Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[CH2:23]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:6][CH:7]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OCCCCCCCCc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCCCCCCCCc1ccc(OCc2ccccc2)cc1
Yield: 71 %

Procedure:
A suspension comprising 3.0 g of 8-(4-hydroxyphenyl)octanol, 3.0 g of anhydrous potassium carbonate, 50 ml of dry acetone and 1.9 ml of benzyl bromide was heated under reflux for 16 hours. After the completion of the reaction, the potassium carbonate was filtered off and the filtrate was concentrated on an evaporator. The white solid thus obtained was precipitated from chloroform-hexane (1:4). As a result, 3.0 g of the desired compound was obtained (yield: 71%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:30]=3[N:29]=[CH:28][CH:27]=[CH:26]4)(=[O:20])=[O:19])[CH:10]=2)O1.I[C:33]1[CH:38]=[CH:37][N:36]=[C:35]([S:39][CH3:40])[N:34]=1.C(OCC)(=O)C>C(=O)([O-])[O-].[K+].[K+].O.O1CCCC1.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>[CH3:40][S:39][C:35]1[N:36]=[C:37]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:30]=3[N:29]=[CH:28][CH:27]=[CH:26]4)(=[O:20])=[O:19])[CH:10]=2)[CH:38]=[CH:33][N:34]=1
Reactant: CC1(C)OB(c2cn(S(=O)(=O)c3cccc4cccnc34)c3ncccc23)OC1(C)C
Reactant: CSc1nccc(I)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CSc1nccc(-c2cn(S(=O)(=O)c3cccc4cccnc34)c3ncccc23)n1
Temperature: 120 °C

Procedure:
In a microwave reaction tube, 8-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrrolo[2,3-b]pyridine-1-sulfonyl]-quinoline (47, 70 mg, 0.16 mmol), 4-iodo-2-methylsulfanyl-pyrimidine (101 mg, 0.402 mmol), and tetrakis(triphenylphosphine)palladium(0) (9.3 mg, 0.008 mmol) were mixed in 1.0 M potassium carbonate in water (0.48 mL) and tetrahydrofuran (0.77 mL). The resulting mixture was heated at 120° C. in a CEM Discover microwave unit for 10 minutes. Ethyl acetate and water were added, and the two layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. Concentration under reduced pressure afforded the crude material, which was purified by column chromatography (50% ethyl acetate in hexane) to yield the desired product in light yellow solid (46, 10 mg, 0.023 mmol). MS(ESI) [M+H+]+=434.0.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([Cl:20])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:23][C:24]1[CH:30]=[C:29]([CH3:31])[C:28]([O:32][C:33]([O:35][CH3:36])=[O:34])=[CH:27][C:25]=1[NH2:26]>C(O)(C)C>[ClH:20].[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:26][C:25]3[CH:27]=[C:28]([O:32][C:33]([O:35][CH3:36])=[O:34])[C:29]([CH3:31])=[CH:30][C:24]=3[F:23])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: COC(=O)Oc1cc(N)c(F)cc1C
Agent: Cl
Solvent: CC(C)O
Product: COC(=O)Oc1cc(Nc2ncnc3cc(OCc4ccccc4)c(OC)cc23)c(F)cc1C
Temperature: 25 °C
Yield: 83.3 %

Procedure:
A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (800 mg, 2.4 mmol), (prepared as described for the starting material in Example 1), and 2-fluoro-5-methoxycarbonyloxy-4-methylaniline (570 mg, 2.89 mmol) in isopropanol (20 ml) was heated at reflux for 2 hours. The mixture was allowed to cool to ambient temperature, the precipitated solid was collected by filtration, washed with isopropanol and dried under vacuum to give 7-benzyloxy-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxyquinazoline hydrochloride (1.0 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:19][O:20][C:21](=[O:34])[C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[C:25]([O:31][CH3:32])=[CH:24][C:23]=1F.CCN(CC)CC>CC#N.C(Cl)Cl>[CH3:19][O:20][C:21](=[O:34])[C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[C:25]([O:31][CH3:32])=[CH:24][C:23]=1[NH:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(OC)cc1F
Reactant: Nc1ccc(CCCc2ccc(Cl)c(Cl)c2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1cc([N+](=O)[O-])c(OC)cc1Nc1ccc(CCCc2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Yield: 41.5 %

