Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][CH:26]([NH2:28])[CH3:27].[C:29]([C:32]1[C:40]2[C:35](=[N:36][CH:37]=[C:38]([C:41]3[C:49]4[CH2:48][CH2:47][CH2:46][CH2:45][C:44]=4[N:43]([CH3:50])[N+:42]=3[O-:51])[N:39]=2)[N:34]([CH2:52][O:53][CH2:54][CH2:55][Si:56]([CH3:59])([CH3:58])[CH3:57])[CH:33]=1)(O)=[O:30]>ClCCl>[CH:26]([NH:28][C:29]([C:32]1[C:40]2[C:35](=[N:36][CH:37]=[C:38]([C:41]3[C:49]4[CH2:48][CH2:47][CH2:46][CH2:45][C:44]=4[N:43]([CH3:50])[N+:42]=3[O-:51])[N:39]=2)[N:34]([CH2:52][O:53][CH2:54][CH2:55][Si:56]([CH3:59])([CH3:58])[CH3:57])[CH:33]=1)=[O:30])([CH3:27])[CH3:25]
Reactant: CC(C)N
Reactant: Cn1c2c(c(-c3cnc4c(n3)c(C(=O)O)cn4COCC[Si](C)(C)C)[n+]1[O-])CCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3c4c(n(C)[n+]3[O-])CCCC4)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
In a 16×100 mm screw cap test tube were added HATU (46.3 mg, 122 μmol.20) and propan-2-amine (24.0 mg, 406 μmol) then 3-(7-carboxy-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-indazole 2-oxide (45 mg, 101 μmol) dissolved in dichloromethane (2.50 mL) was added to give a light yellow solution which immediately formed a white precipitated. The reaction mixture stirred at 25° C. overnight, solvents evaporated and residue purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 50% EtOAc in hexanes over 30 min to yield 3-(7-(isopropylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-indazole 2-oxide (45 mg, 92.8 μmol, 91.5%) as a clear foam. MS (M+H)+=485.1 (100% purity); 1H NMR (CDCl3) δ: 7.91 (s, 1H), 6.41 (d, J=8.1 Hz, 1H), 6.11 (s, 1H), 4.54 (s, 2H), 3.22-3.37 (m, 1H), 2.36-2.46 (m, 2H), 2.31 (s, 3H), 1.22-1.44 (m, 2H), 1.00-1.14 (m, 2H), 0.82-1.00 (m, 4H), 0.16 (d, J=6.6 Hz, 7H), −0.30-−0.12 (m, 2H), −1.19 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH2:4]Cl.[CH3:11][CH2:12][O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15].[OH-].[Na+]>C(O)(C)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH2:4][N:19]1[CH2:18][CH2:17][N:16]([C:14]([O:13][CH2:12][CH3:11])=[O:15])[CH2:21][CH2:20]1
Reactant: ClCc1c(Cl)cccc1Cl
Reactant: CCOC(=O)N1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCOC(=O)N1CCN(Cc2c(Cl)cccc2Cl)CC1
Yield: 87.8 %

Procedure:
A mixture of 95.9 g (0.49 moles) of 2,6-dichlorobenzyl chloride, 77.6 g (0.49 moles) of ethyl N-piperazinocarboxylate, 500 ml of isopropyl alcohol and 70 ml of 10N sodium hydroxide was heated at reflux for 18 hours. The solution was evaporated in vacuo and gave a crystalline residue. The residue in 100 ml of water was extracted twice with 200 ml portions of dichloromethane. The combined organic extract was dried over anhydrous sodium sulfate, filtered, evaporated in vacuo and gave an oil. The oil was subjected to Kugelrohr distillation, bp 117° C./0.45 mm of mercury and gave 136.4 g of 4-(2,6-dichlorobenzyl)-1-piperazinecarboxylic acid, ethyl ester as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]2[C:14](=[O:15])[CH2:13][CH2:12][CH2:11][C:10]2=[O:16])=[C:4]([CH3:17])[CH:3]=1.Cl[C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([Cl:29])[CH:25]=2)[N:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.Cl>[Cl:29][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][C:28]([O:1][C:2]1[CH:3]=[C:4]([CH3:17])[C:5]([CH:9]3[C:14](=[O:15])[CH2:13][CH2:12][CH2:11][C:10]3=[O:16])=[C:6]([CH3:8])[CH:7]=1)=[CH:27]2
Reactant: Cc1cc(O)cc(C)c1C1C(=O)CCCC1=O
Reactant: Clc1ccc2nc(Cl)ccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2cnc3ccc(Cl)cc3c2)cc(C)c1C1C(=O)CCCC1=O
Temperature: 140 °C

