) of 1-(2-hydroxyethyl)-2,4(1H,3H)-quinazolinedione; mp. 273.6° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8](I)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C=O)C.O>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([N:18]=[N+:19]=[N-:20])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)C1CC(I)CN1C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@@H]1C[C@@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of 4-iodo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (20 mmol, 1 equiv) in DMF was added NaN3 (2.5 equiv, 50 mmol), the resulting mixture was heated to 65 centigrade and stirred overnight. The mixture was diluted with water, extracted with AcOEt and dried over Na2SO4. After removal of solvent, the residue was purified by chromatography on silica gel to give title product (4.94 g) as colorless oil in 90% yield. MS m/e=271.5 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])=[CH:19][CH:18]=2)=[C:8]([CH2:10][C:11]([O:13]C)=[O:12])[CH:9]=1)[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])=[CH:19][CH:18]=2)=[C:8]([CH2:10][C:11]([OH:13])=[O:12])[CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c(CC(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c(CC(=O)O)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
To a mixture of methyl 2-[5-ethoxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate (0.56 g), tetrahydrofuran (2 mL) and methanol (2 mL) was added a 1N aqueous sodium hydroxide solution (2.2 mL) and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid and water were added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (0.45 g, 87%) of 2-[5-ethoxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 122-123° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)=O.C(O)(=O)C.[C:23]([O:31][CH2:32][CH3:33])(=[O:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>C1C=CC=CC=1>[C:23]([C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:1][C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCOC(=O)c1cc(C=O)c2ccccn2c1=O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(=Cc1cc(C(=O)OCC)c(=O)n2ccccc12)C(=O)OCC
Temperature: 25 °C
Yield: 81.6 %

Procedure:
A 100 ml round-bottom flask equipped with a Dean-Stark trap was charged with 50 ml benzene, ethyl 1-formyl-4-oxo-4H-quinolizine-3-carboxylate (8) (1.22 g, 5 mmol), acetic acid (5 g, 83 mmol), NH4OAc (5 g, 65 mmol), and diethyl malonate (2.3 g, 9 mmol). The reaction mixture was refluxed for 48 h. The reaction mixture was cooled to room temperature and washed three times with 50 ml water. The solvent was evaporated in vacuo and the crude product was purified by flash chromatography (ethyl acetate) to yield ethyl 1-(2,2-dicarboethoxyvinyl)-4-oxo-4H-quinolizine-3-carboxylate (12) as a yellow powder (1.58 g, 82%). M.p. 149-151° C. 1H NMR (δ, CDCl3): 1.31 (t, J=7 Hz, 3H), 1.36 (t, J=7 Hz, 3H), 1.42 (t, J=7 Hz, 3H), 4.34 (q, J=7 Hz, 2H), 4.36 (q, J=7 Hz, 2H), 4.41 (q, J=7 Hz, 2H), 7.34 (dd, J=7 Hz, J=7 Hz, 1H), 7.82 (dd, J=8 Hz, 1H), 7.96 (d, J=8 Hz, 1H), 8.05 (s, 1H), 8.60 (s, 1H), 9.50 (d, J=7 Hz). MS: m/z 387.1331; required for C20H21NO7: 387.1318.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:18][C:19]1[CH:24]=[C:23]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=3[CH:17]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Reactant: OB(O)c1cccc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3cccc(Cl)c3)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 43.8 %

Procedure:
To a solution of 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (0.13 g, 0.53 mmol) and 3-chlorophenylboronic acid (0.42 g, 2.66 mmol) in methylene chloride (5 mL) was added triethylamine (0.4 mL, 2.87 mmol), and copper (II) acetate (0.19 g, 1.06 mmol) and stirred at room temperature for 2 days. The reaction was partitioned between ammonium chloride solution (sat.) and methylene chloride. The organic layer was washed with sodium bicarbonate solution (sat.), dried over magnesium sulfate, and concentrated. Flash silica gel column separation with 25% ethyl acetate/hexane followed by trituration with an ether/methylene chloride/hexane mixture gave the title compound as a white solid (0.08 g, 43%). 1H NMR (DMSO-d6): δ 8.32 (s, 1H), 7.21 (t, J=8.0 Hz, 1H), 7.13 (dd, J=8.6, 2.3 Hz, 1H), 7.05 (d, J=8.7 Hz, 1H), 6.91 (m, 2H), 6.87 (dd, J=7.6, 1.4 Hz, 1H), 6.77 (d, J=7.8 Hz, 1H), 3.27 (s, 3H), 1.97 (m, 4H), 0.82 (t, J=7.3 Hz, 6H). MS (ESI) m/z 345/347 ([M+H]+); MS (ESI) m/z 343/345 ([M−H]−); Anal. calcd for C19H21ClN2O2: C, 66.18; H, 6.14; N, 8.12. Found: C, 65.70; H, 6.01; N, 7.90.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Oc1cccc2ncccc12
Reactant: BrCCCCBr
Product: BrCCCCOc1cccc2ncccc12
Yield: 40.4 %

