Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:19])[C@H:10]([O:12]C1CCCCO1)[CH3:11].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:19])[C@H:10]([OH:12])[CH3:11]
Reactant: C[C@@H](OC1CCCCO1)C(=O)c1ccc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: C[C@@H](O)C(=O)c1ccc(F)cc1F
Temperature: 55 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
(2R)-2′,4′-Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone (9.62 g, 35.6 mmol, synthesized according to the description in Chem. Pharm. Bull., Vol. 41(6), 1035-1042 (1993)) was dissolved in ethanol (99.5%, 50 mL), and pyridinium p-toluenesulfonate (0.89 g, 3.6 mmol) was added. The mixture was stirred at 50-60° C. for 1 hr. After cooling, the reaction mixture was concentrated under reduced pressure to about 10 mL. Water (20 mL) was flown in and the mixture was extracted twice with ethyl acetate (50 mL). The layers extracted with ethyl acetate were mixed, washed with saturated brine (20 mL) and dried over anhydrous magnesium sulfate. After filtration, the filtrate (ethyl acetate solution) was concentrated. The obtained concentrate (about 9.5 g) was subjected to silica gel column chromatography (SiO2, 30 g) and eluted with n-heptane-ethyl acetate (10:1→5:1). The objective fraction was concentrated to give the title compound as a pale-yellow oil (6.00 g, yield: 91%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14](Br)[CH2:15][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[N+:29]([O-:31])=[O:30].C(OCC)(=O)C.O>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[N+:29]([O-:31])=[O:30])[CH2:15][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC1=Cc2ccc(OCc3ccccc3)cc2CC1
Reactant: COc1ccc(Br)c([N+](=O)[O-])c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C2=Cc3ccc(OCc4ccccc4)cc3CC2)c([N+](=O)[O-])c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 40.7 %

Procedure:
The title compound was synthesized by referring to Tetrahedron Lett., 1993, 34 (21), 3421. A suspension of 7-benzyloxy-3-bromo-1,2-dihydronaphthalene (38 g), 4-bromo-3-nitroanisole (59 g), dichlorobis(triphenylphosphine)palladium (II) (4.5 g) and copper (32 g) in dimethyl sulfoxide (400 ml) was stirred under a nitrogen atmosphere at 120° C. for 1 hour. Ethyl acetate and water was added thereto, the solution was filtered through celite pad, extracted with ethyl acetate, then sequentially washed with aqueous ammonia, water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (19 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH3:10][NH:11][CH3:12].ClC1N=C(N(C)C)C=CC=1C.ClC1N=C(N(C)C)C(C)=CC=1>>[Cl:1][C:2]1[N:3]=[C:4]([N:11]([CH3:12])[CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CNC
Reactant: Cc1cc(Cl)nc(Cl)c1
Agent: Cc1ccc(Cl)nc1N(C)C
Agent: Cc1ccc(N(C)C)nc1Cl
Product: Cc1cc(Cl)nc(N(C)C)c1

Procedure:
The compound was prepared from 2,6-dichloro-4-methylpyridine and dimethylamine using the method described in the preceding example 86 (6-chloro-5-methyl-pyridin-2-yl)-dimethyl-amine and (6-chloro-3-methyl-pyridin-2-yl)-dimethyl-amine).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=1[N:28]=[C:29]=[O:30]>CCCCCC>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[C:29]([NH:28][C:22]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[CH3:20])=[O:30])=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(N=C=O)c(C)c1
Reactant: CCCCc1ccc(CNCCCCCCO)cc1
Solvent: CCCCCC
Product: CCCCc1ccc(CN(CCCCCCO)C(=O)Nc2ccc(C)cc2C)cc1