Procedure:
To a mixture of 2-(4-hydroxy-2,6-dimethylphenyl)cyclohexane-1,3-dione (0.200 g, 0.0009 mol), 2,6-dichloroquinoline (0.170 g, 0.0009 mol) and potassium carbonate (0.350 g, 0.0025 mol) is added N,N-dimethylformamide (3 ml), and the mixture is heated at 140° C. for 40 minutes under microwave irradiation. The reaction mixture is then diluted with ethyl acetate (20 ml) and 2M hydrochloric acid (20 ml), and the organic phase is separated, dried over magnesium sulfate and evaporated under reduced pressure. The crude product is purified by preparative reverse phase HPLC to afford 2-[4-(6-chloroquinolin-3-yloxy)-2,6-dimethylphenyl]cyclohexane-1,3-dione as a cream solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[C:30](=[N:32]O)[NH2:31]>N1C=CC=CC=1>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:30]2[N:31]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[O:9][N:32]=2)[CH:34]=[CH:35][CH:36]=1
Reactant: O=C(O)c1ccccn1
Reactant: COc1cccc(C(N)=NO)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: c1ccncc1
Product: COc1cccc(-c2noc(-c3ccccn3)n2)c1
Yield: 31.6 %

Procedure:
Using modifications of the method of Shine et al., J. Heterocyclic Chem. (1989) 26:125–128, a solution of picolinic acid (123 mg, 1 mmol) in pyridine (1 mL) was treated with 1,1′-carbonyldiimidazole (162 mg, 1 mmol) and the reaction stirred at ambient temperature until the evolution of carbon dioxide ceased (30 min). The intermediate acylimidazole was then treated with 3-methoxybenzamidoxime (166 mg, 1 mmol) and the reaction heated at reflux for 1 hour. Ice cold water was added to the reaction mixture to precipitate the oxadiazole. The solid was collected by filtration, washed with water and dried to afford 80 mg (32%) of 3-(3-methoxyphenyl)-5-(2-pyridyl)-1,2,4-oxadiazole: mp 90–94° C.; GC/EI-MS gave m/z (rel. int.) 253 (M+, 100), 254 (17), 179 (2), 175 (2), 149 (77), 133 (33), 119 (4), 106 (29), 78 (45), 51 (18).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[CH3:10].[OH-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C.ClCCl>[CH3:10][C:4]1[CH:5]=[C:6]([O:9][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:8][C:3]=1[CH2:2][OH:1]
Reactant: Cc1cc(O)ccc1CO
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc(OCc2ccccc2)ccc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.8 %

Procedure:
To a solution of 4-(hydroxymethyl)-3-methylphenol (4.25 g, 30.8 mmol) in ethanol (90 ml) was added 2M aqueous sodium hydroxide (17 ml, 34 mmol) and then benzyl bromide (3.65 ml, 30.8 mmol, Aldrich). The pale yellow mixture was stirred at ambient temperature under nitrogen overnight. The solvent was removed in vacuo to leave an aqueous suspension. The residue was partitioned between dichloromethane (100 ml) and water (100 ml). The phases were separated and the aqueous phase extracted with dichloromethane (50 ml). The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo to leave an orange oil. The residue was loaded in dichloromethane and purified on silica (100 g×3) using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and the solvent evaporated in vacuo to give {2-methyl-4-[(phenylmethyl)oxy]phenyl}methanol (2.59 g).
Reaction SMILES: [Mg].BrCCBr.[CH2:6]([O:8][CH:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)[CH3:10])[CH3:7].[Br:19][C:20]([CH2:22]Br)=[CH2:21]>C1COCC1>[CH2:6]([O:8][CH:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:22][C:20]([Br:19])=[CH2:21])[CH3:10])[CH3:7]
Reactant: C=C(Br)CBr
Reactant: CCOC(C)OCCCCCCBr
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: C=C(Br)CCCCCCCOC(C)OCC
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 75.5 %

