Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:50])[CH2:10][CH:11]([NH:21][C:22]([CH:24]1[N:29]2[C:30](=[O:49])[CH:31]([NH:36][C:37]([C:39]3[CH:48]=[CH:47][C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH:40]=3)=[O:38])[CH2:32][CH:33]=[CH:34][CH2:35][CH:28]2[CH2:27][CH2:26][CH2:25]1)=[O:23])[CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])C1C=CC=CC=1.O>CO.[OH-].[Na+]>[C:17]([Si:14]([CH3:16])([CH3:15])[O:13][CH2:12][CH:11]([NH:21][C:22]([CH:24]1[N:29]2[C:30](=[O:49])[CH:31]([NH:36][C:37]([C:39]3[CH:48]=[CH:47][C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH:40]=3)=[O:38])[CH2:32][CH:33]=[CH:34][CH2:35][CH:28]2[CH2:27][CH2:26][CH2:25]1)=[O:23])[CH2:10][C:9]([OH:50])=[O:8])([CH3:19])([CH3:18])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OCC(CC(=O)OCc1ccccc1)NC(=O)C1CCCC2CC=CCC(NC(=O)c3ccc4ccccc4c3)C(=O)N21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC(CC(=O)O)NC(=O)C1CCCC2CC=CCC(NC(=O)c3ccc4ccccc4c3)C(=O)N21
Reaction time: 5 h

Procedure:
4-(tert-Butyl-dimethyl-silanyloxy)-3-({7-[(naphthalene-2-carbonyl)-amino]-6-oxo-1,3,4,6,7,8,11,11a-octahydro-2H-pyrido[1,2-a]azocine-4-carbonyl}-amino)-butyric acid benzyl ester, 114, (0.52 gm) is dissolved in 10 mL methanol, to which 1.73 mL of 1N aqueous sodium hydroxide is added at RT. The reaction is stirred for 5 h and a second aliquot (0.7 mL) of 1N sodium hydroxide solution is added. The reaction is allowed to proceed for 18 h at RT. Water is added and the mixture is extracted three times with diethyl ether. The aqueous layer is then acidified to pH ˜3 with 10% aqueous citric acid, and extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium chloride, dried over sodium sulfate powder, and concentrated in vauo to afford the desired product.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH2:3][CH2:2]1.[C:8](Cl)(=[O:17])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl>N1C=CC=CC=1>[C:8]([N:5]1[C:4](=[O:6])[CH2:3][CH2:2][C:1]1=[O:7])(=[O:17])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=C1CCC(=O)N1
Reactant: CCCCCCCCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCC(=O)N1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
20 g succinimide were suspended in 100 ml pyridine, 0.5 g N,N-dimethylaminopyridine added, and 39.2 g nonanoic acid chloride added dropwise at ice-bath temperature. Subsequently the mixture was stirred for 1 h at room temperature and 500 ml of 2N HCl solution were added with cooling. The aqueous phase was extracted with ethyl acetate and the organic phase washed with 2N HCl solution and dried (Na2SO4). After removing the solvent, the residue was twice recrystallized from n-hexane. 31.6 g (65%) N-nonanoylsuccinimide were obtained as a colourless solid. Melting point: 59 to 60° C. (n-hexane). The 1H-NMR spectroscopic data are in agreement with the structure.
Reaction SMILES: [NH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[N:4]=[N:3][C:2]1=[N:14][NH2:15].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]=O>C(O)C>[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]=[N:15][NH:14][C:2]1[N:3]=[N:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[N:1]=1
Reactant: O=Cc1ccccn1
Reactant: NN=c1nnc2c([nH]1)[nH]c1ccccc12
Solvent: CCO
Product: C(=NNc1nnc2c(n1)[nH]c1ccccc12)c1ccccn1
Temperature: 60 °C

