Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:5][CH2:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:29]1([CH2:35][S:36](Cl)(=[O:38])=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl>[C:19]([N:16]1[CH2:15][CH2:14][N:13]([C:10]2[CH:9]=[CH:8][C:7]([CH2:6][N:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)[S:36]([CH2:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:38])=[O:37])=[CH:12][CH:11]=2)[CH2:18][CH2:17]1)(=[O:21])[CH3:20]
Reactant: CC(=O)N1CCN(c2ccc(CNC3CCC3)cc2)CC1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2ccc(CN(C3CCC3)S(=O)(=O)Cc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.9 %

Procedure:
To a solution of 1-(4-(4-((cyclobutylamino)methyl)phenyl)piperazin-1-yl)ethanone (185 mg, 0.64 mmol) in dichloromethane (1.5 mL) was added triethylamine (0.18 mL, 1.29 mmol), followed by phenylmethanesulfonyl chloride (185 mg, 0.96 mmol) and the reaction was stirred at ambient temperature for 16 hours. The reaction was then filtered through diatomaceous earth, concentrated and purified by preparative reverse phase HPLC to yield 62 mg of N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-cyclobutyl-C-phenyl-methanesulfonamide. 1H NMR (400 MHz, DMSO) δ 7.46-7.29 (m, 5H), 7.18 (d, J=8.6 Hz, 2H), 6.91 (d, J=8.7 Hz, 2H), 4.36 (s, 2H), 4.18 (s, 2H), 4.14-3.98 (m, 1H), 3.63-3.48 (m, 4H), 3.18-3.10 (m, 2H), 3.10-3.00 (m, 2H), 2.03 (s, 3H), 2.01-1.89 (m, 2H), 1.89-1.72 (m, 2H), 1.54-1.15 (m, 2H); LCMS (m/z) ES+ 442.2 [M+1]+.
Reaction SMILES: C[O:2][C:3](=[O:37])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:34]#[N:35])[CH:30]=3)[C:25]2=[O:36])=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[I-].[Li+].N1C=CC=CC=1>O>[C:34]([C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:36])[N:24]([C:21]1[CH:20]=[CH:19][C:18]([CH2:17][C@@H:4]([C:3]([OH:37])=[O:2])[NH:5][C:6]([C:8]3([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]3)=[O:7])=[CH:23][CH:22]=1)[C:32]2=[O:33])#[N:35]
Reactant: COCCC1(C(=O)N[C@@H](Cc2ccc(N3C(=O)c4ccc(C#N)cc4C3=O)cc2)C(=O)OC)CCCC1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: O
Product: COCCC1(C(=O)N[C@@H](Cc2ccc(N3C(=O)c4ccc(C#N)cc4C3=O)cc2)C(=O)O)CCCC1
Temperature: 25 °C
Yield: 34 %

