Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[S:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[CH:31]([C:33]1[CH:38]=[CH:37][C:36]([CH:39]([CH3:45])[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:35][CH:34]=1)=O>O1CCCC1.CCCCCC>[S:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[CH:31][C:33]1[CH:38]=[CH:37][C:36]([CH:39]([CH3:45])[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:35][CH:34]=1
Reactant: c1ccc([P+](c2ccccc2)(c2ccccc2)C2CCCS2)cc1
Reactant: CCOC(=O)C(C)c1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1ccc(C=C2CCCS2)cc1
Reaction time: 0.5 h
Yield: 60 %

Procedure:
(2-Tetrahydrothienyl)triphenylphosphonium chloride (5.8 g) was dissolved in tetrahydrofuran (30 ml), and to the solution was added dropwise a 1.6 M solution of n-butyllithium in hexane (9.5 ml) at −5° C., and then the mixture was stirred at the same temperature for 30 minutes. Then, to the reaction mixture was added dropwise a solution of ethyl 2-(4-formylphenyl)propionate (3.6 g) in tetrahydrofuran (5.0 ml) at −5° C., and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with 10% aqueous citric acid, and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/1) to give the title compound (2.5 g, 58%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][C:8]2[CH:13]=[C:12]([NH:14]C(=O)C(F)(F)F)[CH:11]=[CH:10][C:9]=2[S:21](Cl)(=[O:23])=[O:22])[N:3]=1.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]2[CH2:33][O:32][B:31]([OH:34])[C:30]=2[CH:35]=1.N1C=CC=CC=1>C(#N)C>[NH2:14][C:12]1[CH:11]=[CH:10][C:9]([S:21]([NH:25][C:26]2[CH:27]=[CH:28][C:29]3[CH2:33][O:32][B:31]([OH:34])[C:30]=3[CH:35]=2)(=[O:22])=[O:23])=[C:8]([CH2:7][C:4]2[N:3]=[C:2]([CH3:1])[O:6][N:5]=2)[CH:13]=1
Reactant: Cc1nc(Cc2cc(NC(=O)C(F)(F)F)ccc2S(=O)(=O)Cl)no1
Reactant: Nc1ccc2c(c1)B(O)OC2
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1nc(Cc2cc(N)ccc2S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)no1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride (490 mg, 1.3 mmol) and 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (627 mg, 4.21 mmol) in 10 mL of ACN was added pyridine (680 uL, 8.4 mmol) dropwise. The reaction mixture was stirred at room temperature for 3 hours. After the mixture was concentrated, the residue was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated to give the desired compound as a yellow residue (555 mg, yield 88%). A small portion of the crude mixture was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the title compound as a yellow solid.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C>[C:1]1([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1nccc2ccccc12
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1ccc(-c2nccc3ccccc23)cc1
Yield: 43 %

Procedure:
3.04 g of phenylboronic acid (24.9 mmol) and 4.09 g of 1-chloroisoquinoline (25.0 mmol), 25 ml of toluene, 12.5 ml of ethanol, and 25 ml of a 2M sodium carbonate aqueous solution were introduced into a 100 ml-three-neck flask. With stirring at room temperature under a nitrogen gas flow, 0.98 g (0.85 mmol) of tetrakis-(triphenylphosphine) palladium (0) was added to the mixture. Thereafter, the resultant was stirred under reflux under a nitrogen gas flow for 8 hours. After completion of the reaction, the reaction product was cooled, and then extracted with cool water and toluene. The organic layer was washed with saline and dried with magnesium sulfate, and then the solvent was dried under reduced pressure. The residue was purified using silica gel column chromatography (eluent: chloroform/methanol: 10/1), to yield 2.20 g of 1-phenylisoquinoline (43.0% yield).