Procedure:
To a solution of (1,9-Dihydro-1,3,4,9-tetraaza-fluoren-2-ylidene)-hydrazine 14d (27 mmol, 1 equiv.) in ethanol (50 mL) is added 2-pyridinecarboxaldehyde (27 mmol, 1 equiv.). The mixture is heated at 60° C. for 10 hours. The solution is allowed to cool to room temperature. The product is filtered and dried under vacuum for 15 hours. N-Pyridin-2-ylmethylene-N′-(9H-1,3,4,9-tetraaza-fluoren-2-yl)-hydrazine 14e is obtained as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[CH:12][C:11]=2[Cl:24])=[O:9])[CH:7]=1.FC(F)(F)S([N:31]=[N+:32]=[N-])(=O)=O.CO.CCOC(C)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[N:1]([C:2]1[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[CH:12][C:11]=2[Cl:24])=[O:9])[CH:7]=1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=NS(=O)(=O)C(F)(F)F
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2)cc1Cl
Agent: [Cu+2]
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(F)cc2)cc1Cl

Procedure:
To a suspension of compound 429 (1.00 g, 2.82 mmol) in DCM (5.0 mL) was added a solution of copper(II) sulphate pentahydrate (35.2 mg, 0.14 mmol) in H2O (4.0 mL), and TEA (1.18 mL, 8.45 mmol). The crude trifluoromethansulfonic azide was added slowly under stirring to the reaction mixture followed by by MeOH (5 mL). After 18 h at RT the reaction mixture was poured into a mixture of EtOAc/NaHCO3(aq.). The organic phase was washed with water, brine, filtered and concentrated in vacuo to give the crude product. The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 0:100 to 25:75 as the eluent to afford the title compound as yellow solid.
Reaction SMILES: [H-].[Li+].[C:3]1([CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I[CH2:24][CH2:25][CH2:26][C:27]1[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=1)[O:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].Cl>CN(C=O)C>[C:3]1([CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]2[CH:11]=[CH:12][C:13](=[O:16])[N:14]([CH2:24][CH2:25][CH2:26][C:27]3[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=3)[O:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:15]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=c1ccc(C(c2ccccc2)c2ccccc2)c[nH]1
Reactant: CCOC(=O)COc1cccc(CCCI)c1
Agent: Cl
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(CCCn2cc(C(c3ccccc3)c3ccccc3)ccc2=O)c1
Reaction time: 24 h
Yield: 74.4 %

