Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[C:12](=[O:23])[CH:11]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:30][CH:31](Br)[CH3:32].CN(C=O)C>C(Cl)(Cl)Cl>[Br:30][CH2:31][CH2:32][O:22][C:19]1[CH:18]=[CH:17][C:16]([N:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[CH:11][C:12]2=[O:23])=[CH:21][CH:20]=1
Reactant: CC(Br)Br
Reactant: O=c1cc(OCc2ccc(Cl)cn2)ccn1-c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccc(Cl)cn2)ccn1-c1ccc(OCCBr)cc1
Temperature: 80 °C
Reaction time: 14.5 h
Yield: 89 %

Procedure:
A mixture of 4-[(5-chloro-2-pyridinyl)methoxy]-1-(4-hydroxyphenyl)-1H-pyridin-2-one (1.0 g, 3.1 mmols), cesium carbonate (5.0 g, 15 mmols), dibromoethane (5 mL) and DMF (10 mL) was stirred at 80° C. for 14.5 hours. Chloroform was added to the reaction liquid, followed by filtration. Concentrating the solvent under reduced pressure, the residue was purified on silica gel column chromatography (KP-Sil FLASH 25+ M, chloroform:methanol=1:0→100:2) to provide the title compound (1.2 g, 89%).
Reaction SMILES: [Si:1]([O:18][C:19]1[C:24]2[CH2:25][CH2:26][CH2:27][C:28]([CH2:30][OH:31])=[CH:29][C:23]=2[CH:22]=[CH:21][CH:20]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si]([O:49]C1C2CCC=C(CO)CC=2C=CC=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.B.O1CCCC1.[OH-].[Na+].OO>C1COCC1>[Si:1]([O:18][C:19]1[C:24]2[CH2:25][CH2:26][CH2:27][CH:28]([CH2:30][OH:31])[CH:29]([OH:49])[C:23]=2[CH:22]=[CH:21][CH:20]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCC=C(CO)C2)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCCC(CO)=C2)(c1ccccc1)c1ccccc1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](Oc1cccc2c1CCCC(CO)C2O)(c1ccccc1)c1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a solution of a mixture of [1-(tert-butyldiphenylsilyloxy)-8,9-dihydro-7H-benzocyclohepten-6-yl]methanol and [1-(tert-butyldiphenylsilyloxy)-8,9-dihydro-5H-benzocyclohepten-6-yl]methanol (1.10 g) in THF (10 ml) was added borane-tetrahydrofuran complex (1M THF solution, 7.71 ml) at −30 to −20° C. The mixture was stirred at the same temperature for 30 minutes, and then at room temperature for 18 hours. The reaction mixture was cooled to 5° C. After addition of borane-tetrahydrofuran complex (1M THF solution, 2.57 ml), the mixture was stirred at room temperature for 3 hours. After addition of 2N NaOH solution (2.59 ml) and 30% H2O2 solution (1.76 ml) at 5° C., the resultant was stirred at room temperature for 3 hours. The mixture was extracted with EtOAc. The organic layer was washed with water and then brine. It was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc 3:2 to 1:2) to give first (5RS,6RS)-1-(tert-butyldiphenylsilyloxy)-6-hydroxymethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (719.8 mg) as an amorphous solid and then (6SR,7RS)-1-(tert-butyldiphenylsilyloxy)-6-hydroxymethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ol (181.4 mg) as an amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][CH:7]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH3:21])=[CH:14][CH:13]=2)[C:8]([O:10]C)=[O:9])=[CH:4][CH:3]=1.[OH-].[K+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH:20]([O:22][C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[CH3:21])=[CH:16][CH:17]=2)[C:8]([OH:10])=[O:9])=[CH:30][CH:31]=1
Reactant: COC(=O)C(Oc1ccc(Cl)cc1)c1ccc(OCC(C)Oc2ccc(Cl)cc2)cc1
Agent: [K+]
Agent: [OH-]
Product: CC(COc1ccc(C(Oc2ccc(Cl)cc2)C(=O)O)cc1)Oc1ccc(Cl)cc1
Yield: 98.3 %

