Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:35]=[CH:34][C:13]2=[C:14]3[C:19](=[C:20]([NH2:22])[N:21]=[C:12]2[CH:11]=1)[N:18]=[CH:17][C:16]([C:23]#[C:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[CH3:33])=[CH:15]3)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)C.[H][H]>[Pd].C(Cl)Cl>[Si:1]([O:8][CH2:9][C:10]1[CH:35]=[CH:34][C:13]2=[C:14]3[C:19](=[C:20]([NH2:22])[N:21]=[C:12]2[CH:11]=1)[N:18]=[CH:17][C:16]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[CH3:33])=[CH:15]3)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: COc1ccc(C#Cc2cnc3c(N)nc4cc(CO[Si](C)(C)C(C)(C)C)ccc4c3c2)c(C)c1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(CCc2cnc3c(N)nc4cc(CO[Si](C)(C)C(C)(C)C)ccc4c3c2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round bottom flask was added 8-((tert-butyldimethylsilyloxy)methyl)-2-(4-methoxy-2-methylphenyl)ethynyl)benzo[f][1,7]naphthyridin-5-amine (from step 4) (1 equiv.) with a stirring bar. Ethanol and methylene chloride (1:2, 0.2 M) were added, followed by palladium in carbon (activated powder, wet, 10% on carbon, 0.1 equiv.). The contents were vacuumed followed by hydrogen flush for three times. The reaction mixture was stirred vigorously under hydrogen balloon at room temperature overnight. Afterwards the reaction mixture was filtered through a celite pad, and the celite pad was washed subsequently with methylene chloride and EtOAc until filtrate has no UV absorption. Combined organic washes were concentrated. Flash chromatography (silica gel, 0-50% EtOAc in CH2Cl2) afforded 8-((tert-butyldimethylsilyloxy)methyl)-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-5-amine as a yellow solid.
Reaction SMILES: COC[O:4][C:5]1[CH:28]=[C:27]([O:29]COC)[CH:26]=[CH:25][C:6]=1[C:7](=[O:24])[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16]COC)=[C:12]([O:20]COC)[CH:11]=1>Cl.CO>[OH:4][C:5]1[CH:28]=[C:27]([OH:29])[CH:26]=[CH:25][C:6]=1[C:7](=[O:24])[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:20])[CH:11]=1
Reactant: COCOc1ccc(C(=O)C=Cc2ccc(OCOC)c(OCOC)c2)c(OCOC)c1
Agent: Cl
Solvent: CO
Product: O=C(C=Cc1ccc(O)c(O)c1)c1ccc(O)cc1O
Temperature: 0 °C
Yield: 22.4 %

Procedure:
Then, 4.0 g of the so-obtained 2',3,4,4'-tetrakis(methoxymethoxy)chalcone was dissolved in 36 ml of a hydrochloric acid/methanol reagent, and the solution was refluxed for 10 minutes. The reaction liquid was poured into ice water, and the precipitated crystal was recovered by filtration, washed with water, dried and subjected to the column chromatograpy 280 g of 230-400 mesh Kieselgel, eluting solvent=hexane/ethyl acetate (1/1), 0.4 kg/cm2). Fractions of 50 ml were collected, and the 32th to 70th fractions were combined to obtain 543.2 mg (yield=22.1%) of 2',3,4,4'-tetrahydroxychalcone.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([C:16]([OH:18])=[O:17])[CH2:11]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[NH2:9][C:4]1[N:3]=[C:2]([N:10]2[CH2:15][CH2:14][CH2:13][C@H:12]([C:16]([OH:18])=[O:17])[CH2:11]2)[CH:7]=[C:6]([Cl:8])[N:5]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: O=C(O)[C@H]1CCCNC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(Cl)cc(N2CCC[C@H](C(=O)O)C2)n1
Temperature: 140 °C

Procedure:
A mixture of 4,6-dichloro-2-pyrimidinamine (1.397 g, 8.52 mmol), (3S)-3-piperidinecarboxylic acid (1 g, 7.74 mmol) and Hunig's base (2.70 ml, 15.49 mmol) in NMP (10 mL) was heated in the microwave at 140° C. for 90 minutes. LCMS showed mainly desired product. The reaction was cooled down to room temperature, and poured onto water (160 mL). The formed solid was filtered, and the filtered solid was identified as the SM 4,6-dichloro-2-pyrimidinamine. The product stayed in the aqueous solution. 1N HCl was added to adjust the pH=7. Then the aqueous solution was extracted 3× with a mixture of CHCl3 and isopropanol (200:10 mL). The organic layers were combined and evaporated to afford the title compound (1.99 g) as a yellow solid. LC-MS (ES) m/z=257 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[C:18]([NH2:26])([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:19]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[N:26][C:18]([CH3:20])([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:19])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: CC(C)(C)CC(C)(C)N
Solvent: Cc1ccccc1
Product: CC(C)(C)CC(C)(C)N=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 94.48 %

