Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]([C:24]([O:26]CC)=[O:25])[C:9]([OH:23])([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10]([O:12]CC)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>O1CCOCC1.C(OCC)(=O)C>[CH2:1]([CH:8]([C:24]([OH:26])=[O:25])[C:9]([OH:23])([CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(O)(CCc1ccccc1)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(O)C(Cc1ccccc1)C(O)(CCc1ccccc1)C(=O)O
Temperature: 60 °C
Reaction time: 48 h
Yield: 94.4 %

Procedure:
To a diethyl 3-benzyl-2-hydroxy-2-phenethylsuccinate (806 mg, 2.1 mmol) in 1,4-dioxane (8.0 mL) was added 1 M aqueous lithium hydroxide solution (8.4 mL, 8.4 mmol) at room temperature, and the mixture was stirred at 60° C. for 48 h. The reaction mixture was quenched and adjusted to pH 1 with 1 M hydrochloric acid with stirring under ice cooling. The solvent was evaporated under reduced pressure, and the residue thus obtained was dissolved in ethyl acetate, and washed with water and brine. The organic layer was concentrated under reduced pressure and dried in vacuum to give 651 mg (crude) of 3-benzyl-2-hydroxy-2-phenethylsuccinic acid
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH:22]1[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]1>>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[CH2:23]1
Reactant: O[C@@H]1CCNC1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(N3CC[C@@H](O)C3)cc2c1=O
Yield: 60 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with (R)-pyrrolidin-3-ol according to the GPA affording 25.6 mg (60%) of a red powder. Rt=3.09 min.
Reaction SMILES: Br[CH2:2][C:3]1[NH:7][C:6](=[O:8])[NH:5][C:4]=1[C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.[CH3:19][NH:20][CH3:21]>C(O)C>[CH3:19][N:20]([CH2:2][C:3]1[NH:7][C:6](=[O:8])[NH:5][C:4]=1[C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[CH3:21]
Reactant: CNC
Reactant: COc1ccc(C(=O)c2[nH]c(=O)[nH]c2CBr)cc1
Solvent: CCO
Product: COc1ccc(C(=O)c2[nH]c(=O)[nH]c2CN(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3.1 g of 5-(bromomethyl)-1,3-dihydro-4-(4-methoxybenzoyl)-2H-imidazol-2-one, 12 ml of 30% aqueous dimethylamine and 24 ml of ethanol is stirred at 25° C. for 2 hours. The solvent is then evaporated from the mixture under reduced pressure and the resultant residue is recrystallized twice from ethanol to give 4-[(dimethylamino)methyl]-1,3-dihydro-5-(4-methoxybenzoyl)-2H-imidazol-2-one melting at about 165°-167° C. with decomposition.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:15]1[N:20]([CH3:21])[C:19](=[O:22])[CH:18]=[C:17]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[F:29])[N:16]=1.C(N(CC)CC)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:15]3[N:20]([CH3:21])[C:19](=[O:22])[CH:18]=[C:17]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][C:24]=4[F:29])[N:16]=3)[CH2:9]2)=[CH:6][CH:7]=1
Reactant: Brc1ccc([C@H]2CCCNC2)cc1
Reactant: Cn1c(Cl)nc(-c2ccncc2F)cc1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCC[C@H](c3ccc(Br)cc3)C2)nc(-c2ccncc2F)cc1=O
Temperature: 95 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
A solution of (3R)-3-(4-bromophenyl)piperidine obtained in Reference Example 15 (0.21 g, 0.9 mmol), 2-chloro-6-(3-fluoropyridin-4-yl)-3-methyl-3H-pyrimidine-4-one (0.21 g, 0.9 mmol), and triethylamine (0.30 g, 3.0 mmol) in tetrahydrofuran (10 ml) was stirred at 95° C. for 3 hours. The solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to afford 2-((3R)-3-(4-bromophenyl)piperidin-1-yl)-6-(3-fluoropyridin-4-yl)-3-methyl-3H-pyrimidine-4-one (0.24 g, 62%) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([CH3:17])[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:16][N:15]1[C:11]([C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([O:1][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=3)[CH:3]=2)=[O:10])=[CH:12][C:13]([CH3:17])=[N:14]1
Reactant: Cc1cc(C(=O)Nc2cccc(O)c2)n(C)n1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc([N+](=O)[O-])cn3)c2)n(C)n1
Temperature: 60 °C
Reaction time: 15 h
Yield: 98.3 %

