Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[C:11]2[CH:10]=[C:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[CH:20]=[C:19]([C:24]([O:26]C)=[O:25])[CH:18]=[CH:17]4)=[O:13])[CH:8]=[CH:7][C:6]=2[C:5]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)=[CH:4][CH2:3]1.O.O.[OH-].[Li+].Cl>O1CCCC1.CO>[CH3:1][C:2]1([CH3:35])[C:11]2[CH:10]=[C:9]([CH:12]([OH:13])[C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[CH:20]=[C:19]([C:24]([OH:26])=[O:25])[CH:18]=[CH:17]4)[CH:8]=[CH:7][C:6]=2[C:5]([C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)=[CH:4][CH2:3]1
Reactant: COC(=O)c1ccc2cc(C(=O)c3ccc4c(c3)C(C)(C)CC=C4c3ccc(C)cc3)ccc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C2=CCC(C)(C)c3cc(C(O)c4ccc5cc(C(=O)O)ccc5c4)ccc32)cc1

Procedure:
0.5 g (1.08 mmol) of methyl 6-(8,8-dimethyl-5-p-tolyl-7,8-dihydro-2-naphthylcarbonyl)-2-naphthalenecarboxylate is dissolved in 15 ml of tetrahydrofuran, 15 ml of water and 5 ml of methanol, and 0.14 g (3.25 mmol) of lithium hydroxide monohydrate is then added. The medium is refluxed for 2 hours, treated with 1N hydrochloric acid solution and extracted with ethyl acetate. The residue obtained is recrystallized from an ethyl acetate/heptane mixture. A white solid is obtained (0.45 g; yield=94%; 110° C.).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][CH2:21][C:22]([OH:24])=O)[C:8]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:31][NH:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CCOC(C)=O.Cl>[CH:1]1([C:7]2[C:15]3[CH:14]=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]=3[N:9]3[CH2:20][CH2:21][C:22](=[O:24])[N:32]([CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[CH2:31][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[C:8]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CNCCN(C)C)n(CCC(=O)O)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCC(=O)N(CCN(C)C)Cc1ccccc1-3
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-[3-cyclohexyl-2-[2-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-6-(methoxycarbonyl)-1H-indol-1-yl]propanoic acid in DCM (0.01 M), 3.5 eq of DIPEA and 1.5 eq of HATU were added and the mixture was stirred at RT for 4 h. The solution was diluted with EtOAc and HCl (1 N), the aqueous phase was re-extracted with EtOAc (twice) and the combined organics then washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude was used in the next step without further purification; MS (ES+) m/z 488 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:10][C:9]2=[O:23])=[CH:4][C:3]=1[NH:24][CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH:59]1([CH2:62][C:63](O)=O)[CH2:61][CH2:60]1>CN(C=O)C>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][C:11]2[CH:12]=[CH:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]4[N:1]=[C:63]([CH2:62][CH:59]5[CH2:60][CH2:61]5)[N:24]([CH3:25])[C:3]=4[CH:4]=3)[C:9](=[O:23])[CH:10]=2)=[CH:21][CH:20]=1
Reactant: O=C(O)CC1CC1
Reactant: CNc1cc(-n2ccc(OCc3ccc(Cl)cc3)cc2=O)ccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(CC2CC2)nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(4-amino-3-(methylamino)phenyl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (90 mg), HATU (101 mg), N,N-diisopropylethylamine (0.130 ml), cyclopropylacetic acid (0.024 ml) and DMF (2 ml) was stirred at room temperature for 1 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in AcOH (2.00 ml), and the mixture was stirred at 90° C. for 2 h. After evaporation, the residue was purified by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from EtOH to give the title compound (56.3 mg) as an off-white solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[O:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[CH2:30][CH:29]1[CH2:37]O.C(P(CCCC)CCCC)CCC.N(/C(N1CCCCC1)=O)=N\C(N1CCCCC1)=O>C(OCC)(=O)C.O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:37][CH:29]2[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:28]2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: OCC1Cc2ccccc2O1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(/N=N/C(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(CC2Cc3ccccc3O2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), 2,3-dihydro-1-benzofuran-2-ylmethanol (1.02 g), tributylphosphine (2.1 mL), 1,1′-[(E)-diazene-1,2-diyldicarbonyl]dipiperidine (1.72 g) and tetrahydrofuran (60 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, and the insoluble solid was filtered off. The solvent of the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless viscous substance (0.86 g, 52%).
Reaction SMILES: [C:1]([O:3][CH2:4][CH3:5])#[CH:2].B.O1CCCC1.[Cl:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[C:15](Cl)[N:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[C:15](/[CH:2]=[CH:1]/[O:3][CH2:4][CH3:5])[N:14]=1
Reactant: C[Si](C)(C)CCOCn1cnc2c(Cl)nc(Cl)nc21
Reactant: C#COCC
Agent: [Pd+2]
Agent: B
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCO/C=C/c1nc(Cl)nc2c1ncn2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.3 %