Procedure:
As described in Example 73, 6.2 g of methyl (p-chlorophenoxy){p-[2-(p-chlorophenoxy)propoxy]phenyl}acetate is hydrolyzed with 4 g of potassium hydroxide to give 5.91 g of gum. Crystallization from hexane-ether gives 4.73 g of off-white crystals. Recrystallization from chloroform-hexane gives white crystals, mp 146°-148° C.
Reaction SMILES: [OH-].[Na+].[C:3]([O-:22])(=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[Na+].Cl>O.S([O-])([O-])(=O)=O.[Mn+2].S([O-])([O-])(=O)=O.[Zn+2]>[C:3]([OH:22])(=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]
Agent: [Mn+2]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O
Temperature: 90 °C

Procedure:
The fine magnetic particles are prepared by dissolving 0.1 mol of manganese sulfate, 0.4 mol of zinc sulfate and 0.5 mol of ferric sulfate in one liter of water, adding dropwise 6N sodium hydroxide to the aqueous solution while maintaining the temperature at 90° C. with stirring to reach a pH 11, whereby a colloid of Mn-Zn ferrite is formed. The liquid temperature is adjusted to 80° C., and 250 ml of a 10% sodium oleate solution is added to the mixture with stirring. After cooling the mixture to room temperature, aqueous 3N hydrochloric acid solution is added until a pH 6 is reached. Coagulated colloid particles are washed with water sufficiently and dried, thereby obtaining fine Mn-Zn ferrite particles coated with oleic acid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][CH:10]([F:40])[O:11][CH:12]([C:17]1[C:22]2[N:23]3[CH2:29][CH2:28][CH2:27][N:26]([C:30]4[C:31]([CH3:39])=[N:32][C:33]([O:37][CH3:38])=[N:34][C:35]=4[CH3:36])[C:24]3=[N:25][C:21]=2[CH:20]=[CH:19][CH:18]=1)[C:13]([F:16])([F:15])[F:14]>C(#N)C.C(=O)([O-])O.[Na+]>[Br:1][C:20]1[C:21]2[N:25]=[C:24]3[N:26]([C:30]4[C:35]([CH3:36])=[N:34][C:33]([O:37][CH3:38])=[N:32][C:31]=4[CH3:39])[CH2:27][CH2:28][CH2:29][N:23]3[C:22]=2[C:17]([CH:12]([O:11][CH:10]([F:9])[F:40])[C:13]([F:16])([F:15])[F:14])=[CH:18][CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1nc(C)c(N2CCCn3c2nc2cccc(C(OC(F)F)C(F)(F)F)c23)c(C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1nc(C)c(N2CCCn3c2nc2c(Br)ccc(C(OC(F)F)C(F)(F)F)c23)c(C)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.3 %

Procedure:
N-Bromosuccinimide (190 mg, 1.07 mmol) was added to a stirred solution of 6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (469 mg, 1.02 mmol) in acetonitrile (5.0 mL) at room temperature, and the mixture was stirred at room temperature for 5 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 70-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give a solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound as colorless crystals (330 mg, 0.615 mmol, 60%).
Reaction SMILES: OC(COC1C=CC=CC=1OC)CN1CCC([N:10]2[CH2:14][CH2:13][N:12](C3C=CC(Cl)=CC=3)C2=O)CC1.[Cl:33][C:34]1[CH:40]=[CH:39][C:37](N)=[CH:36][CH:35]=1.Br.BrCCN>C(C(CC)=O)C>[Cl:33][C:34]1[CH:40]=[CH:39][C:37]([CH:13]([NH2:12])[CH2:14][NH2:10])=[CH:36][CH:35]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COc1ccccc1OCC(O)CN1CCC(N2CCN(c3ccc(Cl)cc3)C2=O)CC1
Agent: Br
Agent: NCCBr
Solvent: CCC(=O)CC
Product: NCC(N)c1ccc(Cl)cc1
Temperature: 70 °C

