Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]2[C:11](=[O:21])[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:14][C:9]=2[O:8][CH:7]=1)=[O:5])C.[OH-].[Na+]>C1COCC1>[C:4]([C:6]1[C:10]2[C:11](=[O:21])[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:14][C:9]=2[O:8][CH:7]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1coc2c1C(=O)CC(c1ccccc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1coc2c1C(=O)CC(c1ccccc1)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.2 %

Procedure:
In THF (10 ml) was dissolved 3-ethoxycarbonyl-6-phenyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.71 g). To the solution was added 1N sodium hydroxide (5.0 ml), and the mixture was stirred at room temperature overnight (12 hours). The reaction solution was concentrated under reduced pressure, and to the residue was added potassium hydrogensulfate to make the mixture acidic. To the mixture was added ethyl acetate, and the mixture was subjected to extraction. The upper layer was washed with saturated brine, dried (anhydrous magnesium sulfate) and concentrated under reduced pressure, and the residue was washed with isopropylether to give 3-carboxy-6-phenyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.59 g).
Reaction SMILES: [NH2:1][N+:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[CH3:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:28]=1[CH:29]=O.[OH-].[K+]>O1CCOCC1.O>[CH3:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:28]=1[C:29]1[N:8]=[C:7]2[CH:6]=[CH:5][C:4]([C:9]([O:11][CH3:12])=[O:10])=[CH:3][N:2]2[N:1]=1
Reactant: Cc1cccc(C)c1C=O
Reactant: COC(=O)c1ccc(N)[n+](N)c1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3c(C)cccc3C)nn2c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
To a solution of methyl 1,6-diaminopyridin-1-ium-3-carboxylate; 2,4,6-trimethylbenzenesulfonate (6.0 g, 16.3 mmol) in 1,4-dioxane (50 mL) is added 2,6-dimethylbenzaldehyde (1.72 g, 13.00 mmol) and the reaction mixture is heated at 90° C. for 2 hours. The reaction mixture is cooled to room temperature, 1 N KOH solution (15 mL) is added, and the mixture is stirred overnight at room temperature. The reaction mixture is diluted with water (50 mL) and extracted with EtOAc (2×100 mL). The combined organic extracts are washed with water (100 mL) and saturated brine solution (100 mL), dried over sodium sulphate, filtered, and concentrated. The crude material is purified by silica gel chromatography (combiflash) eluting with 12% EtOAc in hexanes to give the title compound as a yellow liquid (0.35 g, 16%). LCMS m/z 282 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:33]1([CH2:39][CH2:40][S:41][CH:42]([C:46](O)=[O:47])[C:43](O)=[O:44])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[CH:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[O:17][C:43](=[O:44])[C:42]([S:41][CH2:40][CH2:39][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[C:46]([OH:47])[CH:16]=3)=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(=O)c1ccc(OCC2CCCCC2)cc1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(OCC3CCCCC3)cc2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-(cyclohexylmethoxy) acetophenone (2.50 g, 10.77 mmol), lithium bis(trimethylsilyl)amide (2.70 g, 16.16 mmol), chlorotrimethylsilane (2.05 mL,16.16 mmol), THF (107 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 130-132° C.; 1H NMR (400 MHz, DMSO-d6) δ1.15 (m, 5 H), 1.81 (m, 6 H), 2.77 (t, 2 H), 2.97 (t, 2 H), 3.85 (d, 2 H), 6.67 (s, 1 H), 7.21 (m, 5 H), 7.45 (q, 1 H), 7.74 (d, 2 H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[C:16]([CH3:23])[CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>CO.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.CCO>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:17]1[CH:18]=[CH:19][C:14]([F:13])=[CH:15][C:16]=1[CH3:23])=[N:3][N:4]=[CH:5]2
Reactant: Clc1ccc2c(Cl)nncc2c1
Reactant: Cc1cc(F)ccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: COCCOC
Product: Cc1cc(F)ccc1-c1nncc2cc(Cl)ccc12
Temperature: 80 °C

