Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:18][CH2:19][CH2:20][NH:21][S:22]([C:25]3[N:26]=[CH:27][N:28]([CH3:30])[CH:29]=3)(=[O:24])=[O:23])[CH:8]=2)[CH2:3]1.Br[CH2:32][CH:33]([CH3:36])[CH2:34]Cl.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O.ClCCl>[CH2:11]([CH:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:18][CH2:19][CH2:20][NH:21][S:22]([C:25]3[N:26]=[CH:27][N:28]([CH3:30])[CH:29]=3)(=[O:24])=[O:23])[CH:8]=2)[CH2:3][CH:2]1[N:1]1[CH2:34][CH:33]([CH3:36])[CH2:32]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cn1cnc(S(=O)(=O)NCCOc2ccc3c(c2)C(Cc2ccccc2)C(N)C3)c1
Reactant: CC(CCl)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: CC1CN(C2Cc3ccc(OCCNS(=O)(=O)c4cn(C)cn4)cc3C2Cc2ccccc2)C1
Reaction time: 0.67 h

Procedure:
To N-(2-(2-amino-3-benzyl-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide (43 mg, 0.101 mmol; see example 193), 1-bromo-3-chloro-2-methylpropane (0.093 mL, 0.807 mmol) and potassium carbonate (111 mg, 0.807 mmol) in water (1 mL) +1 drop acetonitrile were added. Microwave at 120° C. for 40 min. Evaporated acetonitrile, re-dissolved in dichloromethane and extracted with water and brine, dried over sodium bicarbonate, filtered and evaporated to obtain the crude product as a brown oil, that was purified by flash silica gel chromatography on 4 g SiO2-cartridge using 10% methanol in dichloromethane to afford N-(2-(3-benzyl-2-(3-methylazetidin-1-yl)-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide as a yellow oil. m=4.9 mg (10%)
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10](=S)[NH:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:5]=[CH:4][C:3]=1[NH:20][C@@H:21]1[CH2:26][C@@H:25]2[CH2:27][C@@H:23]([C:24]2([CH3:29])[CH3:28])[C@H:22]1[CH3:30].[N:31]([Si](C)(C)C)=[N+:32]=[N-:33].C(OCC)(=O)C>ClCCl.[Fe](Cl)(Cl)Cl>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[N:33]=[N:32][N:31]=2)[N:5]=[CH:4][C:3]=1[NH:20][C@@H:21]1[CH2:26][C@@H:25]2[CH2:27][C@@H:23]([C:24]2([CH3:29])[CH3:28])[C@H:22]1[CH3:30]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=S)NCc3ccncc3)c(=O)c1Br)C2(C)C
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: Cl[Fe](Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(Cc3nnnn3Cc3ccncc3)c(=O)c1Br)C2(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 23.4 %

Procedure:
2-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-N-(pyridin-4-ylmethyl)ethanethioamide (38 mg, 0.077 mmol) in dichloromethane (1 mL) was mixed with azidotrimethylsilane (41 μL, 0.308 mmol) and iron trichloride (30 mg, 0.185 mmol) at room temperature and stirred at room temperature for 17 hours. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform/methanol=50/1) to give the desired product (9 mg, 24% yield).
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.F[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Br:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([C:25]3[C:26]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:22]=[CH:23][CH:24]=3)[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=3
Reactant: Fc1cccc2ccccc12
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Brc1ccc2c(c1)c1cc(Br)ccc1n2-c1cccc2ccccc12
Temperature: 145 °C
Reaction time: 36 h

Procedure:
Into a flask, 10.00 g of 3,6-dibromo-9H-carbazole, 4.1 ml of 1-fluoronaphthalene, 12.06 g of cesium carbonate, and 300 ml of dimethylsulfoxide were put, and the solution was stirred at 145° C. for 36 hours under nitrogen atmosphere. After heating, the reaction liquid was cooled to room temperature and then filtrated, and the filtrates were concentrated by a vacuum pump. The concentrates were purified by silica gel column chromatography, and then washed by methanol, and thus 5.5 g of 3,6-dibromo-9-naphthalene-1-yl-carbazole was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:1]([O:5][C:6]([C:8]1([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][Br:20])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C2(C(=O)OC(C)(C)C)CCCC2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)C1(c2ccc(CBr)cc2)CCCC1
Yield: 111.3 %