Procedure:
Many of the novel ureas and thioureas of this invention are prepared by reacting arylisocyanates and arylisothiocyanates with secondary amines. These reactions may be performed in aprotic solvents such as hexane, diethyl ether, toluene, tetrahydrofuran, and the like at temperatures from room temperature or below up to the boiling point of the solvent used. The ureas and thioureas are isolated by filtration or by evaporation of the solvent, and they may be purified by recrystallization, absorption chromatography, or distillation under reduced pressure. Examples of this process are the reaction of 2,4-dimethylphenylisocyanate with N-benzyl-N-(n-butyl)amine to yield 1-benzyl-1-(n-butyl)-3-(2,4-dimethylphenyl)urea and the reaction of 6-[[(4-butylphenyl)methyl]amino]-1-hexanol with 2,4-dimethylphenyl isocyanate in hexane at room temperature to yield 1-[(4-butylphenyl)methyl]-3-(2,4-dimethylphenyl)-1-(6-hydroxyhexyl)urea.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[N:13][C:12](Cl)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[CH3:16][NH:17][NH2:18].[CH2:19](O)CCC>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[N:13][C:12]([N:17]([CH3:16])[NH2:18])=[CH:11][C:10]=2[CH3:19])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(-c2ccc(Cl)nn2)cc1
Reactant: CNN
Reactant: CCCCO
Product: Cc1cc(N(C)N)nnc1-c1ccc(C#N)cc1

Procedure:
A mixture of 7.5 g. of 6-(p-cyanophenyl)-3-chloropyridazine, 3.5 g. of methylhydrazine and 75 ml. of n-butanol is refluxed for 3 hours. The mixture is cooled and filtered to give the product. Recrystallization from dioxane gives 6-(p-cyanophenyl)-5-methyl-3-(1-methylhydrazino)pyridazine as tan crystals, m.p. 149°-152° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.O=S(Cl)[Cl:14].[C:16]1([CH3:22])C=CC=CC=1>>[Br:1][C:2]1[C:3]([F:11])=[C:4]([C:5](=[O:7])[CH2:22][CH2:16][Cl:14])[CH:8]=[CH:9][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(Br)c1F
Reactant: Cc1ccccc1
Product: O=C(CCCl)c1cccc(Br)c1F
Reaction time: 2.5 h

Procedure:
To a solution of 3-bromo-2-fluorobenzoic acid (15 g) in toluene (200 mL) was added SOCl2 (12.2 g) at r.t. and the suspension was heated to reflux with stirring for 2.5 h. The volatiles were removed under reduced pressure. The residue was taken up in DCM (20 mL) and added to a solution of AlCl3 (9.1 g) in dichloroethane at 10-20° C. Ethylene was bubbled through the solution for 4 hours after which the resulting mixture was stirred for 15 hours and then quenched with 4 N HCl (100 mL). The resulting layers were separated and the aqueous phase was extracted with DCM (100 mL×3). The combined organic layers were washed with water (50 mL×3), brine (50 mL) and dried over Na2SO4. After filtration, the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: DCM/PE 1:200) to provide the subtitle compound. MS ESI+: m/z=265 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:21][CH2:22][OH:23])[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].CCN(CC)CC.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:21][CH2:22][O:23][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(CC(CCO)c1ccc(Cl)c(Cl)c1)Nc1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCC(CC(=O)Nc1ccc(Cl)cc1)c1ccc(Cl)c(Cl)c1
Yield: 89.8 %

