Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([C:17]1[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[C:20]([O:26][CH3:27])=[CH:19][C:18]=1[CH3:28])[C:6]([NH:8][NH:9]C(OC(C)(C)C)=O)=[O:7].Cl.C(OCC)(=O)C.[OH-].[Na+]>C(OCC)(=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([C:17]1[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[C:20]([O:26][CH3:27])=[CH:19][C:18]=1[CH3:28])[C:6]([NH:8][NH2:9])=[O:7]
Reactant: COc1cc(C)c(C(CCCCl)C(=O)NNC(=O)OC(C)(C)C)cc1C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COc1cc(C)c(C(CCCCl)C(=O)NN)cc1C(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 95.2 %

Procedure:
tert-Butyl N′-[5-chloro-2-(5-isopropyl-4-methoxy-2-methylphenyl)pentanoyl]hydrazinecarboxylate (6.1 g) was dissolved in ethyl acetate (50 mL). A 4 N hydrochloric acid-ethyl acetate solution (50 mL) was added and the mixture was stirred at room temperature for 3.5 hours. The reaction solution was made alkaline with a 5 N sodium hydroxide solution under ice-cooling, and the organic layer was separated. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration, and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (4.4 g). The property values of the compound are as follows.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].S(OC)(O[CH3:18])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[C:3]([O:13][CH3:18])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: COS(=O)(=O)OC
Reactant: CC(=O)c1cc(Cl)c(C)c(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1c(C(C)=O)cc(Cl)c(C)c1Br
Yield: 83.4 %

Procedure:
A mixture of 1-(3-bromo-5-chloro-2-hydroxy-4-methylphenyl)ethanone (10 g, 38 mmol), dimethyl sulfate (4.3 mL, 46 mmol) and potassium carbonate (11 g, 76 mmol) in acetone (200 mL) was heated at reflux overnight. After evaporation to dryness, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and evaporated to dryness. The residue was purified on silica gel, eluting with 0 to 20% ethyl acetate in hexane, to yield the desired product (8.8 g, 84%). LCMS calculated for C10H11BrClO2 (M+H)+: m/z=277.0. found: 277.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][CH:14]=2)=[C:9]([OH:12])[NH:10][N:11]=1.[CH2:23](O)[CH2:24]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][CH:14]=2)=[C:9]2[O:12][CH2:23][CH2:24][N:10]2[N:11]=1
Reactant: Oc1[nH]nc(-c2ccccn2)c1-c1ccnc2ccccc12
Reactant: OCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: c1ccc(-c2nn3c(c2-c2ccnc4ccccc24)OCC3)nc1
Yield: 74.9 %

Procedure:
To a solution of 5-pyridin-2-yl-4-quinolin-4-yl 2H-pyrazol-3-ol (50 mg, 0.17 mmol), ethylene glycol (15 mg, 0.24 mmol) and tri-n-butylphosphine (100 mg, 0.50 mmol) in tetrahydrofuran (15 mL) is added 1,1′-(azodicarbonyl)dipiperidine (120 mg, 0.48 mmol). The solution is heated at reflux for 5 h, cooled, and filtered through an SCX cartridge. The residue is chromatographed on SiO2 (15:1 dichloromethane:methanol). The product residue is converted to the disoxylate salt to give the title compound 40 mg (46%).
Reaction SMILES: [NH:1]([C:5]1[S:6][C:7]([C:11]([OH:13])=O)=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3].CN(C=O)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:44][CH2:45][CH2:46][CH2:47][O:48][CH2:49][C:50]([O:52][CH2:53][CH2:54][CH2:55][CH3:56])=[O:51]>C(OCC)(=O)C>[NH:1]([C:5]1[S:6][C:7]([C:11]([NH:44][CH2:45][CH2:46][CH2:47][O:48][CH2:49][C:50]([O:52][CH2:53][CH2:54][CH2:55][CH3:56])=[O:51])=[O:13])=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: Cc1nc(NC(=N)N)sc1C(=O)O
Reactant: CCCCOC(=O)COCCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCOC(=O)COCCCNC(=O)c1sc(NC(=N)N)nc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
175 mg of 2-guanidino-4-methyl-thiazole-5-carboxylic acid, 2.6 ml of DMF, 0.29 ml of N-MM and 332 mg of HBTU are stirred at room temperature (RT) for one hour, treated with 197 mg of butyl (3-amino-propoxy)-acetate hydrochloride and stirred at RT for a further 18 hrs. For the working up, the mixture is diluted with ethyl acetate, washed with dilute sodium carbonate solution, dilute sodium chloride solution and saturated sodium chloride solution, dried and evaporated in a vacuum. Chromatography on silica gel with methylene chloride-alcohol gives 162 mg of butyl {3-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-propoxy}-acetate, mass spectroscopy (MS): 372 (M+H)+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH:11]1([SH:16])[CH2:15][CH2:14][CH2:13][CH2:12]1.Cl[C:18]1[N:22]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:24]=2)[N:21]=[CH:20][C:19]=1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>CN(C=O)C.CCOC(C)=O>[CH:11]1([S:16][C:18]2[N:22]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:24]=3)[N:21]=[CH:20][C:19]=2[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)c1ccc(-n2ncc(C(=O)OC(C)(C)C)c2Cl)cc1
Reactant: SC1CCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2ncc(C(=O)OC(C)(C)C)c2SC2CCCC2)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
Sodium bis(trimethylsilyl)amide (7.13 mL, 7.13 mmol) was added dropwise to cyclopentanethiol (0.761 mL, 7.13 mmol) in DMF (25 mL) under nitrogen. The resulting solution was stiffed at 20° C. for 30 minutes. A solution of tert-butyl 5-chloro-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylate (Intermediate#9) (2 g, 5.94 mmol) in DMF (10 mL) was then added dropwise and the resulting mixture was stirred at 20° C. for 2 hours. The reaction mixture was diluted with EtOAc (200 mL), and washed sequentially with water (4×50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 25% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 5-(cyclopentylthio)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylate (1.380 g, 57.7%) as a colourless oil which crystallised on standing.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:11][C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][CH2:17][N:18]2N)=[CH:14][CH:13]=1>N1C=CC=CC=1>[Cl:11][C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][CH2:17][N:18]2[C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:14][CH:13]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: NN1CCc2ccc(Cl)cc21
Solvent: c1ccncc1
Product: Clc1ccc2c(c1)N(c1ncnc3[nH]ccc13)CC2
Temperature: 85 °C
Yield: 6.3 %