Procedure:
The 1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-[2-(4-chloroanilino)-ethylamino]-piperidine can be prepared as follows: A mixture of 38 g of p-chloroaniline and 31 g of 2-bromoethylamine-hydrobromide is heated to 70° C. with stirring. After 30 minutes 75 ml of diethyl ketone are added and the mixture is refluxed for 4 hours. The black solution is then concentrated under reduced pressure. The residue is made alkaline with 2 N sodium carbonate solution and extracted with three 100 ml portions of chloroform. The residual oil is fractionally distilled in vacuo to yield 1-(4-chlorophenyl)-ethylenediamine with a boiling point of 130°-135° C. (1.5 torr).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25]>>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH:25][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: COc1ccccc1CN
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: COc1ccccc1CNc1nccc(-n2cnc3ccccc32)n1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 2-methoxybenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 332.1 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.63 (s, 1H); 8.41 (br s, 1H); 8.12 (br s, 1H); 7.86 (m, 1H); 6.94 (m, 2H); 6.79 (d, J=5.2 Hz, 1H); 5.95 (br s, 1H); 4.74 (d, J=5.9 Hz, 2H); 3.92 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[Cl-].[Al+3].[Cl-].[Cl-].[C:17](Cl)(=[O:19])[CH3:18].Cl>ClCCl.C1(C)C=CC=CC=1>[C:17]([C:6]1[CH:5]=[CH:4][C:3]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:2]([CH3:1])[CH:7]=1)(=[O:19])[CH3:18]
Reactant: Cc1ccccc1NS(C)(=O)=O
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(NS(C)(=O)=O)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(2-methylphenyl)methanesulfonamide (1.84 g, 10 mmol) in dichloromethane (2 mL) was added aluminum chloride (3.3 g, 25 mmol) carefully at 0° C. Then acetyl chloride (1.07 ml, 15 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 0.5 hours, the reaction was monitored by using TLC and 1H-NMR, and after completion of the reaction, the reaction mixture was diluted with toluene and poured into 2N HCl aqueous solution with stirring at 0° C. The precipitate solid was filtered, washed with H2O, and dried to give a mixture of the title compound and by-product (N-acetylated product) (2.31 g, ratio; title compound: by-product=81:19 (ratio was determined by 1H-NMR)) as a flesh color powder.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([Cl:18])[CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[Cl:18][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCCNC2=O
Product: Cc1c2n(c3c(-c4ccc(F)cc4)cc(Cl)cc13)CCCNC2=O

Procedure:
The title compound, off-white solid (75 mg, 88%), MS (ISP) m/z=343.4 [(M+H)+], mp 260° C., was prepared in accordance with the general method of example 1 from 7-bromo-9-chloro-11-methyl-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 13) (81.9 mg, 0.25 mmol) and commercially available 4-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33].CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([S:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:18][CH:19]=2)(=[O:13])=[O:12])[CH2:10][CH2:9][N:8]([C:32](=[O:34])[CH3:33])[CH2:7][CH2:6]1)=[O:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCNCC2)cc1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(C(C)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To a solution of product from step 3 (105 mg, 0.23 mmol) in methylene chloride (1 ml) was added triethylamine (93 mg, 0.92 mmol), acetyl chloride (18 mg, 0.23 mmol) followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred for 8 hours at room temperature, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 75 mg (80%) of the product as a solid.
Reaction SMILES: [CH2:1]1[O:32][C:31]2[CH:30]=[CH:29][C:5]([CH2:6][N:7]([S:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([O:25][CH3:26])=[C:20]([CH3:27])[C:19]=3[CH3:28])(=[O:17])=[O:16])[C@H:8]([CH:12]([CH3:14])[CH3:13])[C:9](O)=[O:10])=[CH:4][C:3]=2[O:2]1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.C[Si](C)(C)[NH:46][O:47][Si](C)(C)C>C(Cl)Cl.CO>[OH:47][NH:46][C:9](=[O:10])[C@H:8]([N:7]([CH2:6][C:5]1[CH:29]=[CH:30][C:31]2[O:32][CH2:1][O:2][C:3]=2[CH:4]=1)[S:15]([C:18]1[C:23]([CH3:24])=[CH:22][C:21]([O:25][CH3:26])=[C:20]([CH3:27])[C:19]=1[CH3:28])(=[O:17])=[O:16])[CH:12]([CH3:14])[CH3:13]
Reactant: C[Si](C)(C)NO[Si](C)(C)C
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@@H](C(=O)O)C(C)C)c(C)c1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@@H](C(=O)NO)C(C)C)c(C)c1C
Reaction time: 4 h
Yield: 62.4 %

