Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:33][C:19]3=[N:20][CH:21]=[C:22]([C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27]([OH:29])=[O:28])[CH:23]=[C:18]3[CH:17]=2)=[CH:12][CH:11]=1.CN(C=O)C>C1COCC1>[Br:8][C:17]1[C:18]2[C:19](=[N:20][CH:21]=[C:22]([C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=3)[C:27]([OH:29])=[O:28])[CH:23]=2)[O:33][C:16]=1[C:13]1[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=1
Reactant: O=C(O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)cc3c2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(Br)c3c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
NBS (125 mg, 0.702 mmol) was added to a stirred suspension of 3-(2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)benzoic acid (215 mg, 0.645 mmol) in THF (5 mL)/DMF (1 mL). The solids dissolved and the reaction was stirred at room temperature for 30 min, then quenched with 10% Na2S2O3, and acidified with 1 N HCl. The solvent was evaporated and the material was diluted with water, filtered and dried to afford a mixture of starting material and product. The material was resubjected to the reaction conditions (80 mg of NBS in 3 mL THF/0.5 mL DMF). After 3 h, the reaction was quenched by the addition of 10% Na2S2O3, and the solution was acidified with 0.1 N HCl. The volatiles were removed and the resulting off-white precipitate was collected by filtration, rinsed with water and Et2O, and air-dried to afford the expected product 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)benzoic acid (140 mg, 53% yield) as an off-white powder consistent by LCMS and NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.73 (1H, d, J=2.26 Hz), 8.27-8.33 (2H, m), 8.19-8.26 (2H, m), 8.05-8.12 (1H, m), 8.03 (1H, d, J=7.78 Hz), 7.68 (1H, t, J=7.78 Hz), 7.45-7.55 (2H, m). LC-MS retention time: 1.20 min; m/z (MH+): 412, 414. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH2:1]([S:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:16](=[O:19])(=[O:18])[NH2:17])[C:14]=1[Cl:15])[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4].Cl.[CH2:21](O)[CH3:22]>>[CH2:1]([S:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:16](=[O:18])(=[O:19])[NH2:17])[C:14]=1[Cl:15])[C:9]([O:11][CH2:21][CH3:22])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCO
Reactant: CCCCSc1cc(C(=O)O)cc(S(N)(=O)=O)c1Cl
Agent: Cl
Product: CCCCSc1cc(C(=O)OCC)cc(S(N)(=O)=O)c1Cl

Procedure:
3-Butylthio-4-chloro-5-sulfamylbenzoic acid (1.8 g) in a saturated solution of hydrogen chloride in ethanol (40 ml) is stirred for 18 hours. The precipitate is collected by filtration and washed with ethanol and petroleum ether to yield ethyl 3-butylthio-4-chloro-5-sulfamylbenzoate with a melting point of 160° - 162°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:33])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1.CO.[BH4-].[Na+]>CCOC(C)=O.CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:33])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:30])[CH3:31])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCC(=O)c3ccccc3F)CC2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCC(O)c3ccccc3F)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a 50-mL round-bottomed flask charged with N-(3-{1-[7-(2-fluorophenyl)-7-oxoheptyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.0 mmol) and methanol (20 mL) was added NaBH4 (7.5 mmol) at 0° C. in an ice-bath. The reaction mixture was warmed to 25° C. and stirred for 2 h. The reaction was monitored by TLC (EtOAc:MeOH 95:5). If necessary, another 5.0 mmol of NaBH4 was added to the reaction mixture and the reaction mixture was refluxed for 1 h. The reaction was quenched with water (5.0 mL) and diluted with EtOAc (10 mL). The organic layer was separated, washed with saturated NaHCO3 solution (10 mL), dried over MgSO4 and concentrated in vacuo. The crude product was purified by chromatography (EtOAc:MeOH 97:3) to give the desired product (90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:24])[N:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=[C:12]([C:14]([O:16][CH3:17])=O)[CH:13]=1.Br[C:26]1[C:27](=O)[N:28](C2C=CC=CC=2)[CH:29]=[C:30](C(OC)=O)[CH:31]=1.ClC1C=CC=CC=1B(O)O.C(Cl)(=O)C(Cl)=O>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:24])[N:10]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:11]=[C:12]([C:14]2[O:16][C:17]3[CH:29]=[CH:30][CH:31]=[CH:26][C:27]=3[N:28]=2)[CH:13]=1