Procedure:
To a solution of 1-(4-methylphenyl)cyclopentane carboxylic acid t butyl ester (2.00 g, 7.68 mmol) in CCl4 (80 mL) was added N-bromosuccinimide (1.37 g, 7.68 mmol) and benzoyl peroxide (0.050 g). This mixture was brought to reflux by heating, and maintained at reflux for 2 hours using a sun lamp (250 W). Additional N-bromosuccinimide (0.34 g, 1.9 mmol) was added, and after 20 minutes the solution was concentrated to 40 mL. The white precipitate was removed by filtration. The filtrate was concentrated to give 1-(4-bromomethylphenyl)cyclopentane carboxylic acid t butyl ester (2.9 g, 100%) as a yellow oil which was used without additional purification.
Reaction SMILES: [CH2:1](Cl)[Cl:2].[CH:4]([Cl:7])(Cl)[Cl:5].[Cl:8][C:9](Cl)=[C:10](Cl)[Cl:11]>>[CH3:1][Cl:2].[Cl:5][C:4]([Cl:7])=[C:10]([Cl:11])[CH2:9][Cl:8]
Reactant: ClC(Cl)Cl
Reactant: ClC(Cl)=C(Cl)Cl
Reactant: ClCCl
Product: CCl
Product: ClCC(Cl)=C(Cl)Cl

Procedure:
Appropriate operating conditions of a dividing wall column will depend on the separation desirably being conducted therein, and those of ordinary skill in the art of chemical engineering are readily able to determine the same. For the exemplary reaction of methyl chloride and perchloroethylene to provide 1,1,2,3-tetrachloropropene, wherein methyl chloride, methylene chloride, chloroform, perchloroethylene, and 1,1,2,3-tetrachloropropene are desirably separated, suitable operating conditions for the dividing wall column include a pressure of about 266 psia and temperature of about 91° C. at the feed stream, a pressure of about 63 psia and a temperature of about 16° C. at the overhead, and a pressure of about 68 psia and a temperature of about 186° C. at the column bottom.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[CH:5]=[CH:6][CH:7]=1.[CH3:19][C:20](C)([O-:22])[CH3:21].[K+].C(C1OC1)Br>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][CH:20]2[CH2:21][O:22]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccccc1CCCCc1cccc(Cl)c1
Reactant: CC(C)(C)[O-]
Agent: BrCC1CO1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Clc1cccc(CCCCc2ccccc2OCC2CO2)c1
Yield: 86.5 %

Procedure:
Following a procedure similar to that described in Example 1(a), 800 mg of 2-[4-(3-chlorophenyl)butyl]phenol (prepared as described in Preparation 17), 344 mg of potassium t-butoxide and 835 mg of epibromohydrin were reacted in 20 ml of dimethylacetamide. The crude product, extracted as described in Example 1(a), was purified as described in Example 1(a), to give 840 mg (yield 86%) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:13]([C:15]3[C:16]([O:34][CH3:35])=[C:17]([CH:23]4[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24]4)[C:18]([F:22])=[C:19]([Cl:21])[CH:20]=3)[CH3:14])[N:9]=[C:10]([CH:11]=[CH2:12])[C:3]=12.C[N+]1([O-])CC[O:40]CC1.[OH2:44]>C(O)(C)(C)C.[Os](=O)(=O)(=O)=O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:13]([C:15]3[C:16]([O:34][CH3:35])=[C:17]([CH:23]4[CH2:24][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26]4)[C:18]([F:22])=[C:19]([Cl:21])[CH:20]=3)[CH3:14])[N:9]=[C:10]([CH:11]([OH:40])[CH2:12][OH:44])[C:3]=12
Reactant: C=Cc1nn(C(C)c2cc(Cl)c(F)c(C3CN(C(=O)OC(C)(C)C)C3)c2OC)c2ncnc(N)c12
Reactant: O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)(C)O
Product: COc1c(C(C)n2nc(C(O)CO)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 3-{3-[1-(4-amino-3-vinyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-fluoro-2-methoxyphenyl}azetidine-1-carboxylate (340 mg, 0.680 mmol) in tert-butyl alcohol (5 mL) was added N-methylmorpholine N-oxide (87 mg, 0.74 mmol) and water (2.1 mL). To this solution was then added 4% osmium tetraoxide (0.21 mL, 0.034 mmol). After stirring for 3 h, another equivalent of N-methylmorpholine N-oxide was added. The reaction was stirred at room temperature overnight. The solution was diluted with water, and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated to give the crude product (0.4 g, 100%) which was used directly in the next step. LCMS calculated for C24H31 ClFN6O5 (M+H)+: m/z=537.2; Found: 537.2.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][CH2:5][CH:6]1[O:10][C:9]([NH2:11])=[N:8][CH2:7]1.[CH3:16][C:17]([CH3:19])=O>>[CH2:16]([NH:11][C:9]1[O:10][CH:6]([CH2:5][O:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[CH3:1])[CH2:7][N:8]=1)[CH2:17][CH3:19]
Reactant: CC(C)=O
Reactant: Cc1ccccc1OCC1CN=C(N)O1
Product: CCCNC1=NCC(COc2ccccc2C)O1
Reaction time: 48 h