Procedure:
A mixture of N-(3-hydroxyphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (1.58 g, 6.83 mmol), 2-chloro-5-nitropyridine (1.03 g, 6.51 mmol), potassium carbonate (1.42 g, 10.2 mmol) and N,N-dimethylformamide (10 mL) was stirred at 60° C. for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (hexane/ethyl acetate=70/30→0/100) to give the title compound (2.26 g, 94%) as a white solid.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][OH:9].Br[CH2:17][CH2:18][O:19]C1CCCCO1.[OH-].[K+].O>CS(C)=O>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][O:9][CH2:17][CH2:18][OH:19]
Reactant: OCCc1ccccc1-c1ccccc1
Reactant: BrCCOC1CCCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: OCCOCCc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of the alcohol prepared above (8.5 g, 43 mmol), 2-bromoethyltetrahydro-2-pyranylether (17.9 g, 86 mmol) and potassium hydroxide (9.6 g, 171 mmol) in dimethylsulfoxide (100 ml) was stirred at ambient temperature for 72 h. An extra batch of 2-bromoethyltetrahydro-2-pyranylether (3.6 g, 17 mmol) was added and the mixture stirred for 48 h at ambient temperature. Water (350 ml) was added and the mixture was extracted with diethylether (2×250 ml). The organic phases were combined, washed with water (100 ml), dried (MgSO4) and concentrated in vacuo. The residue was submitted to column chromatography on silica gel (400 ml) using heptane and ethyl acetate (3:2) as eluent to give 6.6 g of 2-(2-(biphenyl-2-yl)ethoxy)ethanol as an oil.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C(CCCC)C(O)=O)C.[C:28](OC)(=[O:35])/[CH:29]=[CH:30]\[C:31]([O:33][CH3:34])=[O:32]>ClC1C=CC=CC=1Cl>[CH2:11]([N:10]1[C:29](=[CH:30][C:31]([O:33][CH3:34])=[O:32])[C:28](=[O:35])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]1=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(NCc1ccccc1)Nc1ccccc1
Reactant: COC(=O)/C=C\C(=O)OC
Agent: CCCCC(CC)C(=O)O
Solvent: Clc1ccccc1Cl
Product: COC(=O)C=C1C(=O)N(c2ccccc2)C(=O)N1Cc1ccccc1

Procedure:
113 g of N-phenyl-N'-benzyl-urea were dissolved in 1000 g of o-dichlorobenzene; the solution was made acid with 2-ethyl-hexanoic acid and reacted with 72 g of dimethyl maleate. After a reaction time of 6 hours at 175° C, the solvent was distilled off and the residue triturated with ether. The product separated by suction filtration can be obtained pure by recrystallisation from toluene. The white crystals obtained have a melting point of 130° C and their structure was demonstrated by the IR and NMR spectra and elementary analysis.
Reaction SMILES: Br[C:2]1[C:19]([CH2:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[CH3:15].O.[CH3:23][N:24](C)C=O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C-]#N.[Zn+2].[C-]#N>[C:23]([C:2]1[C:19]([CH2:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[CH3:15])#[N:24]
Reactant: CN(C)C=O
Reactant: CCc1cccc(Oc2ccc(C(=O)OC)cc2C)c1Br
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CCc1cccc(Oc2ccc(C(=O)OC)cc2C)c1C#N
Temperature: 140 °C
Reaction time: 12 h
Yield: 61 %