Procedure:
A slurry of 5.6 g of magnesium turnings (230 mmol) in 100 ml of THF was treated with a small amount of 1,2-dibromoethane. 1-(1-Ethoxyethoxy)-6-bromohexane (38.5 g, 152 mmol) was fed slowly to the reaction mixture, maintaining the temperature at 40-50° C. At the end of the addition the reaction mixture was held 20 minutes, then transferred by cannula to solution of 33.4 g (167 mmol) of 2,3-dibromopropene in 25 ml of THF at 0° C. The reaction mixture was stirred at 0° C. for 15 minutes, then stirred at room temperature for 15 minutes, then quenched with water. The reaction mixture was transferred into a separatory funnel. A small amount of 1 N HCl was added, the phases were separated, the ether phase was washed with water and brine, then dried over magnesium sulfate, filtered, and stripped to give 33.63 g of a yellow liquid which was used without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16]([Cl:26])=[C:17]3[C:22](=[CH:23][C:24]=2[Cl:25])[CH:21]=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:26][C:16]1[C:15]([O:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[C:24]([Cl:25])[CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][N:20]=[CH:21]2
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2c(Cl)cc3cnccc3c2Cl)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cc2cnccc2c(Cl)c1OC1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
150 mg 4-(5,7-Dichloro-isoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (377, already partially deprotected) were dissolved in 10 ml of dichloromethane and 1 ml of trifluoroacetic acid is added at 0° C. The solution is stirred for 2 h at room temperature. For working up, 50 ml Dichloromethane were added and the solution was washed with saturated NaHCO3-solution. The layers were separated and the aqueous phase was extracted once with Dichloromethane. The combined organic layers were again washed with saturated NaHCO3-solution, dried with MgSO4 and evaporated. The residue was purified by preparative HPLC. The product fractions were evaporated and the residue dissolved in 2 N HCl. After evaporation, the title compound was isolated as HCl-salt. Rt=0.90 min (Method #2). Detected mass: 297.1/299.1 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:3]=1.CCCCCC.[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(OCC)C>[C:27]1([NH:33][C:34]([C:2]2[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[C:4]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)[N:3]=2)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CSc1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Reactant: O=C=Nc1ccccc1
Solvent: CCCCCC
Solvent: CCOCC
Product: CSc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)Nc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.8 g (0.0022 mol) of 2-bromo-4-methylmercapto-6-{3-(trifluoromethyl)phenoxy} pyridine was dissolved in about 15 ml of diethyl ether. While cooling the obtained solution in a dry ice-acetone bath in an argon atmosphere, 1.5 ml of a 1.6M-hexane solution of BuLl (0.0022×1.1 mol) was added to the solution, followed by stirring the resultant mixture for about 10 minutes. After 0.52 g (0.0022×2.0 mol) of phenyl isocyanate dissolved in about 5 ml of diethyl ether was added to the reaction solution, the obtained solution was removed from the bath and stirred at room temperature for about 30 minutes. The reaction solution was mixed with about 5 ml of a 1.2N-aqueous hydrochloric acid solution, and then distributed in ethyl acetate-water, followed by washing with saturated sodium bicarbonate water and saturated brine. The organic phase of the obtained solution was dried with anhydrous sodium sulfate, concentrated and subjected to silica gel column chromatography (eluting solution: ethyl acetate/hexane) to separate a main fraction therefrom. The fraction was concentrated and then subjected to precipitation using hexane, thereby obtaining an aimed product.
Reaction SMILES: C(C1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:14])(=O)C.C1C2CC(=[O:22])C(C2)C1.N1CCOCC1>C1(C)C=CC=CC=1>[O:22]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][CH:5]1[OH:14]
Reactant: O=C1CC2CCC1C2
Reactant: CC(=O)c1c(O)ccc2ccccc12
Solvent: C1COCCN1
Solvent: Cc1ccccc1
Product: OC1CCc2ccccc2O1
Reaction time: 5 h

