Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:7]1[O:11]C=[N:9][C:8]=1C(OCC)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[ClH:17]>>[ClH:17].[O:11]=[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:8][NH2:9]
Reactant: CCCCCCc1ocnc1C(=O)OCC
Agent: Cl
Product: CCCCCCC(=O)CN
Yield: 40 %

Procedure:
In a 100 ml-three-necked flask, 2.26 g (20,0 mM) of ethylisocyanoacetate and 27 ml of tetrahydrofuran were placed. To the mixture, 2.99 ml (20.0 mM) of 1,8-diazobicyclo[5,4,0]-7-undecene (DBU) was added on an ice water bath under stirring. To the mixture, a solution of 4.84 g (20.0 mM) of heptanoic anhydride in 7 ml of tetrahydrofuran was added dropwise on the ice water bath under stirring, followed by stirring for 4.5 hours at room temperature. The reaction mixture was further left standing for 2 days at room temperature. The resultant reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate and further dried under reduced pressure. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=100/1) to provide 4.28 g of ethyl 5-hexyloxazole-4-carboxylate (Yield: 95.1%). Then, 2.10 g (9.32 mM) of ethyl 5-hexyloxazole-4-carboxylate and 28.4 ml of 6N-hydrochloric acid were placed in a 100 ml-round-bottomed flask, followed by heat-refluxing for 5 hours under stirring. After the reaction, the reaction mixture was washed two times with ethyl acetate. The water layer was dried under reduced pressure. The residue was recrystallized from a mixture solvent of methanol-isopropyl ether to obtain 0.67 g of 2-oxooctylamine hydrochloride (Yield: 40.0%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[C:7]3[C:14](=O)[NH:13][CH2:12][CH2:11][N:8]3[C:9]=2[CH:10]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C([O-])(=O)C(C(C([O-])=O)O)O.[K+].[K+]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[C:7]3[CH2:14][NH:13][CH2:12][CH2:11][N:8]3[C:9]=2[CH:10]=1
Reactant: O=C1NCCn2c1cc1ccc(F)cc12
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Fc1ccc2cc3n(c2c1)CCNC3
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A 0.47 g portion of the compound obtained in Example 8- (5) was suspended in 50 ml of tetrahydrofuran, mixed with 0.2 g of lithium aluminum hydride and then stirred at 60° C. for 8 hours. The reaction solution was cooled to 0° C., mixed carefully with saturated potassium tartarate aqueous solution to terminate the reaction and then extracted with chloroform. The organic layer was washed with saturated brine and dried with anhydrous sodium sulfate, and then the solvent was evaporated to obtain 0.46 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:30][C:31](=[O:33])[CH3:32])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:16]=[C:17]([CH:18]=[CH2:19])[C:10]=12.B.[OH-:35].[Na+].OO>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:30][C:31](=[O:33])[CH3:32])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:21])=[O:22])[CH:16]=[C:17]([CH2:18][CH2:19][OH:35])[C:10]=12
Reactant: [OH-]
Reactant: C=Cc1cn(S(=O)(=O)c2ccc(C)cc2)c2nccc(Oc3ccc(NC(C)=O)cc3F)c12
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Oc2ccnc3c2c(CCO)cn3S(=O)(=O)c2ccc(C)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At 0° C., 890 mg (1.91 mmol) of N-[3-fluoro-4-({1-[(4-methylphenyl)sulfonyl]-3-vinyl-1H-pyrrolo[2,3-b]-pyridin-4-yl}oxy)phenyl]acetamide are initially charged in 28 ml of THF. 7.65 ml (7.65 mmol) of a 1M solution of borane in THF are added dropwise, and the mixture is stirred at RT for one hour. 14 ml of 1N aqueous sodium hydroxide solution and 14 ml of 30% strength hydrogen peroxide solution are then added carefully to the reaction mixture. The mixture is heated at 60° C. for one hour. For work-up, the reaction solution is partitioned between ethyl acetate and sodium bicarbonate solution. The aqueous phase is extracted with ethyl acetate and the combined organic phases are dried over sodium sulfate. The solvent is removed under reduced pressure. The product is purified by chromatography-on silica gel (mobile phase: dichloromethane/acetone 20:1 to 6.5:1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:13]([C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=O.N1CCCCC1>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:12])[CH:11]=[CH:13][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: COC(=O)c1ccc(C=CC(=O)c2ccc([N+](=O)[O-])cc2)cc1
Yield: 77.2 %