Procedure:
In a reactor are introduced 0,01 mol of 5-[(2-methylphenoxy)methyl]-4,5-dihydro-oxazol-2-ylamine and 100 ml of acetone. Once dissolution is complete, 0,005 mol of 1-bromopropyl are added and the whole is heated to ebullition during 48 hours. After filtering off the formed solid and evaporating the solvent, the crude desired product is purified by separation by column chromatography (eluent: chloroform/ammonia, 95:5).
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)CCC.C([O-])(=O)C.[Na+].[N+]([C:37]1[CH:42]=CC=[CH:39][CH:38]=1)([O-])=O>C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:42]([C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:37][CH2:38][CH3:39]
Reactant: CCCCNc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: O=C1c2ccccc2C(=O)c2c(Cl)cccc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CCCCc1c(Nc2ccccc2)ccc2c1C(=O)c1ccccc1C2=O

Procedure:
The pleochroic dye 1-butylphenylamino anthraquinone was prepared by dissolving 1-chloroanthraquinone in a 10-fold excess of 4-n butylaniline. Copper acetate and sodium acetate were added as in Example 70. Since the n-butylaniline is a solvent in this case no nitrobenzene was added. The dye, when tested as in Example 70, had an absorption maxima at 515 nm and an order parameter of 0.65.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[CH2:8]([C@:15]1([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:22](=[O:23])[N:21]2[C@@H:17]([S:18][CH2:19][C@H:20]2[C:24]([OH:26])=[O:25])[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCCCCC.CO>[CH2:8]([C@:15]1([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:22](=[O:23])[N:21]2[C@@H:17]([S:18][CH2:19][C@H:20]2[C:24]([O:26][CH3:1])=[O:25])[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N[C@]1(Cc2ccccc2)C[C@@H]2SC[C@@H](C(=O)O)N2C1=O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)[C@@H]1CS[C@H]2C[C@@](Cc3ccccc3)(NC(=O)OC(C)(C)C)C(=O)N21
Temperature: 25 °C

