Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.Cl.C([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:20][CH:19]([N:21]([CH3:23])[CH3:22])[CH2:18]2)[CH2:13][CH2:12]1)C1C=CC=CC=1.O>CC(O)C.[Pd]>[ClH:1].[ClH:1].[ClH:1].[CH3:22][N:21]([CH3:23])[CH:19]1[CH2:18][N:17]([CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)[CH2:20]1
Reactant: CN(C)C1CN(C2CCN(Cc3ccccc3)CC2)C1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: CN(C)C1CN(C2CCNCC2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 297.8 %

Procedure:
To a solution of a crude product of N-[1-(1-benzylpiperidin-4-yl)azetidin-3-yl]-N,N-dimethylamine trihydrochloride (14.1 g) in 2-propanol (380 ml)-water (380 ml) was added 10% palladium on carbon (5.0 g), followed by stirring at room temperature under a hydrogen atmosphere for 12 hr. The catalyst was removed by filtration. Concentration of the filtrate provided a crude product of the titled compound as colorless crystals (10.7 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH2:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1.O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH:26][C:37]([CH:34]2[CH2:36][CH2:35]2)=[O:38])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CC1
Reactant: CCC(N)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(NC(=O)C1CC1)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.3 %

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-amine (100 mg, 0.24 mmol) and triethylamine (0.17 mL, 1.22 mmol) in tetrahydrofuran (5.0 mL) was added cyclopropanecarbonyl chloride (0.0664 mL, 0.73 mmol) at 0° C. The mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture and recrystallization from ethyl acetate/n-hexane to give the title compound (55.4 mg, 0.116 mmol, 48%) as colorless crystals.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[CH2:11][NH2:12].[S:13](N)([NH2:16])(=[O:15])=[O:14]>O1CCOCC1>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[CH2:11][NH:12][S:13]([NH2:16])(=[O:15])=[O:14]
Reactant: NS(N)(=O)=O
Reactant: NCC1CCc2ccccc2O1
Solvent: C1COCCO1
Product: NS(=O)(=O)NCC1CCc2ccccc2O1

Procedure:
The oily amine (1.63 g, 10 mmol) and sulfamide (1.92 g, 20 mmol) were combined in dioxane (50 mL) and brought to reflux for 2 h. The solution was cooled and evaporated in vacuo to yield an oil, which was purified via column chromatography (DCM:Methanol 10:1) to yield a white solid. The solid was recrystallized from ethyl acetate/hexane to yield chroman-2-ylmethylsulfamide as a white solid.
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:29]=[CH:28][C:27]([CH2:30][OH:31])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:39][O:40][CH2:41][C:42](Cl)=[O:43]>C(Cl)Cl>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:29]=[CH:28][C:27]([CH2:30][O:31][C:42](=[O:43])[CH2:41][O:40][CH3:39])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Reactant: COCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)OCc1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Reaction time: 1 h
Yield: 40.5 %

Procedure:
{6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-pyridin-3-yl}-methanol (80 mg, 0.194 mmol), CH2Cl2 (1 mL), and triethylamine (40 μL, 2.916 mmol) are added to a flask. Add methoxyacetyl chloride (23.2 mg, 0.214 mmol) dropwise at room temperature. Stir 1 h. The crude mixture is purified by flash chromatography on silica gel (MeOH/CH2Cl2) to afford the title compound (38 mg, 40%).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.O.[C:10]1(C)C=CC(S(O)(=O)=O)=CC=1.[C:21](=[O:24])(O)[O-].[Na+]>CO>[Br:1][C:2]1[O:6][C:5]([CH:7]([O:24][CH3:21])[O:8][CH3:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=Cc1ccc(Br)o1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(OC)c1ccc(Br)o1
Temperature: 25 °C
Yield: 62 %

