Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][C:10]1[C:11]([CH3:56])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[O:16][C:15]([CH2:23][O:24][C:25]1[CH:54]=[CH:53][C:28]([CH2:29][C:30]3([CH2:45][C:46]([O:48]C(C)(C)C)=[O:47])[S:34][C:33](=[O:35])[N:32]([CH2:36][C:37]([O:39]C(C)(C)C)=[O:38])[C:31]3=[O:44])=[CH:27][CH:26]=1)([CH3:22])[CH2:14][C:13]2=[O:55])=[O:7])(C)(C)C.Cl>O1CCOCC1>[C:6]([CH2:8][O:9][C:10]1[C:11]([CH3:56])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[O:16][C:15]([CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][C:30]3([CH2:45][C:46]([OH:48])=[O:47])[S:34][C:33](=[O:35])[N:32]([CH2:36][C:37]([OH:39])=[O:38])[C:31]3=[O:44])=[CH:53][CH:54]=1)([CH3:22])[CH2:14][C:13]2=[O:55])([OH:7])=[O:5]
Reactant: Cc1c(C)c2c(c(C)c1OCC(=O)OC(C)(C)C)C(=O)CC(C)(COc1ccc(CC3(CC(=O)OC(C)(C)C)SC(=O)N(CC(=O)OC(C)(C)C)C3=O)cc1)O2
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(C)c2c(c(C)c1OCC(=O)O)C(=O)CC(C)(COc1ccc(CC3(CC(=O)O)SC(=O)N(CC(=O)O)C3=O)cc1)O2

Procedure:
A mixture of 340 mg of di-t-butyl α,α'-{5-[4-(6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethyl -4-oxochroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidine-3,5-diyl}diacetate (prepared as described in Example 50) and 4 ml of a 4N dioxane solution of hydrogen chloride was treated in the same manner described in Example 61, to give the title compound as a pale yellow powder, softening at 105°-110° C.
Reaction SMILES: [C:1]1([CH3:38])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:13][CH:12]([NH:29]C(OC(C)(C)C)=O)[C:11]2=[O:37])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1>Cl.O1CCOCC1>[C:1]1([CH3:38])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:28])[CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[CH2:13][CH:12]([NH2:29])[C:11]2=[O:37])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)CC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(N)CN2C(=O)CC(C)(C)C
Temperature: 50 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1.00 g) was suspended in4N HCl-dioxane (10 ml), the suspension was stirred for one hour at 50° C. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium bicarbonate was added, and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, to thereby obtain 741 mg of the titled compound (Yield: 91.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]([CH3:22])=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.[H-].[Na+].Br[CH2:30][CH:31]=[CH2:32]>CN(C=O)C>[CH2:32]([N:8]([C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]=1[CH3:22])[CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH2:10]1)[CH:31]=[CH2:30]
Reactant: COC(=O)c1cc(Cl)cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN(c1cc(Cl)cc(C(=O)OC)c1C)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 39 %

Procedure:
To a stirred solution of tert-butyl 4-((5-chloro-3-(methoxycarbonyl)-2-methylphenyl)amino)piperidine-1-carboxylate (0.70 g, 1.82 mmol) in DMF (7 mL), was added NaH (0.052 g, 2.19 mmol) at 0° C. After stirring for 20 minutes, 3-bromoprop-1-ene (0.44 g, 3.64 mmol) was added and the mixture was heated at 80° C. for 15 h. On completion, the reaction mass was quenched with ice cold water and extraction was carried out using DCM. The combined organic layers were dried, concentrated under reduced pressure and the residue was purified by column chromatography to afford the title compound (0.3 g, 39%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.[H][H]>C1COCC1.[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: [H][H]
Reactant: COc1cc(N2CCC(N3CCCC3)CC2)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: COc1cc(N2CCC(N3CCCC3)CC2)ccc1N

Procedure:
321 mg (1.053 mmol) 1-(3-methoxy-4-nitro-phenyl)-4-pyrrolidin-1-yl-piperidine are dissolved in 10 ml THF, combined with 30 mg Raney nickel and then shaken for 9 days at 20° C. under 4 bar hydrogen atmosphere. The catalyst is filtered off and washed again with THF. The solvent is eliminated in vacuo.
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:16])=O.Cl.S(=O)=O>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:16])=[O:10])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Agent: Cl
Agent: O=S=O
Solvent: Cc1ccccc1
Product: CCCCc1ccc(C(=O)Cl)cc1