Procedure:
To a nitrogen-charged 250 mL, 4-necked round bottom flask equipped with a TEFLON-coated magnetic stirrer, a thermometer, nitrogen gas flow, addition funnel, and a Dean-Stark apparatus equipped with a condenser and a receiver was added 9.8590 g (0.042 moles) of 3,5,-di-t-butyl-4-hydroxybenzaldehyde followed by 100 mL of toluene with vigorous stirring. The solution was not clear and the aldehyde was not soluble in toluene at room temperature. 5.8 gm of t-octylamine was added into the reaction via addition funnel. The reaction flask was slowly heated to 60° C. by heating mantle, and the temperature was controlled by a THERM-O-WATCH® Controller/Monitor. The solution became clear dark reddish brown. The reaction was monitored for 2 hours at 60° C. by Thin Layer Chromatography (TLC). Then the temperature was raised to 110° C. to remove the water by azeotrope with toluene. The azeotrope of water and toluene was collected in a receiver attached to Dean-Stark. After the calculated amount of water was removed, the reaction was cooled to room temperature. The completion of the reaction was monitored by Infra Red Spectroscopy (IR) analysis and by the amount of water collected in the Dean-Stark receiver. The IR analysis confirmed the disappearance of wave number 1682 cm−1 (aldehyde C═O) and appearance of wave number 1621 cm−1 (imine C═N). The imine was collected by evaporating toluene using a rotary evaporator under water aspiration with 94.48% yield.
Reaction SMILES: C[C:2]1([C:8]([O:10][CH3:11])=[O:9])[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].[CH3:12][O-].[Na+]>CO>[CH3:12][CH:4]1[CH2:5][CH2:6][CH:2]([C:8]([O:10][CH3:11])=[O:9])[C:3]1=[O:7]
Reactant: C[O-]
Reactant: COC(=O)C1(C)CCCC1=O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CCC(C)C1=O
Temperature: 25 °C
Yield: 64 %

Procedure:
Methyl 1-methyl-2-oxocyclopentanecarboxylate (61.0 g, 0.39 mol) was added dropwise to a freshly prepared solution of NaOMe (0.78 mol) in MeOH (1 L) at ambient temperature. The solution was heated under reflux for 3 h and then concentrated. The residue was dissolved in toluene (1 L) and the resulting solution was heated under reflux for 5 h. The mixture was cooled to ambient temperature, washed with saturated aqueous NaHCO3 (500 mL×3) and brine (300 mL×1), dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was purified by distillation to afford methyl 3-methyl-2-oxocyclopentanecarboxylate (39.0 g, 64% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].Br[CH2:21][C:22]#[CH:23]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:23][C:22]#[CH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C#CCBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: C#CCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 58.1 %

Procedure:
To the degassed solution of piperazine-1-carboxylic acid tert-butyl ester (1.0 g, 5.37 mmol) in acetonitrile (10 ml) were added Na2CO3 (1.708 g, 16.11 mmol) and mixture was stirred for 20 min. The suspension was heated to 50° C. and 3-bromo-propyne (0.9 mL, 8.055 mmol) was added. The solvent was evaporated and the residue was extracted with Et-Ac and water (2×50 mL). Organic layer was washed with NaCl and NaHCO3 (2×50 ml). The organic layer was dried over K2CO3 and evaporated in vacuum yielding (0.70 g) oil title intermediate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[CH:6]=[CH:5]2.[CH:22]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)=[CH2:23].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][NH:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2](/[CH:23]=[CH:22]/[C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH:3]=2)[N:8]=1
Reactant: C=Cc1ccncc1
Reactant: COc1ccccc1CNc1ccc2cc(Br)ccc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccccc1CNc1ccc2cc(/C=C/c3ccncc3)ccc2n1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
(6-Bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine (200 mg, 0.583 mmol) was dissolved in 2 mL dimethylformamide. 4-Vinylpyridine (80 mg, 0.762 mmol), triethylamine (77 mg, 0.760 mmol), tri-o-tolylphosphin (7 mg, 0.023 mmol) and palladium(II)acetate (3 mg, 0.013 mmol) were added. The reaction mixture was stirred in a sealed tube at 100° C. for 16 h. The reaction mixture was poured into 30 mL water and extracted three times with ethyl acetate (30 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The residue purified by flash chromatography on silica gel (dichloromethane/methanol 100:0->90:10 gradient). The title compound was obtained as a light yellow solid (65 mg, 30%), MS: m/e=368.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH3:21])[CH:16]=3)[CH:11]([C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[CH:10]2[C:31]([O:33]C)=[O:32])=[C:5]([O:35][CH2:36][O:37][CH3:38])[CH:4]=1.[OH-].[Na+]>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH3:21])[CH:16]=3)[CH:11]([C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[CH:10]2[C:31]([OH:33])=[O:32])=[C:5]([O:35][CH2:36][O:37][CH3:38])[CH:4]=1
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCOC)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCOC)C(C(=O)O)C2c1ccc2c(c1)OCO2
Yield: 85 %