Procedure:
Following the same procedure as in Example 32-(a), reaction and treatment were carried out using 1.0 g of 5-hydroxyquinoline and 2.3 g of 1,4-dibromobutane to obtain 0.78 g of 5-(4-bromobutoxy)quinoline. Furthermore, the same procedure as in Example 32-(b) was repeated with the exception that 0.78 g of N-diphenylmethylpiperazine was used, in order to perform reaction and treatment, so that 0.8 g of the desired compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][CH:13]([CH3:15])[CH3:14])(=[O:11])=[O:10].N1C=CC=CC=1.[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[CH3:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([S:9]([NH:12][CH:13]([CH3:15])[CH3:14])(=[O:11])=[O:10])[C:2]=1[NH:1][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][C:25]([O:24][C:23]([F:22])([F:34])[F:35])=[CH:26][CH:27]=1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1cccc(S(=O)(=O)NC(C)C)c1N
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1cccc(S(=O)(=O)NC(C)C)c1NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.2 %

Procedure:
To 0.30 g (1.4 mmol) of the material from Step B in 5 mL of chloroform was added 0.28 ml (3.5 mmol) of pyridine and 0.27 mL (1.7 mmol) of 4-(trifluoromethoxy)benzoyl chloride. The reaction mixture was stirred overnight at room temperature and then heated at reflux for 5 hours. After cooling to room temperature the reaction mixture was washed with 1N HCl, dried (sodium sulfate) and filtered. The volatiles were removed with a rotary evaporator. The residue was purified by MPLC (5–25% ethyl acetate in hexanes as eluant) to afford 0.10 g of the title compound, a compound of the invention, as a white solid melting at 104–107° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].CCN(C(C)C)C(C)C.[Br:21][CH2:22][C:23](Cl)=[O:24]>ClCCl>[Br:21][CH2:22][C:23]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)=[O:24]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)CBr
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CBr)Nc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 64 %

Procedure:
3-Trifluoromethylaniline (1.6 g, 10 mmol) was dissolved in dichloromethane with DIEA (3.4 mL, 20 mmol), cooled to 0° C., and to this solution bromoacetyl chloride was added as a neat liquid (exothermic). After 1 hour the reaction mixture was washed with 1N HCl, dried and concentrated to a brown oil which was purified by column chromatography (10 to 40% EtOAc/hexanes) to give a light brown oil, 1.8 g, 6.4 mmol, 64% yield. 1H NMR (500 MHz, CDCl3) δ 8.19 (s, 1H), 7.75 (s, 1H), 7.68 (d, J=8.1 Hz, 1H), 7.41 (t, J=7.9 Hz, 1H), 7.35 (d, J=7.8 Hz, 3.96 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](/[CH:12]=[C:13](/[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=2)\[C:14]#[N:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]>C(#N)C>[N+:1]([C:4]1[CH:5]=[C:6](/[CH:12]=[C:13](\[C:16]2[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=2)/[C:14]#[N:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: COc1ccc(/C=C(\C#N)c2cc(OC)c(OC)c(OC)c2)cc1[N+](=O)[O-]
Solvent: CC#N
Product: COc1ccc(/C=C(/C#N)c2cc(OC)c(OC)c(OC)c2)cc1[N+](=O)[O-]
Yield: 49.8 %

Procedure:
2.0 g of (Z)-3-(3-nitro-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-prop-2-ene-nitrile were dissolved in 500 ml of acetonitrile and exposed to visible light rays for 60 minutes. The reaction liquid was concentrated and crystallized from ethyl acetate to obtain 996 mg of the intended compound. The yield was 49%.
Reaction SMILES: C([NH:9][C:10]([NH:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][CH2:15]1)=[S:11])(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CO.O>[CH2:23]([O:22][C:21](=[O:30])[NH:20][CH:17]1[CH2:16][CH2:15][CH:14]([CH2:13][NH:12][C:10]([NH2:9])=[S:11])[CH2:19][CH2:18]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(NC1CCC(CNC(=S)NC(=O)c2ccccc2)CC1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: NC(=S)NCC1CCC(NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.7 %

Procedure:
To a solution of benzyl N-[4-({[(benzoyl-amino)carbothioyl]amino}methyl)-cyclohexyl]carbamate (5.023 g, 11.4 mmol) in MeOH (110 ml) was added a solution of K2CO3 (3.5 g, 25.3 mmol) in water (30 ml). The solution was stirred for 24 hours at room temperature and the solvent was removed in vacuo with repeated additions of MeOH to azeotropically remove water. The resulting solid was treated with acetone (60 ml) and filtered. The filtrate was evaporated to yield 95% (3.47 g) of a yellow solid.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][O:14][C:15](=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=O.Cl.[NH2:25][CH2:26][C:27]([C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1[O:36][CH3:37])=[O:28].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:13][O:14][C:15](=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][C:20](=[O:22])[NH:25][CH2:26][C:27]([C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1[O:36][CH3:37])=[O:28]
Reactant: COC(=O)CCCCC(=O)O
Reactant: COc1ccc(Cl)cc1C(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCCCC(=O)NCC(=O)c1cc(Cl)ccc1OC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 65.6 %