Reactant: COC(=O)c1cc(Br)c(=O)n(-c2ccccc2)c1
Reactant: COC(=O)c1cc(-c2ccccc2Cl)c(=O)n(-c2ccccc2)c1
Agent: O=C(Cl)C(=O)Cl
Agent: OB(O)c1ccccc1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=c1c(-c2ccccc2Cl)cc(-c2nc3ccccc3o2)cn1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
19 mg of carboxylate obtained by hydrolyzing the ester group of 3-(2-chlorophenyl)-5-(methoxycarbonyl)-1-phenyl-1,2-dihydropyridin-2-one (synthesized from 3-bromo-5-(methoxycarbonyl)-1-phenyl-1,2-dihydropyridin-2-one and 2-chlorophenylboronic acid in accordance with the method of Referential Example 3) was dissolved in 20 ml of dichloromethane. Under ice-cooling, a solution of 11 mg of oxalyl chloride in dichloromethane was added dropwise thereinto and a catalytic amount of dimethylformamide was added thereto, followed by stirring at room temperature in nitrogen atmosphere for 1 hour. The reaction solution was evaporated, and the residue was dissolved in dichloromethane. The solution was added dropwise into a solution of 19 mg of 2-aminophenol in dichloromethane under ice-cooling. After heating to room temperature, dichloromethane was evaporated. To the residue was added 1 ml of polyphosphoric acid, followed by stirring at 180° C. overnight. After cooling to room temperature, the reaction mixture was neutralized with 1N aqueous solution of sodium hydroxide and saturated aqueous solution of sodium hydrogen carbonate under ice-cooling. The mixture was extracted with ethyl acetate, and the resulting organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate system), to give 3 mg of the title compound as white crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][C:11]([C:20]([OH:22])=[O:21])=[CH:10][C:9]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N12CCCN=C1CCCC[CH2:30]2.IC>C1COCC1>[CH3:30][O:21][C:20]([C:11]1[CH:10]=[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]([O:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=1)=[O:22]
Reactant: COCCOCOc1c(-c2ccccc2)cc(C(=O)O)cc1-c1ccccc1
Reactant: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: CI
Product: COCCOCOc1c(-c2ccccc2)cc(C(=O)OC)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
At 0° C., to a stirred solution of 2′-(2-methoxyethoxymethoxy)-[1,1′;3′,1″]terphenyl-5′-carboxylic acid (1.72 g, 4.55 mmol) in THF (4.55 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene. After 0.5 h, to the reaction was added iodomethane and the reaction was stirred for 16 h, eventually warming to ambient temperature. The reaction was filtered and the filtrate concentrated. The crude product was dissolved in EtOAc, washed sequentially with sat. aq. NaHCO3 (3×), with 1 N HCl (3×), brine (3×), dried (K2CO3) and concentrated. Purification on Biotage KP-Sil eluting with 20% acetone/hexane gave 1.641 g (92%) of the title compound as a yellow oil. 1H NMR (DMSO-d6) δ 2.77-2.80 (m, 2H), 2.88-2.91 (m, 2H), 3.01 (s, 3H), 3.87 (s, 3H), 4.40 (s, 2H), 7.40-7.53 (m, 6H), 7.60-7.62 (m, 4H), 7.90 (s, 2H).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9](=[O:11])[CH3:10])[CH2:3]1.Cl.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([NH:21]N)[CH:18]=[CH:19][CH:20]=1.O>CC(O)=O>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:18]([C:7]3[CH2:6][CH2:5][CH:4]([NH:8][C:9](=[O:11])[CH3:10])[CH2:3][C:2]=3[NH:21]2)=[CH:19][CH:20]=1
Reactant: COc1cccc(NN)c1
