Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si](C)(C)C)=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([Li])CCC.Cl[C:38]([O:40][CH3:41])=[O:39]>C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:38]([O:40][CH3:41])=[O:39])=[CH:4][CH:3]=1
Reactant: COC(=O)Cl
Reactant: C[Si](C)(C)C#Cc1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: COC(=O)C#Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-(4-fluorophenyl)-2-trimethylsilylacetylene (64 g, 0.33 mol) in dry diethyl ether (400 mL) was cooled to 0° C. under a nitrogen atmosphere. To this solution was added, dropwise over 45 minutes, a solution of tetrabutylammonium fluoride (1 M in tetrahydrofuran, 330 mL, 0.33 mol) via a dropping funnel maintaining the internal temperature below 2° C. The mixture was allowed to warm to room temperature over about 1 hour. Diethyl ether (300 mL) was added to the mixture and the organic solution was washed with water, saturated brine and then dried over anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration and the filtrate was cooled to about −78° C. n-Butyl lithium (1.6M in hexanes, 450 mL, 0.72 mol) was added dropwise via a dropping funnel over about 1 h while the temperature was maintained below −66° C. After complete addition the mixture was stirred at −78° C. for about 1 h and then a precooled solution of methyl chloroformate (110 mL, 1.4 mol) in dry diethyl ether (200 mL) was added in a continuous stream as fast as possible. The mixture was allowed to cool to −78° C. and then allowed to warm to room temperature over 1.5 h. The organic reaction mixture was washed with water and saturated brine and then dried over anhydrous magnesium sulfate. The solvents are remove under reduced pressure and the residue dried under reduced pressure to give the title compound as a brown solid, 36.5 g (61%). 1H NMR (CDCl3) δ 7.58 (dd, 2H, J=9, 5.4 Hz), 7.07 (t, 2H, J=8.5 Hz), 3.84 (s, 3H). MS (+ve ion electrospray) 178 (30), (M+).
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1([CH3:32])[CH2:16][CH2:15][C:14]2[C:9](=[C:10]([CH3:31])[C:11]([CH3:30])=[C:12]([S:18]([NH:21][C:22](=[NH:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:20])=[O:19])[C:13]=2[CH3:17])[O:8]1)=[O:5])C.CCOC(C)=O.Cl>C(O)C.[OH-].[Na+]>[C:4]([CH2:6][C:7]1([CH3:32])[CH2:16][CH2:15][C:14]2[C:9](=[C:10]([CH3:31])[C:11]([CH3:30])=[C:12]([S:18]([NH:21][C:22](=[NH:29])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)(=[O:19])=[O:20])[C:13]=2[CH3:17])[O:8]1)([OH:5])=[O:3]
Reactant: CCOC(=O)CC1(C)CCc2c(C)c(S(=O)(=O)NC(=N)c3ccccc3)c(C)c(C)c2O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1c(C)c(S(=O)(=O)NC(=N)c2ccccc2)c(C)c2c1OC(C)(CC(=O)O)CC2
Temperature: 25 °C
Reaction time: 30 h
Yield: 103.1 %

Procedure:
A solution of N-(2-ethoxycarbonylmethyl-2,5,7,8-tetramethylchroman-6-sulfonyl)benzamidine (1.54 g) in a mixture of ethanol (EtOH) (30 ml) and 1N NaOH (7.05 ml) was stirred at room temperature for 30 hours. EtOH was evaporated under reduced pressure to give a residue. A mixture of AcOEt and 1N HCl was added to the residue. The organic phase was washed with water and brine, and dried over MgSO4. After filtration, the filtrate was concentrated under reduced pressure to give N-(2-carboxymethyl-2,5,7,8-tetramethylchroman-6-sulfonyl)benzamidine as a glass (1.49 g).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][NH:15][C:14](=[O:19])[C:13]=3[CH:20]=2)O1.BrC1C=CN(C)C(=O)C=1.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[O:18]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:20][C:13]=2[C:14](=[O:19])[NH:15][CH2:16][CH2:17]1
Reactant: CC1(C)OB(c2ccc3c(c2)C(=O)NCCO3)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cn1ccc(Br)cc1=O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1NCCOc2ccccc21
Temperature: 85 °C