Procedure:
A solution was prepared by dissolving 10 g (0.054 mole) of 1-acetyl-2-naphthol, 6.6 g (0.06 mole) of norcamphor and 8.7 g (0.10 mole) of morpholine in 300 cc of toluene, and the solution was boiled for 5 hours and water was separated. After termination of the reaction toluene was removed under reduced pressure, and the remaining chromanone compound was recrystallized from acetone, and the chromanon compound was dissolved in 200 cc of methanol and lithium aluminum hydride was added to the solution to form a chromanol compound. Then, 6.49 g of this chromanol compound was heated at 170° to 180° C. together with anhydrous copper sulfate in a carbon dioxide current for 10 minutes and the obtained brown viscous liquid was purified by the chromatography on silica gel to obtain 5.1 g of a chromene compound represented by the following formula: ##STR68##
Reaction SMILES: C([S:8][CH:9]([CH2:42][N:43]1[CH2:48][CH2:47][S:46][CH2:45][CH2:44]1)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:18][C:17]=2[N:28]([CH2:38][CH:39]1[CH2:41][CH2:40]1)[S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)(=[O:31])=[O:30])=O)C1C=CC=CC=1.C1(SC)C=CC=CC=1.C(=O)(O)[O-:58].[Na+]>ClCCl>[CH:39]1([CH2:38][N:28]([C:17]2[CH:18]=[C:19]([O:23][CH2:24][CH2:25][O:26][CH3:27])[CH:20]=[C:21]3[C:16]=2[NH:15][C:14]([C:12]2[S:8][CH:9]([CH2:42][N:43]4[CH2:48][CH2:47][S:46](=[O:58])[CH2:45][CH2:44]4)[CH2:10][N:11]=2)=[CH:22]3)[S:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)(=[O:30])=[O:31])[CH2:40][CH2:41]1
Reactant: COCCOc1cc(N(CC2CC2)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(CN3CCSCC3)SCc3ccccc3)cc2c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CSc1ccccc1
Solvent: ClCCl
Product: COCCOc1cc(N(CC2CC2)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CN4CCS(=O)CC4)S3)cc2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 47 %

Procedure:
A mixture of N-[2-(benzylthio)-3-thiomorpholinopropyl]-7-[(cyclopropylmethyl)(pyridin-2-ylsulfonyl)amino]-5-(2-methoxyethoxy)-1H-indole-2-carboxamide (355 mg), thioanisole (0.12 mL) and dichloromethane (3 mL) was added thereto at 0° C., and the mixture was stirring at 0° C. for 10 min. Aqueous sodium bicarbonate solution was added to the reaction mixture, and the organic layer was separated. The organic layer was extracted with concentrated hydrochloric acid, and after basified with the aqueous layer with potassium carbonate, the whole mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give the amorphous solid from a fraction eluted with ethyl acetate. To the mixture of the obtained amorphous solid, tetrahydrofurane (5 mL), ethanol (5 mL) and water (5 mL) was added OXONE (registered trade mark, 369 mg) at room temperature, and the mixture was stirred at room temperature for 1 hr. To the resulting mixture was added 10% aqueous sodium sulfite solution, and the mixture was extracted with a mixed solvent of ethyl acetate and tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give amorphous solid, which was crystallized from diisopropyl ether to give the title compound (146 mg, yield 47%) as colorless crystals.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[OH:11][CH:12]([C:14]1([CH2:18][CH2:19][CH3:20])[CH2:17][O:16][CH2:15]1)[CH3:13].N1C=CC=CC=1>CCOCC>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:11][CH:12]([C:14]2([CH2:18][CH2:19][CH3:20])[CH2:17][O:16][CH2:15]2)[CH3:13])=[O:7])=[CH:4][CH:3]=1
Reactant: CCCC1(C(C)O)COC1
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCC1(C(C)OC(=O)c2ccc(I)cc2)COC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 4-iodobenzoyl chloride (3.5 g) in dry ether (25 ml) was added to a stirred solution of 3-(1-hydroxyethyl)-3-n-propyloxetane (1.7 g) and pyridine (1.8 ml) in ether (50 ml) at 0° C. The resulting mixture was stirred for 24 hours at room temperature. After this time the mixture was washed with water and brine. The organic extracts were dried over anhydrous magnesium sulphate and then evaporated in vacuo. The residue was purified by column chromatography on silica (pre-eluted with 1% triethylamine in hexane) and eluted with hexane/ether mixtures. 3-[1-(4-Iodobenzoyloxy)ethyl]-3-n-propyloxetane was obtained as a colourless oil (1.8 g).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].[C:11]([O:15][C:16](=[O:19])[CH2:17]Br)([CH3:14])([CH3:13])[CH3:12]>CN(C)C=O>[C:11]([O:15][C:16](=[O:19])[CH2:17][N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1ccc([N+](=O)[O-])n1
Yield: 77.2 %