Procedure:
2 g of ethyl ethynyl ether (50% v/v hexane solution) was dissolved in 20 mL of tetrahydrofuran, and 4.7 mL of borane-tetrahydrofuran complex (1.0M tetrahydrofuran solution) was added under an ice-cold condition. After stirring the mixture at room temperature for 3 hours, 50 mL of tetrahydrofuran, 3 g of 2,6-dichloro-9-{[2-(trimethylsilyl)ethoxy]methyl}-9H-purine [56-1], 222 mg of triphenylphosphine, 63 mg of palladium acetate, and 7.0 mL of 4N aqueous solution of sodium hydroxide were added, and the mixture was heated overnight under reflux. The reaction mixture was cooled back to room temperature, diluted with ethyl acetate, and then washed with water and saturated saline in the subsequent order. The obtained organic layer was dried over anhydrous magnesium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, to obtain 676 mg of 2-chloro-6-[(E)-2-ethoxyvinyl]-9-{[2-(trimethylsilyl)ethoxy]methyl}-9H-purine [56-2] as a light brown oily product.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:15]=[C:16]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1)=[O:13].[C:24](Cl)(=[O:26])[CH3:25]>C(O)C.C1(C)C=CC=CC=1>[C:24]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:15]=[C:16]([S:20]([NH2:23])(=[O:21])=[O:22])[CH:17]=[CH:18][CH:19]=1)=[O:13])(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: Nc1c(C(=O)c2cccc(S(N)(=O)=O)c2)[nH]c2cc(Cl)ccc12
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)Nc1c(C(=O)c2cccc(S(N)(=O)=O)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-(3-amino-6-chloroindole-2-carbonyl)benzenesulfonamide (Example 142) and acetyl chloride. m.p.: 250-251° C. (ethanol/toluene)
Reaction SMILES: [N+](C1C=CC=CC=1)([O-])=O.C(Cl)(Cl)C(Cl)Cl.[C:16]1(=[O:22])[O:21][C:19](=[O:20])[CH2:18][CH2:17]1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([O:30]C)=[CH:26][CH:25]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([OH:30])=[C:28]([CH:29]=1)[C:19]([CH2:18][CH2:17][C:16]([OH:21])=[O:22])=[O:20]
Reactant: O=C1CCC(=O)O1
Reactant: COc1ccc(Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)C(Cl)Cl
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(O)CCC(=O)c1cc(Cl)ccc1O
Temperature: 5 °C

Procedure:
A dry flask was charged with 650 ml. each of nitrobenzene and sym-tetrachloroethane, 104 g. (1.04 moles) succinic anhydride and 130 g. (0.913 mole) p-chloroanisole. The mixture was stirred at 5° C and 276 g. (2.07 moles) of anhydrous AlCl3 was added portionwise over a 90 minute period such that the temperature did not exceed 10° C. The resulting mixture was stirred under nitrogen for 5 days at 7° C and then poured into a mixture of 1 kg. of ice and 176 ml. concentrated hydrochloric acid. The thus quenched mixture was steam distilled until all organic solvents were removed. The residual aqueous-oil combination was cooled to 20° C whereupon the oil phase crystallized. The aqueous supernate was then drawn off and one liter of methylene chloride was added to the remaining crystallized solid mass. The resulting slurry was warmed at 25° C with stirring, and then filtered, and the filtered-off solids washed with CH2Cl2. Upon drying of the washed solids, 84.4 g. of 3-(5-chloro-2-hydroxybenzoyl) propionic acid, m.p. 178°-182° C., was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[CH:15]=[CH:14][C:13](B4OC(C)(C)C(C)(C)O4)=[CH:12][CH:11]=3)[CH2:6][CH2:7]2)[CH2:3]1.Br[C:26]1[CH:27]=[CH:28][C:29]([N:32]2[C:37](=[O:38])[CH:36]=[CH:35][CH:34]=[N:33]2)=[N:30][CH:31]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.C([O-])([O-])=O.[Na+].[Na+]>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>[CH3:1][N:2]1[CH2:9][C@@H:8]2[C@H:4]([N:5]([C:10]3[CH:11]=[CH:12][C:13]([C:26]4[CH:27]=[CH:28][C:29]([N:32]5[C:37](=[O:38])[CH:36]=[CH:35][CH:34]=[N:33]5)=[N:30][CH:31]=4)=[CH:14][CH:15]=3)[CH2:6][CH2:7]2)[CH2:3]1
Reactant: O=c1cccnn1-c1ccc(Br)cn1
Reactant: CN1C[C@H]2CCN(c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)[C@H]2C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN1C[C@H]2CCN(c3ccc(-c4ccc(-n5ncccc5=O)nc4)cc3)[C@@H]2C1
Temperature: 140 °C