Procedure:
To a mixture of 16.5 g of 1-(4-nitrophenyl)ethanone, 16.4 g of methyl 4-formylbenzoate and 100 mL of ethanol was added dropwise 4.0 mL of piperidine at room temperature, followed by heating under reflux for 8 hours. The precipitate was collected by filtration, thereby obtaining 24.6 g of a crude product. The crude product was suspended in 100 mL of ethanol, followed by heating under reflux for 6 hours. The precipitate was collected by filtration, thereby obtaining 24.0 g of methyl 4-[3-(4-nitrophenyl)-3-oxoprop-1-en-1-yl]benzoate.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:11]([C:14]2[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:3]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:21]1([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:3]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(Br)c3ccccc32)cc1
Reactant: C1CNCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(N3CCNCC3)c3ccccc32)cc1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
To a solution of 3-bromo-1-tosylindole (105 mg, 0.3 mmol) and anhydrous piperazine (258 mg, 3.0 mmol) in toluene (4.5 mL) was added palladium acetate (13.4 mg, 0.055 mmol), BINAP (40.3 mg, 0.065 mmol), and cesium carbonate (318 mmol, 0.9 mmol), and the resulting mixture was refluxed for 6 hours. The reaction solution was cooled to room temperature and the precipitated salt was separated by filtration, and the filtrate was concentrated to afford a crude product. The crude product was purified by column chromatography on a silica gel (eluent; ammonia-saturated chloroform) to afford the title compound (69 mg, yield: 65%) as a colorless viscous oil.
Reaction SMILES: [CH3:1][C:2]1[NH:16][CH2:15][CH2:14][C:4]2=[C:5]3[C:10](=[N:11][C:3]=12)[CH:9]=[CH:8][C:7]([O:12][CH3:13])=[CH:6]3.[C:17]1([N:23]=[C:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCOCC>[CH2:1]=[C:2]1[C:3]2[NH:11][C:10]3[C:5](=[CH:6][C:7]([O:12][CH3:13])=[CH:8][CH:9]=3)[C:4]=2[CH2:14][CH2:15][N:16]1[C:24](=[O:25])[NH:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccc2c(c1)=C1CCNC(C)=C1N=2
Reactant: O=C=Nc1ccccc1
Solvent: CCOCC
Product: C=C1c2[nH]c3ccc(OC)cc3c2CCN1C(=O)Nc1ccccc1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
To a solution of 10-methoxyharmalan in anhydrous ether is added phenyl isocyanate. The mixture is stirred for 1 h 30 and then heated at 45° C. for 30 min. The 1-methylene-2-(N-plienyl)carbamoyl-6-methoxy-1,2,3,4-tetrahydro-β-carboline is recovered by filtration and then washed with ether.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1.CC(C[AlH]CC(C)C)C.[NH4+].[Cl-]>C(Cl)Cl>[C:14]1([S:11]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([CH2:3][OH:2])=[CH:9][CH:8]=2)(=[O:12])=[O:13])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(CS(=O)(=O)c2ccccc2)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: O=S(=O)(Cc1ccc(CO)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of the compound (2.3 g, 7.92 mmol) from the process (10-2) in CH2Cl2 (50 mL) at −78° C. was added slowly DIBAL-H (1 M in toluene, 16.6 mL, 16.63 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0° C., and to it an aqueous NH4Cl solution (250 mL) was added slowly. The mixture was extracted with 10% MeOH in CH2Cl2 (1.5 L), and the organic layer was dried (MgSO4) and evaporated under reduced pressure. The crude product was crystallized from MeOH/CH2Cl2/ether to afford the titled compound (1.66 g, 80%) as white solid.
Reaction SMILES: [CH3:1][C:2](=[O:21])[CH:3]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[CH:22]1[CH2:26][CH:25]=[CH:24][CH:23]=1>C(O[Ti](Cl)(Cl)OC(C)C)(C)C.ClCCl>[CH2:5]([CH:4]1[CH:24]2[CH2:25][CH:26]([CH:22]=[CH:23]2)[CH:3]1[C:2](=[O:21])[CH3:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCCCCCC=CC(C)=O
Reactant: C1=CCC=C1
Agent: CC(C)O[Ti](Cl)(Cl)OC(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCC1C2C=CC(C2)C1C(C)=O
Yield: 82.9 %