Reaction SMILES: C[O:2][C:3](=[O:15])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([O:13][CH3:14])[CH:7]=1.[OH-].[Na+].O.CO>O1CCCC1>[CH3:14][O:13][C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]([OH:15])=[O:2])[CH:11]=[CH:10][C:9]=1[CH3:12]
Reactant: COC(=O)C=Cc1ccc(C)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(C=CC(=O)O)ccc1C
Temperature: 50 °C
Yield: 93.2 %

Procedure:
A mixture of 3-methoxy-4-methylbenzaldehyde (19.3 g, 0.129 mol), carbomethoxy methylene triphenylphosphorane (51 g) in toluene (250 ml) was refluxed for 24 h. The mixture was quenched with aqueous ammonium chloride and extracted with ethyl acetate and concentrated in vacuo to give a residue. The residue was purified by flash chromatography using ethyl acetate-heptane (1:1) to give 3-(3-methoxy-4-methyl-phenyl)acrylic acid methyl ester (27 g, 0.126 mol). A mixture of 3-(3-methoxy-4-methylphenyl)acrylic acid methyl ester (27 g), sodium hydroxide (14 g), water (70 ml), methanol (140 ml) and tetrahydrofuran (70 ml) was refluxed at 50° C. for 1 h. The mixture was concentrated in vacuo and then water added. The mixture was filtered and 5 M HCl was added until precipitation occurred. The mixture was filtered and the solid precipitate washed with water and dried in-vacuo to give 3-(3-methoxy-4-methylphenyl)acrylic acid (23.5 g, 0.122 mol).
Reaction SMILES: Cl.[NH2:2][OH:3].O.O.O.C([O-])(=O)C.[Na+].[CH2:12]([C:14]1[N:15]([CH2:22][CH2:23][O:24][C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)[C:16](=[O:21])[CH:17]=[C:18]([CH3:20])[N:19]=1)[CH3:13]>O.C(O)C>[CH2:12]([C:14]1[N:15]([CH2:22][CH2:23][O:24][C:25]2[CH:32]=[CH:31][C:28]([CH:29]=[N:2][OH:3])=[CH:27][CH:26]=2)[C:16](=[O:21])[CH:17]=[C:18]([CH3:20])[N:19]=1)[CH3:13]
Reactant: NO
Reactant: CCc1nc(C)cc(=O)n1CCOc1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCc1nc(C)cc(=O)n1CCOc1ccc(C=NO)cc1
Temperature: 95 °C
Yield: 89.9 %

Procedure:
To a stirred solution of hydroxylamine hydrochloride (10.0 g, 143.0 mmol) and sodium acetate trihydrate (20.0 g, 146.9 mmol) in water (100 ml) at 30° C. was added a hot solution of 4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehyde (5.72 g, 20.0 mmol) (obtained from preparation 3) in ethanol (100 ml). The reaction mixture was immersed in a preheated oil bath (95° C.) and refluxed for 3 h. The reaction mixture was then cooled to room temperature and concentrated to a volume where crystals of oxime started separating out and the mixture was kept aside for 30 min. to 1 h at 25° C. The resultant crystals were filtered and washed with water and dried to obtain the title compound (5.42 g, 90%).