Procedure:
To a mixture of 4-(5-cyano-1,3-dioxo-2H-isoindol-2-yl)-N-[[1-(2-methoxyethyl)cyclopentyl]carbonyl]-L-phenylalanine methyl ester (0.3 mmol, 151 mg) and lithium iodide (3.0 mmol, 397 mg) was added pyridine (6 mL) at room temperature. The solution was refluxed for 15 h at which time TLC analysis of the mixture indicated the absence of starting material. Then, it was cooled to room temperature and diluted with water (15 mL) and the bulk of the pyridine was removed by concentration under reduced pressure. The residue was extracted with ether (2×15 mL) to remove any neutral impurities. The aqueous layer was acidified with 1N HCl and the precipitated white solid was collected by filtration and washed with 20 mL of water and 20 mL of hexane. After air-drying, the crude product was purified by reverse phase HPLC to afford 50 mg (34%) of a white solid, mp 143-146° C. HR MS (C27H27N3O6): Obs mass, 490.1990. Calcd mass, 490.1978 (M+H).
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][O:5][CH3:6].Cl.[C:9]([C:12]1[C:13]([CH:23]2[CH2:26][CH2:25][CH2:24]2)=[CH:14][C:15]([CH3:22])=[C:16]([CH:21]=1)[C:17]([O:19][CH3:20])=[O:18])(=[NH:11])[NH2:10].C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH:23]1([C:13]2[C:12]([C:9]3[NH:10][C:3]([CH2:4][O:5][CH3:6])=[CH:2][N:11]=3)=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([CH3:22])[CH:14]=2)[CH2:24][CH2:25][CH2:26]1
Reactant: COCC(=O)CBr
Reactant: COC(=O)c1cc(C(=N)N)c(C2CCC2)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCc1cnc(-c2cc(C(=O)OC)c(C)cc2C2CCC2)[nH]1
Temperature: 80 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
To a round-bottom flask was added a solution of 1-bromo-3-methoxypropan-2-one (compound 246.2, 505 mg, 1.81 mmol, 1.00 equiv, 60%) in CH3CN (16 mL). Methyl 5-carbamimidoyl-4-cyclobutyl-2-methylbenzoate hydrochloride (compound 245.1, 450 mg, 1.59 mmol, 1.00 equiv) and potassium carbonate (554 mg, 3.61 mmol, 3.00 equiv, 90%) were added to the reaction. The resulting solution was stirred overnight at 80° C. under nitrogen. After cooling to ambient temperature, the reaction was carefully quenched by the addition of water. The resulting mixture was extracted with 2×50 mL of ethyl acetate. The combined organic layers were dried (Na2SO4), and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:2) as eluent to furnish 170 mg (24%) of methyl 4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoate as a white solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[CH:11]=[C:12]([NH:21][C:22]2[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=2)[CH:13]=[C:14]([C:16]2[S:20][CH:19]=[N:18][CH:17]=2)[CH:15]=1.[CH:32]1([C:35]([CH:43]2[CH2:45][CH2:44]2)=[N:36][S@@:37]([C:39]([CH3:42])([CH3:41])[CH3:40])=[O:38])[CH2:34][CH2:33]1.C(O)(=O)C>O1CCCC1>[CH:43]1([C:35]([CH:32]2[CH2:34][CH2:33]2)([C:19]2[S:20][C:16]([C:14]3[CH:13]=[C:12]([NH:21][C:22]4[N:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][N:23]=4)[CH:11]=[C:10]([CH3:9])[CH:15]=3)=[CH:17][N:18]=2)[NH:36][S@@:37]([C:39]([CH3:41])([CH3:42])[CH3:40])=[O:38])[CH2:45][CH2:44]1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncs2)c1
Reactant: CC(C)(C)[S@@](=O)N=C(C1CC1)C1CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(N[S@](=O)C(C)(C)C)(C3CC3)C3CC3)s2)c1
Reaction time: 0.67 h
Yield: 76.3 %

Procedure:
To a solution of lithium diisopropylamide (1.8 M, 2.12 mL, 3.81 mmol) in tetrahydrofuran (5 mL) at −78° C. was added a solution of N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (Intermediate 24, 564 mg, 1.68 mmol) in tetrahydrofuran (5 mL) over 8 minutes. After 40 minutes, a solution of (R)—N-(dicyclopropylmethylidene)-2-methylpropane-2-sulfinamide (0.325 g, 1.52 mmol) in tetrahydrofuran (4 mL) was added all at once. After 90 minutes, acetic acid (0.275 mL) was added and the reaction mixture was partitioned between ethyl acetate (45 mL) and saturated aqueous sodium bicarbonate solution (20 mL). The layers were separated and the organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. Purification of the crude material using silica gel flash chromatography (ethyl acetate/hexanes) yielded (R)—N-{dicyclopropyl[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methyl}-2-methylpropane-2-sulfinamide (638.6 mg, 1.16 mmol, 76% yield) as a yellow film. MS ESI: [M H] m/z 550.1.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[CH:15]([N:18]=[C:19]=[O:20])([CH3:17])[CH3:16]>C(#N)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]([NH:18][CH:15]([CH3:17])[CH3:16])=[O:20])=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CC(C)N=C=O
Solvent: CC#N
Product: CC(C)NC(=O)NCCSCc1ccc(CN(C)C)o1
Reaction time: 8 h
Yield: 93.7 %