Reactant: CC(=O)NC1CCCC(=O)C1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c3c([nH]c2c1)CC(NC(C)=O)CC3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.05 mol of N-(3-oxocyclohexyl)acetamide and 0.05 mol of 3-methoxyphenylhydrazine hydrochloride in 50 ml of glacial HOAc was stirred for 2 hr at room temperature and then refluxed for 2 hr. The cooled reaction mixture was poured into H2O and the product triturated until solid. Filtration, drying, and recrystallization from ethanol gave the title compound, mp 192°-193°.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=1)[C:8]([NH:10][C:11]1[S:12][C:13]2[CH2:40][CH2:39][CH2:38][CH2:37][C:14]=2[C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)=[O:17])=[O:9])(=[O:4])=[O:3].[CH3:44][NH:45][CH2:46][CH2:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49]>ClCCl>[C:51]([O:50][C:48](=[O:49])[CH2:47][CH2:46][N:45]([CH3:44])[S:2]([C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=1)[C:8]([NH:10][C:11]1[S:12][C:13]2[CH2:40][CH2:39][CH2:38][CH2:37][C:14]=2[C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)=[O:17])=[O:9])(=[O:4])=[O:3])([CH3:54])([CH3:53])[CH3:52]
Reactant: CNCCC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)Cl)c4)sc4c3CCCC4)cc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)N(C)CCC(=O)OC(C)(C)C)c4)sc4c3CCCC4)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
A mixture of 250 mg of methyl 4-[2-(4-{[(2-{[3-(chlorosulfonyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 125 mg of tert-butyl 3-(methylamino)propanoate, and 2.5 mL of dichloromethane was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane-chloroform) to obtain 209 mg of methyl 4-{2-[4-({[2-({3-[(3-tert-butoxy-3-oxopropyl)(methyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate as a pale yellow foamed solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([O:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[N+:14]([O-])=O.[H][H]>C(O)C.[Pt](=O)=O>[F:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([O:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[NH2:14]
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1Br
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: COC(=O)Oc1cc(N)c(F)cc1Br
Yield: 106 %

Procedure:
Platinum dioxide (1.0 g) was added to a solution of 2-fluoro-4-bromo-5-methoxycarbonyloxinitrobenzene (30.4 g, 0.1 mol) in ethanol (300 ml) and the solution was stirred in normal atmospheric pressure of hydrogen until absorption of hydrogen was terminated. After completion of the reaction, the catalyst was removed by filtration and the solvent was removed by distillation from the filtrate to give a brown solid (28.0 g) of 2-fluoro-4-bromo-5-methoxycarbonyloxianiline.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14](Br)[CH:15]=[CH2:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)C>[CH2:16]([O:13][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1)[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CCOc1ccc(-c2ccccc2)cc1
Yield: 78.9 %

Procedure:
4-Phenylphenol 64 (25.5 g, 0.15 mol), allyl bromide (20.0g, 0.165mol) and K2CO3 (41.5 g, 0.15 mol) in 75 ml of dry DMF were stirred at room temperature overnight. The reaction mixture was diluted with 500 ml of diethyl ether and washed with water. The ether layer was washed with brine, dried and concentrated to give a lightly brown solid that was recrystallized from hexane to give 24.9 g of 4-allyloxy-biphenyl 65.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C[Al](C)C.[C:17]([C:19]1[CH:20]=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1)#[N:18]>C1(C)C=CC=CC=1>[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:17](=[NH:18])[C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[N:21][CH:20]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: Cc1cncc(C#N)c1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1cncc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a suspension of 4-(methylsulfonyl)aniline hydrochloride (10.5 g, 0.051 mol) in toluene (500 mL) was added trimethylaluminum (2M solution in toluene, 75.0 mL, 0.150 mol) over 15 minutes at 0° C. The reaction mixture was warmed up to room temperature and stirred for 2 hours. A solution of 3-cyano-5-methylpyridine from step 3 in 90 mL of toluene was added over 10 minutes and the mixture was stirred at 85-90° C. for 16 hours. The reaction mixture was cooled to room temperature and filtered through a slurry of silica gel. After filtration, the residue was