Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:13][S:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][CH2:11][NH2:12].[CH2:24](Br)[CH2:25][OH:26].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][C:2]1[C:3]([CH2:13][S:14][C:15]2[NH:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:24][CH2:25][OH:26]
Reactant: Cc1c(SCCCN)ccnc1CSc1nc2ccccc2[nH]1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(SCCCNCCO)ccnc1CSc1nc2ccccc2[nH]1
Reaction time: 2 h

Procedure:
2-((3-Methyl-4-(3-aminopropylthio)-2-pyridyl)methylthio)-1H-benzimidazole (2.0 g) was dissolved in dimethylformamide (20 ml) and thereto were added ethylene bromohydrin (0.83 g) and potassium carbonate (1.25 g). The mixture was stirred at 60°-70° C. for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled away under reduced pressure. The residue was subjected to column chromatography and extracted with chloroform-methanol to give 2-((3-methyl-4-(3-(2-hydroxyethylamino)propylthio)-2-pyridyl)methylthio)-1H-benzimidazole.
Reaction SMILES: [O:1]1[CH2:24][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:23])[NH:10]2.[NH:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:38])[O:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:27][CH2:26]1>C(O)(C)C>[C:17]1([CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:24][N:25]3[CH2:26][CH2:27][CH:28]([NH:31][C:32]([O:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:38])[CH2:29][CH2:30]3)=[C:6]3[C:11]=2[NH:10][C:9](=[O:23])[CH2:8][CH2:7]3)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)COC(=O)NC1CCNCC1
Reactant: O=C1CCc2c(OCC3CO3)ccc(OCc3ccccc3)c2N1
Solvent: CC(C)O
Product: CC(C)COC(=O)NC1CCN(CC(O)COc2ccc(OCc3ccccc3)c3c2CCC(=O)N3)CC1
Yield: 76.2 %

Procedure:
5-(2,3-epoxypropoxy)-8-phenylmethoxy-3,4-dihydrocarbostyril (130 mg) was dissolved in isopropanol (10 mL) and isobutyl 4-piperidylcarbamate (80 mg) was added. The mixture was then heated under reflux for 20 hours with stirring. After completion of the reaction, the isopropanol was evaporated under reduced pressure. The residue was then purified by flash chromatography (AcOEt/MeOH-99:1) to yield 160 mg of the title compound, 8-phenylmethoxy-3,4-dihydro-5-[2-hydroxy-3-(4-(isobutoxycarbonylamino)-1-piperidyl)propoxy]carbostyril.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8](Br)[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2].[N+:13]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14]>C1(C)C=CC=CC=1.C1(P([Pd-4](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)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:13]([O-:15])=[O:14])[CH:21]=2)[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cncc(Br)c1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cncc(-c2cccc([N+](=O)[O-])c2)c1

Procedure:
n.m.r. δ values include 1.5 (t, 3 H), 4.5 (q, 2 H), 7.75 (t, 1 H), 8.0 (d, 1 H), 8.3 (d, 1 H), 8.6-8.5 (m, 2 H), 9.0 (s, 1 H), 9.3 (s, 1 H); from 3-bromo-5-pyridine carboxylic acid ethyl ester (985 mg) in toluene (15 mL), tetrakis(triphenylphosphino)palladium(0) (161 mg) and 3-nitrophenylboronic acid (860 mg).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]1([CH3:18])[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[Ca+2]>C(C(C)=O)C>[Cl:1][CH2:2][C:3]([N:15]1[CH2:16][CH2:17][N:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH3:18])[CH2:13][CH2:14]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCC(C)=O
Product: Cc1ccccc1N1CCN(C(=O)CCl)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
Chloroacetyl chloride (4.5 ml, 56.6 mmol) is added dropwise to a solution of 1-o-tolylpiperazine (8.31 [lacuna], 47.2 mmol) and calcium carbonate (14.2 g, 142 mmol) in methyl ethyl ketone (100 ml) cooled to 0° C. The reaction mixture is stirred at this temperature for 1 h 30 and is then filtered through Celite. The Celite is rinsed several times with ethyl acetate and 3M sodium hydroxide solution. The two phases of the filtrate are then separated and the organic phase is dried over magnesium sulfate, filtered and concentrated to give the expected product in the form of a brown solid.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:15]2[CH2:18][C@@H:17]([OH:19])[C@@H:16]2[CH3:20])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[S:27](Cl)([CH3:30])(=[O:29])=[O:28]>ClCCl>[C:21]1([CH:14]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:15]2[CH2:18][C@@H:17]([O:19][S:27]([CH3:30])(=[O:29])=[O:28])[C@@H:16]2[CH3:20])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1[C@H](O)CN1C(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1[C@H](OS(C)(=O)=O)CN1C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 95.9 %