Procedure:
2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (2.14 g) and isopropylisocyanate (0.89 g) were dissolved in acetonitrile and allowed to stand overnight. Solvents were removed and the residue recrystallised from methanol:ether to give N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl-N'-(1-methylethyl)urea as crystals m.p. 65°-67° (2.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:12])[C:9](=[O:11])[CH3:10].C(O)(=O)C.[Br:17]Br>C(Cl)(Cl)Cl>[Br:17][CH2:10][C:9](=[O:11])[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[O:12]
Reactant: BrBr
Reactant: CC(=O)C(=O)c1ccccc1Cl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=C(CBr)C(=O)c1ccccc1Cl
Temperature: 60 °C

Procedure:
A mixture of 1-(2-chlorophenyl)propane-1,2-dione (1.2592 g, 6.9 mmol), glacial acetic acid (0.20 mL, 3.4 mmol, 0.5 eq), and bromine (0.35 mL, 6.8 mmol, 1 eq) in CHCl3 (17 mL) was heated at 60° C. for 12 h. The mixture was concentrated under reduced pressure to provide 3-bromo-1-(2-chlorophenyl)propane-1,2-dione as yellow liquid. The yellow liquid was carried on crude without purification for the next step. 1H NMR (CDCl3) δ ppm 7.71 (1 H, dd, J=7.8, 1.6 Hz), 7.53-7.59 (1 H, m), 7.40-7.49 (2 H, m), 4.52 (2H, s). Mass Spectrum (ESI) m/e=261.0 [M+1 (79Br)] and 262.9 [M+1 (81Br)].
Reaction SMILES: C(OC([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[S:32][C:33]([Cl:36])=[CH:34][CH:35]=3)=[CH:27][CH:26]=2)[CH2:20][C:19]1=[O:37])=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:36][C:33]1[S:32][C:31]([C:28]2[CH:27]=[CH:26][C:25]([CH2:24][N:21]3[CH2:22][CH2:23][N:18]([CH2:17][C:9]4[NH:8][C:16]5[CH:15]=[CH:14][N:13]=[CH:12][C:11]=5[CH:10]=4)[C:19](=[O:37])[CH2:20]3)=[CH:30][CH:29]=2)=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)n1c(CN2CCN(Cc3ccc(-c4ccc(Cl)s4)cc3)CC2=O)cc2cnccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CN(Cc2ccc(-c3ccc(Cl)s3)cc2)CCN1Cc1cc2cnccc2[nH]1
Yield: 47.1 %

Procedure:
2-{4-[4-(5-Chloro-thiophen-2-yl)-benzyl]-2-oxo-piperazin-1-ylmethyl}-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (0.90 g, 0.17 mmol) is stirred in 30% TFA/CH2Cl2 (8 mL) for 1 h then concentrated to dryness and purified by RP-HPLC using 10-100% acetonitrile/0.1% TFA water as the eluent. The appropriate fractions are collected and lypholized to yield the title product as an amorphous white solid (0.44 mg, 0.08 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:23])[C:5]([CH3:22])=[C:6]([C:8]2[C:9](=[O:21])[NH:10][C:11]3([CH2:18][CH2:17][N:16]([O:19][CH3:20])[CH2:15][CH2:14]3)[C:12]=2[OH:13])[CH:7]=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26].N1C=CC=CC=1.Cl>C(#N)C>[CH2:28]([O:27][C:25](=[O:26])[O:13][C:12]1[C:11]2([CH2:18][CH2:17][N:16]([O:19][CH3:20])[CH2:15][CH2:14]2)[NH:10][C:9](=[O:21])[C:8]=1[C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[C:4]([F:23])[C:5]=1[CH3:22])[CH3:29]
Reactant: CCOC(=O)Cl
Reactant: CON1CCC2(CC1)NC(=O)C(c1cc(Br)cc(F)c1C)=C2O
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CCOC(=O)OC1=C(c2cc(Br)cc(F)c2C)C(=O)NC12CCN(OC)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(5-bromo-3-fluoro-2-methyl-phenyl)-4-hydroxy-8-methoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one (350 mg) and ethyl chloroformate (77 μl) in acetonitrile (2 ml) was added pyridine (80 μA) and the reaction mixture stirred at room temperature for one hour. The mixture was poured on diluted HCl and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/cyclohexane 3:1). Yield: 310 mg of carbonic acid 3-(5-bromo-3-fluoro-2-methyl-phenyl)-8-methoxy-2-oxo-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester ethyl ester (title compound E4) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[CH2:9]2)=[CH:4][CH:3]=1.[CH2:13](O)[CH2:14][OH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.C(OCC)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: O=C1CCc2ccc(Br)cc2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: Brc1ccc2c(c1)CC1(CC2)OCCO1
Yield: 91 %