Procedure:
3,4-Dichloro-beta-(2-hydroxyethyl)-N-(4-chlorophenyl)benzenepropanamide (3.5 g) in CH2Cl2 (60 mL) was cooled to -5° to -10° C. and treated sequentially with Et3N (1.19 g), and methanesulfonyl chloride (1.35 g). After two hours the reaction mixture was washed with water (3×50 mL) and the organic layer separated, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (3.8 g).
Reaction SMILES: CO[C:3]([O:6][CH3:7])([CH3:5])[CH3:4].OC[C@@H:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:5][C:3]1([CH3:4])[N:14]2[C:13](=[O:15])[CH2:12][CH2:11][C@@H:10]2[CH2:7][O:6]1
Reactant: O=C1CC[C@H](CO)N1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)OC[C@H]2CCC(=O)N21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
The reaction was equipped with a Dean-Stark then 2,2-dimethoxypropane (17.09 mL, 139 mmol) was added to a stirred mixture of (R)-(−)-5-(hydroxymethyl)-2-pyrrolidinone (5.353 g, 46.5 mmol) and p-toluenesulfonic acid monohydrate (0.126 g, 0.662 mmol) in toluene (100 mL). The reaction mixture was refluxed for 1.5 h and allowed to stir at room temperature overnight. Solvent was evaporated to afford (R)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (7.22 g, 100% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 4.18 (tt, J=8.8, 6.2 Hz, 1H), 4.00 (dd, J=8.1, 5.8 Hz, 1H), 3.40 (t, J=8.6 Hz, 1H), 2.69 (ddd, J=16.4, 12.1, 8.6 Hz, 1H), 2.33 (dd, J=16.3, 9.1 Hz, 1H), 2.02-2.11 (m, 1H), 1.73 (tt, J=12.1, 8.9 Hz, 1H), 1.53 (s, 3H), 1.33 (s, 3H). m/z (ESI, +ve) 156 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[N-:13]=[C:14]=[O:15].[K+].[C:17]([OH:21])([CH3:20])([CH3:19])[CH3:18].COCCOCCOC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:17]([O:21][C:14]([NH:13][C:2]1[N:7]=[N:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)O
Reactant: [N-]=C=O
Reactant: CCOC(=O)c1ccc(Cl)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COCCOCCOC
Product: CCOC(=O)c1ccc(NC(=O)OC(C)(C)C)nn1

Procedure:
A mixture of ethyl 6-chloro-3-pyridazine carboxylate (6.5 g) [British patent number 856, 409], potassium isocyanate (3.5 g), tert-butanol (6.0 ml), tetrakis(triphenylphosphine)palladium (400 mg) and diglyme (6 ml) in DMF (50 ml) was heated at reflux for 2 hours, cooled and partitioned between diethyl ether and water. The organic layer was dried (MgSO4), filtered through silica gel and evaporated. The resulting solid was purified by crystallisation from iso-hexane to give ethyl 6-(tert-butoxycarbonylamino)-3-pyridazine carboxylate (2.4 g), mp 87°-88° C.
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[C:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26])([CH3:19])([CH3:18])[CH3:17].C1(O)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:18][C:16]([C:20]1[CH:25]=[C:24]([CH:23]=[CH:22][C:21]=1[OH:26])[CH:9]=[O:10])([CH3:19])[CH3:17]
Reactant: CC(C)(C)c1ccccc1O
Reactant: CN(C=O)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Oc1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(C=O)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.5 %

Procedure:
Into 184.4 ml (1.494 mol) of N-methylformanilide were added dropwise, with cooling, 130.9 ml (1.404 mol) of phosphoryl chloride over a period of 20 minutes. The mixture was allowed to warm to room temperature and stirred for one hour. Ortho-tertbutylphenol (138.2 ml; 0.9 mol) was then added dropwise to the reaction solution over a period of 25 minutes. After phenol addition was complete, the resulting reaction mixture was stirred for an additional 30 minutes at room temperature and then heated to approximately 60° C. and stirred for five hours at that temperature. The reaction mixture was poured into a volume of crushed ice and extracted with chloroform. The aqueous layer was separated and washed again with chloroform. The chloroform layers were combined and extracted with 2000 ml of a 5% potassium hydroxide solution. The aqueous potassium hydroxide extract was then added to 1000 ml of chloroform. The pH of the resulting two-phase mixture was adjusted to approximately pH 2.0 with concentrated hydrochloric acid. The mixture's layers were separated and the aqueous layer was again extracted with chloroform. The organic layer from the two-phase mixture and the chloroform extract were combined, washed with water and then dried over sodium sulfate. The volatile components of the solution were removed under reduced pressure to provide a residue. This residue was dissolved in 100 ml of hot toluene and the resulting solution was diluted with 100 ml of hexanes. The solution was slowly cooled to room temperature while a precipitate formed. This precipitate was recovered by filtration, washed with hexanes and then dried under vacuum to provide 20.0 g of the desired subtitled intermediate.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]([O:27]C)=O)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:38][NH2:39]>C(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]([NH:38][NH2:39])=[O:27])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:34])([F:35])[F:36])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: NN
Reactant: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C(=O)NN)cc32)cc1
Temperature: 80 °C