Procedure:
To a mixture of LiH (6.20 g) in DMF (100 mL) was added a solution of 5-(diphenylmethyl)-2(1H)-pyridinone (82.4 g) in DMF (500 mL) at ambient temperature. A solution of ethyl [3-(3-iodopropyl)phenoxy]acetate (118 g) in DMF (300 mL) was added dropwise to the mixture at ambient temperature over 30 minutes and the mixture was stirred at the same temperature for 24 hours. The resulting mixture was poured into 1M HCl aqueous solution (800 mL) at 0° C. and the mixture was extracted with EtOAc (2 L+1 L). The organic layer was washed successively with 12% NaCl aqueous solution and brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=1:1) to afford ethyl (3-{3-[5-(diphenylmethyl)-2-oxo-1(2H) -pyridinyl]propyl}phenoxy)-acetate(113 g) as a slightly yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1Br.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:50]([C:52]([OH:84])([CH2:82][CH3:83])/[CH:53]=[CH:54]/[C:55]1[CH:60]=[CH:59][C:58]([C:61]([CH2:79][CH3:80])([C:64]2[CH:69]=[CH:68][C:67](B3OC(C)(C)C(C)(C)O3)=[CH:66][CH:65]=2)[CH2:62][CH3:63])=[CH:57][C:56]=1[CH3:81])[CH3:51].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:67]1[CH:66]=[CH:65][C:64]([C:61]([CH2:79][CH3:80])([C:58]2[CH:59]=[CH:60][C:55](/[CH:54]=[CH:53]/[C:52]([CH2:82][CH3:83])([OH:84])[CH2:50][CH3:51])=[C:56]([CH3:81])[CH:57]=2)[CH2:62][CH3:63])=[CH:69][CH:68]=1
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1C)CC
Reactant: COC(=O)Cc1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3ccccc3CC(=O)OC)cc2)cc1C)CC
Temperature: 100 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
(2-Bromo-phenyl)acetic acid methyl ester (Example 126-(1); 35 mg, 0.152 mmol), palladium acetate (2.2 mg, 0.010 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (8.2 mg, 0.016 mmol), potassium phosphate (64 mg, 0.303 mmol) and water (0.2 mL) were added to a solution of (E)-3-ethyl-1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol (Example 39-(5); 48.3 mg, 0.101 mmol) in toluene (3 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for two hours. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to give the target compound as a colorless oil (26.6 mg, 53%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:24](OCCCCC)=O>C(#N)C>[Br:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:4]2[C:3]=1[CH:11]=[N:24][NH:5]2
Reactant: CCCCCON=O
Reactant: COc1ccc(N)c(C)c1Br
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2[nH]ncc2c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To a solution of 3-bromo-4-methoxy-2-methylaniline (19.06 g) in acetonitrile (250 mL) was slowly added acetic anhydride (18.9 mL), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture were added potassium acetate (2.60 g) and pentyl nitrite (22.3 g), and the mixture was heated under reflux for 8 hr. The reaction mixture was concentrated, and to the residue was added 6M hydrochloric acid (200 mL), and the mixture was heated under reflux overnight. The reaction mixture was neutralized with 8M sodium hydroxide, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was dissolved in tetrahydrofuran, and the solution was treated with activated carbon. The activated carbon was filtered off, the filtrate was concentrated, and the obtained residue was crystallized from diisopropyl ether. The crystals were collected by filtration, washed with diisopropyl ether, and dried to give the title compound (10.42 g, yield 52%) as yellow crystals. melting point 178-180° C. MS: 229 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(O)[C:9]([O:11]C(C)(C)C)=[O:10])=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)(O)[O-]>ClCCl.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(O)(C(=O)OC(C)(C)C)c2ccccc2)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(C(=O)O)c2ccccc2)cc1

Procedure:
1.49 g (5 mmol) of tert-butyl 2-(4-methyl-phenyl)-2-phenyl-2-hydroxy-acetate are stirred at room temperature in 60 ml of dichloromethane for 3 h with 6.3 ml (40 mmol) of triethylsilane and 12.6 ml (60 mmol) of trifluoroacetic acid. The mixture is diluted with 60 ml of water, adjusted to a pH of 2-3 with saturated aqueous bicarbonate solution and shaken. After removal of the organic phase, the aqueous phase is extracted twice more with dichloromethane. The combined organic phases are dried over sodium sulphate, filtered and concentrated. The product is chromatographed on silica gel 60 using 40-60 petroleum ether/ethyl acetate (6:4).
Reaction SMILES: C(Cl)(=[O:8])C1C=CC=CC=1.[CH3:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O>[CH3:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10].[C:21]1([OH:8])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCCCCCCCCCCC
Solvent: O
Product: Oc1ccccc1
Temperature: 210 °C
Reaction time: 2.5 h
Yield: 27680 %