Procedure:
A mixture of 1,6-dichlorophthalazine (5.39 g, 27.1 mmol), 4-fluoro-2-methylphenylboronic acid (5.00 g, 32.5 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (0.950 g, 1.35 mmol), and sodium carbonate (8.61 g, 81.2 mmol) in a 2:1 mixture of DME and EtOH (40 mL) was heated at 80° C. in an oil bath for 18 h. The mixture was cooled to room temperature, diluted with MeOH and filtered through a pad of Celite. The filtrate was concentrated over silica gel and purified using column chromatography (0-25% EtOAc in hexanes) to provide the title compound as a yellow crystalline solid. MS (ESI, pos. ion) m/z: 272.8 (M+1).
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[O-]CC.[Na+].[N+](N[C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[CH:22][N:21]=1)([O-])=O>C(O)C>[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[CH:22][N:21]=1
Reactant: NCCSCc1cccs1
Reactant: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1cccnc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=c1[nH]c(NCCSCc2cccs2)ncc1Cc1cccnc1
Reaction time: 0.5 h

Procedure:
2-(2-Thienylmethylthio)ethylamine hydrochloride (2 g) in ethanol (25 ml) was added to a solution of sodium ethoxide (prepared from 0.218 g sodium) in ethanol and the mixture was stirred for 0.5 hour. 2-Nitroamino-5-(3-pyridylmethyl)-4-pyrimidone (2.34 g) was added and the mixture was boiled under reflux for 40 hours and evaporated to dryness. Pyridine (50 ml) was added to the residue and the mixture was boiled under reflux for 24 hours and evaporated. The residue was crystallised from ethanol/ethyl acetate and further purified by elution from a column of silica gel with ethyl acetate/methanol (5:1) and recrystallisation from 2-propanol to give 2-[2-(2-thienylmethylthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone m.p. 145°-148°.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@H:12]([C:14]2([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:13])(=O)=O)=CC=1.C(N(CC)CC)C.[C:28]1([SH:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C)C=O>[C:28]1([S:34][CH2:11][CH:12]([C:14]2([OH:19])[CH2:15][CH2:16][CH2:17][CH2:18]2)[CH3:13])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Sc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](C)C2(O)CCCC2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(CSc1ccccc1)C1(O)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4a (3.65 g, 11.9 mmol) and triethylamine (2.5 mL) in N,N-dimethylformamide (18 mL) was added thiophenol (1.8 mL) in one portion. The mixture was stirred at ambient temperature overnight. The mixture was poured into water, and extracted with diethyl ether. The combined organic layers were washed with sodium bicarbonate solution and brine, and dried over sodium sulfate. Filtration and concentration gave 3.26 g of an oily material, which was purified by column chromatography (silica gel 40 g, ethyl acetate in n-hexane, 2.5-20%) to give 2.06 g (73.3%) of 5a, as a pale yellow oil.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6]P(OCC)(OCC)=O)=[O:5].[Li+].CC([N-]C(C)C)C.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:31]([CH3:35])([CH3:34])[CH:32]=O)[CH:28]=[CH:29][CH:30]=1.[Cl-].[NH4+]>C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C.O1CCCC1>[CH2:2]([O:3][C:4](=[O:5])/[CH:6]=[CH:35]/[C:31]([C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=1)([CH3:32])[CH3:34])[CH3:1]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1cccc(C(C)(C)C=O)c1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/C(C)(C)c1cccc(OC)c1
Reaction time: 1 h
Yield: 95.8 %