Procedure:
To a solution of methyl 4-(2-bromo-3-ethylphenoxy)-3-methylbenzoate (1.0 g, 2.9 mmol) in N,N-dimethylformamide was added tetrakis(triphenylphosphine) palladium(0) (0.35 g, 0.3 mmol) and zinc cyanide (1.2 g, 10 mmol). The reaction mixture was stirred at 140° C. for 12 hours. After the reaction, the mixture was poured into water (50 mL) and the solution was extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=20:1) to give the pure product methyl 4-(2-cyano-3-ethylphenoxy)-3-methylbenzoate as a colorless oil (0.52 g, 61%). 1H NMR (300 MHz, CDCl3): δ 7.99 (d, J=1.8 Hz, 1H), 7.89 (dd, J=8.4 Hz, J=2.1 Hz, 1H), 7.55 (d, J=8.7 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 6.86 (d, J=2.4 Hz, 1H), 6.76 (dd, J=8.4 Hz, J=2.4 Hz, 1H), 3.92 (s, 3H), 2.83 (q, J=7.5 Hz, 2H), 2.26 (s, 3H), 1.27 (t, J=7.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][NH:10][C:4]=2[CH:3]=1.Br[C:12]1[N:17]=[C:16]([N:18]2[CH:23]([CH3:24])[CH2:22][CH2:21][CH:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:19]2)[CH:15]=[CH:14][CH:13]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:12]3[N:17]=[C:16]([N:18]4[CH:23]([CH3:24])[CH2:22][CH2:21][CH:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:19]4)[CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1
Reactant: CC1CCC(NC(=O)OC(C)(C)C)CN1c1cccc(Br)n1
Reactant: Clc1cc2[nH]ncc2cn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CC1CCC(NC(=O)OC(C)(C)C)CN1c1cccc(-n2ncc3cnc(Cl)cc32)n1
Temperature: 100 °C
Yield: 64.2 %

Procedure:
A mixture of 6-chloro-1H-pyrazolo[4,3-c]pyridine (100 mg, 0.651 mmol), tert-butyl N-[1-(6-bromo-2-pyridyl)-6-methyl-3-piperidyl]carbamate (422 mg, 1.14 mmol), tris(dibenzylideneacetone)dipalladium(0) (59 mg, 0.065 mmol), xantphos (78 mg, 0.130 mmol), and sodium tert-butoxide (129 mg, 1.30 mmol) in toluene 6.0 mL was stirred at 100° C. 18 h. The reaction was filtered through celite. The crude product was purified by flash chromatography (EtOAc/Heptane) to give the desired product (185 mg) in 64% yield. MS (ESI) m/z: 443.2
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].C(=O)([O-])[O-].[K+].[K+].[C:14]1([N:24]=[C:25]=[O:26])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>C1C=CC=CC=1>[CH3:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[N:1][C:25]([NH:24][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:26]
Reactant: O=C=Nc1cccc2ccccc12
Reactant: CN1CCCC1=N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CN1CCCC1=NC(=O)Nc1cccc2ccccc12
Reaction time: 2 h

Procedure:
A solution of 2-imino-1-methylpyrrolidine (obtained from 6.91 g., 0.051 mole, hydrochloride salt) in benzene is dried over potassium carbonate and filtered. A solution of 1-naphthyl isocyanate (8.45 g., 0.05 mole) in benzene is added by filtration. The mixture is stirred for 11/2 hr. at room temperature and the precipitate separated by filtration. Recrystallization from acetone affords the product, 1-(1-methyl-2-pyrrolidinylidene)-3-(1-naphthyl)urea, m.p. 148°-149° C.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]([OH:14])=[C:7]([CH:15](O)[CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:6]=1[CH:22]([CH3:24])[CH3:23])(=[O:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]2[O:14][C:16]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][C:7]=2[C:6]=1[CH:22]([CH3:24])[CH3:23])(=[O:3])[CH3:2]
Reactant: CCC(CC)C(O)c1c(O)cc(C(C)C)c(OC(C)=O)c1C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCC1(CC)Cc2c(cc(C(C)C)c(OC(C)=O)c2C(C)C)O1
Yield: 89.7 %