Reaction SMILES: [Sn].C(Cl)/C=C(/CCC[C@@H](CCC[C@@H](CCCC(C)C)C)C)\C.[CH3:23][C:24]1[C:33]([CH3:34])=[C:32]2[C:27]([CH2:28][CH2:29][C:30]([CH2:36][CH2:37][CH2:38][CH:39]([CH2:41][CH2:42][CH2:43][CH:44]([CH2:46][CH2:47][CH2:48][CH:49]([CH3:51])[CH3:50])[CH3:45])[CH3:40])([CH3:35])[O:31]2)=[C:26]([CH3:52])[C:25]=1[OH:53].[C:54](OCC)(=[O:56])[CH3:55]>[Cl-].[Zn+2].[Cl-]>[CH3:34][C:33]1[C:24]([CH3:23])=[C:25]([O:53][C:54]([CH3:55])=[O:56])[C:26]([CH3:52])=[C:27]2[CH2:28][CH2:29][C@:30]([CH2:36][CH2:37][CH2:38][C@@H:39]([CH2:41][CH2:42][CH2:43][C@@H:44]([CH2:46][CH2:47][CH2:48][CH:49]([CH3:51])[CH3:50])[CH3:45])[CH3:40])([CH3:35])[O:31][C:32]=12
Reactant: CCOC(C)=O
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Agent: C/C(=C\CCl)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Agent: [Cl-]
Agent: [Sn]
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Yield: 84.5 %

Procedure:
3.040 g of TMHQ, 0.484 g of metallic tin powder and 0.079 g of zinc chloride were suspended in 15 ml of ethyl acetate in an atmosphere of nitrogen. A solution of 7.975 g of phytyl chloride in 10 ml of ethyl acetate was dripped into said suspension over a period of 3 hours under heating and reflux. About 0.1 g metallic tin powder was added eight times, same amount per addition, in order to maintain said tin continuously suspended in the suspension. After addition of the phytyl chloride, the reaction mixture was subjected to heating and reflux for another 3 hours to obtain a reaction mixture of dl-α-tocopherol. The obtained dl-α-tocopherol was acetylated in the same manner as described in Comparative Example 1 without isolating said dl-α-tocopherol to obtain 10.454 of dl-α-tocopheryl acetate. The absorbance of this crude dl-α-tocopheryl acetate was measured: E415 mμ40%EtOH =0.145. Estimation of the crude dl-α-tocopheryl acetate by liquid chromatography indicated that its purity was 76.3% and the yield was 84.5%.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C1(C)C=CC=CC=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:25]([C:22]3[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=3)(=[O:27])=[O:26])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)ncnc32)cc1
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
In a 1 l three-necked flask, introduce, with stirring, 11.8 g of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine and 137 ml of toluene, then 16.11 g of 4-methyl-benzenesulphonyl chloride and 5.2 g of tetra-n-butylammonium hydrogen sulphate, then run in, dropwise, 275 ml of an aqueous solution containing 30.7 g of sodium hydroxide. After 30 minutes at room temperature, add 200 ml of ethyl acetate and 200 ml of water. The organic phase is decanted, dried over magnesium sulphate, and concentrated under reduced pressure. After purification by flash chromatography on silica gel, eluting with dichloromethane, we obtain 22.6 g of 4-chloro-7-(4-methylbenzenesulphonyl)-7H-pyrrolo[2,3-d]pyrimidine, in the form of a white solid with the following characteristics:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([CH2:21][O:22][C:23]([CH3:28])([CH3:27])[C:24](O)=[O:25])[C:9]=2[CH3:29])=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.FC1C(O)=C(F)C(F)=C(F)C=1F.[NH2:54][CH2:55][C:56]1[CH:64]=[CH:63][C:59]([C:60]([OH:62])=[O:61])=[CH:58][CH:57]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([CH2:21][O:22][C:23]([CH3:27])([CH3:28])[C:24]([NH:54][CH2:55][C:56]3[CH:57]=[CH:58][C:59]([C:60]([OH:62])=[O:61])=[CH:63][CH:64]=3)=[O:25])[C:9]=2[CH3:29])=[CH:6][CH:7]=1
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: Cc1c(COC(C)(C)C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(COC(C)(C)C(=O)NCc2ccc(C(=O)O)cc2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 710 mg of 2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-2-methyl-propionic acid in 5 ml of DMF, 360 mg of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC), 345 mg of pentafluorophenol and 392 mg of NEM were added and the reaction mixture was stirred for 3 h at room temperature. Then, 353 mg of 4-Aminomethyl-benzoic acid and 540 mg of NEM in 5 ml of DMF were added. After 16 h the reaction mixture was diluted with water and filtered through a chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. Yield: 288 mg.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1.[CH2:24]([O:31][C:32]1[CH:59]=[CH:58][C:57](Br)=[CH:56][C:33]=1[C:34]([NH:36][C:37]1[CH:49]=[C:48]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:47]=[CH:46][C:38]=1[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(OCC)(=O)C.O>[CH2:24]([O:31][C:32]1[CH:59]=[CH:58][C:57]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[CH:56][C:33]=1[C:34]([NH:36][C:37]1[CH:49]=[C:48]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:47]=[CH:46][C:38]=1[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:35])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(Br)ccc1OCc1ccccc1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(N2CCC3(CC2)OCCO3)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