Procedure:
In a nitrogen-filled glovebox, a 50 mL round bottom flask at room temperature was charged with 3-eicosen-2-one (1.216 g, 4.12 mmol), cyclopentadiene (954 mg, 10.3 mmol), dichloromethane (15 mL), and a magnetic stirbar. The mixture was stirred, and diisopropoxytitanium(IV) chloride (48 mg, 0.2 mmol) was added as a solid. The flask was capped and allowed to stir for 36 h at room temperature. The flask was removed from the glovebox and water (2 mL) was added and the mixture was allowed to stir for 30 minutes. Stirring was stopped and the resulting biphasic mixture was allowed to stand and separate. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (DCM) (3×10 mL). The combined organic solution was dried with MgSO4, filtered, and concentrated under a constant flow of nitrogen. The residue was further concentrated in a vacuum oven for 3 days at 60° C. yielding a colorless oil (1.231 g, 83%). 1H NMR (400 MHz, C6D6) δ 6.1 (dd, 1H, J=5.7, 3.1), 5.8 (dd, 1H, J=5.7, 2.8), 2.8 (m, 1H), 2.4 (m, 1H), 2.0 (dd, 1H, J=4.4, 3.5), 1.9 (m, 1H), 1.7 (bs, 2H), 1.4-1.2 (m, 30H), 0.9 (t, 3H, J=13.7).
Reaction SMILES: OC1C=CC=CC=1C1N=C(N[C@H]2CCN(C(OC(C)(C)C)=O)C2)C2C(=CC=C(C#CCO)C=2)N=1.[CH3:35][O:36][CH2:37]/[CH:38]=[CH:39]/[C:40]1[CH:49]=[C:48]2[C:43]([C:44]([NH:57][C@H:58]3[CH2:62][CH2:61][NH:60][CH2:59]3)=[N:45][C:46]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=3[OH:56])=[N:47]2)=[CH:42][CH:41]=1>>[CH3:35][O:36][CH2:37][CH2:38][CH2:39][C:40]1[CH:49]=[C:48]2[C:43]([C:44]([NH:57][C@H:58]3[CH2:62][CH2:61][NH:60][CH2:59]3)=[N:45][C:46]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=3[OH:56])=[N:47]2)=[CH:42][CH:41]=1
Reactant: COC/C=C/c1ccc2c(N[C@H]3CCNC3)nc(-c3ccccc3O)nc2c1
Agent: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3ccccc3O)nc3ccc(C#CCO)cc23)C1
Product: COCCCc1ccc2c(N[C@H]3CCNC3)nc(-c3ccccc3O)nc2c1