Procedure:
A mixture of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (200 mg, 0.69 mmol), 4-bromo-1-methylpyridin-2(1H)-one (156 mg, 0.83 mmol), cesium carbonate (674 mg, 2.07 mmol), 1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (49 mg, 0.069 mmol) was dissolved in a degassed mixture of DMF and water 3/1.5 (4.5 mL). The mixture was heated in microwave at 85° C. for 40 min. The mixture was poured into EtOAc and washed with water and brine. The organic layer was collected, dried over sodium sulfate and loaded onto silica gel. A flash column (5% MeOH in EtOAc) and reverse phase chromatography gave 7-ethyl-2-oxo-1,2-dihydropyridin-4-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@H:11]1[C:16]2[CH:17]=[CH:18][C:19]([N:21]3[CH2:25][CH2:24][CH2:23][S:22]3(=[O:27])=[O:26])=[CH:20][C:15]=2[CH2:14][CH2:13][O:12]1)(C(C)(C)C)(C)C.OCC[C@H]1C2C=CC(C(N)=O)=CC=2CCO1>>[O:27]=[S:22]1(=[O:26])[CH2:23][CH2:24][CH2:25][N:21]1[C:19]1[CH:18]=[CH:17][C:16]2[C@H:11]([CH2:10][CH2:9][OH:8])[O:12][CH2:13][CH2:14][C:15]=2[CH:20]=1
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1OCCc2cc(N3CCCS3(=O)=O)ccc21
Agent: NC(=O)c1ccc2c(c1)CCO[C@H]2CCO
Product: O=S1(=O)CCCN1c1ccc2c(c1)CCO[C@H]2CCO

Procedure:
Prepared from 2-[(1S)-1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3,4-dihydro-1H-2-benzopyran-6-yl]isothiazolidine 1,1-dioxide, as described for the preparation of (1S)-1-(2-hydroxyethyl)-3,4-dihydro-1H-2-benzopyran-6-carboxamide.
Reaction SMILES: [H-].[Na+].[C:3](#[N:5])[CH3:4].C([O:8][C:9]([CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=O)C.Cl>O1CCOCC1>[CH:11]1([C:9](=[O:8])[CH2:4][C:3]#[N:5])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC#N
Reactant: CCOC(=O)C1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: N#CCC(=O)C1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (350 mg, 8.8 mmol, 1.2 eq) in 1,4-dioxane (10 mL) was added acetonitrile (450 μL, 8.8 mmol, 1.2 eq). The mixture was stirred at room temperature for 30 min. Then cyclopentanecarboxylic acid ethyl ester (660 μL, 7.3 mmol, 1 eq) was added. After stirring for 30 min at room temperature, the mixture was heated at 105° C. during 16 h. After cooling, the solvent was evaporated to dryness and water was added (30 mL). The mixture was extracted with dichloromethane (3×30 mL) to get rid of the starting material and the aqueous phase was acidified with a 1N solution of hydrochloric acid and extracted with dichloromethane (3×30 mL). The combined organic phases were dried over magnesium sulfate, filtered and dried in vacuo to afford 3-cyclopentyl-3-oxo-propionitrile as very volatile yellow oil (1.0 g, quant. yield)
Reaction SMILES: [O:1]=[C:2]([C:19]1[CH:20]=[CH:21][C:22]2[S:27][C:26]3[N:28]=[CH:29][CH:30]=[N:31][C:25]=3[NH:24][C:23]=2[CH:32]=1)[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6][CH2:5]1.[BH4-].[Na+].C(OCC)(=O)C>C(O)C>[OH:1][CH:2]([C:19]1[CH:20]=[CH:21][C:22]2[S:27][C:26]3[N:28]=[CH:29][CH:30]=[N:31][C:25]=3[NH:24][C:23]=2[CH:32]=1)[CH2:3][N:4]1[CH2:5][CH2:6][CH:7]([CH2:10][CH2:11][CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8][CH2:9]1
Reactant: CCOC(=O)C(C)CCC1CCN(CC(=O)c2ccc3c(c2)Nc2nccnc2S3)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)CCC1CCN(CC(O)c2ccc3c(c2)Nc2nccnc2S3)CC1
Yield: 66 %