Procedure:
4,4′-methylene diphenyl dicarbamate (38 g, 86.8 mmole) and inhibitor benzoyl chloride (0.09 g, 0.6 mmole) were charged to 500 ml three-neck bottle with solvent n-dodecane (250 ml, 189.19 g). The mixture was stirred with a magnetic stirbar and heated to 210° C. with an oil bath. One neck of the bottle was equipped with a thermometer and charged with nitrogen, and another neck was connected to a divide tube which was further connected to a condenser to charge with cold water. The upper end of the condenser was connected to a grease seal. The reaction was carried out for 2.5 hours. The progress of the reaction was monitored by FT-IR. It was observed that the absorption peak at 1720 cm−1 and the absorption peak at 3335 cm−1 disappeared completely, and the absorption peak appeared at 2270 cm−1. After part of n-dodecane (100 ml) and produced phenol (15.63 g) was retrieved from the divide tube, the heating was stopped and the reaction ended.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[NH:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][CH:14]3[CH2:19][CH2:18][CH2:17][N:16]([CH:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:21]([OH:23])=O)[CH2:15]3)=[CH:10][CH:11]=2)[CH:6]=[N:5]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>CN(C)C=O.CN(C1C=CC=CN=1)C>[CH3:1][N:2]([CH3:3])[C:21](=[O:23])[CH:20]([N:16]1[CH2:17][CH2:18][CH2:19][CH:14]([NH:13][C:9]2[CH:8]=[C:7]3[C:12](=[CH:11][CH:10]=2)[NH:4][N:5]=[CH:6]3)[CH2:15]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CNC
Reactant: O=C(O)C(c1ccccc1)N1CCCC(Nc2ccc3[nH]ncc3c2)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Product: CN(C)C(=O)C(c1ccccc1)N1CCCC(Nc2ccc3[nH]ncc3c2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.7 %

Procedure:
Dimethylamine (100 mg) and the compound prepared in Example 222 (350 mg) were dissolved in dimethylformamide (5 ml), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (257 mg), 1-hydroxybenzotriazole (227 mg), and dimethylaminopyridine (5 mg) were added to the solution. The reaction mixture was stirred at room temperature for 18 hr. A saturated aqueous sodium hydrogencarbonate solution (5 ml) was then added thereto, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC [chloroform/methanol]t to give 180 mg of the title compound as two diastereomers (ratio=ca. 50:50)).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][NH:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([O:21]CC3C=CC=CC=3)=[CH:18][CH:19]=2)[CH:14]=[CH:13]1.[H][H].[ClH:31]>C(O)C.CO.CCOCC.[Pd]>[ClH:31].[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][NH:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=2)[CH:14]=[CH:13]1
Reactant: [H][H]
Reactant: Fc1cnccc1CCCNn1ccc2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Solvent: CCOCC
Product: Oc1ccc2c(ccn2NCCCc2ccncc2F)c1

Procedure:
In a 500 ml Parr hydrogenation bottle, 10% Pd/C (1.5 g) was suspended in 50 ml ethanol, and to this was added a solution of 1-[(3-fluoro-4-pyridinyl)propylamino]-5-phenylmethoxy-1H-indole (15.0 g) in 200 ml ethanol. The mixture was shaken under 50 psi hydrogen gas for three hours at 50° C. Upon cooling, the mixture was filtered, and the filtrate was concentrated to give a solid, 11.4 g. This material was eluted on a silica gel column with ethyl acetate/dichloromethane (1:3) via HPLC, and the desired fractions were concentrated to give a solid, 8.5 g, m.p. 90°-95° C. A 2.0 g sample of this material was dissolved in 50 ml methanol, the pH was adjusted to 1 with ethereal HCl, and the solution was diluted with 200 ml ether. The resultant precipitate was collected and dried to give 2.1 g of the product, m.p. 218° C. (dec.).
Reaction SMILES: [OH:1][CH:2]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:3][CH2:4][CH:5]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])=[CH:12][CH:11]=2)[CH:6]1[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1.[CH:38]1[CH:43]=[C:42]2[CH:44]([CH2:51][O:52][C:53]([NH:55][C@H:56]([C:67](O)=[O:68])[CH2:57][C:58]3[CH:63]=[CH:62][C:61]([N:64]=[N+:65]=[N-:66])=[CH:60][CH:59]=3)=[O:54])[C:45]3[C:50]([C:41]2=[CH:40][CH:39]=1)=[CH:49][CH:48]=[CH:47][CH:46]=3.C1C2C(COC(=O)N(CCCCC(=O)NC3C=CC(N4C(=O)C(CCC(O)C5C=CC=CC=5)C4C4C=CC(OC)=CC=4)=CC=3)C3C=CC=CC=3)C3C(=CC=CC=3)C=2C=CC=1>CN(C)C=O>[CH:43]1[C:42]2[CH:44]([CH2:51][O:52][C:53](=[O:54])[NH:55][CH:56]([C:67](=[O:68])[NH:22][CH2:21][CH2:20][CH2:19][CH2:18][C:17](=[O:23])[NH:16][C:13]3[CH:12]=[CH:11][C:10]([N:7]4[C:8](=[O:9])[CH:5]([CH2:4][CH2:3][CH:2]([OH:1])[C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)[CH:6]4[C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)=[CH:15][CH:14]=3)[CH2:57][C:58]3[CH:59]=[CH:60][C:61]([N:64]=[N+:65]=[N-:66])=[CH:62][CH:63]=3)[C:45]3[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:41]=2[CH:40]=[CH:39][CH:38]=1
Reactant: COc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(NC(=O)CCCCN)cc2)cc1
Reactant: [N-]=[N+]=Nc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Agent: COc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(NC(=O)CCCCN(C(=O)OCC3c4ccccc4-c4ccccc43)c3ccccc3)cc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(NC(=O)CCCCNC(=O)C(Cc3ccc(N=[N+]=[N-])cc3)NC(=O)OCC3c4ccccc4-c4ccccc43)cc2)cc1
Yield: 82.2 %