Procedure:
To 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (10.0 g, 0.065 mol) in dry pyridine (90 ml) was added 6chloro2,3dihydroindol-1-yl amine (14.8 g, 0.078 mol), and the mixture was heated in an 85° C. oil bath for 2 days. The reaction was cooled to ambient temperature and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (375 g, 40 mm mesh) using 5% MeOH/CH2Cl2 to afford the title compound as a pink-orange solid (1.1 g, 4.3%): HRMS: Calculated 271.0750, Found 271.0729; anal. RP18-HPLC RT: 4.88 minutes.
Reaction SMILES: [C:1]1([CH:7]([O:9][C:10]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.N[CH:20]1[CH:25]2CCN(C[CH2:24]2)[CH2:21]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:1]1([CH:7]([O:9][C:10](=[O:11])[NH:12][CH:16]2[CH:25]3[CH2:24][CH2:13][N:14]([CH2:21][CH2:20]3)[CH2:15]2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC1CN2CCC1CC2
Reactant: CC(OC(=O)n1ccnc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(OC(=O)NC1CN2CCC1CC2)c1ccccc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of imidazole-1-carboxylic acid 1-phenyl-ethyl ester 0.50 g (2.31 mmol) in 5 ml dimethylformamide, 3-aminoquinuclidine dihydrochloride 0.46 g (2.31 mmol) and sodium carbonate 0.49 g (4.62 mmol) are added. The suspension is heated up to 80° C. and stirred for 18 hours at this temperature. The reaction mixture is then cooled and extracted with water and ethylacetate. The combined organic phases are dried and evaporated. The oily residue is dried, dissolved in ether and acidified with a 4 M hydrochloric acid dioxane solution. The precipitating crystals are filtered, washed with ether and dried to give the title product. Mp=71-72° C. (decomposition).
Reaction SMILES: C(O[C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([N:22]([CH3:24])[CH3:23])[CH2:13][C:12]2=1)=[O:7])(C)(C)C.[Cl:25][C:26]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:27]=1C(Cl)=O>>[Cl:25][C:26]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:27]=1[C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([N:22]([CH3:23])[CH3:24])[CH2:13][C:12]2=1)=[O:7]
Reactant: CN(C)C1CCc2[nH]c3ccc(NC(=O)OC(C)(C)C)cc3c2C1
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccc(F)cc4Cl)cc3c2C1
Yield: 94.1 %