Procedure:
To a solution of 5-bromofuran-2-carboxaldehyde (350 mg, 2.00 mmol) in methanol (15 mL) was added p-toluenesulfonic acid monohydrate (38 mg, 0.20 mmol), and the mixture was heated at reflux for 2 h. The reaction mixture was cooled to room temperature, and aqueous sodium bicarbonate was added. The mixture was extracted with ether, and the organic layer was washed with brine, dried on anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to afford 2-bromo-5-dimethoxymethylfuran (274 mg, 62%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1([CH3:30])[CH:19]=C[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:16]=2)[O:11]1.CS(C)=O.C(O)(C)C.[C:39](=[O:41])=O>O>[Br:1][CH:19]1[C:10]([CH3:30])([CH3:9])[O:11][C:12]2[CH:17]=[CH:16][C:15]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])=[CH:14][C:13]=2[CH:39]1[OH:41]
Reactant: O=C=O
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)(=O)c2ccc3c(c2)C=CC(C)(C)O3)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: CC(C)O
Product: Cc1ccc(S(=O)(=O)c2ccc3c(c2)C(O)C(Br)C(C)(C)O3)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
14.2 g (0.08 mole) of freshly recrystallized N-bromosuccinimide are introduced into 12.6 g (0.04 mole) of 2,2-dimethyl-6-(4-methylphenylsulfonyl)chromene in a solution composed of 70 ml of dimethyl sulfoxide and 1.4 ml of water while cooling (isopropanol/dry ice) at about 15° C. The temperature rises transiently to 27°. It is cooled to 20° C. and, after stirring for one hour, introduced into ice/ethyl acetate. The ethyl acetate phase is washed several times with water and dried over Na2SO4. The bromohydrin derivative crystallizes on concentration. Crystals of melting point: 141°-142° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[C:15]([F:20])[CH:14]=1
Reactant: CCCCCCCCCCBr
Reactant: Oc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCOc1ccc(Br)cc1F

Procedure:
A solution of 1-bromodecane in butanone was added dropwise to a stirred refluxing solution of 4-bromo-2-fluorophenol and potasium carbonate. The stirred mixture was heated under reflux for 24 hr. The potassium carbonate was filtered off and the solvent removed. The product was distilled at 130° C. at 0.05 mmHg.
Reaction SMILES: [Br-].[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:12]=1.[Li]CCCC.[OH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][N:49]1[C:58]2[C:53](=[CH:54][C:55]([CH:59]=[CH:60][CH:61]=O)=[CH:56][CH:57]=2)[CH2:52][CH2:51][CH2:50]1.O>C1(C)C=CC=CC=1>[OH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][N:49]1[C:58]2[C:53](=[CH:54][C:55]([CH:59]=[CH:60][CH:61]=[CH:17][C:14]3[CH:13]=[CH:12][C:11]([C:3]4[O:2][C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[N:4]=4)=[CH:16][CH:15]=3)=[CH:56][CH:57]=2)[CH2:52][CH2:51][CH2:50]1
Reactant: Cc1ccc(-c2nc3ccccc3o2)cc1[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC=Cc1ccc2c(c1)CCCN2CCCCCCO
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: OCCCCCCN1CCCc2cc(C=CC=Cc3ccc(-c4nc5ccccc5o4)cc3)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of 110 g (0.2 mole) of 4-(benzoxazol-2-yl)tolyltriphenylphosphonium bromide in toluene is added dropwise 0.2 mole of n-BuLi at room temperature. After 2 hours a solution of 28.7 g (0.1 mole) of 3-(N-hydroxyhexyl-1,2,3,4-tetrahydroquinolin-6-yl)acrolein in toluene is added dropwise to the mixture, and the reaction is stirred for 18 hours at room temperature. Water is added, and the solids are isolated by vacuum filtration, washed with 60% ethanol/water, and dried under vacuum. The product is purified by recrystallization from benzene.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[NH:11][CH2:12][CH2:13][N:7]3[C:6]=2[C:5]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][N:28]=1>O1CCCC1.O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:31]([C:30]4[CH:29]=[N:28][C:27]([Cl:26])=[CH:35][CH:34]=4)=[O:32])[CH2:12][CH2:13][N:7]3[C:6]=2[C:5]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3C(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.9 %

Procedure:
To a suspension of 8-chloro-5-(1-ethylpropyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole (31.2 mg, 0.118 mmol) in tetrahydrofuran (0.5 mL) were added triethylamine (19.8 μL, 0.142 mmol) and 6-chloronicotinoyl chloride (25.0 mg, 0.142 mmol). The reaction mixture was stirred at room temperature for 4 hrs. The mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-30% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from n-hexane to give the title compound as a colorless powder (27.1 mg, 0.0672 mmol, 57%).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[O:29])[CH:7]([CH:13]([C:15]1[CH:16]=[N:17][C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:19][CH:20]=1)[CH3:14])[C:8]([O:10]CC)=[O:9])[CH3:4]>CCO.C(Cl)Cl>[CH2:3]([O:5][C:6](=[O:29])[CH:7]([CH:13]([C:15]1[CH:16]=[N:17][C:18]([NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])=[CH:19][CH:20]=1)[CH3:14])[C:8]([OH:10])=[O:9])[CH3:4]
Reactant: CCOC(=O)C(C(=O)OCC)C(C)c1ccc(NC(=O)OC(C)(C)C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(C(=O)O)C(C)c1ccc(NC(=O)OC(C)(C)C)nc1
Yield: 65.2 %