Procedure:
50 g (0.495 mol) of triethylamine are added to a solution of 77.33 g (0.329 mol) of trans-1-diphenylmethyl-3-hydroxy-2-methylazetidine in 600 ml of dichloromethane and the mixture is cooled to 0° C. The temperature is maintained, a solution of 50 g (0.437 mol) of mesyl chloride is added dropwise and the mixture is left for 24 hours at room temperature. The resulting solution is washed twice with water (300 ml), dried with anhydrous sodium sulphate and evaporated, and an oil is obtained which, when crystallized with petroleum ether, gives 104.6 g (96%) of trans-1-diphenylmethyl-2-methyl-3-methylsulphonyloxyazetidine, melting point 68°-71° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[C:13]([C:21]([O-:23])=[O:22])=[N:14][C:15]([N:18]([CH3:20])[CH3:19])=[CH:16][CH:17]=2)[N:4]=1.[K+].[CH2:25]([O:27][C:28]([O:30][CH:31](Cl)[CH3:32])=[O:29])[CH3:26].O>CN(C)C=O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[C:13]([C:21]([O:23][CH:25]([O:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:26])=[O:22])=[N:14][C:15]([N:18]([CH3:19])[CH3:20])=[CH:16][CH:17]=2)[N:6]=1
Reactant: COc1cc(OC)nc(Oc2ccc(N(C)C)nc2C(=O)[O-])n1
Reactant: CCOC(=O)OC(C)Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)OC(C)OC(=O)c1nc(N(C)C)ccc1Oc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2.0 g (5.6 mmol) of potassium 3-(4,6-dimethoxypyrimidin-2-yl)oxy-6-dimethylaminopicolinate and 0.8 g (5.7 mmol) of 1-(ethoxycarbonyloxy) ethylchloride were suspended in 5 ml of dimethylformamide, and were stirred at room temperature for 6 hours. The reaction mixture was poured into water, and was extracted with ethyl acetate twice. The organic layer was then washed with water and dried, and the solvent was distilled off to obtain a viscous product which was then column-purified to obtain an aimed compound.
Reaction SMILES: C([N:3](CC)CC)C.[CH2:8]([O:10][C:11](=[O:28])[C:12]([CH:14](N)[C:15]1[S:19][C:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:17][CH:16]=1)=[CH2:13])[CH3:9].[C:29]([OH:32])(=[S:31])[CH3:30]>>[CH2:8]([O:10][C:11](=[O:28])[CH:12]([CH2:13][S:31][C:29](=[O:32])[CH3:30])[CH2:14][C:15]1[S:19][C:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:17][C:16]=1[NH2:3])[CH3:9]
Reactant: CC(O)=S
Reactant: C=C(C(=O)OCC)C(N)c1cnc(C(=O)OC(C)(C)C)s1
Reactant: CCN(CC)CC
Product: CCOC(=O)C(CSC(C)=O)Cc1sc(C(=O)OC(C)(C)C)nc1N
Temperature: 25 °C
Reaction time: 48 h
Yield: 51.6 %