Procedure:
To a solution of 0.8 g of ethyl 4-[1-[2-oxo-2-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl]ethyl]piperidin-4-yl]-2-methylbutanoate in ethanol (30 ml) was added 70 mg of sodium borohydride and the resulting mixture was reacted at room temperature for 30 minutes. After adding ethyl acetate, the reaction mixture was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 0.53 g of the title compound as a yellow oily substance.
Reaction SMILES: I.C[O:3][C:4]1[CH:5]=[C:6]([CH:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[CH:7]=[CH:8][CH:9]=1>C(Cl)(Cl)Cl>[OH:3][C:4]1[CH:5]=[C:6]([CH:10]2[C:11](=[O:20])[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]2=[O:19])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(C2C(=O)c3ccccc3C2=O)c1
Agent: I
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)C1c1cccc(O)c1
Temperature: 20 °C

Procedure:
Hydroiodic acid (50%, 205 parts) was added to 2-(3-methoxyphenyl)-1,3-indandione (67.1 parts) and the mixture was stirred under reflux for 10 minutes. By-product methyl iodide was removed by distillation and the solution was cooled to 20° C. The aqueous layer was decanted to leave a red oil. The oil was dissolved in chloroform (250 parts), washed with water (100 parts), separated and dried over anhydrous magnesium sulphate. The chloroform was removed by evaporation under reduced pressure to leave an orange solid. The solid was crystallised from toluene (1800 parts) to yield 2-(3-hydroxyphenyl)-1,3-indandione (30.6 parts), m.pt. 139°-141° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1.C1C=C(Cl)C=C(C(OO)=[O:21])C=1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][CH2:2][C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=[CH:5][N+:4]=1[O-:21]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1cccnc1CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc[n+]([O-])c1CCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-(chloromethyl)pyridine-3-carboxylate (20.73 g, 112 mmol) was taken up in dichloromethane (225 mL) and mCPBA (27.5 g, 123 mmol) was added. The resulting solution was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate was added and the products extracted into dichloromethane (2×). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (silica, 0-20% methanol/ethyl acetate) gave the title compound as a white solid. 1H NMR (d6-DMSO, 600 MHz) δ 8.50 (dd, 1H), 7.75 (dd, 1H), 7.53 (dd, 1H), 5.07 (s, 2H), 3.86 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([NH:11][CH2:12][C:13]([C:15]2[CH:16]=[N:17][N:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19]=2[CH2:20][CH3:21])=O)[CH:5]=1.[C:29]([S-:31])#[N:30].[K+]>CC(O)=O>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[CH:12]=[C:13]([C:15]3[CH:16]=[N:17][N:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:19]=3[CH2:20][CH3:21])[N:30]=[C:29]2[SH:31])[CH:5]=1
Reactant: N#C[S-]
Reactant: CCc1c(C(=O)CNc2cc(C(=O)OC)ccc2C)cnn1-c1ccccc1
Agent: [K+]
Solvent: CC(=O)O
Product: CCc1c(-c2cn(-c3cc(C(=O)OC)ccc3C)c(S)n2)cnn1-c1ccccc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 63.7 %