Procedure:
A solution of KOH (113.6 mg, 2.04 mmol) in EtOH (2 mL) was added dropwise to a solution of 2-[1-(6-tert-butoxycarbonylamino-pyridin-3-yl)-ethyl]-malonic acid diethyl ester (0.7 g, 1.84 mmol) in methylene chloride (4 mL) and EtOH (10 mL) at 0° C. under argon and the reaction mixture was stirred over night. 1M KOH (100 mL) was added and the mixture was washed with methylene chloride. The aqueous phase was acidified to pH 2 using 2 M HCl and extracted with EtOAc. The organic phase was dried and concentrated under reduced pressure to give the crude 2-[1-(6-tert-butoxycarbonylamino-pyridin-3-yl)-ethyl]-malonic acid monoethyl ester (423 mg, 65%).
Reaction SMILES: [CH3:1][C:2]([C:23]#[N:24])([CH3:22])[CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][C:17]([C:20]#[N:21])([CH3:19])[CH3:18])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1.[H-].C([Al+]CC(C)C)C(C)C.O>C1(C)C=CC=CC=1.CO>[CH3:18][C:17]([CH3:19])([CH2:20][NH2:21])[CH2:16][C:12]1[CH:11]=[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][C:2]([CH3:1])([CH3:22])[CH2:23][NH2:24])[CH:5]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C#N)Cc1cccc(-c2cccc(CC(C)(C)C#N)c2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: CC(C)(CN)Cc1cccc(-c2cccc(CC(C)(C)CN)c2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a 2-liter flask, equipped as described in Example 1(b), was put 10.90 g of 3,3'-bis(2-methyl-2-cyanopropyl)biphenyl and 500 ml of reagent grade toluene which had been passed through acid alumina under nitrogen directly into the reaction vessel. With stirring at room temperature, 118 ml of a 25% solution of diisobutylaluminum hydride in toluene was added in 25 minutes. The mixture was refluxed for 18 hrs, and then allowed to stand at room temperature for 1 day. After the mixture had been cooled in an ice-water bath, a solution of 7 ml of water in 35 ml of methanol was added dropwise with stirring. This was followed by the dropwise addition of a solution of 33 ml of water in 66 ml of methanol. The ice-water bath was removed, and the mixture was stirred for 1 hour. The mixture was filtered under nitrogen, the solid was washed thoroughly with toluene on the filter, and the combined filtrate and rinsings were distilled on the water pump. The cloudy viscous residue weighed 10.8 g after it was evacuated for several hours with the oil pump at room temperature. Distillation of this material through a small Vigreux still gave 5.94 g of 3,3'-bis(2,2-dimethyl-3-aminopropyl)biphenyl as a clear, colorless, viscous liquid boiling at 159° to 168°/0.2-0.5 mm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([OH:21])=O)=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]2([C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[C:30]2[CH3:38])[CH2:26][CH2:25]1)=[O:23].[CH2:39]([S:41]([NH2:44])(=[O:43])=[O:42])[CH3:40]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:44][S:41]([CH2:39][CH3:40])(=[O:43])=[O:42])=[O:21])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:25][CH2:26][C:27]2([C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[C:30]2[CH3:38])[CH2:28][CH2:29]1)=[O:23]
Reactant: CCS(N)(=O)=O
Reactant: CC1=Cc2ccccc2C12CCN(C(=O)c1cnc3c(C(=O)O)cnn3c1Nc1cc(C)ccc1C)CC2
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CCC4(CC3)C(C)=Cc3ccccc34)cnc12
Yield: 52.5 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2,5-dimethylphenylamino)-6-(2-methylspiro[inden-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.053 g, 0.105 mmol) obtained in step 2 and ethanesulfonamide (0.057 g, 0.587 mmol), the title compound (0.033 g, 52%) was obtained.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[C:11]([NH:20][CH2:21][CH2:22][OH:23])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC(CO)[CH2:26][OH:27].CCOC(C)=O.O>CN1C(=O)CCC1>[CH2:1]([S:8][C:9]1[N:14]=[C:13]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[CH:12]=[C:11]([NH:20][CH:21]([CH2:26][OH:27])[CH2:22][OH:23])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Nc1cc(NCCO)nc(SCc2ccccc2)n1
Reactant: NC(CO)CO
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)Nc1cc(NC(CO)CO)nc(SCc2ccccc2)n1
Temperature: 100 °C