Procedure:
To a solution of 3-Nitro-1H-pyrazole (1.00 g, 8.84 mmol) in anhydrous N,N-dimethylformamide (20 mL), a 60% dispersion of sodium hydride in mineral oil (390 mg, 9.73 mmol) was added while stirring under nitrogen. After the effervescence ceased and the mixture was stirred for additional 1 h, tert-butyl-bromoacetate (1.44 mL, 9.73 mmol) was added. The mixture was continued to stir under nitrogen for an additional 2 h. The solvent was removed in vacuo and purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% ethyl acetate/hexanes to 50% ethyl acetate/hexanes, 30 min) afforded (3-nitro-pyrazol-1-yl)-acetic acid tert-butyl ester (1.55 g, 77%) as a white powder. H1-NMR (400 MHz, CDCl3) δ: 1.42 (9H, s), 4.86 (2H, s), 6.87 (1H, d, J=2.4 Hz), 7.54 (1H, d, J=2.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3I)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:19][CH:20]([OH:23])[C:21]#[CH:22]>C(NCC)C.C(Cl)CCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:22]#[C:21][CH:20]([OH:23])[CH3:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C#CC(C)O
Reactant: CN1Cc2c(I)ncn2-c2cccc(Cl)c2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: ClCCCl
Product: CC(O)C#Cc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2

Procedure:
7.47 g (20 mmol) of 7-chloro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to boiling under reflux for 4 hours with 1.75 g (25 mmol) of 3-butyn-2-ol, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 10 mg of copper(I) iodide in 50 ml of diethylamine and 20 ml of ethylene chloride. After removal of the solvent by evaporation the residue was taken up in methylene chloride and the thus-obtained suspension was suction filtered. The material obtained was washed with methylene chloride and, after recrystallization from ethyl acetate, there was obtained 7-chloro-4,5-dihydro-3-(3-hydroxy-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 251°-252°.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.[Li+].CC([N-]C(C)C)C.[CH2:16]([N:23]=[C:24]=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C1COCC1>[CH2:16]([NH:23][C:24]([C:4]1[S:3][C:2]([Br:1])=[N:6][C:5]=1[Br:7])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C=NCc1ccccc1
Reactant: Brc1csc(Br)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCc1ccccc1)c1sc(Br)nc1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
To a stirred solution of 2,4-dibromo-thiazole (4.95 g, 20.4 mmol) in THF at −78° C. was added LDA (1.8M in THF/hexanes, 13.6 ml, 24.5 mmol) slowly. The reaction was then stirred at −78° C. for 30 min., when benzylisocyanate (3.8 ml, 30.6 mmol) was added slowly. The mixture was then stirred at −78° C. for 30 min. before it was slowly warmed up to RT. Water was then added carefully to quench the reaction. The mixture was extracted with EtOAc and the combined extracts were dried over sodium sulfate and concentrated. The crude product was purified by column chromatography on silica gel (10% EtOAc/hexanes) to give 2,4-dibromo-thiazole-5-carboxylic acid benzylamide 26B as a white solid (5.05 g, 13.43 mmol, 66%).
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+].CC(C)=O>O>[CH2:18]([O:1][C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Oc1ccc2ccc3cccc4ccc1c2c34
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: c1ccc(COc2ccc3ccc4cccc5ccc2c3c45)cc1
Yield: 25.1 %