Procedure:
0.51 g of 4-acetoxy-2-(2-ethyl-1-hydroxybutyl)-3,5-diisopropylphenol dissolved in 10 ml of toluene, 0.58 g of p-toluenesulfonic acid monohydrate was added, and the mixture was heated under reflux for 1.5 hours. The reaction mixture was combined with a 2N aqueous sodium hydroxide solution and extracted with hexane. The organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 1% ethyl acetate) to give 433 mg of 5-acetoxy-2,2-diethyl-4,6-diisopropyl-2,3-dihydrobenzofuran as a yellow oil (yield 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13](I)[C:5]([NH:6][CH2:7][CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:4]([F:16])[CH:3]=1.[CH2:17]([OH:20])[C:18]#[CH:19]>CCN(CC)CC.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]I>[Cl:1][C:2]1[CH:14]=[C:13]2[C:5](=[C:4]([F:16])[CH:3]=1)[N:6]([CH2:7][CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:18]([CH2:17][OH:20])=[CH:19]2
Reactant: C#CCO
Reactant: CS(=O)(=O)CCNc1c(F)cc(Cl)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CCn1c(CO)cc2cc(Cl)cc(F)c21
Yield: 95.4 %

Procedure:
A mixture of 4-chloro-2-fluoro-6-iodo-N-(2-(methylsulfonyl)ethyl)aniline (450 mg, 1.2 mmol) and prop-2-yn-1-ol (135 mg, 2.4 mmol) in Et3N (20 ml) was degassed and refluxed under N2 atmosphere. PdCl2(PPh3)2 (90 mg, 0.12 mmol) and CuI (45 mg, 0.24 mmol) were added successively to the reaction mixture. After being stirred under reflux overnight, the mixture was concentrated in vacuo and the residue was poured into water and extracted with EtOAc (50 mL×3). The combined organic layers were dried over Na2SO4 and then concentrated in vacuo. The residue was purified by preparative-TLC (PE: EtOAc=5:1) to give {5-chloro-7-fluoro-1-[2-(methylsulfonyl)ethyl]-1H-indol-2-yl}methanol as a yellow solid (350 mg, yield: 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH:3]=1.[CH2:22]([Mg]Br)[CH3:23]>C1COCC1>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH2:22][CH3:23])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH:3]=1
Reactant: CON(C)C(=O)c1ccc(Cl)cc1Nc1ccccc1Cl
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(=O)c1ccc(Cl)cc1Nc1ccccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
In a 500 mL round bottom flask, 4-chloro-2-(2-chloro-phenylamino)-N-methoxy-N-methyl-benzamide (1.0 g, 3.08 mmol) was added to THF (60 mL) to give a colorless solution. The reaction was cooled to 0° C. in an ice bath and ethyl magnesium bromide (3.0 M in THF, 3.59 mL, 10.8 mmol) was added slowly dropwise. The mixture was stirred at 0° C. for 1 hr. TLC and HPLC indicated the presence of starting material. The reaction was warmed to room temperature overnight. TLC the next day still showed the presence of starting material. The reaction was re-cooled to 0° C. and additional amount of ethylmagnesium bromide (3.59 mL, 10.8 mmol) was added. The reaction was stirred at 15° C. for 2.5 hr. TLC indicated complete consumption of starting material. The reaction mixture was quenched with cold water and extracted twice with ethyl acetate. The combined organic layers were washed with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude material was purified by flash chromatography using 0-20% dichloromethane-hexanes to give 1-[4-chloro-2-(2-chloro-phenylamino)-phenyl]-propan-1-one (584 mg, 65% yield) as a yellow oil. 1H NMR (DMSO-d6) δ ppm 10.67 (s, 1H) 8.05 (d, J=8.7 Hz, 1H) 7.58 (ddd, J=12.8, 8.1, 1.1 Hz, 2H) 7.32-7.48 (m, 1H) 7.12-7.27 (m, 1H) 7.02 (d, J=2.0 Hz, 1H) 6.91 (dd, J=8.6, 1.9 Hz, 1H) 3.10 (q, J=7.3 Hz, 2H) 1.09 (t, J=7.2 Hz, 3H). MS calcd. for C15H13Cl2NO [(M+H)+] 295.0, obsd. 294.1.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[C:22]([C:24]1[CH:25]=[C:26]([CH2:30][CH2:31][CH2:32]O)[CH:27]=[CH:28][CH:29]=1)#[N:23].C1C=CC=CC=1>C(#N)C>[Br:20][CH2:32][CH2:31][CH2:30][C:26]1[CH:25]=[C:24]([C:22]#[N:23])[CH:29]=[CH:28][CH:27]=1
Reactant: BrBr
Reactant: N#Cc1cccc(CCCO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: c1ccccc1
Product: N#Cc1cccc(CCCBr)c1
Temperature: 25 °C
Yield: 101.1 %