Procedure:
A solution of 7-bromo-2-tetralone (1.1 g, 4.9 mmol), ethylene glycol (0.62 g, 10 mmol), and p-toluensulfonic acid (80 mg, 0.42 mmol) in benzene (20 ml) was stirred under N2 at reflux utilizing a Dean-Stark trap for 45 minutes. The cooled solution was diluted with diethyl ether (60 ml), washed with saturated NaHCO3 solution (2×10 ml), dried (MgSO4) and concentrated in vacuo to give 7'-bromo-3',4'-dihydrospiro[1,3-dioxolane-2,2'(1'H)-naphthalene] as an oil (1.2 g). 1H NMR (CDCl3, 200 MHz) δ: 1.95 (t, J=7 Hz, 2H, CH2), 2.91 (t, J=7 Hz, 2H, CH2), 2.95 (s, 2H, CH2), 4.01 (s, 4H, OCH2CH2O), 6.97 (d, J=8 Hz, 1H, Ar), 7.15-7.27 (m, 2H, Ar).
Reaction SMILES: CN(C)[CH:3]=[O:4].[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[C:22]([OH:23])=[C:21]([O:24][CH3:25])[C:20]([O:26][CH3:27])=[CH:19][C:18]=1C>N1C=CC=CC=1>[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[C:22](=[O:23])[C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[C:3](=[O:4])[C:18]=1[CH3:19]
Reactant: CN(C)C=O
Reactant: COc1cc(C)c(CCCCCCCCCCO)c(O)c1OC
Solvent: c1ccncc1
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCO)=C(C)C1=O
Reaction time: 72 h

Procedure:
To a dimethylformamide solution (30 ml) of 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methylphenol (1.6 g) are added bis(3-methoxysalicylidene)ethylenediiminocobalt(II) (0.06 g) and pyridine (10 mg), and the mixture is stirred in air streams at atmospheric temperature and pressure for 72 hours. After the reaction has been completed, the reaction product is isolated in the same manner as described in Example 7. The crude crystals thus obtained are recrystallized from ether-hexane (1:3). The above procedure yields 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (1.1 g) as orange-yellow needles melting at 51° C.-53° C.
Reaction SMILES: N#N.[F:3][C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][CH:33]=1)[CH2:7][NH:8][C:9]([NH:11][C:12]1[S:13][CH:14]=[C:15]([CH2:17][N:18]([CH3:30])[C:19]([C:21]2[CH:26]=[C:25]([O:27][CH3:28])[N:24]=[N:23][C:22]=2Cl)=[O:20])[N:16]=1)=[O:10].[CH3:34][Al](C)C.CO>O1CCOCC1.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>[F:3][C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][CH:33]=1)[CH2:7][NH:8][C:9](=[O:10])[NH:11][C:12]1[S:13][CH:14]=[C:15]([CH2:17][N:18]([CH3:30])[C:19]([C:21]2[CH:26]=[C:25]([O:27][CH3:28])[N:24]=[N:23][C:22]=2[CH3:34])=[O:20])[N:16]=1
Reactant: C[Al](C)C
Reactant: COc1cc(C(=O)N(C)Cc2csc(NC(=O)NCc3cccc(F)c3)n2)c(Cl)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc(C(=O)N(C)Cc2csc(NC(=O)NCc3cccc(F)c3)n2)c(C)nn1
Yield: 52 %

Procedure:
N2 was bubbled for 15 minutes through a solution of 1-(3-fluorobenzyl)-3-(4-((3-chloro-6-methoxy-N-methylpyridazine-4-carboxamido)methyl)-thiazol-2-yl)urea (118 mg, 0.25 mmol) in 1,4-dioxane. Pd(PPh3)4 (15 mg, 13 μmol) was added followed by AlMe3 (250 μl, 2 M in toluene, 0.51 mmol). The mixture was refluxed for 4 hours and MeOH was added. Silica (300 mg) was added and the volatiles were removed in vacuo. The residue was brought on a column and purified by chromatography (CH2Cl2+5% 7N NH3 in MeOH) to afford the title product (60 mg, 0.13 mmol) as an off-white solid in 52% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=O.[C:25]1([CH3:37])[CH:30]=[CH:29][C:28]([S:31]([N:34]=C=O)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:23])([F:22])[F:24])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([NH:34][S:31]([C:28]1[CH:29]=[CH:30][C:25]([CH3:37])=[CH:26][CH:27]=1)(=[O:32])=[O:33])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)NC(=O)c2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc2[N+](=O)[O-])cc1