1,4-Dioxa-8-azaspiro[4,5]decane (0.12 mL), cesium carbonate (0.35 g), tris(dibenzylideneacetone)dipalladium(0) (3.3 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (8.5 mg), and palladium(II) acetate (1.6 mg) were added to a toluene (3.0 mL) solution of tert-butyl 2-(2-(benzyloxy)-5-bromobenzamido)-4-phenylbenzoate (0.20 g), followed by heating to reflux under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, and then tris(dibenzylideneacetone)dipalladium(0) (3.3 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (8.5 mg), and palladium(II) acetate (1.6 mg) were added to the reaction mixture, followed by heating to reflux under a nitrogen atmosphere for 5 hours. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. The insoluble substance was removed by filtration. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 90-65% hexane/ethyl acetate] to obtain 0.18 g of tert-butyl 2-(2-(benzyloxy)-5-(1,4-dioxa-8-azaspiro[4,5]decan-8-yl)benzamido)-4-phenylbenzoate.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[C:14](OCC)(=O)[CH2:15][C:16]([C:18]([O:20]CC)=[O:19])=O.[Na].C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[CH3:13][O:12][C:11]1[C:2]2[NH:1][C:14]3=[CH:15][C:16]([C:18]([OH:20])=[O:19])=[N:7][N:6]3[C:4](=[O:5])[C:3]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Reactant: COc1cccc(C(=O)NN)c1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1cccc2c(=O)n3nc(C(=O)O)cc3[nH]c12

Procedure:
A mixture of 2-amino-3-methoxybenzoic acid hydrazide (23,6 g; 0.13 mole) and 90% diethyl oxalacetate, sodium salt (32.7 g; 0.14 mole) in water (400 ml) is heated under reflux for 1.5 hrs. To the resulting yellow solution is added sodium carbonate (14.8 g; 0.14 mole) and the solution is refluxed for an additional hour. The cooled reaction mixture is cautiously treated with conc. HCl (0.28 mole) and the precipitated solid is filtered off, washed with water and recrystallized from methanol (1500 ml). Yield 5.8 g; mp 271°-272° C. (d).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][N:7]=[C:6](Cl)[C:5]=1[CH3:11].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(=[NH:74])(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>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].O.C1(C)C=CC=CC=1.O1CCOCC1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH2:74])[C:5]=1[CH3:11]
Reactant: COC(=O)c1ccnc(Cl)c1C
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1ccnc(N)c1C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
The mixture of 520 mg of 2-chloro-3-methylisonicotinic acid methyl ester [48-1], 161 mg of bis(dibenzylideneacetone)palladium, 324 mg of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 1.28 g of cesium carbonate, 564 μL of benzophenoneimine, 5 mL of 1,4-dioxane, and 5 mL of toluene, was stirred overnight at 80° C. After cooling the reaction mixture back to room temperature, water and a saturated aqueous solution of sodium bicarbonate were added, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was dissolved in 28 mL of methanol. Thereto, 1.1 g of sodium acetate and 700 mg of hydroxyamine hydrochloride were added, and stirred for 1 hour. Then, a 0.1 N aqueous solution of sodium hydroxide was added, and extracted with chloroform. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, to obtain 92.1 mg of 2-amino-3-methylisonicotinic acid methyl ester [48-2] as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]2[S:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=O)[CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH2:20]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[C:21]1[CH:29]=[CH:28][C:27]2[O:26][CH2:25][O:24][C:23]=2[CH:22]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:19]=[CH:18][C:7]2[S:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11]([N:33]3[CH2:34][CH2:35][N:30]([CH2:20][C:21]4[CH:29]=[CH:28][C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=4)[CH2:31][CH2:32]3)=[CH:12][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2Sc2ccccc21