Procedure:
A total of 1.5 ml of a 2 molar solution of trimethylsilyldiazomethane in hexane is added in portions to a solution of 250 mg of (3R,6R,7aS)-6-benzyl-6-tert-butoxycarbonylamino-5-oxohexahydropyrrolo[2,1-b]thiazole-3-carboxylic acid in 8 ml of methanol while stirring at room temperature. After the reaction is complete, the excess trimethylsilyldiazomethane is destroyed by dropwise addition of glacial acetic acid, and the volatile constituents are stripped off in a rotary evaporator at 40° C. The residue is purified on a column (silica gel, mobile phase:ethyl acetate:n-heptane=1:1.5).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13]C)=[O:6].B(Cl)(Cl)Cl.CCCCCCC.C(=O)(O)[O-].[Na+]>ClCCl>[OH:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:5]([C:4]1[CH:15]=[CH:16][CH:17]=[CH:18][C:3]=1[O:2][CH3:1])=[O:6]
Reactant: COc1ccccc1C(=O)c1ccccc1OC
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCCC
Solvent: ClCCl
Product: COc1ccccc1C(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
This procedure is based on that reported in Tetrahedron Lett., 1966, 4153. To a solution of 2,2′-dimethoxybenzophenone (11) (6.7 g, 0.0277 mol) in anhydrous dichloromethane (95 mL) cooled to −65° C. under nitrogen was added 52 mL of a 1.0 M solution of boron trichloride in heptane (0.052 mol). The mixture was allowed to warm to room temperature and stirred for 75 minutes. The reaction mixture was slowly poured into a cold (0° C.) solution of saturated aqueous sodium bicarbonate, which was then extracted with dichloromethane. The organic extracts were washed with water and saturated with NaCl, followed by drying over anhydrous sodium sulfate. Analytically pure product was obtained after removal of the solvent in quantitative yield.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][CH:15]([N:18]4[C:27](=[O:28])[C:26]5[C:21](=[CH:22][CH:23]=[C:24]([CH3:29])[CH:25]=5)[N:20]([CH3:30])[C:19]4=[O:31])[CH2:14][CH2:13]3)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:32][CH3:33].Br[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>>[CH2:39]([O:38][C:36]([CH2:35][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][CH:15]([N:18]4[C:27](=[O:28])[C:26]5[C:21](=[CH:22][CH:23]=[C:24]([CH3:29])[CH:25]=5)[N:20]([CH3:30])[C:19]4=[O:31])[CH2:14][CH2:13]3)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:32][CH3:33])=[O:37])[CH3:40]
Reactant: CCOC(=O)CBr
Reactant: COc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)ncnc2cc1O
Product: CCOC(=O)COc1cc2ncnc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OC
Yield: 89 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 500.0 mg (1.12 mmol) of Compound 89 obtained in Example 79 was used in place of Compound 24 and ethyl bromoacetate was used in place of methyl iodide. As a result, 530.0 mg (yield: 89%) of Compound 93 was obtained as white crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:7])[CH2:6][CH2:5][CH2:4][NH:3]1.[H-].[Na+].Br[C:11]1[C:12]2[N:13]([CH:18]=[CH:19][N:20]=2)[N:14]=[C:15]([Cl:17])[CH:16]=1>CN(C=O)C>[Cl:17][C:15]1[CH:16]=[C:11]([N:3]2[CH2:4][CH2:5][CH2:6][C:2]2([CH3:7])[CH3:1])[C:12]2[N:13]([CH:18]=[CH:19][N:20]=2)[N:14]=1
Reactant: CC1(C)CCCN1
Reactant: Clc1cc(Br)c2nccn2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CCCN1c1cc(Cl)nn2ccnc12
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
To a solution of 2,2-dimethylpyrrolidine (0.248 g, 2.5 mmol) in DMF (8 mL) was added NaH (0.060 g, 60% dispersion in mineral oil, 2.5 mmol) and stirred for 0.5 h. To this mixture was added 8-bromo-6-chloroimidazo[1,2-b]pyridazine (0.233 g, 1 mmol) under N2. The mixture was stirred at room temperature for 16 h. Then it was partitioned between 15 mL of saturated NH4Cl solution and 15 mL of ether. The organic layer was washed with water (10 mL×3) and saturated NaCl solution (10 mL×3), dried over NaSO4, concentrated in vacuo, and purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=3:1) to give 6-chloro-8-(2,2-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazine (0.140 g, 22%) as a light brown solid. LC-MS: [M+H]+, 251.1, tR=1.698 min.
Reaction SMILES: C=C[C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2(C)[C:10](=[CH:11][C:12](=[O:22])[CH:13]=[CH:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.N1C=CC=CC=1.C1C=C[NH+]=CC=1.Br[Br-]Br.C1(O)C=CC=CC=1>C(OCC)(=O)C>[CH3:21][C@:20]12[CH2:19][CH2:18][C:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C:15]=3[CH2:14][CH2:13][C:12](=[O:22])[CH:11]=4)[C@@H:6]1[CH2:5][CH:4]=[CH:3]2
Reactant: C=C[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: c1cc[nH+]cc1
Solvent: Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C[C@@]12C=CC[C@H]1[C@@H]1CCC3=CC(=O)CCC3=C1CC2
Reaction time: 0.02 h
Yield: 30.8 %