Procedure:
A solution of methyl(1RS,2RS,3RS)-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (2.42 g, 4.6 mmol) in isopropyl alcohol (30 ml) with aqueous NaOH (8 ml of 5N solution) was refluxed for 4 h. The resultant mixture was partitioned between EtOAc and 3N HCl. The organic extract was washed with H2O then brine, dried (Na2SO4) and solvent removed in vacuo to afford the title compound as a colorless oil (1.98 g, 84%).
Reaction SMILES: Br[C:2]1[C:3]([O:16][CH2:17][CH2:18][CH3:19])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[BH:20]([OH:22])[OH:21]>>[CH2:17]([O:16][C:3]1[CH:2]=[CH:11][C:10]2[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=2[C:4]=1[B:20]([OH:22])[OH:21])[CH2:18][CH3:19]
Reactant: CCCOc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Reactant: OBO
Product: CCCOc1ccc2c(c1B(O)O)C(C)(C)CCC2(C)C

Procedure:
In a similar manner to Example 3(a), by reaction of 8 g (24.6 mmol) of 3-bromo-2-propyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene, 5.7 g (80%) of the expected boronic acid are obtained, with a melting point of 138-9° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[CH:9]1([C:15]#[CH:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.CCCCCC>COCCOC.C(OCC)(=O)C.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>[CH:9]1([C:15]#[C:16][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C#CC1CCCCC1
Reactant: Cc1cccc(Br)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1cccc(C#CC2CCCCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
2-Bromo-6-methyl pyridine (2.0 g, 11.6 mmol) and Cui (440 mg, 2.3 mmol) were combined in DME (30 mL), and argon gas was bubbled through the suspension for several minutes to deoxygenate the mixture. Triethylamne (8.0 mL, 58 mmol) and PdCl2(PPh3)2 (814 mg, 1.16 mmol) were added, followed by the dropwise addition of cyclohexylethyne (1.25 g, 11.6 mmol). The reaction was stirred at ambient temperature overnight. GC/MS showed no starting 2-bromo-6-methylpyridine remaining. The mixture was diluted with ethyl acetate (100 mL), and filtered through Celite.™ The pad was then thoroughly washed with ethyl acetate and the combined filtrates were washed with water (200 mL), brine (200 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography eluting with hexane then 98:2, 96:4 hexane:ethyl acetate to afford 2-(cyclohexylethynyl)-6-me-thylpyridine (1.78 g, 77% yield) as a pale brown liquid that partially solidified on standing in the freezer. 1H NMR (CDCl3, 300 MHz) Δ7.52-7.46 (m, 1H), 7.20 (d, J=9 Hz, 1H), 7.03 (d, J=9 Hz, 1H), 2.6 (m, 1H), 2.54 (s, 3H), 2.93-2.89 (m, 2H), 1.78-1.73 (m, 2H), 1.57-1.54 (m, 3H), 1.36-1.32 (m, 3H). MS (ESI) 200.1 (M++H).
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:17][C:18]1([CH3:26])[O:25][C:23](=[O:24])[CH2:22][C:20](=[O:21])[O:19]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C=O)C>[CH3:17][C:18]1([CH3:26])[O:25][C:23](=[O:24])[C:22](=[C:12]([OH:14])[CH:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:16][CH2:15]2)[C:20](=[O:21])[O:19]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(O)=C2C(=O)OC(C)(C)OC2=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A cooled (0° C.) solution of Boc-isonipecotic acid (5.97 g, 26.0 mmol) and Meldrum's acid (3.75 g, 26.0 mmol) in DMF (54 mL) was treated dropwise with diethyl cyanophosphonate (4.34 mL, 28.6 mmol) and triethylamine (11.2 mL, 80.7 mmol). After stirring at 0° C. for an additional 30 min the reaction mixture was permitted to warm to rt and stir over 3 days. The reaction mixture was concentrated under reduced pressure and ether and 1N HCl solution were added. The aqueous layer was extracted again with ether and the ethereal layers were combined and washed with 1N HCl solution, twice with water, and lastly with brine. He ethereal layer was then dried over anhydrous MgSO4, filtered, and concentrated to give tert-butyl 4-[(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)(hydroxy)methyl]piperidine-1-carboxylate which contained approximately 10% of Boc-isonipecotic acid.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1>O>[CH:1]([O:4][C:8]1[CH:13]=[C:12]([CH:11]=[CH:10][N:9]=1)[C:14]#[N:15])([CH3:3])[CH3:2]
Reactant: CC(C)O
Reactant: N#Cc1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)Oc1cc(C#N)ccn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 53 %