Procedure:
The title compound was synthesised using methods analogous to those described in Synthesis 60 and 85-A, with (S)-tert-butyl 3-(2-(2-hydroxyphenyl)-6-(3-hydroxyprop-1-ynyl)quinazolin-4-ylamino)pyrrolidine-1-carboxylate replaced with (S,E)-2-(7-(3-methoxyprop-1-enyl)-4-(pyrrolidin-3-ylamino)quinazolin-2-yl)phenol in Synthesis 60.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=O)=[C:4]([CH3:29])[CH:3]=1.Cl.[NH2:31][OH:32].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)[CH2:9]/[C:10](=[N:31]\[OH:32])/[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[C:4]([CH3:29])[CH:3]=1
Reactant: NO
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1

Procedure:
In analogy to example 1, step 2, from 4-[1-(4-chloro-2-methyl-phenyl)-3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-propyl]-benzoic acid (example 332, step 2) and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a light yellow oil, MS (ESI+): m/z=425.1 ([M+H]+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]=[C:13]=[S:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[N:23]=[CH:22][CH:21]=[C:20]2[O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][C:31]=1[CH3:37].C1(C)C=CC=CC=1>C(O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[N:23]=[CH:22][CH:21]=[C:20]2[O:29][C:30]1[CH:36]=[CH:35][C:33]([NH:34][C:13]([NH:12][C:10](=[O:11])[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[S:14])=[CH:32][C:31]=1[CH3:37]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3C)c2cc1OC
Reactant: O=C(N=C=S)c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc([N+](=O)[O-])cc4)cc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.7 %

Procedure:
Commercially available 4-nitro-1-benzenecarbonyl isothiocyanate (30 mg) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (79 mg, yield 94%).
Reaction SMILES: [CH2:1]([C:3]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]([CH2:12][CH3:13])[C:4]=1[CH:5]=[O:6])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:21][CH3:22]>>[CH2:21]([O:11][C:10]1[C:3]([CH2:1][CH3:2])=[C:4]([C:7]([CH2:12][CH3:13])=[CH:8][CH:9]=1)[CH:5]=[O:6])[CH3:22]
Reactant: CCI
Reactant: CCc1ccc(O)c(CC)c1C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOc1ccc(CC)c(C=O)c1CC

Procedure:
3-Ethoxy-2,6-diethyl-benzaldehyde was prepared from 2,6-diethyl-3-hydroxy-benzaldehyde, cesium carbonate and iodoethane in analogy to Example 213b): yellow oil; 1H-NMR (CDCl3): 1.21 (3H, t, CH3), 1.23 (3H, t, CH3), 1.43 (3H, t, CH3), 2.86 (2H, q, CH2), 2.96 (2H, q, CH2), 4.04 (2H, q, OCH2), 6.96 (1H, d, ArH), 7.05 (1H, d, ArH), 10.57 (1H, s, CH═O).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@H:4]([CH:5]=[C:6]2[CH2:9][CH2:8][CH2:7]2)[C@H:3]1[C:10](Cl)=[O:11].[CH:14]([OH:17])([CH3:16])[CH3:15]>>[CH3:1][C:2]1([CH3:13])[C@H:4]([CH:5]=[C:6]2[CH2:9][CH2:8][CH2:7]2)[C@H:3]1[C:10]([O:17][CH:14]([CH3:16])[CH3:15])=[O:11]
Reactant: CC1(C)[C@H](C=C2CCC2)[C@H]1C(=O)Cl
Reactant: CC(C)O
Product: CC(C)OC(=O)[C@@H]1[C@@H](C=C2CCC2)C1(C)C
Reaction time: 8 h