Procedure:
Triethyl amine (32 μl; 0.23 mmol) was added to a solution of 2-(2-tert-butoxycarbonyl-amino-thiazol-5-ylmethyl)-acrylic acid ethyl ester (67 mg; 0.21 mmol) in thioacetic acid (0.4 mL) at 0° C. The reaction mixture was stirred at room temperature for 48 hours, and then poured onto ice-water. The aqueous layer was extracted with CH2Cl2. The combined organic phases were washed with saturated NaHCO3, dried and concentrated to yield 190 mg of the crude product. The crude product was purified by flash chromatography (Heptane/EtOAc: 1:0→68:32) to yield 2-acetylsulfanylmethyl-3-(2-tert-butoxycarbonyl-amino-thiazol-5-yl)-propionic acid ethyl ester (43 mg, 51.6%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([O:36]C)=[O:35])=[CH:30][CH:29]=2)[C:7](=[O:27])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:4].CO.[OH-].[Na+].O>C(OCC)(=O)C>[C:34]([C:31]1[CH:32]=[CH:33][C:28]([N:6]2[C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:14]([C:15]3[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=3)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:27])=[CH:29][CH:30]=1)([OH:36])=[O:35]
Reactant: COC(=O)c1ccc(-n2c(C(=O)OC)c(-c3cc(OC)c(OC)c(OC)c3)c3ccccc3c2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2ccccc2c(=O)n1-c1ccc(C(=O)O)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 16.7 %

Procedure:
To the compound obtained in Example 20 (1.51 g) are added methanol (150 ml) and 1M aqueous sodium hydroxide solution (3 ml), and the mixture is stirred at 60° C. overnight. To the reaction solution is further added 1M aqueous sodium hydroxide solution (1.5 ml) which is divided to two portions, and the mixture is refluxed for 12 hours. The reaction mixture is allowed to stand for cooling, and thereto are added water and ethyl acetate. The aqueous layer is separated, and acidified with hydrochloric acid, and further extracted with ethyl acetate. The ethyl acetate layers are combined, washed, dried, and concentrated under reduced pressure. The residue is crystallized from diethyl ether to give 2-(4-carboxyphenyl)-3-methoxycarbonyl-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone (245 mg) as listed in Table 4.
Reaction SMILES: I[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[CH2:16][CH2:17][OH:18].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>ClCCl.FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][O:18][CH2:17][CH2:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[F:8])[CH3:7]
Reactant: CCOC(=O)CI
Reactant: OCCc1cc(F)ccc1F
Agent: [Ag+]
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)COCCc1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 54.2 %