Procedure:
To a solution of 2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3-methylbutyric acid (3.82 g, 8.24 mmol) in dry methylene chloride (20 mL) was added oxalyl chloride (2.2 mL, 24.72 mmol) and a drop of dimethylformamide. The reaction mixture was stirred for 4 h and then concentrated. The residue was dissolved in methylene chloride 20 mL) and N,O-bis-trimethylsilylhydroxylamine (8.8 mL, 41.2 mmol) was added. After 4 h, methanol (1 mL) was added and the stirring was continued for 30 min. Silica gel (10 g) was added and the material was concentrated to dryness. The resultant powder was flash chromatographed on a silica gel column and eluted with 50% ethyl acetate/hexanes to give N-hydroxy-2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3-methylbutyramide (2.46 g).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:14])[S:10](Cl)(=[O:12])=[O:11].[CH3:15][C:16]([C:25]([F:28])([F:27])[F:26])([CH:23]=[CH2:24])[CH2:17][C:18]1[N:19]=[CH:20][NH:21][CH:22]=1>C(Cl)Cl.O>[CH3:8][N:9]([CH3:14])[S:10]([N:21]1[CH:22]=[C:18]([CH2:17][C:16]([CH3:15])([C:25]([F:26])([F:27])[F:28])[CH:23]=[CH2:24])[N:19]=[CH:20]1)(=[O:12])=[O:11]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: C=CC(C)(Cc1c[nH]cn1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C=CC(C)(Cc1cn(S(=O)(=O)N(C)C)cn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (3 mL, 14.02 mmol) followed by dimethylsulfamoyl chloride (1.5 mL, 14.02 mmol) were added to an ambient temperature solution of 4-[2-methyl-2-(trifluoromethyl)but-3-en-1-yl]-1H-imidazole (1.43 g, 7.01 mmol) in methylene chloride (20 mL). After stirring at ambient temperature overnight, the reaction mixture was diluted with water and extracted with ethyl acetate and methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% ethyl acetate/hexane afforded the title compound.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5](=[O:12])[CH2:6][CH2:7][C:8]([O:10]C)=[O:9].[CH2:14]([OH:17])[CH2:15][OH:16].O.[OH-].[K+]>C1C=CC=CC=1.C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:14]1[O:17][C:3]([OH:2])([CH2:4][C:5](=[O:12])[CH2:6][CH2:7][C:8]([OH:10])=[O:9])[O:16][CH2:15]1
Reactant: COC(=O)CCC(=O)CC(=O)OC
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: c1ccccc1
Solvent: O
Product: O=C(O)CCC(=O)CC1(O)OCCO1
Reaction time: 2.5 h
Yield: 100.3 %