Procedure:
(3aR,6aR)-5-Methyl-1-(4-(4,4,5,5-tetramethyl-1,3-dioxaborolan-2-yl)phenyl)octa-hydro-pyrrolo[3,4-b]pyrrole (50 mg, 0.15 mmol), 2-(5-bromopyridin-2-yl)pyridazin-3(2H)-one (42 mg, 0.17 mmol), Pd(PPh3)2Cl2 (11 mg, 0.01 mmol), 2-(dicyclohexylphosphino)biphenyl (5.6 mg, 0.016 mmol) and Na2CO3 (1M, 225 μL) were placed in a microwave tube, purged with N2 and a mixture of solvents (EtOH:dioxane=1:1, 1 mL) was added. The mixture was heated to 140° C. in a microwave reactor for 15 minutes, cooled to ambient temperature, was filtered, and concentrated under reduced pressure. The residue was purified via chromatography (SiO2, 0-10% MeOH in CH2Cl2) to provide the title compound. 1H NMR (300 MHz, CDCl3): δ=8.82 ppm (d, J=2.8 Hz, 1H), 7.98 (m, 2H), 7.73 (d, J=8.2 Hz, 1H), 7.52 (m, 2H), 7.28 (dd, J=10.1, 3.7 Hz, 1H), 7.09 (dd, J=10.1, 1.7 Hz, 1H), 6.67 (m, 2H), 4.39 (m, 1H), 3.66 (m, 1H), 3.30 (m, 3H), 2.87 (m, 2H), 2.59 (s (br), 3H), 2.23 (m, 2H), 2.05 (m, 1H). MS (ESI, M+1): 374.2.
Reaction SMILES: [C:1]1([CH:7]2[N:11]([CH:12]([CH3:21])[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH:9]([CH2:22][OH:23])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>N1C=CC=CC=1>[CH3:34][C:24]1[CH:29]=[CH:28][C:27]([S:30]([OH:8])(=[O:32])=[O:31])=[CH:26][CH:25]=1.[C:1]1([CH:7]2[N:11]([CH:12]([CH3:21])[CH2:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:10][CH:9]([CH2:22][OH:23])[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CC(CCc1ccccc1)N1CC(CO)OC1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 95 (7.6 g, 0.025 mol) in pyridine (15 ml) was cooled in an ice bath and p-toluenesulfonyl chloride (4.7 g, 0.025 mol) was added while keeping the internal temperature below 30° C. After stirring for 3 hours at room temperature, a saturated solution of Na2CO3 was added and the mixture extracted with CH2Cl2 (3×). The organic extracts were dried, filtered and concentrated under reduced pressure below 50° C. initially using water aspirator pressure and finally high vacuum to yield the p-toluene sulfonate of 95 (0.025 mol).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[N:13]=[C:12]([C:14]2[N:18]([CH3:19])[C:17]([CH3:20])=[N:16][CH:15]=2)[CH:11]=[CH:10][N:9]=1.I[C:22]1[CH:27]=[CH:26][C:25]([S:28]([F:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1.O>O1CCOCC1.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].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:19][N:18]1[C:14]([C:12]2[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:22]3[CH:27]=[CH:26][C:25]([S:28]([F:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[N:13]=2)=[CH:15][N:16]=[C:17]1[CH3:20]
Reactant: Cc1ncc(-c2ccnc(N)n2)n1C
Reactant: O=S(=O)(F)c1ccc(I)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ncc(-c2ccnc(Nc3ccc(S(=O)(=O)F)cc3)n2)n1C
Temperature: 80 °C
Yield: 70.8 %