Procedure:
Beginning with 0.081 gm (0.245 mMol) 6-(t-butoxycarbonyl)amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 0.046 gm (0.27 mMol) 2-chloro-4-fluorobenzoyl chloride, 0.089 gm (94%) of the title compound were recovered as a light beige solid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@H:9]1[C:13](=[O:14])[CH2:12][C@H:11]([OH:15])[C@@H:10]1[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23].[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@H:9]1[C:13](=[O:14])[CH2:12][C@H:11]([OH:15])[C@@H:10]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: [H][H]
Reactant: CCCCC[C@H](O)/C=C/[C@H]1C(=O)C[C@H](O)[C@@H]1C/C=C\CCCC(=O)O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCC[C@H](O)/C=C/[C@H]1C(=O)C[C@H](O)[C@@H]1CCCCCCC(=O)O

Procedure:
A solution of PGD2 (Example 16) in ethyl acetate is shaken with hydrogen at about one atmospheric pressure at ambient temperature in the presence of a 5 percent palladium-on-charcoal catalyst. Hydrogenation is stopped when one equivalent of hydrogen per equivalent of PGD2 is absorbed. Catalyst is removed by filtration and the filtrate is then concentrated under reduced pressure and the residue chromatographed on silica gel, eluting with ethyl acetate and Skellysolve B. Fractions shown to contain pure product are combined yielding the title compound.
Reaction SMILES: [CH:1]([O:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:3])[CH3:2].[C:16]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH:1]([O:4][N:5]([CH3:16])[C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([CH3:3])[CH3:2]
Reactant: CC(C)ONC(=O)OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CC(C)ON(C)C(=O)OCc1ccccc1
Temperature: 70 °C
Yield: 93.3 %

Procedure:
An ACE® pressure tube was charged with benzyl isopropoxycarbamate (4.98 g, 23.80 mmol), anhydrous K2CO3 (4.94 g, 35.70 mmol), methyl iodide (6.7 mL, 107.10), and anhydrous acetone (30 mL). The reaction mixture was heated at 70° C. for 24 h. The reaction mixture was filtered, and the acetone was evaporated. The resulting slurry was dissolved in EtOAc, washed with water (3×50 mL), dried (Na2SO4), and filtered. The solvent was removed to yield benzyl isopropoxy(methyl)carbamate (4.96 g, 93%). 400 MHz 1H-NMR (DMSO-d6, ppm) 7.41-7.30 (5H, m), 5.12 (2H, s), 4.08 (1H, septet, J=6.2 Hz), 3.08 (3H, s), 1.12 (6H, d, J=6.2 Hz).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][CH:17]([CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:22]=1)=[O:19]>>[CH3:16][CH:17]([CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:9]=3)[CH2:29][CH2:28]2)[CH:22]=1)=[O:19]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc(Oc4ccccc4)c3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 3-phenoxybenzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 429.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([NH:21]C(=O)C)=[CH:20][C:7]=2[N:6]=1)([F:4])[CH3:3].[OH-].[Na+].CO>O>[F:4][C:2]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[C:8]2[CH:17]=[CH:18][C:19]([NH2:21])=[CH:20][C:7]=2[N:6]=1)([F:1])[CH3:3]
Reactant: CC(=O)Nc1ccc2c(c1)nc(C(C)(F)F)n2CC1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(F)(F)c1nc2cc(N)ccc2n1CC1CCOCC1
Temperature: 70 °C

Procedure:
A mixture of N-[2-(1,1-difluoroethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]acetamide (1.07 g, 3.17 mmol), 6 M aqueous solution of NaOH (5 mL) and MeOH (5 mL) was heated to 70° C. for 24 h. The reaction mixture was diluted with water (200 mL) and the product was extracted with EtOAc (4×100 mL). The combined organic layers were dried over anhydrous Na2SO4 and the solvent was concentrated to provide the title compound as white solid. Yield: 0.90 g (96%); MS (ESI) (M+H)+=296.2.
Reaction SMILES: [CH3:1][C:2]1([CH2:15][C:16]([OH:18])=O)[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[CH2:19]([N:21](CC)[CH2:22]C)C.ClC(OCC)=O.CNC>O1CCCC1>[CH3:19][N:21]([CH3:22])[C:16](=[O:18])[CH2:15][C:2]1([CH3:1])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: CC1(CC(=O)O)OCCc2c1[nH]c1ccccc21
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)CC1(C)OCCc2c1[nH]c1ccccc21
Temperature: -5 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid (15 g, 0.061 mole), prepared as described in Example 1, in dry tetrahydrofuran (300 ml), cooled to -5° C., is added triethylamine (18.5 g, 0.183 mole), followed by ethyl chloroformate (16.6 g, 0.153 mole). The mixture is stirred at -5° C. for 2 hr. This mixture, which now contains the mixed anhydride of the above starting material, is added dropwise to a cooled 40% aqueous solution of the amine, dimethylamine (225 ml). The resulting mixture is stirred at room temperature for one-half hour. Most of the tetrahydrofuran is evaporated, and the residue partitioned between chloroform and water. The organic phase is washed with water, dried over sodium sulfate, and evaporated under reduced pressure. The residue is subjected to chromatography on silica gel. Elution with 20% ethyl acetate in benzene, followed by crystallization of the eluate from ethyl acetate affords the title compound, m.p. 149° - 151° C., νmaxCHCl3 3375, 1634 cm-1.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:33]=[CH:32][C:16]([O:17][C:18]([CH:20]([NH:24]C(=O)OC(C)(C)C)[CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:15][CH:14]=3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:24][CH:20]([CH:21]([CH3:23])[CH3:22])[C:18]([O:17][C:16]1[CH:32]=[CH:33][C:13]([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:14][CH:15]=1)=[O:19]
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)Oc1ccc(C2(c3ccccc3)CCCCC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(N)C(=O)Oc1ccc(C2(c3ccccc3)CCCCC2)cc1