Procedure:
Ethyl iodoacetate (340 □l, 2.9 mmol) was added to an ice cold solution of 2-(2,5-difluoro-phenyl)-ethanol (500 mg, 2.4 mmol), silver trifluoromethanesulfonate (685 mg, 2.7 mmol) and 2,6-di-tert-butylpyridin (820 □l, 3.6 mmol) in dichloromethane (5 ml). The reaction mixture was stirred at ambient temperature for 14 h, diluted with dichloromethane and filtered over speedex. Ice water/0.1 N aqueous HCl 1/1 was added to the filtrate and the filtrate was extracted two times with dichloromethane. The combined extracts were washed with aqueous NaHCO3 solution and brine and dried over sodium sulfate. Removal of the solvent under reduced pressure left a colorless oil which was purified by column chromatography (silica gel, isopropyl acetate/heptane) to give the title compound (320 mg, 1.3 mmol; 54%) as colorless oil. MS: m/e=245.0 [M+H+].
Reaction SMILES: Br[C:2]12[CH2:12][C:6]3([CH3:13])[CH2:7][C:8]([CH3:11])([CH2:10][C:4]([C:14]45[CH2:24][C:18]6([CH3:25])[CH2:19][C:20]([CH3:23])([CH2:22][C:16](Br)([CH2:17]6)[CH2:15]4)[CH2:21]5)([CH2:5]3)[CH2:3]1)[CH2:9]2.[C:27]1([OH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O>[OH:33][C:27]1[CH:32]=[CH:31][C:30]([C:2]23[CH2:12][C:6]4([CH3:13])[CH2:7][C:8]([CH3:11])([CH2:10][C:4]([C:14]56[CH2:24][C:18]7([CH3:25])[CH2:19][C:20]([CH3:23])([CH2:22][C:16]([C:30]8[CH:31]=[CH:32][C:27]([OH:33])=[CH:28][CH:29]=8)([CH2:17]7)[CH2:15]5)[CH2:21]6)([CH2:5]4)[CH2:3]2)[CH2:9]3)=[CH:29][CH:28]=1
Reactant: CC12CC3(C)CC(Br)(C1)CC(C14CC5(C)CC(C)(CC(Br)(C5)C1)C4)(C2)C3
Reactant: Oc1ccccc1
Solvent: O
Product: CC12CC3(C)CC(c4ccc(O)cc4)(C1)CC(C14CC5(C)CC(C)(CC(c6ccc(O)cc6)(C5)C1)C4)(C2)C3
Temperature: 155 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
In a 5 L recovery flask, 48.4 g of 3,3′-dibromo-5,5′,7,7′-tetramethyl-1,1′-biadamantane (100 mmol), 688 g of phenol (7.3 mol) and a stirrer were charged and agitated at 155° C. for 30 minutes under nitrogen flow. After cooling the mixture to room temperature, 4.3 L of ion-exchange water was added thereto and agitated at 80° C. for ten minutes. Solid precipitate was collected by filtration, then washed with 7 L of ion-exchange water and dried under reduced pressure, thus obtaining 50.6 g of 3,3′-bis(4-hydroxyphenyl)-5,5′,7,7′-tetramethyl-1,1′-biadamantane (99.0 mmol; yield: 99.0%).
Reaction SMILES: [O:1]=[C:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH:11]=[CH2:12]>O.C(O)(C)(C)C>[C:2]([C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])([CH2:12][CH2:11][C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:12][CH2:11][C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:1])[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: C=CC(=O)OC(C)(C)C
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)C(CCC(=O)OC(C)(C)C)(CCC(=O)OC(C)(C)C)C(C)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of ethyl 3-oxobutanoate (45 g, 345 mmol) and Triton-B (40%, weight % solution in water, 1.08 mg, 6.90 mmol) in tert-BuOH (54 mL) was added tert-butyl acrylate (100.72 g, 691 mmol) dropwise over a period of 30 min under N2 atmosphere. The solution was stirred at room temperature for 24 h. The reaction mixture was partitioned between water (200 mL) and EtOAc (200 mL). The aqueous layer washed with EtOAc (2×50 mL). The combined organic layers were washed with water (200 mL), brine (200 mL), dried over Na2SO4 and concentrated under reduced pressure to provide compound D28-1 (140 g, quant) as a pale yellow oil. 1H NMR (CDCl3, 400 MHz): δ 4.20 (q, J=7.2 Hz 2H), 2.24-2.09 (m, 8H), 1.58 (s, 3H), 1.43 (s, 18H), 1.31 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O.[C:18]1([P:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1C=CC=CC=1.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br-:10].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][P+:24]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1c(Cl)cccc1Cl
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: Clc1cccc(Cl)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Yield: 98.9 %