Procedure:
A mixture of 1.1 g. of p-n-butyl benzoic acid, 2.5 g. of thionylchloride, 5 ml. of toluene and a small amount of zeolite was refluxed for about 4 hours to react them. After the reaction, excess of thionylchloride, dissolved hydrogen-chloride gas, sulfur dioxide gas, and toluene were vaporized to remove them by a rotary evaporator. A crude p-n-butyl benzoylchloride was obtained as a residue. On the other hand, 1.1 g. of 2,3-dichloroaniline was dissolved in 10 ml. of acetone and 1.3 g. of potassium carbonate was gradually added with stirring to suspend it.
Reaction SMILES: [CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.[N:37]1[CH:42]=[CH:41][N:40]=[CH:39][C:38]=1[NH2:43]>ClCCl>[CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([NH:43][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][N:37]=2)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Reactant: Nc1cnccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cnccn1)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 4b) (50 mg, 0.16 mmol) in dichloromethane (5 mL) was added oxalylchloride (0.02 mL, 0.25 mmol) at 0° C. and the reaction mixture was stirred at 25° C. for 3 h. Solvent was removed in vacuo and the residue was dissolved in dry dichloromethane. To this was added DIPEA (0.2 mL, 0.99 mmol) followed by 2-pyrazinamine (CAN 5049-61-6, 19 mg, 0.21 mmol) at 25° C. and the reaction mixture was stirred for 12 hours at that temperature. The solvent was removed in vacuo and the crude residue was purified by prep-HPLC to give 5-cyclohexyl-N-pyrazin-2-yl-6-(2,2,2-trifluoro-ethoxy)-nicotinamide as off white solid (10 mg, 15.9%); MS (ESI): 381.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][O:15][CH3:16])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33]Cl)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.[CH:35]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=[O:36]>COCCO>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][O:15][CH3:16])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33][N:40]3[CH2:41][CH2:42][N:37]([CH:35]=[O:36])[CH2:38][CH2:39]3)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)c(OC)cc23)c2c1OCO2
Reactant: O=CN1CCNCC1
Solvent: COCCO
Product: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCN(C=O)CC4)c(OC)cc23)c2c1OCO2
Yield: 63.6 %

Procedure:
This was prepared using the method described in example 13 using N-[5-chloro-7-(4-methoxybut-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (200 mg, 0.40 mmol) and 1-formylpiperazine (226 mg, 1.98 mmol) in 2-methoxyethanol (4 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent. There was thus obtained the title compound (148 mg, 64%) as a pale brown solid; NMR Spectum:(DMSOd6) 1.96 (quintet, 2H), 2.36 (m, 2H), 2.41 (m, 2H), 2.50 (t, 2H), 2.71 (t, 2H), 3.31 (s, 3H), 3.39 (m, 4H), 3.52 (t, 2H), 3.93 (s, 3H), 4.20 (t, 2H), 6.14 (s, 2H), 7.07 (s, 1H), 7.20 (s, 1H), 7.82 (s, 1H), 8.00 (s, 1H), 8.32 (s, 1H), 9.48 (s, 1H); Mass Spectrum: M+H+ 582/584.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:27]#[N:28])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:29][C:30]([CH3:36])([CH3:35])[CH2:31][C:32]([OH:34])=[O:33].C[O-].[Na+].[OH-].[Na+]>CN(C=O)C.O>[C:27]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:19][C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:29][C:30]([CH3:36])([CH3:35])[CH2:31][C:32]([OH:34])=[O:33])=[O:7])[N:9]=1)#[N:28]
Reactant: CCCCOC(=O)c1nc(C#N)c2cc(Oc3ccc(F)cc3)ccc2c1O
Reactant: CC(C)(N)CC(=O)O
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(CC(=O)O)NC(=O)c1nc(C#N)c2cc(Oc3ccc(F)cc3)ccc2c1O
Yield: 35.6 %