Procedure:
A suspension of 3.75 g (9.94 mmol) of 3-[2-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-ethylamino]-4-methyl-benzoic acid methyl ester and 2.9 g (30 mmol) of KSCN in 25 mL of HOAc was stirred at 100° C. for 4 h. The mixture was allowed to cool overnight before being filtered and washed with cold MeOH. The solids were dried to provide 2.65 g of 3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-2-mercapto-imidazol-1-yl]-4-methyl-benzoic acid methyl ester as an off-white solid. ESI MS m/z 419 [C23H22N4O2S+H]+.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][S:9]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])(=[O:11])=[O:10])=[O:7])=[CH:4][C:3]=1[N+:19]([O-])=O.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][S:9]([N:12]([CH:14]([CH3:15])[CH3:16])[CH3:13])(=[O:11])=[O:10])=[O:7])=[CH:4][C:3]=1[NH2:19]
Reactant: [H][H]
Reactant: CC(C)N(C)S(=O)(=O)NC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CC(C)N(C)S(=O)(=O)NC(=O)c1ccc(F)c(N)c1
Temperature: 27.5 °C
Reaction time: 12 h

Procedure:
89.0 g (0.28 mol) of N-(4-fluoro-3-nitrobenzoyl)-N′-isopropyl-N′-methylsulfamide in methanol were admixed with 5.9 g (10 mol %) of Pd/C and hydrogenated with 2-5 bar of hydrogen with stirring at 25-30° C. After 12 h the solution was depressurized, the reaction mixture was filtered and the solvent was removed by distillation. This gave 80.1 g (98%) of the title compound in the form of a beige solid (m.p.: 148-150° C.).
Reaction SMILES: [N:1]([CH:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][C:9]=2[CH:10]=1)[CH3:5])=[N+]=[N-].C1C[O:23][CH2:22][CH2:21]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(=O)C)(=O)C>C(OCC)(=O)C.O>[C:22]([NH:1][CH:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][C:9]=2[CH:10]=1)[CH3:5])(=[O:23])[CH3:21]
Reactant: CCOC(=O)c1ccc2oc(C(C)N=[N+]=[N-])cc2c1
Reactant: C1CCOC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1ccc2oc(C(C)NC(C)=O)cc2c1
Yield: 53 %

Procedure:
Using ethyl 2-(1-azidoethyl)-1-benzofuran-5-carboxylate (4.34 g, 16.7 mmol) obtained in Reference Example 88, THF (17 mL), water (1.7 mL); triphenylphosphine (6.58 g, 25.1 mmol), ethyl acetate (5 mL) and acetic anhydride (2.4 mL, 25.1 mmol), an operation in the same manner as in Reference Example 37 was performed to give the title compound (2.42 g, yield 53%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[C:22]3[O:21][CH:20]=[C:19]([Cl:23])[C:18]=3[CH:17]=[C:16]([Cl:24])[C:15]=2[F:25])[C@H:10]([CH3:26])[CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[ClH:23].[CH3:26][C@H:10]1[C@@H:11]([C:14]2[C:22]3[O:21][CH:20]=[C:19]([Cl:23])[C:18]=3[CH:17]=[C:16]([Cl:24])[C:15]=2[F:25])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1c(F)c(Cl)cc2c(Cl)coc12
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1CNCC[C@@H]1c1c(F)c(Cl)cc2c(Cl)coc12

Procedure:
Fractions containing cis-1-(tert-butoxycarbonyl)-3-methyl-4-(3,5-dichloro-6-fluorobenzofur-7-yl)piperidine were combined and concentrated under reduced pressure to provide 0.107 gm. (Ion Spray MS: m/e=403 (M+1)). A solution of this material in 3.5 mL 4N hydrogen chloride in dioxane was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in methanol. This solution was subjected to ion exchange chromatography (Varian SCX) and the column was eluted sequentially with methanol followed by 2N ammonia in methanol. Fractions containing cis-3-methyl-4-(3,5-dichloro-6-fluorobenzofur-7-yl)piperidine were combined and concentrated under reduced pressure. This residue was dissolved in diethyl ether and treated with hydrogen chloride in diethyl ether. The suspension was concentrated under reduced pressure and the residue suspended in diethyl ether. This suspension was filtered and to provide 0.066 gm of cis-3-methyl-4-(3,5-dichloro-6-fluorobenzofur-7-yl)piperidine hydrochloride as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([OH:9])[C:5]([F:8])([F:7])[F:6].[F:10][C:11]([F:24])([O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O)[CH:12]([F:14])[F:13].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[F:10][C:11]([F:24])([O:15][C:16]1[CH:17]=[C:18]([CH2:19][NH:1][CH2:2][CH2:3][CH:4]([OH:9])[C:5]([F:8])([F:7])[F:6])[CH:21]=[CH:22][CH:23]=1)[CH:12]([F:13])[F:14]
Reactant: NCCC(O)C(F)(F)F
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: OC(CCNCc1cccc(OC(F)(F)C(F)F)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 36.8 %