Procedure:
Dissolve 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (8.0362 g, 41.92 mmol), 4-(dimethylamino)pryidine (1.0525 g, 8.62 mmol) and adipic acid monomethyl ester (6.71 g, 41.90 mmol) in 100 mL of CH2Cl2 and allow it to stir at room temperature for 45 minutes. Add crude 2-amino-1-(5-chloro-2-methoxy-phenyl)-ethanone hydrochloride (10.99 g, 46.55 mmol) and triethylamine (9.42 g, 93.1 mmol) to the reaction mixture and allow it to stir at ambient temperature for 21 hours. Dilute the reaction with 200 mL of CH2Cl2 and wash it with 1 N HCl (2×), saturated aqueous NaHCO3 (2×) and brine (1×). Dry the organic layer with MgSO4. Filter off the drying agent and concentrate in vacuo to afford 9.39 g of the crude titled product: mass spectrum: m/z=342.1 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Cl:13][C:14]1[CH:15]=[C:16]([NH:20][C:21](=[O:24])[CH2:22]Cl)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[Cl:13][C:14]1[CH:15]=[C:16]([NH:20][C:21](=[O:24])[CH2:22][N:10]2[CH2:9][CH2:8][N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:12][CH2:11]2)[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(CCl)Nc1cccc(Cl)c1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CN1CCN(c2ccccn2)CC1)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.2 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(3-chloro-phenyl)-2-chloroacetamide (41 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure and the residue purified by preparative HPLC to provide 16 mg (32%) of the desired product. 1H NMR (500 MHz, DMSO-d6) δ 2.60 (t, J=4 Hz, 4H), 3.20 (s, 2H), 3.58 (t, J=4 Hz, 4H), 6.63 (t, J=5 Hz, 1H), 6.83 (d, J=6 Hz, 1H), 7.13 (d, J=6 Hz, 1H), 7.38 (t, J=6 Hz, 1H), 7.58 (m, 2H), 7.95 (s, 1H), 8.12 (d, J=5 Hz, 1H), 9.95 (s, 1H); MS (ESI/APCI+) m/e 331 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[NH:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]3[N:23]([C:24]=2[CH:25]=O)[CH:22]=[CH:21][S:20]3)=[CH:13][CH:12]=1.[OH-].[Na+]>C(O)C.C(OCC)(=O)C.CCCCCC>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]3[N:23]([C:24]=2/[CH:25]=[CH:2]/[C:1]([C:4]2[NH:5][CH:6]=[CH:7][CH:8]=2)=[O:3])[CH:22]=[CH:21][S:20]3)=[CH:13][CH:12]=1
Reactant: COc1ccc(-c2nc3sccn3c2C=O)cc1
Reactant: CC(=O)c1ccc[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nc3sccn3c2/C=C/C(=O)c2ccc[nH]2)cc1
Temperature: 27 °C
Reaction time: 4 h
Yield: 81.9 %

Procedure:
To a stirred solution of 2-acetyl pyrrole (109 mg, 1.0 mmol) and a 6-(4-methoxyphenyl) imidazo[2,1-b]thiazol-5-carbaldehyde (258 mg, 1.0 mmol) in ethanol (20 ml) 10% aqueous solution of NaOH was added (5 ml). The reaction mixture was stirred at room temperature 27° C. for 4 h and the reaction was monitored by TLC using ethyl acetate-hexane (3:7) as a solvent system. The solvent was evaporated under vacuum then the residue was dissolved in ethylacetate/water. The organic layer was washed with brine and evaporated. This was further purified by column chromatography using ethyl acetate:hexane (2:8) as a solvent system to obtain the pure product (17a) as yellow solid (286 mg, 82% yield). Mp: 177-179° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[S:11]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH2:18])=[CH:12]1.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>ClCCl>[CH2:23]([O:22][C:20](=[O:21])[NH:18][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][S:11][CH:12]=1)[CH3:24]
Reactant: NCCc1ccsc1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)NCCc1ccsc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 60 %

Procedure:
Add diisopropylethylamine (54.0 g, 418.0 mmol) to a suspension of 2-thiophene-3-yl-ethylamine hydrochloride in dichloromethane (400 mL) and stir the mixture for 40 min at RT. Cool the mixture to 0° C. and add dropwise ethyl chloroformate (22.7 g, 209.0 mmol) over 15 min. After the addition is complete, stir the reaction for 1 h at 0° C. Wash with 10% sodium bisulfate (500 mL). Extract the aqueous portion with dichloromethane (2×100 mL) and dry the combined organic portions over Na2SO4, filter and concentrate in vacuo. Purify the resulting residue by silica gel chromatography, using an eluent of 100% dichloromethane to give 22.6 g (60%) of the title compound. MS/ES m/z 200.3 [M+H]+.