washed with methanol (800 mL). The combined filtrate was concentrated under reduced pressure and the residue was treated with a mixture of ether and hexane (2/1, 1000 mL). The brownish solid was filtered and washed with more ether and hexane to give 11.8 g of N-[4-(methylsulfonyl)phenyl]-5-methylnicotinamidine (80%). To a mixture of the above crude amidine (11.3 g, 0.039 mol) and sodium bicarbonate (9.83 g, 0.12 mol) in isopropanol (400 mL) was added 3-bromo-1,1,1-trifluoroacetone (11.2 g, 0.059 mol) quickly at room temperature. After hearing the reaction mixture at 75-80° C. for 16 hours, the solvent was removed and the residue was partitioned between water and methylene chloride. The organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (ethyl acetate/acetone, 98:2) to give pure 3-methyl-5-[4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine as a yellow solid (3.85 g, 25%): mp (DSC) 237-239° C.; Anal. Calc'd. for C17H16F3N3O3S: C, 51.12, H, 4.04, N, 10.52, S, 8.03. Found: C, 51.02, H, 3.94, N, 10.19, S, 8.11.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH:5]=[C:6]2[CH2:9][CH2:10][OH:11].[H-].[Na+].Cl[CH2:16][C:17]([OH:19])=[O:18].[OH-].[Na+]>C(COC)OC.O>[CH3:1][C:2]1([CH3:12])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH:5]=[C:6]2[CH2:9][CH2:10][O:11][CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C(O)CCl
Reactant: CC1(C)C2CC=C(CCO)C1C2
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: CC1(C)[C@H]2CC=C(CCOCC(=O)O)[C@@H]1C2
Temperature: 45 °C
Yield: 52609 %

Procedure:
To a solution of (−)-nopol (Aldrich) (100 g, 0.60 mmol) in dimethoxy ethane (350 mL) was added NaH (60% oil dispersion, 31.1 g, 0.81 mmol). The mixture was refluxed for 2.5 hours, cooled to 45° C., and 2-chloroacetic acid (23.5 g 0.25 mmol) in dimethoxy ethane (180 mL) was added drop wise over a period of 1.5 hours. The reaction mixture was refluxed for 1 hour. After cooling at room temperature, water (75 mL) was added slowly, followed by 10% aqueous NaOH. The mixture was extracted with ether (1 L) (discarded), the aqueous phase was acidified and extracted with ether. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was distilled under reduced pressure to yield the title compound (29.5 g, 135-137° C. at 1.0 mm of Hg). n25D 1.4914, mp 78-80° C.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[N:15][C:16]([N:19]([CH3:30])[CH:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)=[CH:17][CH:18]=2)=[C:9]([O:31][C:32]([F:35])([F:34])[F:33])[CH:8]=1)(=[O:5])=[O:4].C(O)(=[O:40])C.C(O)(=O)C.IC1C=CC=CC=1>CC(O)=O.CC(OC(C)=O)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:37][C:2]([F:36])([F:1])[S:3]([O:6][C:7]1[CH:8]=[C:9]([O:31][C:32]([F:33])([F:34])[F:35])[C:10]([C:13]2[N:14]=[N:15][C:16]([N:19]([CH3:30])[CH:20]3[CH2:21][C:22]([CH3:29])([CH3:28])[NH:23][C:24]([CH3:26])([CH3:27])[CH2:25]3)=[CH:17][CH:18]=2)=[C:11]([OH:40])[CH:12]=1)(=[O:4])=[O:5]
Reactant: CN(c1ccc(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2OC(F)(F)F)nn1)C1CC(C)(C)NC(C)(C)C1
Reactant: CC(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)OC(C)=O
Solvent: Ic1ccccc1
Product: CN(c1ccc(-c2c(O)cc(OS(=O)(=O)C(F)(F)F)cc2OC(F)(F)F)nn1)C1CC(C)(C)NC(C)(C)C1
Temperature: 60 °C

Procedure:
A mixture of 4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3-(trifluoromethoxy)phenyl trifluoromethanesulfonate (360 mg, 0.647 mmol), iodobenzene diacetate (375 mg, 1.164 mmol) and Pd(OAc)2 (7.3 mg, 0.032 mmol) in AcOH (3.0 mL) and Ac2O (3.0 mL) was heated at 60° C. overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was basified with aqueous NaHCO3 solution and extracted with DCM. The combined organic layers were dried over Na2SO4, and concentrated. The crude material was loaded onto a SCX column, washed with MeOH and diluted with 2 M NH3 in MeOH. The product-containing fractions were concentrated. Compound 3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(trifluoromethoxy)phenyl trifluoromethanesulfonate was obtained as a yellow solid (110 mg, 28%) after flash column chromatography and HPLC purification. MS (M+1)=573.2.