Procedure:
The 4amino-2-hydroxy-1,1,1-trifluorobutane (1.0 g, 7.0 mmol) from EX-611A and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (1.5 g, 7.0 mmol) were dissolved in 20 mL of dichloroethane and acetic acid (0.40 mL, 7.7 mmol), then solid NaBH(OAc)3 (1.8 g, 8.4 mmol) was added. The mixture was stirred at room temperature for 3 d, then quenched with water and extracted with ether. The ether layer was washed with water and brine, then dried over MgSO4, and evaporated to give 1.6 g of crude product, which was purified by reverse phase HPLC to give 0.90 g (37%) of the desired 4-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-butanol product as a yellow oil. HRMS calcd. for C13H14F7NO2: 350.0991 [M+H]+, found: 350.0971.
Reaction SMILES: ClCCl.[O:4]=[C:5]1[NH:9][C:8](=[O:10])[CH:7]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH:20]=2)[C:17]([OH:19])=O)[S:6]1.C(Cl)(=O)OCC.[F:29][C:30]([F:40])([F:39])[C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1>C(N(CC)CC)C>[O:4]=[C:5]1[NH:9][C:8](=[O:10])[CH:7]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH:20]=2)[C:17]([NH:36][CH2:35][C:34]2[CH:33]=[CH:32][C:31]([C:30]([F:29])([F:39])[F:40])=[CH:38][CH:37]=2)=[O:19])[S:6]1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(CC2SC(=O)NC2=O)cc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CC2SC(=O)NC2=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Reaction time: 0.17 h
Yield: 59.5 %

Procedure:
To 49 mL of dichloromethane were added 6.30 g of triethylamine and 7.00 g of 5-[(2,4-dioxothiazolidin-5-yl) methyl]-2-methoxybenzoic acid. After 2.71 g of ethyl chlorocarbonate were added, the mixture was stirred for 10 minutes. Further, 4.59 g of 4-trifluoromethylbenzylamine were added and the mixture was stirred for 1 hour. After washed the reaction mixture with water, solvent was distilled off and to the residue were added 109 mL of water and 33 mL of ethanol, to which solution 2 mol/L hydrochloric acid was added dropwise to adjust to pH 2.0. The precipitated crystals were collected by filtration and washed with water to obtain 10.25 g of crude crystals. By recrystallizing 10.25 g of crude crystals twice from 90% ethanol, 6.49 g of 5-[(2,4-dioxothiazolidin-5-yl) methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl] benzamide (KRP-297) were obtained (yield 61.3%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.C1(O[C:19](=O)[C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)C=CC=CC=1.C1(O)C=CC=CC=1>>[OH:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]2[O:7][C:6]([C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=3)=[N:8][N:9]=2)=[CH:21][CH:22]=1
Reactant: NNC(=O)c1ccc(O)cc1
Reactant: O=C(Oc1ccccc1)c1ccc(O)cc1
Solvent: Oc1ccccc1
Product: Oc1ccc(-c2nnc(-c3ccc(O)cc3)o2)cc1
Temperature: 210 °C
Reaction time: 0.29 h
Yield: 45 %