Procedure:
To a RB flask equipped with overhead stirrer, condenser and N2 inlet line with bubbler was added 1-hydroxypyrene (Cambridge Chemical, Inc., 5.0 g, 23 mmol), benzyl bromide (Aldrich, 15.64 g, 92 mmol, 10.94 mL), K2CO3 (Mallinckrodt, 12.72 g, 92 mmol) and acetone (100 mL). The mixture was refluxed overnight, cooled and then poured into H2O (250 mL) and extracted with EtOAc (3×100 mL). The EtOAc layers were combined and washed successively with 1N NaOH (100 mL), H2O (100 mL) and saturated NaCl solution (2×100 mL). The solution was then dried (K2CO3) and the solvent removed by rotary evaporation to give the crude product. This material was purified by passing it through a plug of SiO2 using PhCH3 as the eluting solvent. The solvent was then removed from the appropriate fractions by rotary evaporation and the solid recrystallized from CH2Cl2 /hexane to give 1.78 g (25.9% yield) of 1-benzyloxypyrene, mp 105°-106°, (C,H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:17]1[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]1
Reactant: CN1CCNCC1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Product: COc1cc([N+](=O)[O-])ccc1N1CCN(C)CC1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
Heat 1-chloro-2-methoxy-4-nitro-benzene (1.0 g, 5.33 mmol) and 1-methylpiperazine (1.33 g, 13.30 mmol) at 100° C. in a sealed tube for 16 h. Cool the mixture to room temperature and partition between dichloromethane (50 mL) and water (50 mL). Separate the organic portion and extract the aqueous portion with dichlorormethane (2×20 mL). Dry the combined organic portions (Na2SO4), filter and concentrate in vacuo to give 1.05 g (78%) of the title compound. MS/ES m/z 252.0 [M+H]+.
Reaction SMILES: [O:1]=[C:2]([N:7]1[CH2:11][CH2:10][CH2:9][CH:8]1[C:12](=[O:17])[CH2:13][CH2:14][CH:15]=[CH2:16])[C:3]([O:5]C)=O.[CH3:18][CH:19]([CH3:24])[CH2:20][CH2:21][Mg]Cl>C1COCC1>[CH3:18][C:19]([CH3:24])([CH2:20][CH3:21])[C:3](=[O:5])[C:2]([N:7]1[CH2:11][CH2:10][CH2:9][CH:8]1[C:12](=[O:17])[CH2:13][CH2:14][CH:15]=[CH2:16])=[O:1]
Reactant: C=CCCC(=O)C1CCCN1C(=O)C(=O)OC
Reactant: CC(C)CC[Mg]Cl
Solvent: C1CCOC1
Product: C=CCCC(=O)C1CCCN1C(=O)C(=O)C(C)(C)CC
Reaction time: 2.5 h

Procedure:
A solution of methyl 2-oxo-2-(2-pent-4-enoylpyrrolidinyl)acetate (21.0 g; 88 mmol) in 150 ml THF was cooled to −78° C., under nitrogen, and treated with 200 ml (180 mmol) of 0.9 M 3,3-dimethylpropyl magnesium chloride. After stirring for 2.5 hours, TLC indicated that the reaction was complete. It was quenched with 300 ml of saturated NH4Cl followed by 200 ml of ethyl acetate. The layers were separated and the aqueous layer was extracted once more with 300 ml of ethyl acetate. The combined organic layers were dried over MgSO4, filtered, concentrated, and the product purified on silica gel with 20% ethyl acetate in hexane, to obtain 3,3-dimethyl-1-(2-pent-4-enoylpyrrolidinyl)pentane-1,2-dione as a light yellow oil, 21.0 g (85%).