Procedure:
200 mg (0.40 mmol) of product 9 and 340 mg (0.79 mmol) of Fmoc -p-azido-Phe-OH 10 (Bachem) are solved in 4 ml DMF (dimethylformamide) and reacted according to production of product 8. 300 mg (82%) of product 11 is obtained in form of an amorphic solid compound: C54H53N7O7 (912.07) MS (ESI+) 912.5 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][O:17]C)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:19]([C:22]1[O:26][C:25]([CH:27]=O)=[CH:24][CH:23]=1)([O-:21])=[O:20]>C1C=CC=CC=1.C(OCC)C.FB(F)F>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15](=[CH:27][C:25]2[O:26][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][CH:24]=2)[CH:16]=[O:17])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC=Cc1ccc(OCc2ccccc2)cc1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Agent: FB(F)F
Solvent: c1ccccc1
Solvent: CCOCC
Product: O=CC(=Cc1ccc([N+](=O)[O-])o1)c1ccc(OCc2ccccc2)cc1
Reaction time: 2 h

Procedure:
6.4 g of 1-(4-benzyloxyphenyl)-2-methoxyethylene, diluted with 10 cc of benzene, are added dropwise at 0°-5° to 11.15 g of 5-nitrofuran-2-aldehyde in 30 cc of dry benzene after the addition of a few drops of diethyl ether/trifluoroborane. The mixture is stirred at 40° for 11/2 hours, is washed with a 5% aqueous sodium acetate solution and with water, dried with magnesium sulphate and concentrated by evaporation. The residue is heated to 90° for 4 hours with 10% hydrochloric acid and glacial acetic acid. The mixture is again concentrated by evaporation, is taken up in ether and the acid salt portion is filtered off. After concentration, orange crystals having a M.P. of 145°-155°, crystallize from the ether solution.
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[CH3:11][S:12]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[CH:23][C:22]=1[NH2:31])(=[O:14])=[O:13].Cl.N1C=CC=CC=1>C(#N)C>[CH3:11][S:12]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][N:20]1[C:21]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[CH:23][C:22]=2[N:31]=[CH:1]1)(=[O:14])=[O:13]
Reactant: CS(=O)(=O)CCOCCNc1c(N)cnc2ccccc12
Reactant: CCOC(OCC)OCC
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CS(=O)(=O)CCOCCn1cnc2cnc3ccccc3c21
Reaction time: 0.33 h
Yield: 67.9 %