Procedure:
A catalyst amount (ca. 10 gm) of N,N-dimethylaminopyridine (available from the Aldrich Chemical Co. Ltd.) was added to a stirred mixture of 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoic acid (260 gm, 0.72 moles) in 350 ml toluene under nitrogen. A solution of para-toluenesulfonylisocyanate (available from the Aldrich Chemical Co., Ltd., 180 gm, 0.94 moles) in toluene (150 ml) was then added dropwise to the above solution with stirring. After the addition was complete the mixture was brought to reflux for six hours. Toluene in the cooled solution was then removed in vacuo. The resulting waxy solid was further recrystalized from toluene to yield 170 gm (0.33 moles, 46%,) of the desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[C:11]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[N:12][CH:13]=[CH:14][CH:15]=2)[C:5]([C:22]([F:25])([F:24])[F:23])=[CH:4][N:3]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]([OH:35])[CH3:34])=[CH:29][CH:28]=1.OP([O-])([O-])=O.[K+].[K+]>CS(C)=O>[OH:35][CH:33]([C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:2]2[N:7]=[C:6]([NH:8][CH2:9][C:10]3[C:11]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[N:12][CH:13]=[CH:14][CH:15]=3)[C:5]([C:22]([F:25])([F:24])[F:23])=[CH:4][N:3]=2)=[CH:28][CH:29]=1)[CH3:34]
Reactant: CN(c1ncccc1CNc1nc(Cl)ncc1C(F)(F)F)S(C)(=O)=O
Reactant: CC(O)c1ccc(N)cc1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CS(C)=O
Product: CC(O)c1ccc(Nc2ncc(C(F)(F)F)c(NCc3cccnc3N(C)S(C)(=O)=O)n2)cc1
Temperature: 100 °C
Reaction time: 36 h

Procedure:
A solution of C9 (0.253 mmol) and anhydrous DMSO (0.5 ml) was treated with 1-(4-aminophenyl)ethanol (0.277 mmol) followed by potassium phosphate dibasic (0.746 mmol). The mixture was stirred at 100° C. for 1.5 days, and treated with additional 1-(4-aminophenyl)ethanol (0.583 mmol). The mixture was stirred at 100° C. for 15 hours and concentrated. The resultant residue was purified first by column chromatography (silica gel; 10% (NH4OH/MeOH)/CH2Cl2) followed by preparatory thin layer chromatography developed in 5% MeOH/CH2Cl2 to provide 12. Yield: 13.6 mg, 10.8%. 1H NMR (CD3OD) δ: 8.39 (d, 1H), 8.13 (s, 1H), 7.73 (d, 1H), 7.33 (m, 3H), 7.14 (d, 2H), 4.87 (s, 2H), 4.72 (q, 1H), 3.17 (s, 3H), 3.10 (s, 3H), 1.37 (d, 3H). MS: m/z 497 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[C:5](Cl)=[CH:4][C:3]=1[CH:11]=[O:12].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[C:24]1([SH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[C:24]1([S:30][C:2]2[CH:7]=[C:6]([CH:8]=[O:9])[C:5]([S:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:4][C:3]=2[CH:11]=[O:12])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Sc1ccccc1
Reactant: O=Cc1cc(Cl)c(C=O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Sc2ccccc2)c(C=O)cc1Sc1ccccc1
Reaction time: 0.08 h
Yield: 69.9 %