Procedure:
To a mixture of 21.8 g (0.083 moles) of triphenyl phosphine stirred in 30 ml acetonitrile, 13.2 g (4.26 ml) bromine in 75 ml acetonitrile was added dropwise with stirring in an ice bath. After the addition was complete, the ice bath was removed and the mixture warmed to room temperature. Then a mixture of 12.1 g (0.075 mole) of 3-(3-cyanophenyl)-1-propanol (the product of step (b)) in 30 ml acetonitrile was added dropwise. The resulting mixture was allowed to warm to about 45°-50° C., was stirred overnight and then stripped. Benzene (50 ml) was added to the residue; the mixture was evaporated. Then, additional benzene (50 ml) was added. The mixture was stirred, and then filtered to remove the triphenyl phosphine. The filtrate was stripped to give an oil. The oil was chromatographed using a column containing 3.5 inches of 200 mesh silica gel (Merck) eluting with benzene, until TLC showed that no further product was eluted from the column. The eluates were pooled and stripped to give 17 g of an oil. The oil was distilled in a Kugelrohr apparatus, the fraction bpt. 102°-103° C. was collected to give 15.7 g of the above-identified product as an oil.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9](Br)=[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:17](I)([C:20]([C:23]([C:26]([C:29]([C:32]([F:35])([F:34])[F:33])([F:31])[F:30])([F:28])[F:27])([F:25])[F:24])([F:22])[F:21])([F:19])[F:18]>CS(C)=O.[Cu]>[F:18][C:17]([F:19])([C:2]1[C:3]2[C:8]([C:9]([C:17]([F:19])([F:18])[C:20]([F:21])([F:22])[C:23]([F:24])([F:25])[C:26]([F:27])([F:28])[C:29]([F:31])([F:30])[C:32]([F:35])([F:34])[F:33])=[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:20]([F:22])([F:21])[C:23]([F:25])([F:24])[C:26]([F:28])([F:27])[C:29]([F:31])([F:30])[C:32]([F:35])([F:34])[F:33]
Reactant: Brc1c2ccccc2c(Br)c2ccccc12
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: [Cu]
Solvent: CS(C)=O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)c1c2ccccc2c(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c2ccccc12
Reaction time: 4 h

Procedure:
Under a nitrogen atmosphere, 9,10-dibromoanthracene (0.6 g, 1.78 mmol) and a copper powder (1.14 g, 17.8 mmol) were added to a 200 mL reaction vessel and were dissolved in anhydrous dimethyl sulfoxide (25 mL). α,α,α-Benzotrifluoride (25 mL) and C6F13I (1.96 mL, 8.93 mmol) were added thereto and reaction was carried out at 130° C. for 4 hours. After quenching with ice-water, the reaction solution was extracted with methylene chloride. Thereafter, the obtained organic layer was dried over anhydrous sodium sulfate and then filtrated. The filtrate was subjected to solvent removal on a rotary evaporator and, thereafter, separation and purification were conducted by using column chromatography. A 9,10-bis(perfluorohexyl)anthracene was obtained as a yellow solid.
Reaction SMILES: O.NC1[NH:8][C:7]2[CH:9]=[C:10]([Cl:13])[N:11]=[CH:12][C:6]=2[S:5](=[O:15])(=[O:14])[N:4]=1.OS(O)(=O)=O.C([O-])(O)=O.[Na+]>O>[NH2:8][C:7]1[C:6]([S:5]([NH2:4])(=[O:15])=[O:14])=[CH:12][N:11]=[C:10]([Cl:13])[CH:9]=1
Reactant: NC1=NS(=O)(=O)c2cnc(Cl)cc2N1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Nc1cc(Cl)ncc1S(N)(=O)=O
Temperature: 0 °C