Procedure:
To a mixture of 1-cyano-7-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (60 mg, 0.16 mmol) and 3-amino-3-methyl-butyric acid (92 mg, 0.79 mmol) in DMF (1.5 mL) was added NaOMe solid (34 mg, 0.63 mmol). The resultant mixture was stirred in a 150-160° C. oil bath for 4 h. Reaction mixture was diluted with water (60 mL) and basified by 1 N NaOH to pH=10. It was extracted with EtOAc (30 mL), which was discarded. Aqueous layer was acidified by 1 N HCl to pH=3-4. Precipitate was collected and dried. Crude product was then triturated with MeOH (4 mL). Solid was collected and dried in vacuo to provide the title compound 24 mg (0.057 mmol) in 35% yield. LC-MS ESI−: 422.07 (M−1)−.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([CH2:12][CH:13]([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[NH:39][C:38](=[O:40])[O:37][N:36]=2)=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH3:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[NH:39][C:38](=[O:40])[O:37][N:36]=2)=[CH:27][CH:28]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)n(CC(O)c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CCCCc1nc(C)n(CC(=O)c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
A mixture of 6-butyl-3-(2-hydroxy-2-phenylethyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one (0.25 g), 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.3 g) and methylene chloride (10 mL) was stirred at room temperature for 2 hr. A saturated aqueous sodium hydrogen carbonate solution and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr and extracted with chloroform. The chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.2 g, 78%).
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[CH:6]=[CH:5][N:4]=1.[CH3:10][C:11]1[CH:12]=[C:13]([CH:15]=[C:16]([CH3:18])[CH:17]=1)[NH2:14]>C(OCCOCCOCC)C>[CH3:10][C:11]1[CH:12]=[C:13]([NH:14][C:3]2[NH:8][C:7](=[O:9])[CH:6]=[CH:5][N:4]=2)[CH:15]=[C:16]([CH3:18])[CH:17]=1
Reactant: Cc1cc(C)cc(N)c1
Reactant: CSc1nccc(=O)[nH]1
Solvent: CCOCCOCCOCC
Product: Cc1cc(C)cc(Nc2nccc(=O)[nH]2)c1
Temperature: 170 °C

Procedure:
2-(Methylthio)pyrimidin-4(3H)-one (4-1, 2.00 g, 14.1 mmol) and 3,5-dimethylaniline (2.10 ml, 16.9 mmol) were stirred in 14 ml of 2-ethoxyethyl ether and the resulting solution was heated to 170° C. After 3 days the reaction was concentrated in vacuo. The residue was diluted with 95:5 DCM/MeOH. The solid, which did not dissolve, was filtered to afford a sample of pure 2-(3,5-dimethylphenylamino)-3H-pyrimidin-4-one. The filtrate was concentrated in vacuo and the residue was triturated with ether. The mixture was filtered and the solid was washed with ether. The solid sample was combined with the previous precipitate to afford 2-(3,5-dimethyl-phenylamino)-3H-pyrimidin-4-one.
Reaction SMILES: [N:1]([C@H:4]1[C@@H:9]([CH3:10])[CH2:8][C@@H:7]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[NH:17][C:18](=[O:34])[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])[N:20]=2)[CH2:6][C@H:5]1[NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[N+]=[N-]>CO.CCOC(C)=O.[Pd]>[NH2:1][C@H:4]1[C@@H:9]([CH3:10])[CH2:8][C@@H:7]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[NH:17][C:18](=[O:34])[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]3[C:27]([F:33])=[CH:28][CH:29]=[CH:30][C:31]=3[F:32])[N:20]=2)[CH2:6][C@H:5]1[NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39]
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N
Reaction time: 16 h
Yield: 100 %