Procedure:
To a solution of methyl 6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido-[2,3-b][1,5]benzodiazepine-8-carboxylate (intermediate 56, 0.11 g, 0.21 mmol) in ethanol (1.0 mL) at rt was added hydrazine hydrate (0.460 mL). The mixture was heated at 80° C. for 18 h, cooled to rt, and the precipitate was collected by filtration to provide the title compound. LC/MS: m/e 520.1 (M+H)+. 1H NMR (500 MHz, CD3OD): δ 8.00 (1H, s), 7.78 (1H, d, J=8.3 Hz), 7.65 (1H, d, J=7.5 Hz), 7.10-7.16 (3H, m), 6.90-6.95 (3H, m), 4.45-4.70 (2H, br), 1.24 (9H, s).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=2)[C:10]([CH3:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C1COCC1.[Pt]>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[C:10]([CH3:20])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Cc1nn(Cc2ccccc2)c2ccc([N+](=O)[O-])cc12
Agent: [Pt]
Solvent: C1CCOC1
Product: Cc1nn(Cc2ccccc2)c2ccc(N)cc12

Procedure:
1-Benzyl-3-methyl-5-nitroindazole (0.15 g) in THF (15 ml) was treated with platinum on carbon (0.05 g, 5%) under an atmosphere of hydrogen at room temperature. When hydrogen uptake was complete, the mixture was filtered and concentrated in vacuo to give the title compound; m/z (M+1)+268.
Reaction SMILES: O[CH:2]([C:34]1[CH:35]=[N:36][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:39]=1)[C:3]1[C:12]2[C:11](=[O:13])[N:10]([CH2:14][CH2:15][CH2:16][O:17]C3CCCCO3)[C:9](=[O:24])[N:8]([CH3:25])[C:7]=2[N:6]=[CH:5][C:4]=1[O:26][C:27]1[CH:28]=[N:29][CH:30]=[C:31]([CH3:33])[CH:32]=1.O[Li].O>C(O)=O.CC(=O)OCC.O.[Zn]>[OH:17][CH2:16][CH2:15][CH2:14][N:10]1[C:11](=[O:13])[C:12]2[C:3]([CH2:2][C:34]3[CH:35]=[N:36][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:39]=3)=[C:4]([O:26][C:27]3[CH:28]=[N:29][CH:30]=[C:31]([CH3:33])[CH:32]=3)[CH:5]=[N:6][C:7]=2[N:8]([CH3:25])[C:9]1=[O:24]
Reactant: Cc1cncc(Oc2cnc3c(c2C(O)c2ccc(C(F)(F)F)nc2)c(=O)n(CCCOC2CCCCO2)c(=O)n3C)c1
Agent: [Li]O
Agent: [Zn]
Solvent: O
Solvent: O=CO
Solvent: CCOC(C)=O
Product: Cc1cncc(Oc2cnc3c(c2Cc2ccc(C(F)(F)F)nc2)c(=O)n(CCCO)c(=O)n3C)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 19.9 %