Procedure:
A solution of 4.00 g (21 mmol) of 3-ketohexanedioic acid dimethyl ester [B. J. Whitlock and H. W. Whitlock, J. Org. Chem., 39:3144 (1974)] in 100 mL of benzene was refluxed in the presence of 14.5 g (230 mmol) of ethylene glycol and 100 mg of p-toluene-sulfonic acid while water was azeotropically removed in a Dean-Stark trap. After 2.5 h, the mixture was cooled and washed with equal volumes of saturated sodium bicarbonate solution and water. The benzene layer was dried (MgSO4) and reduced to dryness to leave a clear oil; IR (neat) 1740 cm-1, NMR (CDCl3) δ2.30 (A2B2 multiplet, 4), 2.60 (s,2), 3.65 (s,6), and 3.95 (s,4). The oily ketal was immediately hydrolyzed under reflux for 1.5 h in a solution of 4.4 g of 86% KOH in 50 mL of 95% ethanol. After cooling, the slight precipitate formed was dissolved by adding a small amount of water. Sufficient cation exchange resin AG50W-X8 (H+) was added to neutralize the base (pH~6.5) and removal of the resin afforded a filtrate which was reduced to dryness to leave 4.3 g (99%) of 3-ketohexanedioic acid ethylene ketal as a yellowish oil which yielded a very hygroscopic solid after trituration with acetone; IR 1720 cm-1 (broad); NMR δ(D2O) 2.20 (A2B2 multiplet, 4), 2.60 (s,2), and 4.0 (s,4). This compound was not further characterized and used as such in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:4][CH:3]=1.[C:34]([O:38][C:39]([NH:41][C:42]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=S)=[O:40])([CH3:37])([CH3:36])[CH3:35].C(N(CC)CC)C>CN(C=O)C>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:22][CH2:23][N:24](/[C:42](/[NH:44][C:45](=[O:46])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[N:41]\[C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:40])[CH2:25][CH2:26]2)=[CH:32][CH:31]=1
Reactant: O=c1cc(NC2CCNCC2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)/N=C(/NC(=O)OC(C)(C)C)N1CCC(Nc2cc(=O)[nH]c3ccc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a mixture of 6-(bis(4-chlorophenyl)methyl)-4-(piperidin-4-ylamino)quinolin-2(1H)-one (250 mg, 0.523 mmol0, N,N′-bis-tert-butoxycarbonylthiourea (158.8 mg, 0.575 mmol) and triethylamine (0.22 mL, 1.57 mmol) in 3 mL DMF was added mercuric chloride (170.2 mg, 0.63 mmol) at 0° C. The reaction was stirred for 3 h at 0° C. and then quenched with EtOAc. The reaction was filtered through CELITE. The filtrate was washed two times with water, then dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified on ISCO with MeOH—CH2Cl2 and re-purified on HPLC (40-90% CH3CN (0.1% TFA)/H2O (0.1% TFA)) to yield (Z)-tert-butyl ((4-((6-(bis(4-chlorophenyl)methyl)-2-oxo-1,2-dihydroquinolin-4-yl)amino)piperidin-1-yl)((tert-butoxycarbonyl)imino)methyl)carbamate.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1.[OH:8][CH2:9][C:10]([N:12]([CH2:14][C@H:15]([O:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[C:20]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([CH3:36])[CH:30]=1)=[N:21][CH:22]=[N:23]2)[CH3:16])[CH3:13])=[O:11]>>[OH:8][CH2:9][C:10]([N:12]([CH3:13])[CH2:14][C@H:15]([O:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[C:20]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:2][C:3]3[N:4]=[CH:5][S:6][CH:7]=3)=[C:31]([CH3:36])[CH:30]=1)=[N:21][CH:22]=[N:23]2)[CH3:16])=[O:11]
Reactant: Cc1cc(Nc2ncnc3cccc(O[C@H](C)CN(C)C(=O)CO)c23)ccc1O
Reactant: ClCc1cscn1
Product: Cc1cc(Nc2ncnc3cccc(O[C@H](C)CN(C)C(=O)CO)c23)ccc1OCc1cscn1
Yield: 41 %