Procedure:
Caesium carbonate (2.3 g, 7.2 mmol) was added to a degassed solution of 2-amino-4-(1,2-dimethylimidazol-5-yl)pyrimidine (Method 26; 756 mg, 4 mmol), 4-iodosulphonyl fluoride (Method 58; 1.50 g, 5.2 mmol), tris(dibenzylideneacetone)dipalladium (0) (92 mg, 0.18 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (124 mg, 0.18 mmol) in dioxane (36 ml) under nitrogen. The mixture was heated at 80° C. for 18 hours and then allowed to cool to ambient temperature. The mixture was poured into water (50 ml) and extracted with DCM (2×50 ml). The organic extracts were combined, washed with brine (50 ml), dried and the solvent evaporated. The residue was pre-absorbed on to silica gel and purified by column chromatography on silica gel eluting with DCM/2% methanolic ammonia (100:0 increasing in polarity to 97:3) to give the title compound (984 mg, 71%) as a pale yellow solid. NMR 2.38 (s, 3H), 3.96 (s, 3H), 7.28 (d, 1H), 7.65 (s, 1H), 8.00 (d, 2H), 8.13 (s, 2H), 8.47 (d, 1H), 10.32 (s, 1H); m/z 348.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN1CCCC1=O.[F:25][C:26]1[CH:27]=[C:28]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:29]=[CH:30][C:31]=1[OH:32]>C(OCC)(=O)C>[F:25][C:26]1[CH:27]=[C:28]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH:29]=[CH:30][C:31]=1[O:32][C:2]1[CH:7]=[N:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(S(C)(=O)=O)nc2)c(F)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
4.00 g of 5-chloro-2-methanesulfonyl-pyridine and 8.80 g of cesium carbonate were added to an N-methylpyrrolidinone (50 ml) solution of 4.74 g of tert-butyl (3-fluoro-4-hydroxy-phenyl)-carbamate obtained in (step 1), and the reaction liquid was stirred at 100° C. for 2 hours. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/1) to obtain the entitled compound.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[C:36]([CH3:37])=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][C:5]=1[CH3:38].[C:39](OC(=O)C)(=[O:41])[CH3:40].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.O1CCCC1>[ClH:1].[C:39]([NH:3][C:4]1[C:5]([CH3:38])=[CH:6][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:20]=[CH:21][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:31][CH:32]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:35][C:36]=1[CH3:37])(=[O:41])[CH3:40]
Reactant: Cc1cc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc(C)c1N
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)Nc1c(C)cc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc1C
Temperature: 25 °C
Reaction time: 21 h
Yield: 62 %

Procedure:
A mixture of 155 mg of 5-{4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl}thiazolidine-2,4-dione dihydrochloride, 36 mg of acetic anhydride, 107 mg of pyridine, 7.3 mg of 4-(N,N-dimethylamino)pyridine and 5 ml of anhydrous tetrahydrofuran was heated under reflux for 2 hours. The reaction mixture was concentrated by evaporation. Water was added to the concentrate, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. To the residue, 10 ml of 4N hydrochloric acid/ethyl acetate were added, followed by stirring at room temperature for 21 hours. The insoluble product was collected by filtration, followed by washing with ether, whereby 97 mg of the title compound were obtained.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:13]([NH:15][C:16]1S[CH:18]=[CH:19][N:20]=1)=[O:14].N[C:26]1[CH:31]=CC=CN=1>>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:13]([NH:15][C:16]1[CH:31]=[CH:26][CH:18]=[CH:19][N:20]=1)=[O:14]
Reactant: CC(C)CC(C(=O)Nc1nccs1)N1C(=O)c2ccccc2C1=O
Reactant: Nc1ccccn1
Product: CC(C)CC(C(=O)Nc1ccccn1)N1C(=O)c2ccccc2C1=O

Procedure:
The title compound was synthesized according to the method described in connection with Compound 13, except that 2-aminopyridine was used. 1H NMR (400 MHz, MeOH-d4) δ: 8.34 (dd, J=1.2, 6.0 Hz, 1H), 8.12-8.17 (m, 1H), 7.91-7.94 (m, 2H), 7.85-7.88 (m, 2H), 7.79 (d, J=7.2 Hz, 1H), 7.38-7.43 (m, 1H), 5.19 (dd, J=4.4, 11.2 Hz, 1H) 2.35-2.44 (m, 1H), 1.97-2.06 (m, 1H), 1.51 (m, 1H) 1.0 (d, J=6.4 Hz, 3H), 0.97 (d, J=6.4 Hz, 3H). [M+H] calc'd for C19H19N3O3, 338; found, 338.
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([CH:29]=[CH2:30])(=[O:28])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>C1COCC1>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:21][CH2:22][N:23]([S:26]([CH2:29][CH2:30][N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)(=[O:28])=[O:27])[CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1
Reactant: C1COCCN1
Reactant: C=CS(=O)(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCN3CCOCC3)CC2)n1
Yield: 97 %