Procedure:
A mixture of 2,6-dichlorotoluene (20.1 g, 0.125 mol), N-bromosuccinimide (24.6 g, 0.138 mol) and 2,2′-azobisisobutyronitrile (0.41 g, 2.50 mmol) in dry benzene (300 mL) under N2 was stirred at reflux for 6 h with continuous irradiation from a 100W lamp. The resulting reaction mixture was concentrated under vacuum (to 50 mL), cooled and filtered, washing with dry benzene. The filtrate (containing the crude benzyl bromide) was treated directly with triphenylphosphine (49.3 g, 0.188 mol), stirring at reflux for 17 h. After cooling, the precipitate was collected by filtration, washing thoroughly with dry benzene, then pentane, and dried under vacuum at 50° C. to give the phosphonium salt (511) as a cream powder (62.1 g, 99%), mp (benzene) 247–250° C. 1H NMR (CDCl3) δ 7.76 (m, 9H), 7.64 (m, 6H), 7.18 (s, 3H), 5.50 (d, J=14.3 Hz, 2H). Found: C, 60.03; H, 3.76. C25H2,BRCl2P requires C, 59.79; H, 4.01.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:40])[C:8](=[O:9])[N:7]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[C:6]2[CH:16]=[C:17]([C:21]([N:23]([CH:37]([CH3:39])[CH3:38])[C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]3)=[O:22])[C:18]([CH3:20])=[CH:19][C:5]=2[O:4]1.[CH:41]([N:44]([CH:47]([CH3:49])C)[CH2:45]C)([CH3:43])C.N1CCCC1.[OH2:55]>O1CCCC1>[CH:37]([N:23]([C:21]([C:17]1[C:18]([CH3:20])=[CH:19][C:5]2[O:4][C:3]([CH3:40])([CH2:2][O:1][C:45]([N:44]3[CH2:41][CH2:43][CH2:49][CH2:47]3)=[O:55])[C:8](=[O:9])[N:7]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[C:6]=2[CH:16]=1)=[O:22])[C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[CH2:25]1)([CH3:38])[CH3:39]
Reactant: CCN(C(C)C)C(C)C
Reactant: COCCCCN1C(=O)C(C)(CO)Oc2cc(C)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Reactant: O
Solvent: C1CCNC1
Solvent: C1CCOC1
Product: COCCCCN1C(=O)C(C)(COC(=O)N2CCCC2)Oc2cc(C)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (3R)-3-[{[2-(hydroxymethyl)-4-(4-methoxybutyl)-2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (60 mg), N,N′-carbonyldiimidazole (20 mg) in tetrahydrofuran (1 ml) was added diisopropylethylamine (95 μl), and the mixture was stirred at room temperature for one hour. To the reaction mixture was added pyrrolidine (10 μl), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (59 mg).
Reaction SMILES: [N:1]1([CH:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CC#N)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-:25].[Na+].[CH3:27][CH2:28][OH:29]>O>[N:1]1([CH:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:27][C:28]([OH:25])=[O:29])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: [OH-]
Reactant: CCCCCC(CCCCCCCCCCCC#N)n1ccnc1
Reactant: CCO
Agent: [Na+]
Solvent: O
Product: CCCCCC(CCCCCCCCCCCC(=O)O)n1ccnc1
Yield: 81 %

Procedure:
13-(1H-imidazol-1-yl)octadecanenitrile (550 mg, 1.66 mmol) was dissolved in EtOH (10 ml) and water (5 ml), to which was then added NaOH (332 mg, 8.30 mmol) and the mixture refluxed for 16 hr. The reaction mixture was then concentrated and acidified with 1N HCl, extracted with DCM, washed with brine solution, dried over MgSO4 and concentrated. The crude product was purified by silica gel column (4% MeOH in DCM) to give 13-(1H-imidazol-1-yl)octadecanoic acid as a thick oil (470 mg, 81%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:6]=[CH:7][C:8]=1[CH:9]1[C:14](=[O:15])[CH:13]([CH3:16])[O:12][C:11]([CH3:18])([CH3:17])[C:10]1=[O:19])[CH3:2].C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35]>ClCCl.O>[CH2:1]([C:3]1[CH:4]=[C:5]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[C:14](=[O:15])[CH:13]([CH3:16])[O:12][C:11]([CH3:18])([CH3:17])[C:10]=1[O:19][C:34](=[O:36])[CH3:35])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCc1cc(-c2ccc(F)cc2)ccc1C1C(=O)C(C)OC(C)(C)C1=O
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cc(-c2ccc(F)cc2)ccc1C1=C(OC(C)=O)C(C)(C)OC(C)C1=O
Temperature: 0 °C
Reaction time: 5 h
Yield: 61.3 %