Procedure:
Degass a solution of tert-butyl (1R,2S,3S,5R)-2-azido-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methylcyclohexylcarbamate (1.0 equiv.) in MeOH/EtOAc (3/1, 0.04 M). To this solution was added Pd/C (0.2 equiv.) and purge with Ar and H2. The mixture was stirred under H2 for 16 hrs. Filter the mixture over cetlite and wash the cake with MeOH. Concentrate the filtrate to yield tert-butyl (1R,2S,3S,5R)-2-amino-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methylcyclohexylcarbamate in 100% yield). LC/MS (m/z)=556.3 (MH+), Rt=0.73 min.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[CH:31]1([N:36]2[CH2:41][CH2:40][NH:39][C:38](=[O:42])[CH2:37]2)[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH:31]1([N:36]2[CH2:41][CH2:40][N:39]([C:19]3[CH:20]=[CH:21][C:9]4[C:8](=[O:30])[C:7]5[C:6]6[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=6)[NH:13][C:12]=5[C:11]([CH3:16])([CH3:17])[C:10]=4[CH:18]=3)[C:38](=[O:42])[CH2:37]2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C1CN(C2CCCC2)CCN1
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC1(C)c2cc(N3CCN(C4CCCC4)CC3=O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B2-10, the title compound was prepared from Compound B1 and 4-cyclopentylpiperazin-2-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([O:10][CH3:11])=[C:5]([O:12][CH3:13])[C:4]=1[O:14][CH3:15].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:28](O)=[O:29]>>[CH3:1][O:2][C:3]1[C:4]([O:14][CH3:15])=[C:5]([O:12][CH3:13])[C:6]([O:10][CH3:11])=[C:7]([CH3:9])[C:8]=1[CH:28]=[O:29]
Reactant: COc1cc(C)c(OC)c(OC)c1OC
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1c(C)c(C=O)c(OC)c(OC)c1OC
Yield: 90 %

Procedure:
To a solution of 1,2,3,4-tetramethoxy-5-methylbenzene (34.3 g, 162 mmol) in trifluoroacetic acid (200 ml) was added hexamethylenetetramine (25.0 g, 178 mmol), and the solution was heated under reflux for 3 hours. The solvent was distilled off under reduced pressure. Water (200 ml) was added to the residue which was then heated under reflux for one hour, neutralized with 3N sodium hydroxide and extracted with ethyl acetate (200 ml×3), and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was subjected to a silica gel column chromatography to give 34.9 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9](Br)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[C:19]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Br:1][C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9]([C:26]2[CH:27]=[CH:28][C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:24][CH:25]=2)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: Brc1ccc2ccc3c(Br)ccc4ccc1c2c43
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(-c2ccc3ccc4c(Br)ccc5ccc2c3c54)cc1
Temperature: 130 °C
Reaction time: 6 h
Yield: 30.5 %

Procedure:
A mixed solution of 2 g of 1,6-dibromopyrene, 1 g of 4-t-butylphenylboronic acid, 2.4 g of tripotassium phosphate, 0.4 g of tetrabutylammonium bromide, 22 mg of palladium acetate and 60 ml of dimethylformamide was heated and stirred under a nitrogen gas stream at 130° C. for 6 hours. The solution was cooled to room temperature and 30 ml of water was poured into the solution, followed by extraction with 100 ml of dichloromethane. The organic layer was washed twice with 50 ml of water, dried over magnesium sulfate and then evaporated. The concentrate was purified by silica gel column chromatography and then vacuum-dried to obtain 0.7 g of 1-bromo-6-(4-t-butylphenyl)pyrene.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[CH3:13]I>CN(C=O)C>[Cl:1][C:2]1[N:6]([CH3:13])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: CI
Reactant: Clc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(Cl)nc2ccccc21
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
According to the procedure D. Harrison, et al., J. Chem. Soc., 2930, 1963, to a cooled (5° C.), stirred solution of 2-chlorobenzimidazole (26.1 g, 0.171 mol) in DMF (125 mL) was added NaH (60% dispersion in mineral oil; 7.2 g, 0.180 mol) in several portions. After 30 minutes MeI (25.5 g, 0.180 mol) was added. The cooling bath was removed and stirring was continued for 30 minutes. The mixture was recooled, H2O (200 mL) was added, and the resulting precipitate was collected by filtration to give 20.2 g (71%) of product as an off-white solid m.p. 107°-109° C.
Reaction SMILES: [OH-].[K+].C(OC(=O)[NH:7][CH:8]1[CH2:11][C:10]2([CH2:16][CH2:15][N:14]([C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[C:22]([Cl:27])[CH:23]=4)[N:18]=3)[CH2:13][CH2:12]2)[CH2:9]1)C>C(O)C.O>[Cl:27][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([N:14]1[CH2:15][CH2:16][C:10]3([CH2:9][CH:8]([NH2:7])[CH2:11]3)[CH2:12][CH2:13]1)[CH:26]=[CH:25]2
Reactant: CCOC(=O)NC1CC2(CCN(c3ccc4cc(Cl)ccc4n3)CC2)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC1CC2(CCN(c3ccc4cc(Cl)ccc4n3)CC2)C1
Temperature: 110 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
0.726 g (12.95 mmol) of potassium hydroxide is added, at room temperature, to a solution of 0.242 g (0.65 mmol) of ethyl[7-(6-chloroquinolin-2-yl)-7-azaspiro[3.5]non-2-yl]carbamate, obtained in step 12.5., in 3.25 mL of ethanol/water (1/1). The mixture is then heated at 110° C. for 12 hours. 0.363 g (6.47 mmol) of potassium hydroxide is added and the mixture is left stirring for 3 hours. The resulting mixture is allowed to cool to room temperature and is then concentrated under reduced pressure. The residue is taken up in dichloromethane and 1N hydrochloric acid solution. The acidic aqueous phase is washed with dichloromethane and then basified with aqueous 1N sodium hydroxide solution, which is extracted several times with dichloromethane. The combined organic phases are then dried over sodium sulfate and the filtrate is concentrated under reduced pressure. 0.188 g of expected product is thus obtained in the form of an oil.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C@H:17]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH:18]=O)[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:28]([I:31])(I)I>C1COCC1.[Cl-].[Cr+3].[Cl-].[Cl-]>[Si:1]([O:8][C@H:9]([C@H:17]([O:20][Si:21]([C:24]([CH3:25])([CH3:27])[CH3:26])([CH3:22])[CH3:23])/[CH:18]=[CH:28]/[I:31])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: IC(I)I
Reactant: COC(=O)CCC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C=O)O[Si](C)(C)C(C)(C)C
Agent: [Cr+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(=O)CCC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](/C=C/I)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 39.7 %