Procedure:
To a stirred solution at room temperature of tert-butyl 1-((4-(1-phenylcyclohexyl)phenoxy)carbonyl)-2-methylpropylcarbamate (142 mg, 0.31 mmol) in dry DCM (3 mL) was added TFA (300 μL), which caused gas evolution. Stirring was continued. After 1 h the reaction mixture was concentrated in vacuo to afford 96 mg (0.21 mmol; 67%) of colourless oil. LC-MS purity (UV/MS): 92/97%, Rt 5.45 min, M+1: 352.49. 1H NMR (400 MHz, CDCl3): 11.12 (br s), 7.76 (br s), 7.29 (d, 2H, J=8.8 Hz), 7.27 (d, 4H, J=4.8 Hz), 7.13-7.16 (m, 1H), 6.95 (d, 2H, J=8.8 Hz), 6.16 (d, 1H, J=4.0 Hz), 2.40-2.48 (m, 1H), 2.18-2.33 (m, 4H), 1.50-1.58 (m, 6H), 1.05-1.08 (m, 6H).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][NH2:17])=[N:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)[CH:21]=[C:22]([N:28]1[CH:33]=[CH:32][C:31](=[O:34])[CH:30]=[CH:29]1)[C:23](OCC)=[O:24]>>[CH2:1]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:23]([OH:24])=[C:22]([N:28]3[CH:29]=[CH:30][C:31](=[O:34])[CH:32]=[CH:33]3)[CH:21]=[N:17]2)=[N:12][CH:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=CN(C)C)n1ccc(=O)cc1
Reactant: NNc1ccc(C(=O)NCc2ccccc2)cn1
Product: O=C(NCc1ccccc1)c1ccc(-n2ncc(-n3ccc(=O)cc3)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 188 using N-benzyl-6-hydrazinylnicotinamide and ethyl 3-(dimethylamino)-2-(4-oxopyridin-1(4H)-yl)acrylate. MS m/z 388 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.53 (d, J=5.6 Hz, 2H) 6.68 (br. s., 2H) 7.27 (dq, J=8.5, 4.2 Hz, 1H) 7.30-7.41 (m, 4H) 8.29 (br. s., 2H) 8.37-8.54 (m, 3H) 8.97 (s, 1H) 9.27 (t, J=5.8 Hz, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:15][NH2:16])[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[C:26](Cl)=[O:27].C(N(CC)CC)C>O1CCOCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:15][NH:16][C:26]([C:18]4[O:17][C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[CH:19]=4)=[O:27])[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Cl)c1cc2ccccc2o1
Reactant: NCC1(c2ccc3c(c2)OCO3)CCCC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(NCC1(c2ccc3c(c2)OCO3)CCCC1)c1cc2ccccc2o1
Reaction time: 15 h
Yield: 17.9 %

Procedure:
C-(1-Benzo[1,3]dioxol-5-yl-cyclopentyl)-methylamine (43.8 mg, 0.200 mmol) and benzofuran-2-carbonyl chloride (36.1 mg, 0.200 mmol) were dissolved in 2 mL of 1,4-dioxane containing triethylamine (83.6 μL, 0.600 mmol). The reaction mixture was stirred for 15 hours, evaporated to dryness, and purified by reverse phase preparative liquid chromatography to yield the pure product (13.0 mg, 0.0358 mmol, 17.8%). ESI-MS m/z calc. 363.2, found 364.2 (M+1)+. Retention time of 4.22 minutes.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:14]([O:16][C:17]1[C:24]([O:25][CH2:26][CH3:27])=[C:23]([O:28][CH2:29][CH3:30])[CH:22]=[CH:21][C:18]=1[CH:19]=O)[CH3:15].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCl.C(O)(=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:19][C:18]2[CH:21]=[CH:22][C:23]([O:28][CH2:29][CH3:30])=[C:24]([O:25][CH2:26][CH3:27])[C:17]=2[O:16][CH2:14][CH3:15])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOc1ccc(C=O)c(OCC)c1OCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)c(OCC)c1OCC
Temperature: 20 °C
Reaction time: 12 h