Procedure:
To a solution of 4-(3-ethyl-4′-fluorobiphenyl-4-yl)-2,2,6-trimethylpyran-3,5-dione (0.125 g, 0.35 mmol) in dichloromethane (5 ml) is added triethylamine (0.2 ml, 1.38 mmol) and the reaction mixture is cooled to 0° C. Acetyl chloride (0.22 g, 2.8 mmol) is added slowly at 0° C. and the mixture is stirred at 0° C. for 5 hours. The reaction mixture is diluted with water and extracted with dichloromethane (3×25 ml). The organic extracts are combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to afford acetic acid 4-(3-ethyl-4′-fluorobiphenyl-4-yl)-2,2,6-trimethyl-5-oxo-5,6-dihydro-2H-pyran-3yl ester (0.085 g) as a white solid.
Reaction SMILES: CN(C=O)C.[CH3:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1F)=[O:8].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.O>C(OCC)(=O)C>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:7](=[O:8])[CH3:6])=[C:10]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:11]=1
Reactant: CC(=O)c1ccc(F)cc1F
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(F)cc1N1CCOCC1
Yield: 44.9 %

Procedure:
A DMF (5.0 mL) solution of 2,4-difluoroacetophenone (1.0 g) and morpholine (558 mg) was agitated at 110° C. for 6 hours and 30 minutes. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent:heptane-ethyl acetate system), and 642 mg of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=O>C(O)C.N1CCCCC1>[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[NH:12][C:11]1=[O:17]
Reactant: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Reactant: Cc1cc(C)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C)c(C=C2C(=O)Nc3cccc(-c4cccc(Br)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.2 %

Procedure:
To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (32 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (71 mg, 71%).
Reaction SMILES: O/[CH:2]=[C:3]1\[C:4](=[O:13])[NH:5][C:6]2[C:11]\1=[C:10](C)[CH:9]=[CH:8][CH:7]=2.O/C=C1\C(=O)NC2C\1=CC=CC=2.[CH3:26][N:27]([CH3:45])[CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:44]=[CH:43][C:35]([CH2:36][C:37]2[CH:38]=[C:39]([NH2:42])[NH:40][N:41]=2)=[CH:34][CH:33]=1.NC1C=CNN=1>O1CCCC1>[CH3:45][N:27]([CH3:26])[CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:44]=[CH:43][C:35]([CH2:36][C:37]2[CH:38]=[C:39]([NH:42][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:13])[NH:40][N:41]=2)=[CH:34][CH:33]=1
Reactant: CN(C)CCCOc1ccc(Cc2cc(N)[nH]n2)cc1
Reactant: Cc1cccc2c1/C(=C/O)C(=O)N2
Agent: Nc1cc[nH]n1
Agent: O=C1Nc2ccccc2/C1=C/O
Solvent: C1CCOC1
Product: CN(C)CCCOc1ccc(Cc2cc(NC=C3C(=O)Nc4ccccc43)[nH]n2)cc1

Procedure:
The named compound is prepared by substituting E & Z-3-[(hydroxy)-methylene]-4-methyl-1,3-dihydro-indol-2-one for E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one and 5-[4-(3-dimethylamino-propoxy)-benzyl]-2H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-4-methyl-1,3-dihydro-indol-2-one (0.0351 gms.) is reacted with 0.0881 gms. of 5-[4-(3-dimethylamino-propoxy)-benzyl]-2H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (2.0 mL). Recrystallization from a mixture of ethyl acetate and hexanes affords the named compound.