Procedure:
To isopropanol (30.0 mL) was added sodium hydride (0.606 g of 60% dispersion, 15.2 mmol) in small portions over 5 minutes. The resulting gel-like suspension was stirred for an additional 5 minutes at room temperature. 2-Chloro-4-cyanopyridine (2.00 g, 14.4 mmol) was then added in one portion and the resulting solution was heated to reflux. After 1 hour, the reaction mixture was allowed to cool to room temperature. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried (magnesium sulfate) and concentrated to provide a yellow oil. Flash chromatography over silica (hexanes/ethyl acetate) afforded 1.25 g (53%) of product as a colorless oil: 1H NMR (CDCl3) δ 8.27 (d, J=5.2 Hz, 1H), 7.01 (dd, J=5.2, 1.4 Hz, 1H), 6.91 (d, J=1.4 Hz, 1H), 5.31 (sept, J=6.2 Hz, 1H), 3.33 (d, J=6.2 Hz, 6H) ppm.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:22]1([NH:28][C:29]2[CH:30]=[CH:31][C:32]3[N:33]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:34]4[C:39]([C:40]=3[CH:41]=2)=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(C)C=CC=CC=1>[C:22]1([N:28]([C:2]2[C:3]3[C:8]([C:9]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[C:10]4[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]4)=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:29]2[CH:30]=[CH:31][C:32]3[N:33]([C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[C:34]4[C:39]([C:40]=3[CH:41]=2)=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Brc1c2ccccc2c(-c2ccccc2)c2ccccc12
Reactant: c1ccc(Nc2ccc3c(c2)c2ccccc2n3-c2ccccc2)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: c1ccc(-c2c3ccccc3c(N(c3ccccc3)c3ccc4c(c3)c3ccccc3n4-c3ccccc3)c3ccccc23)cc1
Yield: 58.4 %

Procedure:
Into a 100 mL three-neck flask were added 501 mg (1.5 mmol) of 9-bromo-10-phenylanthracene, 504 mg (1.5 mmol) of N,9-diphenyl-9H-carbazol-3-amine (abbreviation: PCA), and 500 mg (5.2 mmol) of sodium-tert-butoxide, and the atmosphere in the flask was substituted by nitrogen. Thereafter, 10 mL of toluene and 0.1 mL of tri(tert-butyl)phosphine (10 wt % hexane solution) were added to the mixture. This mixture was stirred under reduced atmosphere to be degassed. After degassing, 43 mg (0.075 mmol) of bis(dibenzylideneacetone)palladium(0) was added. This mixture was stirred at 80° C. for 3 hours under nitrogen. After the reaction, the mixture was added with about 20 mL of toluene and then washed with water. An aqueous layer was extracted with toluene, and the extracted solution was combined with an organic layer and washed with saturated saline. The organic layer was dried with magnesium sulfate, this mixture was naturally filtered, and the filtrate was concentrated. A solid obtained was purified by silica gel column chromatography (developing solvent; hexane:toluene=7:3). Recrystallization of the obtained solid with a mixed solvent of chloroform and hexane gave 514 mg of 9-[N-phenyl-N-(9-phenylcarbazol-3-yl)amino]-10-phenylanthracene (abbreviation: PCAPhA) as yellow powder in 67% yield.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[C@H:12]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11](=[O:24])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].N[CH:26]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2.N(OCC(C)C)=O>ClCCl>[CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[C@H:12]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11](=[O:24])[N:6]2[C:7]=1[C:8]([O:10][CH:26]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=2[C:33]2[C:38]1=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:9]
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Reactant: NC1c2ccccc2-c2ccccc21
Agent: CC(C)CON=O
Solvent: ClCCl
Product: CC1=C(C(=O)OC2c3ccccc3-c3ccccc32)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1