Procedure:
The procedure described in Example 3 was repeated using 4-(chloromethyl)-1,3-thiazole and 2-hydroxy-N-[(2R)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)propyl]-N-methylacetamide (obtained as described in Example 90, preparation of starting materials) to give the title compound as a white solid in 41% yield; NMR spectrum (DMSO-d6 373K) 1.43 (d, 3H), 2.24 (s, 3H), 2.97 (s, 3H), 3.57 (m, 1H), 4.07 (m, 3H), 5.13 (m, 1H), 5.25 (s, 2H), 7.09 (d, 1H), 7.11 (d, 1H), 7.34 (d, 1H), 7.57 (m, 2H), 7.69 (m, 2H), 8.42 (s, 1H), 9.07 (d, 1H), 9.82 (s, 1H); Mass spectrum MH+ 494.
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2([CH3:20])[CH3:19].[H-].[Na+].ClC(Cl)(Cl)[C:25]([N:27]=C=O)=[O:26]>CN(C=O)C.C(Cl)Cl>[CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:25]([NH2:27])=[O:26])[C:13](=[O:18])[C:12]2([CH3:19])[CH3:20]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)C(C)(C)C(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1SC(=O)NN=C1c1ccc2c(c1)C(C)(C)C(=O)N2C(N)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 22.3 %

Procedure:
1.45 g (5 mmol) 5-(3,6-dihydro-6-methyl-2-oxo-2H-1,3,4-thiadiazin-5-yl)-1,3-dihydro-3,3-dimethyl-2H-indol-2-one (Example 3) in 30 ml DMF were cooled to 0° C. 0.12 g (5 mmol) sodium hydride from a 55% dispension in mineral oil was added and the mixture was stirred for 0.5 hr at 0° C. then 0.5 hr at 20° C. After cooling to 0° C. a solution of 1 g trichloroacetyl isocyanate in 5 ml dry methylene chloride was added dropwise. The reactional mixture was stirred at room temperature overnight. The solvent was evaporated under vacuum, the residue taken up in 50 ml ethyl acetate and 40 g neutral aluminum oxide was added. The compound was then extracted from the aluminum oxide on a column with ethyl acetate. The solvent was evaporated and the residue was purified by chromatography on silica (eluent:methylene chloride/ethyl acetate: 2/1) to yield 0.37 g (22%) of the desired compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([O:16][CH3:17])=[CH:11][C:10]=1[NH:18][C:19]1[C:24]([C:25]#[N:26])=[CH:23][N:22]=[C:21]2[CH:27]=[C:28]([C:30]3[CH:34]=[C:33]([CH:35]=O)[S:32][CH:31]=3)[S:29][C:20]=12.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O.C(O)(=O)C>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([O:16][CH3:17])=[CH:11][C:10]=1[NH:18][C:19]1[C:24]([C:25]#[N:26])=[CH:23][N:22]=[C:21]2[CH:27]=[C:28]([C:30]3[CH:34]=[C:33]([CH2:35][N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[S:32][CH:31]=3)[S:29][C:20]=12
Reactant: COc1cc(Nc2c(C#N)cnc3cc(-c4csc(C=O)c4)sc23)c(Cl)cc1Cl
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4csc(CN5CCN(C)CC5)c4)sc23)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 49.8 %

Procedure:
1-Methylpiperazine (70 μL, 0.63 mmol) is added to a suspension of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(5-formylthien-3-yl)thieno[3,2-b]pyridine-6-carbonitrile (225 mg, 0.49 mmol) in 4 mL of dichloromethane and 1 mL of N,N-dimethylformamide. The reaction mixture is cooled to 0° C. and sodium triacetoxyborohydride (520 mg, 2.45 mmol) is added. After stirring at 0° C. for 10 minutes, 2 drops of acetic acid are added and the reaction mixture is allowed to warm to room temperature and stirred for 4 hours. The reaction is quenched by the addition of water and then partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 5% methanol in dichloromethane. The fractions containing product are combined and concentrated in vacuo. The residue is washed with diethyl ether to provide 133 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2{5-[(4-methylpiperazin-1-yl)methyl]thien-3-y}thieno[3,2-b]pyridine-6-carbonitrile as white crystals, mp 224–226° C.; 1H NMR (DMSO-d6) δ 2.18 (s, 3H), 2.25–2.55 (m, 8H), 3.68 (s, 2H), 3.85 (s, 3H), 7.35 (s, 1H), 7.37 (s, 1H), 7.74 (s, 1H), 7.75 (s, 1H), 7.82 (s, 1H), 8.58 (s, 1H), 9.68 (s, 1H); MS 523.1, 544.2 (M+H)+.