Procedure:
Triethyl orthoformate (2 mL, 12 mmol) was added to a stirred solution of N4-{2-[2-(methylsulfonyl)ethoxy]ethyl}quinoline-3,4-diamine (3.1 g, 10 mmol) in acetonitrile (50 mL). Pyridine hydrochloride (0.3 g) was added and the reaction mixture was heated to reflux with the volatiles being collected in a Dean Stark trap. After 20 minutes analysis by TLC indicated that the starting material was consumed. The reaction mixture was concentrated under reduced pressure to provide a viscous oil. The oil was triturated with ethyl acetate. The resulting solid was isolated by filtration and washed with ethyl acetate to provide 2.17 g of 1-{2-[2-(methylsulfonyl)ethoxy]ethyl}-1H-imidazo[4,5-c]quinoline as an off-white powder.
Reaction SMILES: C(N[C:10](=[O:25])[C:11]([CH3:24])=[CH:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=1[NH2:23])CC1C=CC=CC=1.NC1C=C(OC)C(OC)=CC=1C=C(C)C(O)=O.[CH:43]1[C:48]([N+:49]([O-:51])=[O:50])=[CH:47][CH:46]=[C:45]([OH:52])[CH:44]=1.CN(C1C=CC=CN=1)C.Cl.C(N=C=NCCCN(C)C)C>CCCCCC.C(OCC)(=O)C.ClCCl>[N+:49]([C:48]1[CH:43]=[CH:44][C:45]([O:52][C:10](=[O:25])[C:11]([CH3:24])=[CH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=2[NH2:23])=[CH:46][CH:47]=1)([O-:51])=[O:50]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1cc(N)c(C=C(C)C(=O)NCCc2ccccc2)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: COc1cc(N)c(C=C(C)C(=O)O)cc1OC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1cc(N)c(C=C(C)C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1OC
Yield: 12 %

Procedure:
Into 20 ml of dichloromethane, 0.82 g (3.5 mmol) of (E) 3-(2-amino-4,5-dimethoxyphenyl)-2-methyl-2-propenoic acid and 0.97 g (7 mmol) of p-nitrophenol (manufactured by Wako Pure Chemical Industries, Ltd.) were dissolved, and 40 mg of dimethylaminopyridine (manufactured by Wako Pure Chemical Industries, Ltd.) were added thereto. While this mixture was stirred under cooling with ice, 0.81 g (4.2 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC/HCl) (manufactured by Wako Pure Chemical Industries, Ltd.) were added thereto in portions. The mixture was returned to room temperature and then was stirred for 20 hours. After the end point of the reaction was verified by TLC, the reaction liquid was concentrated under a reduced pressure and then was dissolved in 100 ml of ethyl acetate. After this solution was washed and dried, the solvent was evaporated, whereby a syrupy crude product was obtained. This product was refined by a silica gel column chromatography (n-hexane/ethyl acetate=2/1), whereby 0.15 g of the aimed compound was obtained as a yellow crystal (yield: 12%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH2:19])[N:13]=2)[CH:5]=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[C:25]([Cl:27])[CH:26]=1>>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([C:23]3[CH:22]=[C:21]([Cl:20])[CH:26]=[C:25]([Cl:27])[CH:24]=3)[N:15]=[C:14]([NH2:19])[N:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: Nc1nccc(NCCNc2cc(Cl)nc(N)n2)n1
Product: Nc1nccc(NCCNc2cc(-c3cc(Cl)cc(Cl)c3)nc(N)n2)n1

Procedure:
The product of Example 6A (62 mg, 0.221 mmol) and 3,5-dichlorophenyl boronic acid (46 mg, 0.243 mmol) were treated under the conditions described in Example 6B to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.92 (s, 2H) 7.66 (t, J=2.03 Hz, 1H) 7.61 (d, J=5.76 Hz, 1H) 6.99 (s, 1H) 6.86 (s, 1H) 6.33 (s, 1H) 6.15 (s, 2H) 5.85 (s, 2H) 5.74 (d, J=5.76 Hz, 1H) 3.33-3.51 (m, 4H); MS (ESI+) m/z 390.9 (M+H)+.