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc2c(c1)C=C(N1CCN(Cc3ccc4c(c3)OCO4)CC1)c1ccccc1S2
Temperature: 25 °C
Yield: 17 %

Procedure:
To a stirred solution of 2-nitro-10-oxo-dibenzo[b,f]thiepine (0.54 g, 2.00 mmol) and 1-piperonylpiperazine (2.04 g, 9.26 mmol) in toluene (15 mL) was added titanium tetrachloride (0.24 mL, 2.2 mmol) at room temperature under argon. The resulted mixture was heated at reflux for 3.5h and then cooled down to room temperature. The whole mixture was poured into a saturated sodium bicarbonate solution (50 mL). After separation, the aqueous phase was extracted with dichloromethane (2×50 mL). The combined organic solution was dried (MgSO4), filtered and concentrated in vacuo to dryness. The residue was subjected to column chromatography using ethyl acetate/hexanes (1/2) as eluent. Thus 0.161 g (17%) of the title compound was obtained as a yellow solid; m.p. 188°-190° C.; MS 474 (M+ +1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH:11][C:12](=[O:32])/[C:13](=[CH:18]/[C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]2)=[C:21]([F:31])[CH:20]=1)/[CH2:14][CH2:15][CH2:16]Cl)[CH3:10].[H-].[Na+].O.C(=O)(O)[O-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([N:11]1[CH2:16][CH2:15][CH2:14]/[C:13](=[CH:18]\[C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]3)=[C:21]([F:31])[CH:20]=2)/[C:12]1=[O:32])[CH3:10]
Reactant: Cc1cn(-c2ccc(/C=C(\CCCCl)C(=O)NC(C)c3ccc(F)cc3F)cc2F)cn1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cn(-c2ccc(/C=C3\CCCN(C(C)c4ccc(F)cc4F)C3=O)cc2F)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
DIEA (0.12 mL), WSC (88 mg), and HOBT (62 mg) were added to a solution of (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}valeric acid trifluoroacetate (100 mg) and 1-(2,4-difluorophenyl)ethylamine (54 mg) in DMF (5 mL) at room temperature, and the reaction solution was stirred at room temperature for one hour. Ethyl acetate was added to the reaction solution, which was then sequentially washed with saturated sodium bicarbonate water, water, a saturated ammonium chloride solution, and brine. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain 98 mg of (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}valeric acid [1-(2,4-difluorophenyl)ethyl]amide. (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}valeric acid [1-(2,4-difluorophenyl)ethyl]amide (98 mg) was dissolved in DMF (3 mL). 60% sodium hydride (10 mg) was added to the reaction solution at room temperature, and the reaction solution was stirred at room temperature for 30 minutes. Saturated sodium bicarbonate water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting extraction layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain 69 mg of the title compound as a racemate. The compound (20 mg) was separated by CHIRALCEL OJ-H manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: ethanol-hexane system) to obtain the title optically active compound with a retention time of 18 minutes (Example 82) (7 mg) and the title optically active compound with a retention time of 24 minutes (Example 83) (4 mg). The property values of the title compound are as follows.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:29])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=3[O:27][CH3:28])[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:30][CH2:31][S:32][CH3:33])[C:9]1=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C[Si]([Cl:40])(C)C>CC(CC)=O>[ClH:40].[CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:29])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=3[O:27][CH3:28])[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:30][CH2:31][S:32][CH3:33])[C:9]1=[O:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)Cl
Agent: COc1ccc(C(=O)N2CCC3(CC2)N[C@@H](CCSC)C(=O)N3Cc2ccccc2)c(OC)c1
Solvent: O
Solvent: CCC(C)=O
Product: Cl
Reaction time: 8 h

Procedure:
1-benzyl-8-(2,4-dimethoxybenzoyl)-3-(S)-(2-methylsulfanylethyl)-1,4,8-triazaspiro[4,5]decan-2-one (290 mg, 0.6 mmol) was dissolved in ethyl methyl ketone (2 mL), and water (6 μL) and TMSCl (80 μL) were added and the mixture was stirred overnight. The precipitated solid matter was isolated by filtration and dried in vacuo. The product 1-benzyl-8-(2,4-dimethoxybenzoyl)-3-(S)-(2-methylsulfanylethyl)-1,4,8-triazaspiro[4,5]decan-2-one hydrochloride was obtained in a yield of 105 mg (95%).