Procedure:
To a solution of the subtitle product of Example 19 step (0.20 g) in NMP (0.5 ml) was added 2-aminopropane-1,3-diol (1.0 g) and the reaction was heated at 100° C. for 2 days. To the reaction was added EtOAc (50 ml) and H2O (50 ml). The organic layer was separated and washed with H2O (2×20 ml) and brine (20 ml). The organic layer was dried (MgSO4) and the solvent removed under reduced pressure to give a solid. This was purified by column chromatography (1:1 EtOAc/iso-hexane then EtOAc) to give the title compound as a solid.
Reaction SMILES: C([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([OH:13])=O)=[CH:7][C:6]=1[O:16][CH3:17])(=O)C.P(Cl)(OCC)(OCC)=O.C(N(CC)CC)C.[CH3:34][N:35]([CH3:46])[CH2:36][CH2:37][NH:38][C@H:39]1[CH2:44][CH2:43][C@@H:42]([CH3:45])[CH2:41][CH2:40]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:34][N:35]([CH3:46])[CH2:36][CH2:37][N:38]([C@H:39]1[CH2:40][CH2:41][C@@H:42]([CH3:45])[CH2:43][CH2:44]1)[C:11](=[O:13])[CH:10]=[CH:9][C:8]1[CH:14]=[CH:15][C:5]([OH:4])=[C:6]([O:16][CH3:17])[CH:7]=1
Reactant: CN(C)CCN[C@H]1CC[C@@H](C)CC1
Reactant: COc1cc(C=CC(=O)O)ccc1OC(C)=O
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C=CC(=O)N(CCN(C)C)[C@H]2CC[C@@H](C)CC2)ccc1O

Procedure:
Using 2.5 g of 4-acetoxy-3-methoxycinnamic acid, 2.8 ml of diethyl chlorophosphate, 2.7 ml of triethylamine, 100 ml of methylene chloride, 3 ml of N-(2-dimethylaminoethyl)-cis-4-methylcyclohexylamine (Example 110), and 0.5 g of 4-dimethylaminopyridine, a reaction similar to that conducted in Example 75 was carried out. As a result, 1.6 g of N-(2-dimethylaminoethyl)-N-(cis-4-methylcyclohexyl)-4-hydroxy-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [OH:1][CH2:2][C:3]([F:28])([F:27])[C:4]([F:26])([F:25])[C:5]([F:24])([F:23])[C:6]([F:22])([F:21])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19].[F:29][C:30]1[C:35]([N+:36]([O-:38])=[O:37])=[C:34]([F:39])[C:33]([F:40])=[C:32](F)[C:31]=1[F:42].C(N(CC)CC)C.Cl>CN1C(=O)CCC1.O>[N+:18]([C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][CH2:7][C:6]([F:21])([F:22])[C:5]([F:23])([F:24])[C:4]([F:25])([F:26])[C:3]([F:27])([F:28])[CH2:2][O:1][C:32]1[C:31]([F:42])=[C:30]([F:29])[C:35]([N+:36]([O-:38])=[O:37])=[C:34]([F:39])[C:33]=1[F:40])([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)CO)c([N+](=O)[O-])c1
Reactant: O=[N+]([O-])c1c(F)c(F)c(F)c(F)c1F
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=[N+]([O-])c1ccc(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)COc2c(F)c(F)c([N+](=O)[O-])c(F)c2F)c([N+](=O)[O-])c1
Yield: 93.1 %