Procedure:
3-Methyl-7β-phenoxyacetamidoceph-3-em-4-carboxylic acid (3.48 g., 10 m. moles) was dissolved with 9-aminofluorene (17.5 m moles) in dichloromethane (50 ml) together with isobutyl nitrite (3.62 g., 35 m. moles) and warmed at 35° for 18 hours. The reaction mixture was worked up as described in Example 7 except that a small quantity of ester (0.24, 0.48 m. moles) was filtered from the solution after the acid aqueous wash. On removal of the solvent the crystalline ester was slurried with warm isopropanol (50 ml), cooled and filtered to give the previously unreported title compound (2.60 g) m.pt. 214°, pure by t.l.c. Together with the previously filtered solid the weight of ester isolated represents a 56.8% yield based on the input acid. An analytical sample of the ester crystallised from acetone-methanol had m.pt. 221° - 222.5°; ν max (1% CHBr3 solution) 3390 (--NHCO--), 1778 (β-lactam) 1718 (αβ-unsaturated ester), 1688 + 1520 cm-1 (amide carbonyl); τ (8% CDCl3 solution) 2.2 - 3.2 (complex, phenoxy ring + (--NHCO--) + fluorenyl 9-C + fluorenyl ring), 5.47 (singlet, phenoxy methylene acetamido group, H2), 4.20 (doublet of doublets, J 10, 5 Hz, C-7, H), 5.04 (doublet, J 5 Hz, C-6, H), 6.45 + 6.89 (two doublets [branches of a quartet], J 18 Hz, H2), 7.84 (singlet, C-3, H3). Found C, 67.68; H, 4.64; N, 5.47. C29H24N2O5S requires C, 67.97; H, 4.72; N, 5.47%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[C:25]1([N:31]2[C:35](Cl)=[N:34][N:33]=[N:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([C:35]4[N:31]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:32]=[N:33][N:34]=4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: Clc1nnnn1-c1ccccc1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1n(-c2nnnn2-c2ccccc2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 80 °C
Yield: 10 %

Procedure:
To a stirred solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (50 mg, 0.14 mmol), prepared as described in Example 1, in 0.7 mL of DMF was added N-phenyl-5-chlorotetrazole (25 mg, 0.14 mmol) and 19 mg of K2CO3. The resulting red solution was heated at 80° C. for 4 days and, upon cooling to room temp, the mixture was diluted with 50 mL of ethyl acetate and 50 mL of 1N HCl. The layers were extracted, and the organic layer was washed with 50 mL of saturated aqueous NaCl. The organic layer was dried over MgSO4, filtered and evaporated to an orange solid. The material was purified via silica gel column chromatography followed by reverse phase HPLC to give the title compound, 7,8-bis(4-chlorophenyl)-2-(1-phenyl-1H-tetrazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (7 mg, 10%) yield as a yellow solid. LCMS Anal. Calc'd for C24H14Cl2N8O, 500.07, [M+H] 501 observed; 1H NMR (400 MHz, CD3CN) δ 8.30 (s, 1H), 7.69-7.55 (m, 5H), 7.39 (dt, 2H, J=2.1, 6.6 Hz), 7.28 (dt, 2H, J=1.9, 8.6 Hz), 7.23 (dt, 2H, J=2.2, 8.6 Hz), 7.06 (dt, 2H, J=2.1, 8.7 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:15])[N:10]=[N:11][C:12]=1[CH2:13][OH:14].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([O:15][S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])=[N:10][NH:11][C:12]=1[CH2:13][OH:14]
Reactant: O=C1N=NC(CO)=C1c1ccccc1F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2n[nH]c(CO)c2-c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.4 %

Procedure:
To a suspension of 4-(2-fluorophenyl)-5-(hydroxymethyl)pyrazol-3-one (28.7 g, 0.138 mol) in dry dichloromethane (300 ml) was added p-toluenesulfonyl chloride (28.9 g, 0.152 mol) followed by triethylamine (21.2 ml, 0.152 mol) dropwise. The solution was stirred at room temperature for 2 days. Dichloromethane (300 ml) was then added to dilute and the solution was washed with brine (300 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography with 0%→40% ethyl acetate/dichloromethane as eluent to give the title compound (23.7 g). Data for the title compound: 1H NMR (360 MHz, DMSO) δ 2.34 (3H, s), 4.66 (2H, s), 6.94 (1H, t), 7.06 (3H, m), 7.17-7.25 (2H, m), 7.51 (2H, d); MS (ES+) m/e 362 [MH]+.