Procedure:
33.6 g (114.3 mmol) of phosphonoacetic acid triethyl ester is introduced into 148 ml of tetrahydrofuran. At 0° C., 79.7 ml of a 2 M solution of LDA in THF/heptane/ethylbenzene is added in drops (one and one-half hours). After one hour of stirring, 24.3 g (136.34 mmol) of 2-(3-methoxyphenyl)-2-methylpropanal, dissolved in 130 ml of tetrahydrofuran, is added in drops at 0° C. After five days of stirring at room temperature, the reaction mixture is poured onto 250 ml of dilute ammonium chloride solution and extracted twice with 400 ml each of diethyl ether. The combined organic extracts are treated as usual, and the residue that is obtained is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 27.2 g (80.4%) of the desired compound is isolated.
Reaction SMILES: [N:1]1([C:7]2[O:8][C:9]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].Cl.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30]Cl)[CH:25]=1>CN(C)C=O>[N:1]1([C:7]2[O:8][C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:30][C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)=[CH:16][CH:15]=3)=[CH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=c1cc(-c2ccc(O)cc2)oc(N2CCOCC2)c1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2ccc(OCc3cccnc3)cc2)oc(N2CCOCC2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
2-Morpholinyl-6-(4-hydroxyphenyl)-4-pyrone, as prepared in Example 5, (273 mg, 1.0 mmole) was suspended in 6 ml dimethylformamide in a 25 ml one neck round bottom flask under nitrogen. The suspension was treated with sodium hydride suspension (192 mg, 4.0 mmole) and the reaction mixture was warmed to 60° C. for 40 minutes. The reaction was treated with 3-picolyl chloride hydrochloride (492 mg, 3.0 mmole) and the mixture was stirred 2 hours at 60° C. The reaction was poured into 50 ml 2N sodium hydroxide/ice and the mixture was extracted with 4×20 ml dichloromethane. The combined organics were washed with 4×25 ml 50% saturated sodium chloride and were dried over magnesium chloride. The dried organics were concentrated in vacuo to a yellow solid. The crude material was recrystallized twice from ethyl acetate to provide 229 mg (62%) of Compound 5 as a golden crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)[CH2:8][CH2:7]2.[N:23]1[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([N:9]2[CH2:8][CH2:7][C:6]3[C:11](=[C:2]([NH:1][CH2:29][C:26]4[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=4)[CH:3]=[CH:4][CH:5]=3)[C:10]2=[O:12])=[CH:14][CH:15]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: O=Cc1ccncc1
Reactant: CC(C)(C)c1ccc(N2CCc3cccc(N)c3C2=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)c1ccc(N2CCc3cccc(NCc4ccncc4)c3C2=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the amine (Step E) and CH2Cl2 (5 mL) was added 4-pyridinecarboxaldehyde and NaBH(OAc)3. The reaction was stirred at RT for 18 h. Purification by silica flash chromatography (25-75% EtOAc:hexane) gave the desired product as a light-yellow oil. MS m/e 386 (M+H)+. Calc'd for C25H27N3O-385.50.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]1([S:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:36]=[CH:35][O:34][C:33]=3[C:37]([OH:39])=[O:38])=[C:28](O)[C:27]=2[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:16]1([S:22]([CH2:25][C:26]2[C:27]([C:41]([O:43][C:44]([CH3:47])([CH3:45])[CH3:46])=[O:42])=[C:28]3[C:29]([C:32]4[CH:36]=[CH:35][O:34][C:33]=4[C:37](=[O:39])[O:38]3)=[CH:30][CH:31]=2)(=[O:23])=[O:24])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2C(=O)O)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc2c1oc(=O)c1occc12
Reaction time: 72 h
Yield: 137.5 %

Procedure:
N,N′-dicyclohexylcarbodiimide (0.014 g) was added to a solution of 3-[4-(benzenesulfonylmethyl)-3-tert-butoxycarbonyl-2-hydroxyphenyl]-furan-2-carboxylic acid (Intermediate 21, 0.028 g) and DMAP (0.0003 g) in DCM (5 mL) and the mixture was stirred for 72 hours. Water and DCM were added and the organic layer was separated, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 30-40% to give tert-butyl 7-(benzenesulfonylmethyl)-4-oxo-4H-furo[2,3-c]chromene-6-carboxylate (0.037 g) as a white solid.
Reaction SMILES: [CH:1]([C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][N:20]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:18].[N:20]1[CH:19]=[CH:24][C:23]([N:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=[C:9]2/[CH:1]=[CH:2]/[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[N:22][CH:21]=1
Reactant: Clc1ccncn1
Reactant: C(=Cc1nc2ccccc2[nH]1)c1ccccc1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: C(=C/c1nc2ccccc2n1-c1ccncn1)\c1ccccc1