Procedure:
A mixture of 12 g of (1R,trans) 2,2-dimethyl-3-cyclobutylidenemethyl-cyclopropane-1-carboxylic acid chloride in 25 ml of isopropanol was stirred for 8 hours and was distilled to dryness at 45° C. under reduced pressure. The residue was taken up in isopropyl ether and the solution was washed with water, dried and evaporated to dryness under reduced pressure at 45° C. The residue was chromatographed over silica gel and was eluted with a 9-1 petroleum ether (b.p.=60°-80° C.)-isopropyl ether mixture to recover the fraction with an Rf=0.35. The solvent was evaporated under reduced pressure to obtain 7.8 g of isopropyl (1R,trans) 2,2-dimethyl-3-cyclobutylidenemethyl-cyclopropane-1-carboxylate with a boiling point of 64°-66° C. at 0.1 mm Hg and a specific rotation of [α]D20 =-24.5° (c=2% in chloroform).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:4][S:5][CH3:6].C1C(O)=CC=CC=1C.[F:23][C:24]1[CH:25]=[C:26](O)[CH:27]=[CH:28][CH:29]=1>>[F:23][C:24]1[CH:29]=[C:28]([CH:27]=[CH:26][CH:25]=1)[O:1][CH2:2][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:4][S:5][CH3:6]
Reactant: Oc1cccc(F)c1
Reactant: CSC[C@@H](CO)NC(=O)OC(C)(C)C
Solvent: Cc1cccc(O)c1
Product: CSC[C@@H](COc1cccc(F)c1)NC(=O)OC(C)(C)C

Procedure:
By the operation similar to that in Step 2 of Example 15 except that t-butyl (1R)-2-hydroxy-1-[(methylsulfanyl)methyl]ethylcarbamate (1 g) obtained in Step 1 was used as a starting material and m-cresol was changed to 3-fluorophenol, the title compound (300 mg) was obtained.
Reaction SMILES: [N:1]1([CH2:8][C@H:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH:25]4[CH3:29])=[CH:16][CH:15]=3)[C:12](=O)[CH2:11][CH2:10]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:40]2)=CC=1.C1(C)C=CC=CC=1.O>C(Cl)(Cl)Cl>[N:1]1([CH2:8][C@H:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH:25]4[CH3:29])=[CH:16][CH:15]=3)[C:12](=[S:40])[CH2:11][CH2:10]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1CCCN1CCCOc1ccc(N2C(=O)CC[C@H]2CN2CCCCCC2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC1CCCN1CCCOc1ccc(N2C(=S)CC[C@H]2CN2CCCCCC2)cc1
Yield: 35 %

Procedure:
(5S)-5-(azepan-1-ylmethyl)-1-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}pyrrolidin-2-one 20 (0.1 g, 0.24 mmol, 1 eq) is dissolved in chloroform (5 ml) and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide a49 (Lawesson's reagent, 0.05 g, 0.12 mmol, 0.5 eq) is added. Toluene (5 ml) is added and the mixture is refluxed for 6 h. Water is then added, and after phase separation, the organic layer is dried over magnesium sulfate and concentrated to give 0.2 g of crude material. Purification by chromatography over silicagel (dichloromethane/methanol/ammonia 94/6/0.6) affords 0.05 g of pure (5S)-5-(azepan-1-ylmethyl)-1-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}pyrrolidine-2-thione 21.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH2:22][CH2:21][CH2:20][C:19]=3[CH2:23][C:24]3[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=3)[O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2N=C(C3C(CC4C=C(C=CC=4)OCC(OCC)=O)CCC=3)[O:46]C=2C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl>[C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH2:22][CH2:21][CH2:20][C:19]3([CH2:23][C:24]3[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=3)[O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[OH:46])[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)COc1cccc(CC2=C(c3nc(-c4ccccc4)c(-c4ccccc4)o3)CCC2)c1
Reactant: CCOC(=O)COc1cccc(CC2CCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)COc1cccc(CC2(O)CCCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 2 h