Procedure:
The synthesis is carried out in argon condition. 1.1 g (5.9 mmol) of N-Boc-piperazine and 1.40 g (5.9 mmol) of 2,3,4-triethoxybenzaldehyde are mixed in 25 ml of dry dichloromethane. After dissolution 2 drops of acetic acid is added, then 2.12 g (10 mmol) of NaBH(OAc)3 is added and the mixture is stirred for 12 h at 20° C. Then 10 ml of 5% NaHCO3 aqueous solution is added dropwise with care to the reaction mixture. The organic layer is separated, washed with 5% Na2CO3 solution, dried over sodium sulfate, filtered off and concentrated in vacuum at 50÷80° C. The residue (2.2 g of yellowish oil) is used on the next step.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][NH:13][C:12](=[O:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl[CH2:18][CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.Cl.ClCCN1CCCC1>CN(C)C(=O)C.C1(C)C=CC=CC=1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:18][CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:12](=[O:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: ClCCN1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(CCN2CCCC2)C(=O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
Sodium hydride (55% dispersion in mineral oil, 1.96 g, 45 mmol) was added portionwise at room temperature to a solution of 3-oxo-piperazine-1-carboxylic acid tert-butyl ester (6.01 g, 30.0 mmol) in N,N-dimethylacetamide (150 ml), then a solution of 1-(2-chloroethyl)-pyrrolidine in toluene [prepared from commercially available 1-(2-chloroethyl)-pyrrolidine hydrochloride (16.1 g, 94.5 mmol) by partitioning between toluene (70 ml) and 1 M aq. sodium hydroxide solution (70 ml) and drying of the organic layer with Na2SO4] was added dropwise. The reaction mixture was stirred at room temperature for 16 h, then heated at 75° C. for 80 min. After cooling, the reaction mixture was partitioned between diethyl ether and sat. aq. sodium hydrogen-carbonate solution. The organic layer was dried (Na2SO4) and evaporated. Crystallization of the residue from diethyl ether afforded the title compound (3.74 g, 42%). White solid, MS (ISP)=298.2 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:19]=[CH:18][CH:17]=[C:11]2[C:12]([NH:14][C:15](=[O:16])[C:10]=12)=[O:13].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(#N)C>[N:20]1([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][CH:17]=[C:11]3[C:12]([NH:14][C:15](=[O:16])[C:10]=23)=[O:13])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: O=C1NC(=O)c2c(CCCCCCCBr)cccc21
Reactant: C1COCCN1
Solvent: CC#N
Product: O=C1NC(=O)c2c(CCCCCCCN3CCOCC3)cccc21

Procedure:
7-Bromoheptylphthalimide (489 mg; 2.0 mmoles) and morpholine (0.35 ml; 4.0 mmoles) were dissolved in anhydrous acetonitrile (5 ml). Reaction times and process as per Example 1.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:15][CH:14]=2)[C:3]1=[O:31].C1CCN2C(=NCCC2)CC1.[O:43]=O>>[CH3:1][N:2]1[C:3](=[O:31])[C:4]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:17][CH:18]=2)=[C:5]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[C:6]1=[O:43]
Reactant: O=O
Reactant: CN1CC(c2ccncc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Solvent: C1CCC2=NCCCN2CC1
Product: CN1C(=O)C(c2ccncc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Yield: 48 %

Procedure:
To a stirred solution of 1-methyl-4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (200 mg, 0.49 mmol) in AcN (10 mL) was added DBU (224.5 mg, 1.47 mmol) dropwise and then the reaction mixture was stirred for 6 h under a continuous flow of oxygen. The reaction mixture was quenched with 1N HCl and extracted with EtOAc (2×20 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to afford 1-methyl-3-(pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrole-2,5-dione (100 mg, 48%) as a solid. 1H NMR (500 MHz, CDCl3): δ 8.18-8.09 (m, 1H), 8.0-7.95 (m, 3H), 7.65-7.59 (m, 3H), 7.48-7.39 (m, 1H), 7.28-7.18 (m, 4H), 7.1-7.09 (m, 2H), 5.25 (s, 2H), 2.86 (s, 3H);