Procedure:
Free base of the titled compound was prepared from 2-styryl-1H-benzimidazole and 4-Chloropyrimidine according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method B). The free base was treated with a 10% methanol solution of hydrogen chloride and concentrated to dryness. The residue was recrystallized from ethyl acetate/n-hexane to give the titled compound. MW: 234.81; mp: 191.0-192.0° C.; 1H-NMR (CDCl3) δ: 9.42 (1H, br.s), 9.15 (1H, br.s), 8.26 (1H, d, J=16.5 Hz), 8.08-7.94 (1H, m), 7.82-7.71 (4H, m), 7.58-7.33 (6H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([B:20]([O:22]C12CC(C1(C)C)CCC2(O)C)[OH:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Cl)(Cl)Cl>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([B:20]([OH:21])[OH:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(O)CCC2CC1(OB(O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C2(C)C
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1ccccc1)B(O)O)OCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of 2.93 g. (7 mmol) of (+)-pinanediol-1-benzyloxycarbonylamino-2-phenylethane boronate (IV) in 20 ml of CH2Cl2 at -78° C. is added 24 ml of boron trichloride. The mixture is kept at 20° C. for 2 hrs., then concentrated under vacuum and the residue is washed with ether, treated with methanol, concentrated and dissolved in water. The solution is then neutralized with Dowex 1-x8 ion exchange resin bicarbonate, concentrated and crystallized from THF/water to give (R)-1-benzyloxycarbonylamino-2-phenylethane boronic acid and its anhydride.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[CH2:5][CH:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36])(OCC)=O>O.C(#N)C>[C:27]1(=[O:36])[N:13]([CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][C:4]([O:3][CH3:2])=[O:14])[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: COC(=O)CC(N)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COC(=O)CC(c1ccccc1)N1C(=O)c2ccccc2C1=O
Reaction time: 1 h
Yield: 39.4 %

Procedure:
To a stirred solution of 3-amino-3-phenylpropionic acid methyl ester hydrochloride (0.50 g, 2.3 mmol) and sodium carbonate (0.25 g, 2.3 mmol) in 10 mL of water was added N-carboethoxyphthalimide (0.51 g, 2.3 mmol) in 7 mL of acetonitrile. The reaction progress was monitored by TLC (ethyl acetatethexane; 1:2) which showed that the reaction was complete in one hour. The reaction mixture was partially concentrated to remove the acetonitrile. The resulting slurry was filtered and the solid was washed with 20 mL of water. The solid was dried in vacuo (60° C., <1 mm) to afford 280 mg (39.4%) of methyl 3-phthalimido-3-phenylpropionate as a white powder: mp 75-76° C.; 1H NMR (DMSO-d6, 250 MHz) δ7.26-7.83 (m, 9H), 5.68-5.75 (m, 1H), 3.55 (S, 3H), 3.37-3.66 (m, 2H); 13C NMR (DMSO-d6) δ170.7, 167.6, 138.6, 134.7, 131.0, 128.6, 127.8, 126.9, 123.3, 51.6, 49.9, 35.3. Anal. Calcd for C18H15NO4: C, 69.89; H, 4.89; N, 4.53; Found: C, 69.69; H, 4.83; N, 4.49.
Reaction SMILES: [CH2:1]([CH:4]1[C:8](O)([CH3:9])[CH:7]=[CH:6][C:5]1=[O:11])[CH:2]=[CH2:3].[CH:12]([SH:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([C:4]1[C:5](=[O:11])[CH2:6][CH:7]([S:15][CH:12]([CH3:14])[CH3:13])[C:8]=1[CH3:9])[CH:2]=[CH2:3]
Reactant: CC(C)S
Reactant: C=CCC1C(=O)C=CC1(C)O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CCC1=C(C)C(SC(C)C)CC1=O
Reaction time: 5 h
Yield: 96.2 %

Procedure:
Into the same flask as used in Example 1, 2-allyl-3-hydroxy-3-methyl-4-cyclopentenone (15.2 g), isopropylmercaptan (20 g), triethylamine (1 g) and toluene (45 g) were charged, and the mixture was stirred under a nitrogen stream at a temperature of 40° to 70° C. for 5 hours. After completion of the reaction, the mixture was washed with an acid, an alkali and water in order. The organic layer was separated and concentrated to give 2-allyl-3-methyl-4-isopropylthio-2-cyclopentenone (20.2 g). Yield, 96.3%. The product was purified by silica gel chromatography using toluene-ethyl acetate (10:1 by volume). nD20 1.5196.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][C:16]([CH3:24])([CH3:23])[C:15]=3[CH:14]=[C:13]([C:25](=[O:27])[CH3:26])[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:28]([C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1)([OH:30])=[O:29].[OH-].[K+]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:20]3[C:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][C:16]([CH3:24])([CH3:23])[C:15]=3[CH:14]=[C:13]([C:25](=[O:27])/[CH:26]=[CH:35]/[C:34]3[CH:37]=[CH:38][C:31]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)[CH:12]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1cc(-c2ccc(C(C)(C)C)cc2)c2c(c1)C(C)(C)CCC2(C)C
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C)c1ccc(-c2cc(C(=O)/C=C/c3ccc(C(=O)O)cc3)cc3c2C(C)(C)CCC3(C)C)cc1
Yield: 61 %