Procedure:
A solution of (5S,6S)-methyl 5,6-bis(tert-butyldimethylsilyloxy)-7-oxoheptanoate (389 mg, 0.929 mmol) and iodoform (2.19 g, 5.57 mmol) in THF (20 mL) was allowed it to stir for about 10 min. In a separate round bottom flask added chromium chloride (II)(1.36 mg, 11.1 mmol) and dissolved it in THF (10 mL) and cooled the reaction mixture to 0° C. The aldehyde and iodoform mixture were transferred to a stirring solution of chromium chloride at 0° C., warmed to room temperature and allowed to stir for 3 h. The reaction was quenched with water, extracted with ether, dried, and concentrated. Purification by flash chromatography (silica gel, hexanes) afforded 200 mg (40% yield) of (5S,6R,E)-methyl 5,6-bis(tert-butyldimethylsilyloxy)-8-iodooct-7-enoate. 1H NMR (250 MHz, CDCl3): δ 6.46 (dd, J=14.9 Hz, J=7.2 Hz 1H), 6.18 (d, J=15.4 Hz, 1H), 3.85 (m, 1H), 3.63 (s, 3H), 3.52 (m, 1H), 2.27 (t, J=7.1 Hz, 3H), 1.62 (m, 2H), 1.47 (m, 2H), 0.850 (s, 9H), 0.849 (s, 9H), 0.023 (s, 6H), 0.013 (s, 3H), −0.005 (s, 3H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1.[CH3:22][C:23]1[CH:32]=[C:31]([NH:33][C:34](NC2C3C(=CC=CC=3)N=C(C)C=2)=[O:35])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1>C1COCC1>[CH2:15]([C:9]1([C:12]([OH:14])=[O:13])[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][NH:3][C:34]([NH:33][C:31]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=[C:23]([CH3:22])[CH:32]=2)=[O:35])[CH2:7][CH2:8]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cc(NC(=O)Nc2cc(C)nc3ccccc23)c2ccccc2n1
Reactant: NCCN1CCC(Cc2ccccc2)(C(=O)O)CC1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)NCCN2CCC(Cc3ccccc3)(C(=O)O)CC2)c2ccccc2n1

Procedure:
1-(2-Amino-ethyl)-4-benzyl-piperidine-4-carboxylic acid dihydrochloride (3.35 g, 10 mmol), 1,3-bis-(2-methyl-quinolin-4-yl)-urea (3.43 g, 10 mmol) and TEA (5 mL, 36 mmol) are suspended in THF (50 mL) and heated at reflux for 48 h. The solvent is evaporated and the residue purified by HPLC to provide the title compound.