Procedure:
Estra-5(10,16-dien-3-one (3) (0.38 g, 1.5 mmole), in pyridine (5.0 ml, 62 mmol) was cooled in an ice-salt bath to −13 C and pyridinium bromide perbromide (1.58 g, 4.94 mmole) was added in small portions so that T<−4 C. After swirling 1 min. phenol (0.25 g, 2.7 mmole) was added and reaction continued 24 h at room temperature. Ethyl acetate (50 ml) was added and the reaction mixture was washed with 25 ml of 1N HCI, two 25 ml portions of saturated copper sulfate, 25 ml of 5% sodium hydroxide, and 25 ml of brine. After drying our magnesium sulfate, filtration, and concentration under reduced pressure the residue was taken up in 10 ml of abs. ethanol, granular zinc (0.33 g, 5.0 mg-atom) was added, and the mixture was refluxed ½ h. The supernatant was removed, the residue was washed with 10 ml of abs. ethanol, and the combined supernatants were concentrated under reduced pressure. The resulting resin was flash chromatographed on silica gel using 15% ethyl acetate/hexane as eluent. Appropriate fractions were pooled, concentrated, and then recrystallized from hexane to give solid product (117.5 mg, 0.4619 mmol, 31%), m.p. 87-92 C.
Reaction SMILES: C([N:8]1[CH:13]=[CH:12][C:11]2=[C:14]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[N:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[N:16]=[C:10]2[C:9]1=O)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:34]>>[Cl:34][C:9]1[C:10]2=[N:16][N:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:14]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)=[C:11]2[CH:12]=[CH:13][N:8]=1
Reactant: O=c1c2nn(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2ccn1Cc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc(-c2c3ccnc(Cl)c3nn2-c2ccccc2Cl)cc1
Yield: 77 %

Procedure:
A stirred suspension of 6-benzyl-2-(2-chlorophenyl)-3-(4-chlorophenyl)-2H-pyrazolo[3,4-c]pyridin-7(6H)-one (1A-3, 925 mg, 2.07 mmol) in POCl3 (20 ml) was heated at reflux for 5 days. After the reaction was cooled and concentrated, in vacuo, an ethyl acetate solution of the residue was washed with saturated aqueous NaHCO3 and then brine. The solution was dried (Na2SO4), concentrated, in vacuo, and then purified on a Biotage™ Flash 40S column using 0-40% ethyl acetate in hexanes to afford I-9A-1a as an off-white solid (600 mg, 77%): +ESI MS (M+1) 374.3; 1H NMR (400 MHz, CD2Cl2) δ 8.00 (d, J=6.2 Hz, 1H), 7.60-7.45 (m, 5H), 7.38 (d, J=8.7 Hz, 2H), 7.27 (d, J=8.7 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]([C@H:12]2[CH2:17][CH2:16][C@H:15](C3C=CC(CNC)=CC=3)[CH2:14][CH2:13]2)[CH2:9][C:10]#[CH:11])=[O:7])=[CH:4][CH:3]=1.Br[CH2:30][CH2:31][CH2:32][OH:33]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]([C@H:12]2[CH2:17][CH2:16][C@H:15]([C:4]3[CH:3]=[CH:2][C:28]([CH2:30][CH2:31][CH2:32][OH:33])=[CH:27][C:5]=3[CH2:6][NH:8][CH3:9])[CH2:14][CH2:13]2)[CH2:9][C:10]#[CH:11])=[O:7])=[CH:4][CH:3]=1
Reactant: OCCCBr
Reactant: C#CCN(C(=O)c1ccc(Cl)cc1)[C@H]1CC[C@H](c2ccc(CNC)cc2)CC1
Solvent: ClCCl
Solvent: CO
Product: C#CCN(C(=O)c1ccc(Cl)cc1)[C@H]1CC[C@H](c2ccc(CCCO)cc2CNC)CC1