Procedure:
In a manner similar to that of Example 2b, by reacting 710 mg (2.0 mmol) of 1-[4-(4-tert-butylphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]ethanone with 260 mg (1.8 mmol) of 4-carboxybenzaldehyde and 1.0 mL (8 mmol) of 47% KOH. The desired product is obtained in the form of white crystals (m=590 mg; yield=61%; m.p.=241° C.).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1>C(Cl)Cl>[C:5]([O:16][C:13]1[CH:14]=[CH:15][C:10]([Br:9])=[CH:11][CH:12]=1)(=[O:7])[CH3:6]
Reactant: Oc1ccc(Br)cc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)Oc1ccc(Br)cc1
Temperature: 0 °C
Yield: 84.8 %

Procedure:
Anhydrous aluminum chloride (84 g, 0.486 mol) was suspended in methylene chloride (1200 mL), and then acetyl chloride (49.2 g, 0.629 mol) was added while stirring and cooling on ice. The mixture was stirred for 20 minutes while cooling on ice and 4-bromophenol (98 g, 0.57 mol) was added. The reaction mixture was stirred at room temperature for 1 h, and then ice water was added and extraction was performed with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to yield 4-bromophenyl acetate (104 g, 85%). 1H-NMR (CDCl3): 2.28 (s, 3H), 6.98 (d, 2H), 7.48 (d, 2H).
Reaction SMILES: Br[C:2]1[C:3]([S:7]([N:10]2[C:14]([C:15]3[C:16]([F:21])=[N:17][CH:18]=[CH:19][CH:20]=3)=[C:13]([F:22])[C:12]([CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:11]2)(=[O:9])=[O:8])=[CH:4][S:5][CH:6]=1.[CH3:33][N:34](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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]>[C:33]([C:2]1[C:3]([S:7]([N:10]2[C:14]([C:15]3[C:16]([F:21])=[N:17][CH:18]=[CH:19][CH:20]=3)=[C:13]([F:22])[C:12]([CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:11]2)(=[O:9])=[O:8])=[CH:4][S:5][CH:6]=1)#[N:34]
Reactant: CN(C)C=O
Reactant: CN(Cc1cn(S(=O)(=O)c2cscc2Br)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [C-]#N
Solvent: CCOC(C)=O
Product: CN(Cc1cn(S(=O)(=O)c2cscc2C#N)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Temperature: 120 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of tert-butyl {[1-[(4-bromo-3-thienyl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (229 mg) in dimethylformamide (3 mL) was added zinc cyanide (74.6 mg) at room temperature, and the mixture was sufficiently deaerated under an argon atmosphere. Tetrakis(triphenylphosphine)palladium (0) (145 mg) was added and the mixture was further deaerated and stirred at 120° C. for 2 hr. The reaction mixture was diluted with ethyl acetate and filtrated. The filtrate was washed with water, and separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→3:2) to give the title compound as a pale-yellow oil (yield 181 mg, 88%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[N:4][CH:5]=[CH:6][N:7]=1.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:8]([CH3:13])([CH3:12])[C:9]([NH:14][CH:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: CC(C)(C(=O)O)c1nccnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)C(C)(C)c2nccnc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(3-chloropyrazin-2-yl)-2-methylpropanoic acid (2.0 g, 9.97 mmol), tert-butyl 4-amino-1-piperidinecarboxylate (2.396 g, 11.96 mmol), DIEA (2.61 ml, 14.95 mmol), and hatu (4.17 g, 10.97 mmol) in DMF (30 mL) was stirred at RT overnight. The reaction mixture was then heated to 55° C. for 4 h, cooled, and H2O was added, the light brown solid was collected, dried and used in the next step (3.1 g, 81%). MS (M+1): 383.1