Procedure:
A mixture of 4-[3-(3,4-dichloro-phenyl)propyl]phenylamine (0.94 g, 3.3 mmol), 2-fluoro-4-methoxy-5-nitro-benzoic acid methyl ester (0.75 g, 3.3 mmol), and Et3N (0.46 mL) in CH3CN (30 mL) was heated to reflux for 120 hours. The reaction mixture was cooled to room temperature, diluted with CH2Cl2 and washed with saturated NaHCO3. The organic layer was dried (Na2SO4) and concentrated to give a solid. Recrystallization with MeOH yielded 0.67 g (1.37 mmol, 42%) of the desired product.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:14][C:15]1[CH:16]=[C:17]([O:23][CH3:24])[C:18]([O:21][CH3:22])=[CH:19][CH:20]=1>C(N(CC)CC)C>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([NH:14][C:11]([C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[O:12])[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: COc1ccc(N)cc1OC
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)C23CC4CC(CC(C4)C2)C3)cc1OC

Procedure:
Subject 1.35 g. (6.8 mmoles) of adamantane carboxylic acid chloride, 1.0 g. (6.5 mmoles) of 4-amino veratrole and 4.0 ml. of triethylamine to the process of Example 11 and obtain thereby the title product, m.p. 224°-226°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:16][CH2:17][CH2:18][CH2:19][OH:20])(=[O:11])=[O:10].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:16][CH2:17][CH2:18][CH:19]=[O:20])(=[O:11])=[O:10]
Reactant: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCCO)c1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCC=O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
Sulfur trioxide pyridine complex (1.87 g, 11.7 mmol) was added portionwise over 15 min to a solution of 3-[3-(2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propanol (2.07 g, 5.9 mmol, as prepared in the preceding step), N,N-diisopropylethylamine (2.15 mL, 12.3 mmol), and anhydrous dimethyl sulfoxide (1.25 mL, 17.6 mmol) in anhydrous dichloromethane (14 mL) at 0° C. under a nitrogen atmosphere. The solution was stirred at 0° C. for 1 h, then the reaction was quenched with 5% aqueous citric acid (50 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (15 mL). The combined organic extracts were washed with 5% aqueous citric acid (50 mL), pH 7 buffer (40 mL) and brine (50 mL), dried over Na2SO4, filtered, and evaporated. The residual gold oil was purified by flash column chromatography (3:2 diethyl ether/hexane) to give the title compound (1.28 g, 62%) as a colorless oil. 1H-NMR (300 MHz, CDCl3) δ 9.82 (t, 1 H, J=1.5 Hz), 7.82 (dd, 1 H, J=1.7, 7.9 Hz), 7.62 (ddd, 1 H, J=1.8, 7.4, 8.4 Hz), 7.09 (dd, 1 H, J=0.8, 8.4 Hz), 7.02 (m, 1 H), 6.58 (br s, 1 H), 6.54 (br s, 1 H), 6.45 (t, 1 H, J=2 Hz), 4.18 (t, 2 H, J=6.1 Hz), 4.02 (s, 3 H), 2.85 (td, 2 H, J=1.5,6.1Hz), 2.24 (s, 3 H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C17H18O6S: 373.1 (M+Na). Found: 373.0.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH:13]1([CH2:16]O)[CH2:15][CH2:14]1>>[CH:13]1([CH2:16][O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH2:15][CH2:14]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OCC1CC1
Product: O=C1c2ccccc2C(=O)N1OCC1CC1
Yield: 87 %

Procedure:
N-Hydroxyphthalimide and cyclopropyl-methanol were reacted as described for compound LIX in Example 27, to afford LXXXVI in 87% yield. 400 MHz 1 NMR (DMSO-d6, ppm) 7.86 (4H, s), 3.97 (2H, d, J=7.4 Hz), 1.22-1.11 (1H, m), 0.61-0.48 (2H, m), 0.34-0.22 (2H, m).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[CH:21]([Mg]Cl)([CH3:23])[CH3:22].Cl.O>O1CCCC1>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][CH:19]([OH:20])[CH:21]([CH3:23])[CH3:22])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(SCCCO)cc(C(C)(C)C)c1O
Reactant: CC(C)[Mg]Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio] propanol (2.0 g, prepared as described in U.S. Pat. No. 4,857,558) was dissolved in 20 ml of dry tetrahydrofuran under argon and added to 8.5 ml of 2 M isopropylmagnesium chloride in tetrahydrofuran that had previously been added under argon gas to a flask that had been dried in vacuo overnight. Reaction temperature was maintained at 10°-15° C. with an ice bath. When addition was complete, the reaction mixture was allowed warm to room temperature and stirred for 3 hours. 2N hydrochloric acid (2 ml) was added followed by 50 ml of water and the mixture extracted with ethyl acetate three times. The organic extracts were combined, washed with water twice and dried over sodium sulfate. The solvent was removed in vacuo after filtration and the crude product chromatographed on silica to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:17][CH:13]([NH:14][C:15]2=[O:16])[C:12](=O)[CH2:11][CH2:10]3)[CH:6]=[CH:7][CH:8]=1.O.[NH2:20][NH2:21].C(O)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:17][CH:13]([NH:14][C:15]2=[O:16])[C:12](=[N:20][NH2:21])[CH2:11][CH2:10]3)[CH:6]=[CH:7][CH:8]=1
Reactant: NN
Reactant: COc1cccc(C23CCC(=O)C(C2)NC3=O)c1
Solvent: O
Solvent: c1ccccc1
Solvent: CCO
Product: COc1cccc(C23CCC(=NN)C(C2)NC3=O)c1
Yield: 94.2 %