Reaction SMILES: C12[N:8]([C:9]3C=N[C:16]4[C:11](=[CH:12]C=[CH:14][CH:15]=4)[N:10]=3)CC1CCNC2.[CH:19]12[CH2:25][NH:24][CH:23]1[CH2:22][N:21]([C:26]([C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][C:29]=1[N:35]1[N:39]=[CH:38][CH:37]=[N:36]1)=[O:27])[CH2:20]2.ClC1N=C(C)C=C(C)N=1>>[CH3:12][C:11]1[CH:16]=[C:15]([CH3:14])[N:8]=[C:9]([N:24]2[CH2:25][CH:19]3[CH:23]2[CH2:22][N:21]([C:26]([C:28]2[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][C:29]=2[N:35]2[N:39]=[CH:38][CH:37]=[N:36]2)=[O:27])[CH2:20]3)[N:10]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CC3CNC3C2)c1
Reactant: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Agent: Cc1cc(C)nc(Cl)n1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CC3CN(c4nc(C)cc(C)n4)C3C2)c1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using Intermediate 26 and 2-chloro-4,6-dimethylpyrimidine. MS (ESI) mass calcd. for O21H23N7O, 389.46; m/z found, 390.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N+:5]([O-])=[CH:4][CH:3]=1.[CH3:13][S:14]([O:17]S(C)(=O)=O)(=[O:16])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>ClCCl>[CH3:13][S:14]([O:17][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)(=[O:16])=[O:15]
Reactant: [O-][n+]1ccc(O)c2ccccc21
Reactant: CS(=O)(=O)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)Oc1cnc2ccccc2c1O
Reaction time: 4 h

Procedure:
A mixture of 4-hydroxyquinoline-1-oxide (1 g), methanesulphonic anhydride (2 g) and potassium carbonate (2 g) in dichloromethane (20 ml) was stirred at 0° for 4 hours. Water (20 ml) was added to the mixture and the dichloromethane layer separated. The aqueous layer was extracted with dichloromethane (2×60 ml). The combined dichloromethane layer and extracts were dried over magnesium sulphate and evaporated to give a gum which was purified by flash chromatography on a silica gel column eluted with dichloromethane:methanol (19:1) to give the novel compound 4-hydroxyquinol-3-yl methanesulphonate, m.p. 224°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[C:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.[C:33]1([N:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[NH2:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C1COCC1>CS(O)(=O)=O.CN(C)C(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1.[C:33]1([N:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:40]=[C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: NN(c1ccccc1)c1ccccc1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: c1ccc(C(=NN(c2ccccc2)c2ccccc2)c2ccccc2)cc1

Procedure:
In a 100 mL single neck round bottom flask was weighed poly(bisphenol-A-benzophenone) (5.000 g, 11.50 mmol), 1,1 -diphenylhydrazine hydrochloride (2.714 g, 12.30 mmol) , THF (18 g) and N,N-dimethylacetamide (18 g). The flask was fitted with a condensor. The dark slurry was stirred with a magnetic stirrer to dissolve the starting materials. To the dark solution was added methanesulfonic acid (about 6 drops), and the solution heated to reflux . After stirring for about 4 hours, the orange polymer solution was precipitated in water, and chopped in a high speed blender. The yellow fibrous polymer was isolated by filtration, washed in boiling water (about 45 min.), filtered, washed in boiling methanol (about 45 min.), filtered and dried at about 100° C. for about 16 hours. The yield was about 5.29 g. The number average molecular weight of the polymer was about 11.8K.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][CH2:12][Mg+].[Br-].B(F)(F)F.CCOCC>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]1([NH2:5])[CH2:12][CH2:11]1
Reactant: N#Cc1cc(Cl)ccc1Br
Reactant: CC[Mg+]
Agent: FB(F)F
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: NC1(c2cc(Cl)ccc2Br)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.6 %

Procedure:
To a stirred solution of 2-bromo-5-chlorobenzonitrile (10 g, 46 mmol) and Ti(Oi-Pr)4 (16.64 mL, 55 mmol) in THF (200 mL) at −78° C. was added EtMgBr (138 mL, 138 mmol) dropwise. The reaction mixture was allowed to warm up to room temperature and stirred for 2 hours. BF3-Et2O (17.2 mL) was added, and the solution was stirred for another 16 hours before it was quenched with aq. HCl solution and washed with EtOAc. The aqueous phase was adjusted to pH˜10 with aq. NaOH solution, and exacted with EtOAc (3×). The combined organic layers were concentrated to give a crude product which was purified by chromatography to afford title compound (2 g, yield 17.6%). MS: 246.7 (M+H+, 1C1) as oil.