Procedure:
A solution of 1 g of 3-amino-6-chloro-4H- pyrido[4,3-e][1,2,4]thiadiazine 1,1-dioxide monohydrate (compound obtained in Example 31 below) in 30 cm3 of 50% v/v H2SO4 in water is brought to reflux for 15 minutes. After cooling, the solution is thinned down with 300 cm3 of ice-cold water and then neutralized to a pH of 7 using solid NaHCO3. The white crystalline precipitate obtained is collected on a filter, washed with water and dried.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]#[N:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].I[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=1.C([O-])(O)=O.[Na+].O>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:14]([CH:13]=[C:12]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=1)[C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)#[N:15]
Reactant: CCOc1cc(C=CC#N)ccc1OC
Reactant: CC(=O)Nc1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C(=CC#N)c2ccc(NC(C)=O)cc2)ccc1OC
Temperature: 70 °C
Yield: 37.2 %

Procedure:
A mixture of 3-(3-ethoxy-4-methoxy-phenyl)-acrylonitrile (0.7 g, 3.2 mmol), N-(4-iodo-phenyl)-acetamide (1.4 g, 5.4 mmol), NaHCO3 (1.1 g, 12.8 mmol), Bu4NBr (1.2 g, 3.6 mmol) and Pd(OAc)2 (0.04 g, 0.2 mmol) in DMF (15 mL) was heated at 70° C. for 2 days. The cooled mixture was poured into water (150 mL) and was extracted with EtOAc (3×50 mL). The combined organic extracts were washed with water (2×50 mL), brine (50 mL) and dried (MgSO4). Solvent was removed and the residue was purified by flash chromatography (silica gel, CH2Cl2:EtOAc 9:1) to afford N-{4-[2-cyano-1-(3-ethoxy-4-methoxy-phenyl)-vinyl]-phenyl}acetamide (0.4 g, 32%): mp 175-177° C.; 1H NMR (CDCl3) δ 7.51(d, J=8 Hz, 2H), 7.41 (s, 1H), 7.26 (d, J=9.0 Hz, 2H), 7.02-6.89 (m, 3H), 5.57 (s, 1H), 4.11-4.03 (q, J=7 Hz, 2H), 3.92 (s, 3H), 2.19 (s, 3H), 1.44 (t, J=7 Hz, 3H); 13C NMR (CDCl3) δ 168.38, 162.14, 150.93, 147.96, 139.91, 134.84, 129.58, 129.30, 123.08, 119.34, 118.53, 114.06, 111.01, 92.49, 64.53, 55.96, 24.65, 14.66; Anal Calcd for C20H20N2O3: C, 71.46; H, 5.99; N, 8.33. Found: C, 71.46, 6.01; N, 8.25.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[O:20]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:31](=[O:32])[C:30]3[CH:29]=[CH:28][C:27]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:35][CH:34]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1ccc(Oc2ccccc2)cc1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 4-phenoxybenzoyl chloride were combined to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-phenoxybenzamide as a white powder, m.p. 90.5-91.5° C. 1H NMR (500 MHz, DMSO-d6) δ 8.42 (t, J=5.7 Hz, 1H), 8.21 (s, 1H), 8.03 (d, J=7.9 Hz, 1H), 7.81 (d, J=8.9 Hz, 2H), 7.62 (d, J=7.9 Hz, 1H), 7.45-7.40 (m, 3H), 7.21 (m, 2H), 7.07 (d, J=7.6 Hz, 2H), 6.99 (d, J=8.9 Hz, 2H), 6.61 (broad s, 2H), 4.63 (t, J=7.0 Hz, 2H), 3.25 (m, 2H), 1.92 (m, 2H), 1.58 (m, 2H); MS (EI) m/e 451.2008 (451.2008 calcd for C27H25N5O2).