Procedure:
A mixture of 21.73 g of 1-(3-methoxyphenyl)-6-azabicyclo[3,2,1]octane-4,7-dione, 4.9 g of hydrazine hydrate and 170 ml of ethanol is refluxed for 1 hour. After cooling, the mixture is evaporated under reduced pressure to remove solvent. The residue thus obtained is dispersed in benzene and then filtered to give 21.64 g of 1-(3-methoxyphenyl)-6-azabicyclo[3,2,1]octane-4,7-dione-4-hydrazone as crude crystals. A mixture of 21.64 g of 1-(3-methoxyphenyl)-6-azabicyclo[3,2,1]octane-4,7-dione-4-hydrazone, 17.1 g of potassium tert.-butoxide and 400 ml of toluene is refluxed for 2 hours under heating. After cooling, water is added to the mixture, and the aqueous mixture is extracted with ether. The ether extract is washed with water, dried and then evaporated to remove solvent. The residue thus obtained is recrystallized from a mixture of ethylacetate and n-hexane. 17.54 g of 1-(3-methoxyphenyl)-6-azabicyclo[3,2,1]octane-7-one are obtained. M.p. 109° - 111°C.
Reaction SMILES: [C:1]([N:4]1[CH2:11][CH2:10][CH2:9][C@H:5]1[C:6](O)=[O:7])(=[O:3])[CH3:2].O[N:13]1[C:18](=[O:19])[CH2:17][CH2:16][C:14]1=O.[CH2:20]1CCC(N=C=NC2CCCCC2)CC1.N1CCC[C@H]1CO>C1COCC1>[C:18]([N:13]1[CH2:14][CH2:16][CH2:20][C@H:2]1[C:1]([N:4]1[CH2:11][CH2:10][CH2:9][C@H:5]1[CH:6]=[O:7])=[O:3])(=[O:19])[CH3:17]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: OC[C@@H]1CCCN1
Solvent: C1CCOC1
Product: CC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C=O
Temperature: 4 °C
Reaction time: 21 h

Procedure:
In 200 ml of THF was dissolved 15.7 g of acetyl-proline. To this solution were added under cooling with edible salt and ice 11.5 g of HOSu and 20.6 g of DCC, and the mixture was stirred for 21 hours at 4° C. The reaction liquid was filtered and the filtrate was evaporated whereby a semi-solid substance was obtained. This substance was recrystallized from isopropyl alcohol to obtain a white solid substance which was then dissolved in 400 ml of THF. To this solution was added 7.5 g of L-prolinol, and the mixture was stirred for 72 hours at room temperature. After removal of THF by distillation, the residue was dissolved in 300 ml of ethyl acetate and the solution was washed with 100 ml of 1-M Na2CO3, dehydrated with anhydrous Na2SO4 and evaporated until dryness. To the resultant oily substance were added 35.8 g of WBCD.HCl and 160 ml of redistilled DMSO, and the mixture was stirred for 10 minutes. Subsequently, 7.1 ml of a DMSO solution of 2-M anhydrous H3PO4 was added and the mixture was stirred for further 2 hours. The reaction was stopped with 300 ml of a buffer solution of 1-M potassium phosphate of pH 7.5. The reaction mixture was extracted with 350 ml of ethyl acetate, and the extract was dried over anhydrous Na2SO4. The ethyl acetate was distilled off and the residue was dissolved in 300 ml of ethanol. To this solution was added 200 g of NaHSO3 in 350 ml of water, and the mixture was stirred vigorously for 10 minutes. After concentration of the ethanol up to about 300 ml, unreacted materials were eliminated twice with 100 ml of ether, and solid Na2CO3 was added until the pH value of the liquid became 9. After 5 minutes, the reaction liquid was extracted twice with 100 ml of ether, and the ether was then distilled off to leave an oily substance. Yield 5.5 g (23.5%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][CH:8]=2)[CH2:2]1.C(N(CC)CC)C.ClCCl.[CH3:27][CH:28]([CH3:34])/[CH:29]=[CH:30]/[C:31](Cl)=[O:32].ClCCl.C1(C)C(S(Cl)(=O)=O)=CC=CC=1>>[CH3:27][CH:28]([CH3:34])/[CH:29]=[CH:30]/[C:31]([N:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][CH:8]=2)[CH2:2]1)=[O:32]
Reactant: c1ccc2c(N[C@H]3CCNC3)ccnc2c1
Reactant: CC(C)/C=C/C(=O)Cl
Agent: Cc1ccccc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)/C=C/C(=O)N1CC[C@H](Nc2ccnc3ccccc23)C1
Yield: 39 %