Procedure:
To a solution of 5-(hydroxy(6-(trifluoromethyl)pyridin-3-yl)methyl)-1-methyl-6-(5-methylpyridin-3-yloxy)-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (24 mg, 0.04 mmol) in HCOOH (1 mL) was added Zn dust (13 mg, 0.2 mmol). The reaction was heated at 100° C. for 1 h, cooled to RT and filtered. The filtrate was concentrated to a crude intermediate which was dissolved in THF (2 mL) and water (2 mL) then LiOH.H2O (33.6 mg, 0.8 mmol) was added. The reaction was stirred at RT for 30 min then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated a residue which was purified by Prep HPLC to give 3-(3-hydroxypropyl)-1-methyl-6-(5-methylpyridin-3-yloxy)-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (4.0 mg, 20% yield) as a white solid. 1H NMR (CDCl3) δ: 8.68 (s, 1H), 8.38 (s, 1H), 8.27 (s, 1H), 8.17 (d, J=2.4 Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.56 (d, J=7.6 Hz, 1H), 6.98 (s, 1H), 4.86 (s, 2H), 4.25 (t, J=6.0 Hz, 2H), 3.74 (s, 3H), 3.57-3.61 (m, 2H), 2.96 (brd s, 1H), 2.34 (s, 3H), 1.92-1.97 (m, 2H). LCMS: MH+ 502 and TR=2.285 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[N+:4]([O-:17])[CH:3]=1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C.O>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:11]1([CH2:10][CH2:9][NH:8][C:6]2[CH:5]=[N+:4]([O-:17])[CH:3]=[C:2]([C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)[N:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1ccncc1
Reactant: [O-][n+]1cc(Cl)nc(NCCc2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: [O-][n+]1cc(NCCc2ccccc2)nc(-c2ccncc2)c1

Procedure:
A mixture containing 0.250 g (1.0 mmol) of 6-chloro-N-(2-phenylethyl)pyrazin-2-amine 4-oxide, 0.296 g (2.40 mmol) of 4-pyridine boronic acid, 0.60 mL (1.2 mmol) of a 2M solution of sodium carbonate in water and 0.116 g (0.1 mmol) of tetrakis(triphenylphosphine)palladium (0) in 5 mL of a mixture of ethanol/water in the proportions 5/1 was stirred under reflux for 16 h. Cooled water was added and the mixture extracted with dichloromethane, dried over sodium sulfate and evaporated to dryness. The residue obtained was purified by chromatography on silica gel eluting with a mixture of dichloromethane/methanol/diethylamine in the proportions 98/2/0.2 to give after trituration with diethyl ether 0.058 g (20%) of pure product as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([CH2:18][O:17][C:16]3[CH:19]=[C:20]4[C:24](=[CH:25][C:15]2=3)[CH2:23][CH2:22][O:21]4)[C:7]1=[O:26].C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].[I-].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[O:26]=[C:7]1[C:8]2([CH2:18][O:17][C:16]3[CH:19]=[C:20]4[C:24](=[CH:25][C:15]2=3)[CH2:23][CH2:22][O:21]4)[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]1[CH2:5][C:4]1[CH:3]=[C:2]([CH:29]=[CH:28][CH:27]=1)[O:1][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: O=C1N(Cc2cccc(O)c2)c2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Temperature: 40 °C
Reaction time: 16 h
Yield: 93.5 %