Procedure:
1-(6-hydroxy-2,2,3,3,4,4,5,5-octafluorohexyloxy)-2,4-dinitrobenzene (3.7 g) was treated with pentafluoronitrobenzene (2.21 g) and triethylamine (0.96 g) in NMP (5 mL) for 18 hrs at room temperature. The mixture was diluted with water, acidified with hydrochloric acid, and extracted with ethyl ether. The extracts were washed with water, dried (MgSO4), concentrated and purified by chromatography to give 4-[6-(2,4-dinitrophenoxy)-2,2,3,3,4,4,5,5-octaflurohexyloxy]-2,3,5,6-tetrafluoronitrobenzene (5.0 g) as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([C:19]3([CH2:22][O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[CH2:21][CH2:20]3)[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[OH-].[NH4+:31]>CN1CCCC1=O.[Cu-]=O>[NH2:31][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([C:19]3([CH2:22][O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[CH2:21][CH2:20]3)[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1
Reactant: O=C(c1cncc(Br)c1)c1cn(C2(COC3CCCCO3)CC2)c2ncncc12
Reactant: [NH4+]
Agent: O=[Cu-]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Nc1cncc(C(=O)c2cn(C3(COC4CCCCO4)CC3)c3ncncc23)c1
Temperature: 130 °C
Yield: 45 %

Procedure:
To a stirred solution of (5-Bromo-pyridin-3-yl)-{7-[1-(tetrahydro-pyran-2-yloxymethyl)-cyclopropyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-methanone (Preparation 250, 200 mg, 0.45 mmol) in 1-Methyl-pyrrolidin-2-one (1.5 mL) was added ammonium hydroxide (15 mL). Then copper (I) oxide (3 mg, 0.02 mmol) was added and the reaction mixture was heated in a sealed tube at 130° C. for 16 hours. The reaction mixture was cooled to room temperature, extracted with 10% methanol in dichloromethane (5×25 mL). The combined organic layer was dried over sodium sulphate and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of dichloromethane:methanol 100:0 to 96:4) to afford the title compound as a white sticky solid in 45% yield, 80 mg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.CC[CH2:18][CH:19]([C:21](NC1C=CC(C)=C(Cl)C=1)=[O:22])C>C1(C)C=CC=CC=1>[Br:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:18][CH:19]3[CH2:21][O:22]3)[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=3
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Reactant: CCCC(C)C(=O)Nc1ccc(C)c(Cl)c1
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)c1cc(Br)ccc1n2CC1CO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
At rt under an inert atmosphere, (±)-glycyclol (0.129 g, 1.74 mmol, 120 uL) is added into a solution of 3,6-dibromo-9-H-carbazole (0.565 g, 1.74 mmol) in anhydrous toluene (10 mL). Then CMMP (which is prepared according to the protocol of Tetsuto, Tsunoda Tett. Lett. 1996, 37(14), 2459-2462) (0.20 g, 1.74 mmol) is added. The resulting mixture is allowed to stir at rt for 16 hours. The solvent is evaporated and the crude compound is purified via flash chromatography using Biotage device and Petroleum Ether/DCM (3/1) as eluant to give the title compound in a 60% yield as a white solid and 5% of (±)-3,6-dibromo-9-[(1E)-3-(3,6-dibromocarabazol-9-yl)propen-1-enyl]carbazole as a grey powder.
Reaction SMILES: [N+:1]([C:4]12[CH:11]3[CH:6]4[C:7]5([N+:12]([O-:14])=[O:13])[CH:10]3[CH:9]1[CH:8]5[CH:5]24)([O-:3])=[O:2].C(Cl)(=O)C([Cl:18])=O>>[Cl:18][C:8]12[CH:5]3[CH:6]4[CH:11]5[C:4]3([N+:1]([O-:3])=[O:2])[CH:9]1[CH:10]5[C:7]24[N+:12]([O-:14])=[O:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=[N+]([O-])C12C3C4C1C1C2C3C41[N+](=O)[O-]
Product: O=[N+]([O-])C12C3C4C1C1(Cl)C2C3C41[N+](=O)[O-]
Reaction time: 18 h

Procedure:
A mixture of 1,4-dinitrocubane, 1,(388 mg. 2.0 mmol) in oxalyl chloride (50 mL) was photolyzed under a sunlamp for 18 h at room temperature. Oxalyl chloride was removed on a rotary evaporator and the solid residue was partioned between EtOAc (40 mL) and NaOH solution (5%, 30 mL). After stirring for 3 h, the organic phase was separated, washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was chromatographed on silica gel using hexane/CH2Cl2 (1:1) to give 2-chloro-1,4-dinitrocubane 3, m.p. 145°-147° C.; 1H NMR(CDCl3); δ4.84(m, 2H); 4.71 (m, 3H); and 2,5-dichloro-1,4-dinitrocubane, 4, m.p. 188°-190° C.; 1H NMR (CDCl3);δ4.90(dd, 2H); 4.78 (dd,2H).