Procedure:
To N-[(3S)-Pyrrolidin-3-yl]quinolin-4-amine (32 mg, 0.15 mmol) dissolved in 1.5 ml anhydrous dichloromethane triethylamine (0.9 mmol, 91 mg) was added with stirring followed by (E)-4-methylpent-2-enoyl chloride dissolved in anhydrous dichloromethane (29.8 mg, 0.23 mmol). The mixture was stirred at room temperature for 5 minutes after which polymer-supported toluenesulfonyl chloride (600 mg, 1-2 mmol/g) was added and the mixture was shaken for 15 minutes, filtered and the filtrate evaporated to dryness under reduced pressure. The raw product was purified by preparative HPLC (gradient of water containing 0.1% ammonia and acetonitrile) to yield 18 mg of a solid (0.58 mmol, 39%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8](=[O:24])[C:7]2(O)[C:25]1[C:26]([OH:34])=[CH:27][C:28]2[O:32][CH2:31][CH2:30][C:29]=2[CH:33]=1.ClC1C=CC=C2C=1C(O)(C1C(O)=CC3OCCC=3C=1)C(=O)N2C(C1C=CC=CC=1)C1C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH:11]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:8](=[O:24])[CH:7]2[C:25]1[C:26]([OH:34])=[CH:27][C:28]2[O:32][CH2:31][CH2:30][C:29]=2[CH:33]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2c(Cl)cccc2C1(O)c1cc2c(cc1O)OCC2
Agent: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Cl)c2C1(O)c1cc2c(cc1O)OCC2
Product: O=C1C(c2cc3c(cc2O)OCC3)c2cccc(Cl)c2N1C(c1ccccc1)c1ccccc1

Procedure:
Following the procedure as described in PREPARATION 4C, and making non-critical variations using 7-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one to replace 4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one, 7-chloro-1-(diphenylmethyl)-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one was obtained (64%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 9.53 (s, 1H), 7.44-7.20 (m, 13H), 7.01-6.91 (m, 2H), 6.22 (s, 1H), 4.82 (s, 1H), 4.48 (t, J=8.5 Hz, 2H), 3.03 (t, J=8.5 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([O:13]CC)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].[CH2:16]([O:19][C:20]1[C:25]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:24][C:23]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:22][C:21]=1B(O)O)[CH2:17][CH3:18]>>[C:26]([C:25]1[C:20]([O:19][CH2:16][CH2:17][CH3:18])=[C:21]([C:2]2[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])[CH:3]=2)[CH:22]=[C:23]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CCCOc1c(B(O)O)cc(C(C)(C)C)cc1C(C)(C)C
Reactant: CCOC(=O)C=Cc1ccc(O)c(Br)c1
Product: CCCOc1c(-c2cc(C=CC(=O)O)ccc2O)cc(C(C)(C)C)cc1C(C)(C)C
Yield: 4.6 %