Procedure:
To a stirred solution of 1′-(3-hydroxybenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.46 g, 1.18 mmol) in N,N-dimethylformamide (4 mL) were added potassium carbonate (0.32 g, 2.36 mmol), ethyl bromoacetate (0.20 mL, 1.77 mmol), and potassium iodide (0.024 g, 0.14 mmol) at ambient temperature. The mixture was stirred at 40° C. for 16 h. Water (50 mL) and ethyl acetate (150 mL) were added to the mixture. The organic solution was separated and the aqueous layer was extracted with ethyl acetate (2×80 mL). The combined organic solution was washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (hexanes/ethyl acetate from 2:1 to 1:1) to afford ethyl {3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]phenoxy}acetate (0.52 g, 93%): mp 45-46° C.; 1H NMR (300 MHz, CDCl3) δ 7.30-7.15 (m, 3H), 7.06-6.96 (m, 2H), 6.90 (br s, 1H), 6.84-6.76 (m, 2H), 6.50 (s, 1H), 6.43 (s, 1H), 5.07-4.96 (m, 2H), 4.87-4.78 (m, 1H), 4.75-4.68 (m, 1H), 4.60-4.50 (m, 4H), 4.22 (q, J=7.1 Hz, 2H), 3.11-2.91 (m, 2H), 1.26 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 177.9, 168.7, 161.8, 161.3, 158.2, 142.0, 137.6, 132.7, 130.0, 128.7, 123.8, 123.4, 120.7, 120.2, 119.9, 118.9, 114.0, 113.7, 109.2, 93.2, 80.6, 72.4, 65.4, 61.4, 57.7, 44.0, 29.0, 14.1; MS (ES+) m/z 471.9 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([OH:20])[C:5]=1[O:21][CH3:22])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[CH:30]([CH3:32])[CH3:31]>C(#N)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([O:20][CH2:29][CH:30]([CH3:32])[CH3:31])[C:5]=1[O:21][CH3:22])[CH3:2]
Reactant: CCOc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1ccc(-c2cccc3c2CCC3=O)c(OCC(C)C)c1OC
Temperature: 80 °C
Yield: 21.1 %

Procedure:
To a stirring solution of 4-(4-ethoxy-2-hydroxy-3-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.268 mmol) in acetonitrile was added potassium carbonate (111 mg, 0.805 mmol) and isobutyl bromide (110 mg, 0.805 mmol) and the resultant reaction mixture was heated to 80° C. for 2 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded title compound as a solid (20 mg, 21%).
Reaction SMILES: [CH2:1](I)[CH3:2].[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:26]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[C:14]2[N:15]=[C:16]([CH3:25])[N:17]([CH2:20][C:21]([F:24])([F:23])[F:22])[C:18](=[O:19])[C:13]2=[N:12]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:26]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:1][CH3:2])=[CH:31][CH:32]=2)=[C:14]2[N:15]=[C:16]([CH3:25])[N:17]([CH2:20][C:21]([F:24])([F:22])[F:23])[C:18](=[O:19])[C:13]2=[N:12]1
Reactant: Cc1nc2c(-c3ccc(O)cc3)n(-c3ccccc3Cl)nc2c(=O)n1CC(F)(F)F
Reactant: CCI
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCOc1ccc(-c2c3nc(C)n(CC(F)(F)F)c(=O)c3nn2-c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Ethyl iodide (88 μL, 1.1 mmol) was added to a mixture of 2-(2-chlorophenyl)-3-(4-hydroxyphenyl)-5-methyl-6-(2,2,2-trifluoroethyl)-2,6-dihydropyrazolo[4,3-d]pyrimidin-7-one (6A-1, 50 mg, 0.11 mmol), Cs2CO3 (55 mg, 0.17 mmol) in NMP (2 ml) at 85° C. The reaction mixture was stirred at this temperature for 5 h, cooled to room temperature, and diluted with 0.5 M citric acid. The aqueous solution was extracted with EtOAc (2×), and the combined organic extracts were washed with 1 M K2CO3, saturated aqueous NaCl, dried, and concentrated in vacuo. The crude residue was purified on a Chromatotron using 1 mm plates and 33% EtOAc/hexanes to give the desired product 7A-1 as an amorphous glass: MS (m/z) 435.4 (M+H)+; 1H NMR (400 MHz, CD2Cl2): δ 7.61-7.46 (m, 4H), 7.25-7.20 (m, 2H), 6.74-6.69 (m, 2H), 5.02 (q, J=7.1 Hz, 2H), 2.65 (s, 3H).