Procedure:
A mixture of 2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole (from Example 3) (0.536 g, 1 mmol) and morpholine (10 mL) in THF (150 mL) was heated under reflux for 2 hrs. The solvent was removed under vacuum and the residue was diluted with water to give 0.605 g (97% yield) of 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(4-morpholinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole: 1H NMR (CDCl3) δ 7.86 (d, J=7.9 Hz, 1H), 7.44 (t, JHF=53.5 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 6.83 (d, J=7.8 Hz, 1H), 4.05 (s, 3H), 4.00 (m, 4H), 3.89 (m, 4H), 3.79 (m, 4H), 3.37 (m, 4H) 3.39 (m, 4H), 3.14 (dd, J=8.3, 6.4 Hz, 2H), 2.84 (dd, J=8.3, 6.3 Hz, 2H), 2.48 (m, 4H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@@H:28](/[CH:34]=[CH:35]\[CH3:36])[CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C1COCC1.CCO.[OH-].[Na+]>>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@@H:28](/[CH:34]=[CH:35]\[CH3:36])[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: C/C=C\[C@@H](CC(=O)OC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: C/C=C\[C@@H](CC(=O)O)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Reaction time: 17 h
Yield: 72.9 %

Procedure:
To a stirred solution of 8.1 (0.0529 g, 0.11 mmol) in THF (2.00 mL, 24 mmol) and EtOH (2.00 mL, 34 mmol) at 23° C. was added 1N sodium hydroxide (2.00 mL, 2.0 mmol). Stirring continued for 17 hours. The reaction mixture was concentrated in vacuo, 1N HCl was added to reach pH 1, and the resulting mixture was extracted with EtOAc (3×10 mL) dried over MgSO4 and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0%-20% EtOAc in hexanes) to give compound 8 as a clear oil (0.0382 g, 74% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.58 (1H, d, J=8.2 Hz), 7.40 (1H, dd, J=8.2, 2.0 Hz), 7.16 (2H, d, J=9.0 Hz), 7.08 (1H, d, J=2.0 Hz), 7.00 (1H, t, J=8.8 Hz), 6.92 (2H, d, J=9.0 Hz), 6.87 (1H, dt, J=8.9, 3.9 Hz), 6.80 (1H, m), 5.58-5.49 (2H, m), 4.99 (2H, s), 4.14 (1H, m), 3.79 (3H, s), 2.75 (1H, dd, J=15.1, 6.8 Hz), 2.64 (1H, dd, J=15.1, 8.6 Hz), 1.66 (3H, d, J=5.1 Hz), 1.23 (9H, s). m/e: 951.4 (2M−H)+, 475.1 (M−H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH:5]=[CH2:6].[O:7]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>Cl.C(OCC)C>[Cl:1][CH2:2][CH2:3][O:4][CH:5]([O:20][C:17]1[CH:16]=[CH:15][C:14]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:19][CH:18]=1)[CH3:6]
Reactant: C=COCCCl
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: Cl
Solvent: CCOCC
Product: CC(OCCCl)Oc1ccc(Oc2ccccc2)cc1

Procedure:
64 g of freshly distilled 2-chloroethyl-vinyl ether is placed into a flask; one drop of concentrated hydrochloric acid is added, and thereupon an addition is made in portions at room temperature, with stirring, of 93 g of 4-phenoxy-phenol (duration of addition about 1 hour). During the addition of 4-phenoxy-phenol, the temperature rises to about 32°- 34° C, with the 4-phenoxy-phenol completely dissolving. After two further hours' stirring, the reaction mixture is diluted with 300 ml of diethyl ether; the ether solution is washed three times with 10% potassium hydroxide solution and three times with saturated sodium chloride solution. The ether solution is subsequently dried over sodium sulphate, and the ether and the readily volatile constituents (traces of 2-chloroethyl-vinyl ether) are completely removed in vacuo. There is obtained 1-(2-chloroethoxy)-1-[(4-phenoxy)-phenoxy]-ethane in the form of colorless oil having a refractive index of nD20 = 1.5516 (yield 98%).