Procedure:
In a manner similar to that of Example 1(c), by reaction of 1.0 g (3.7 mmol) of ethyl 3-(3-bromo-4-hydroxyphenyl)acrylate obtained in Example 34(d) with 2.14 g (7.33 mmol) of 2-propyloxy-3,5-di-tert-butylphenylboronic acid obtained above, 70 mg (4%) of the expected compound were obtained in the form of a colorless oil.
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23](OC)=[CH:22][CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.Cl.O[CH:30]([CH2:45]OC1C=CC=CC=1C)[CH2:31]NC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:30]([CH3:45])[CH3:31])=[CH:22][CH:21]=1)[CH2:4][NH:5][C:6]([CH3:16])([CH3:17])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(OC)cc2)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccccc2C)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)C)cc2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 356 (M−15, 0.1), 251 (18), 250 (100), 163 (7), 121 (23), 117 (7), 114 (8).
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[CH3:13][NH:14][C:15]1[C:16]([NH2:21])=[N:17][CH:18]=[CH:19][CH:20]=1.[Cl-].[Cl-].[Ca+2]>C1COCC1>[CH3:13][N:14]1[C:15]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[NH:21][C:6]1=[O:7]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CNc1cccnc1N
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cn1c(=O)[nH]c2ncccc21
Yield: 79.7 %

Procedure:
CDI (2.251 g) was added to a solution of N3-methylpyridine-2,3-diamine (1.14 g) in THF (dry) (50 ml) at room temperature. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) over weekend. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-100% EtOAc in hexane) to give 1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.1 g) as a white solid.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].Br[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[CH:18][CH:17]=1.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.COCCOC>[CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]3)=[CH:20][CH:21]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(NS(C)(=O)=O)cc3)cc2)CC1
Yield: 24.6 %

Procedure:
The title compound (11 mg, 25%) was prepared as a tan solid from {4-[(methylsulfonyl)amino]phenyl}boronic acid (22 mg, 0.1 mmol), 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 9, Step 2, 36 mg, 0.1 mmol), Pd(PPh3)2Cl2 (25 mg, 0.04 mmol), 2M Na2CO3 (1 mL) and DME (1 mL) in a manner similar to Example 21, Step 3, and worked up in a manner similar to Example 9, Step 3. 1H NMR (400 MHz, CDCl3): δ 7.55-7.45 (m, 4H), 7.30-7.20 (m, 2H), 6.95 (d, 2H, J=8.6 Hz), 6.38 (s, 1H), 4.99-4.83 (m, 1H), 3.84 (d, 2 H, J=6.4 Hz), 3.03 (s, 3H), 2.84-2.74 (m, 2H), 2.05-1.94 (m, 1H), 1.90-1.80 (m, 2H), 1.37-1.18 (m, 10H); LRMS (ESI), m/z 447 (M+H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][CH:31]=1>O>[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:8]=[C:9]4[C:14](=[CH:15][CH:16]=3)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]4)[CH2:2][CH2:3]2)=[CH:32][CH:31]=1
Reactant: O=C1CCc2cc(N3CCNCC3)ccc2N1
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCc2cc(N3CCN(Cc4ccc(Cl)cc4)CC3)ccc2N1
Reaction time: 4 h
Yield: 32.5 %

Procedure:
To a mixture of 1.0 g of 6-(1-piperazinyl)-3,4-dihydrocarbostyril, 1.11 g of potassium carbonate and 20 ml of DMF was added 780 mg of 4-chlorobenzyl chloride and the mixture was stirred at 70°-80° C. for 4 hours. The reaction mixture was poured into a large amount of water and extracted with chloroform. Chloroform was distilled off and the residue was purified through silica gel column chromatography. Recrystallization from chloroform-methanol gave 500 mg of 6-[4-(4-chlorobenzyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 190°-191.5° C., colorless needles.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1.[CH3:11][NH2:12]>C(#N)C>[CH3:11][NH:12][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1
Reactant: CN
Reactant: N#Cc1ccc(CBr)cc1
Solvent: CC#N
Product: CNCc1ccc(C#N)cc1
Reaction time: 0.5 h
Yield: 38.6 %

Procedure:
A solution of α-bromo-p-tolunitrile (4.90 g, 25 mmol) in acetonitrile (50 mL) was added dropwise to a stirring solution of 40% aqueous methylamine (21.5 mL, 250 mmol) in acetonitrile (50 mL) at 0° C. The reaction mixture was stirred 0.5 h, then concentrated in vacuo. Water was added to the residue and extracted 2× with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give 1.41 g of 4-(methylaminomethyl)benzonitrile as a yellow oil containing ˜30% of N,N-bis(4-benzonitrile)methyl-amine. The aqueous was adjusted to pH>8 and extracted 2× with 9:1 dichloromethane:methanol. The combined extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to give 1.13 g of pure 4-(methylamino)benzonitrile as a colorless oil.