Procedure:
To a solution of a mixture (300 mg) of ethyl [3-[{2-(4,5-diphenyloxazol-2-yl)-1-cyclopenten-1-yl}methyl]phenoxy]acetate and ethyl [3-[{2-(4,5-diphenyloxazol-2-yl)-2-cyclopenten-1-yl}methyl]phenoxy]acetate in methylene chloride (10 ml) were added sodium carbonate (100 mg) and m-chloroperbenzoic acid (200 mg) at 0° C. After being stirred for 2 hours, the reaction mixture was washed with water and brine and dried over magnesium sulfate. After the solvent was evaporated, the residue containing a mixture of ethyl [3-[{2-(4,5-diphenyloxazol-2-yl)-1,2-epoxycyclopentan-1-yl}methyl]phenoxy]acetate and ethyl [3-[(2-(4,5-diphenyloxazol-2-yl)-2,3-epoxycyclopentan-1-yl]methyl]phenoxy]acetate was dissolved in a mixture of ethyl acetate-ethanol (20 ml-10 ml), and thereto was added 10% palladium on carbon (50 mg). After being stirred for 6 hours under hydrogen atmosphere, the reaction mixture was filtered. The solvent was evaporated in vacuo, the residue was chromatographed on silica gel. The first fraction gave ethyl [3-[{2-(4,5-diphenyloxazol-2-yl)-1-hydroxycyclopentan-1-yl}methyl]phenoxy]acetate (70 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N#N>C1COCC1.O>[Cl:13][C:14]1[CH:19]=[C:18]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[NH:4][N:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Agent: N#N
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]nc(-c2cccc(Cl)c2)c2ccccc12
Yield: 85 %

Procedure:
A solution of 1-chlorophthalazine-4-one (1.0 g, 5.5 mmol), 3-chlorophenyl boronic acid (1.3 g, 8.3 mmol), tricyclohexyphosphine (0.058 g, 0.27 mmol), and K3PO4 (2.3 g, 11.0 mmol) in THF (20 mL) and water (5 mL) was degassed with N2 for 30 min then treated with tri(dibenzylideneacetone)-dipalladium (0.050 g, 0.05 mmol) and heated at reflux overnight. The reaction mixture was diluted with water (100 mL) and the product extracted with EtOAc (2×100 mL). The organics were washed with brine, dried over Na2SO4, and concentrated to give 4-(3-chlorophenyl)phthalazin-1(2H)-one (1.2 g), (MS: ESI +ve, 257.12 [M+H]). 1H NMR: (400 MHz, DMSO) δ: 7.58-7.60 (m, 2H), 7.61-7.64 (m, 2H), 7.65-7.67 (m, 1H), 7.90-7.93 (m, 2H), 8.34-8.36 (m, 1H). 12.93 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:7][S:8]([N:11]2[CH2:15][C@@H:14]([C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=4[CH3:31])[CH2:20][CH2:19]3)=[O:17])[NH:13][C:12]2=[O:32])(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:40]1(B(O)O)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[CH:1]1([CH2:7][S:8]([N:11]2[CH2:15][C@@H:14]([C:16]([N:18]3[CH2:19][CH2:20][N:21]([C:24]4[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=4[CH3:31])[CH2:22][CH2:23]3)=[O:17])[N:13]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:12]2=[O:32])(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)[C@@H]3CN(S(=O)(=O)CC4CCCCC4)C(=O)N3)CC2)c1
Reactant: OB(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C)c(N2CCN(C(=O)[C@@H]3CN(S(=O)(=O)CC4CCCCC4)C(=O)N3c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-1-cyclohexylmethanesulfonyl-4-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-imidazolidin-2-one (100 mg) in CH2Cl2 (3 mL) was added cupric acetate (39 mg) and triethylamine (60 μl), followed by phenyl boronic acid (53 mg). The reaction mixture was stirred at room temperature for 16 hours. Additional phenyl boronic acid (53 mg) and triethyl amine (60 μl) was added and stirring was continued for 16 hours at room temperature. The mixture was concentrated in vacuo and the residue was purified by chromatography (SiO2, n-heptane/ethyl acetate 1:1) to give (S)-1-(cyclohexylmethanesulfonyl)-4-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-3-phenyl-imidazolidin-2-one as a white solid. MS: 539.0 ([M+H]+)