Procedure:
A 500 ml Schlenk flask is charged under an inert atmosphere with 2,5-Dichloro-benzene-1,4-dicarbaldehyde (30.45 g, 0.15 mol), potassium carbonate (62.1 g, 0.45 mol) and dry DMF (200 ml). The flask is immersed in an oil bath of 80° C., and then without delay thiophenol (33.0 g, 0.3 mol) is added via a dropping funnel within 15 minutes. To the formed brown suspension is added water (ca. 100 ml) and the mixture is stirred for another 5 minutes. Then the contents of the flask are poured as a thin stream into a beaker which containd 2 L of vigorously stirred water. A yellow solid precipitates, and the mixture is stirred for another hour. The solid is then filtered off, washed with water (twice 250 ml), and recrystallised without further drying from THF (ca. 200 ml). The crystals of the product are filtered off, washed with little iso-propanol (ca. 50 ml) and dried to give the product (36.75 g). From the mother liquors most of the THF is removed on the rotavapor which leads to the crystallisation of another crop. This material is also filtered off and washed with little iso-propanol to give another 4.72 g of product. Bright yellow crystals, mp. 163° C. 1H-NMR (CDCl3, 300 MHz) δ 7.39 (phenyl para H); 7.40 (phenyl ortho H)); 7.41 (phenyl meta H); 7.58 (s, aryl CH); 10.27 (s, 1H, CHO). 13C-NMR (CDCl3, 75 MHz) δ 129.18 (phenyl para CH); 130.19 (phenyl ortho CH); 132.47 (phenyl ipso C); 133.20 (phenyl meta CH); 133.75 (aryl CH); 136.79 (CCHO); 139.54 (CS); 190.45 (CHO).
Reaction SMILES: Cl.Cl[C:3]1[C:4]2[NH:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:5]=2[N:6]=[CH:7][N:8]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[NH:16]([C:3]1[C:4]2[NH:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:5]=2[N:6]=[CH:7][N:8]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1
Reactant: Clc1ncnc2c1[nH]c1ccccc12
Agent: Cl
Solvent: CCO
Product: c1ccc(Nc2ncnc3c2[nH]c2ccccc23)cc1
Yield: 105.3 %

Procedure:
A solution of 4-chloroindolo[3,2-d]pyrimidinehydrochloride (240 mg, 1.0 mmol) [Monge, A.; Palop, J. A.; Goni, T.; Martinez-Crespo, F.; Recalde, I. J. Het. Chem., 1986, 23, 647-9.], and aniline (0.273 mL, 3 mmol) in ethanol (1 mL) is heated at reflux for 3 h, during which time the reaction becomes a thick suspension. After cooling to 25 C. and diluting with ethanol (4 ml) the mixture is filtered, and the crude product washed with water (15 mL), and ethanol (15 mL), giving 274 mg tan solid, which is recrystallized from DMF/water affording pure 4-anilinoindolo[3,2-d]pyrimidine hydrochloride (82 mg, 27%). 1H NMR (DMSO): δ12.79 (1H, brs), 11.04 (1H, brs), 8:94 (1H, s), 8.27 (1H, d, J=8.2 Hz), 7.96 (2H, d, J=7.5 Hz), 7.85 (1H, d, J=8.4 Hz), 7.71 (1H, t, J=7.7 Hz), 7.49 (2H, t, J=8.0 Hz), 7.41 (1H, t, J=7.6 Hz), 7.24 (1H, t, J=7.4 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH3:27])[CH:22]=3)[CH:17]=2)=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH3:27])[CH:22]=3)[CH:17]=2)=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[CH:10]=2)[CH:8]=1
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2)c(-c2cccc(O)c2)c1
Reactant: ClCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc3cc(OC)ccc3c2)c(-c2cccc(OCCN3CCCCC3)c2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
Synthesized from 2-(3′-benzyloxy-5-methoxybiphenyl-2-yl)-6-methoxynaphthalene (205 mg) according to an analogous synthetic method to Example 22, 5′-methoxy-2′-(6-methoxynaphthalen-2-yl)biphenyl-3-ol (176 mg) was obtained. To a solution of 5′-methoxy-2′-(6-methoxynaphthalen-2-yl)biphenyl-3-ol (276 mg) in N,N-dimethylformamide (7 ml) were sequentially added potassium carbonate (220 mg) and 1-(2-chloroethyl)piperidine (280 mg), and the solution was stirred for 2 hours at 60° C. Water was added thereto followed by stirring, the solution was extracted with ethyl acetate, then sequentially washed with water and brine, and the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (319 mg).