Procedure:
from trans-N-(4-chlorobenzoyl)-N-propargyl-4-(4-methylaminomethylphenyl)cyclohexylamine and 3-bromo-1-propanol. Oil. Rf value: 0.53 (alumina, methylene chloride/methanol=50:1, v:v).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH:10]1[CH2:11][CH:12]=[CH:13][C:14]2[C:19]=1[CH:18]=[CH:17][CH2:16][CH:15]=2.S(=O)(O)[O-:21].[Na+]>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:12]2[CH:13]=[C:14]3[C:19](=[CH:10][CH:11]=2)[CH:18]=[C:17]([OH:21])[CH:16]=[CH:15]3)=[CH:5][CH:4]=1
Reactant: C1=CC2=CCC=CC2=CC1
Reactant: O=S([O-])O
Reactant: COc1ccc(N)cc1
Agent: [Na+]
Solvent: O
Product: COc1ccc(Nc2ccc3cc(O)ccc3c2)cc1
Temperature: 25 °C
Yield: 29.5 %

Procedure:
A solution of 1.00 g (8.1 mmol, Aldrich) of p-anisidine, 5.20 g (32.5 mmol, 4 eq., Aldrich) of 2,6-dihydronaphthalene and 3.38 g (32.5 mmol, 4 eq., Aldrich) of sodium bisulfite in 60 ml of H2O was refluxed for 12 hours. The reaction was cooled to room temperature, extracted with EtOAc, dried (MgSO4) and concentrated in vacuo. Initial purification was accomplished via flash chromatography (1:6, 1:4 EtOAc/petroleum ether) and then concentration of appropriate fractions. Ethyl acetate was added, this was washed repeatedly with warm 0.1N NaOH to remove 2,6-dihydroxynaphthalene, dried (MgSO4) and concentrated in vacuo. Final purification by flash chromatography (1:4 THF/petroleum ether) yielded 633 mg (30%) of title compound as a muddy pink solid, m.p. 152°-153° C.
Reaction SMILES: [CH:1]1[C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=[C:3]([Cl:12])[CH:2]=1.S(Cl)(Cl)=O.[CH2:17]([N:19]([CH2:26][CH3:27])[CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22]O)[CH3:18]>C1C=CC=CC=1>[ClH:12].[CH2:17]([N:19]([CH2:26][CH3:27])[CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][C:7]([C:6]1[CH:5]=[CH:4][C:3]([Cl:12])=[CH:2][CH:1]=1)=[C:8]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]([OH:11])=[O:10])[CH3:18]
Reactant: O=C(O)/C=C/c1ccc(Cl)cc1
Reactant: CCN(CC)CC(C)(C)CO
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CCN(CC)CC(C)(C)CC(=C(C(=O)O)c1ccccc1)c1ccc(Cl)cc1
Product: Cl
Reaction time: 8 h

Procedure:
P-Chlorocinnamic acid (27.5 g, 0.15 mole) was added with rapid stirring to thionyl chloride (52.5 ml) and refluxed for 31/2 hours. The mixture was stripped of excess thionyl chloride under reduced pressure, benzene (100 ml) was added and the mixture was again stripped of solvent. The residue was treated with a solution of 3-diethylamino-2,2-dimethylpropanol (24.2 g, 0.15 mole) in benzene (500 ml), refluxed for 3 hours, cooled, diluted with petroleum ether (500 ml), and stored overnight at room temperature. The benzene-petroleum ether solution was decanted, the residue dissolved in H2O (700 ml) and the solution adjusted to pH 10 with saturated aqueous K2CO3 (60 ml). The product was extracted from the aqueous phase with benzene (800 ml) in portions and the extract dried overnight over MgSO4 and Darco. The solution was filtered and the filtrate adjusted to pH 2 with a solution of dry HCl in ether (cooled in an ice bath). Petroleum ether (500 ml) was added and the product oiled out of solution. The benzene-petroleum ether solution was decanted and the product was recrystallized from ethyl acetate (600 ml), yield: 33 g (61%). A sample was recrystallized from ethyl acetate, m.p. 132°-134°.