Procedure:
Into a 250 ml three neck round bottem flask equipped with a magnetic stirbar, nitrogen inlet, glass stopper and distillation head is placed 4-hydroxybenzoic hydrazide (60.9 g, 0.4 mol) and phenyl-4-hydroxybenzoate (85.7 g, 0.4 mol). The mixture is heated to approximately 210° C. by use of a Wood's metal bath. The solids melt and phenol begins to evolve and is removed via the distillation head. The melt begins to solidify after about 15-20 minutes. The temperature is then increased to 300° C. and held for approximately one hour while under nitrogen. After cooling, the tan solid is pulverized and stirred with methanol (150-200 ml). The undissolved solid is collected and dried at 150° C. in a forced air oven. The white solid (approximately 56 g) is recrystallized from N,N-dimethylacetamide (DMAc, 225 ml) and water (105 ml) and after drying at 200° C. under vacuum (45.7 g, 45% yield), it exhibited a melting point of 347° C. by differential thermal analysis (DTA). [Y. Iwakura, U. Keikichi, Y. Imai, and Y. Takase, Die Makromoleculare Chemie, 95, 261 (1966) melting point 338° C⟧ Elemental analysis for C14H10O3N2. Calculated: C, 66.13%; H, 3.96%; O, 18.88%; N, 11.02%. Found C, 66.17%; H, 4.05%; N, 11.12%.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[S:12][CH:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>CO>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[S:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(C)c2c(-c3ccc(C(C)C)cc3)csc2c1
Solvent: CO
Product: Cc1cc(C)c2c(c1)SCC2c1ccc(C(C)C)cc1
Yield: 85 %

Procedure:
Using 3-(4-isopropylphenyl)-4,6-dimethyl-1-benzothiophene obtained in Reference Example 198, the title compound was synthesized in the same manner as in Reference Example 199. Yield 85%. Melting point: 74-75° C. (methanol).
Reaction SMILES: C([N:8]([C:20](=[O:50])[CH2:21][C:22]([C:25]1[CH:30]=[C:29]([P:31]([O:42][CH2:43][CH3:44])([CH2:33][P:34]([O:39][CH2:40][CH3:41])([O:36][CH2:37][CH3:38])=[O:35])=[O:32])[CH:28]=[CH:27][C:26]=1[O:45][C:46](=[O:49])[CH2:47][CH3:48])([CH3:24])[CH3:23])[C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C1C=CC=CC=1>CO.[Pd]>[C:46]([O:45][C:26]1[CH:27]=[CH:28][C:29]([P:31]([O:42][CH2:43][CH3:44])([CH2:33][P:34]([O:36][CH2:37][CH3:38])([O:39][CH2:40][CH3:41])=[O:35])=[O:32])=[CH:30][C:25]=1[C:22]([CH3:24])([CH3:23])[CH2:21][C:20]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:50])(=[O:49])[CH2:47][CH3:48]
Reactant: CCOP(=O)(CP(=O)(OCC)c1ccc(OC(=O)CC)c(C(C)(C)CC(=O)N(Cc2ccccc2)[C@@H](Cc2ccccc2)C(=O)O)c1)OCC
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(CP(=O)(OCC)c1ccc(OC(=O)CC)c(C(C)(C)CC(=O)N[C@@H](Cc2ccccc2)C(=O)O)c1)OCC
Yield: 93.6 %

Procedure:
Compound 125 (240 mg, 0.329 mmol) was dissolved in methanol (10 mL) and hydrogenated over Pd/C (60 mg, 30%) under H2 (1 atm) for 3 hr. The catalyst was filtered off and the solvent removed under reduced pressure resulting in the pale-yellow liquid 126 (197 mg, 94%): 1H NMR (400 MHz, CDCl3) δ 1.23 (t, J=7.0, 3H), 1.25 (t, J=7.0, 3H), 1.29-1.40 (m, 18H), 1.41 (s, 3H), 1.43 (s, 3H), 1.54 (s, 3H), 1.56 (s, 3H), 2.27 (d, J=12.9, 1H), 2.42 (d, J=12.8, 1H), 2.54-2.90 (m, 12H), 2.96 (d, J=6.2, 1H), 2.99 (d, J=6.3, 1H), 3.89-4.30 (m, 12H), 4.56-4.78 (m, 2H), 5.72 (d, J=8.5, 1H), 5.85 (d, J=8.9, 1H), 7.07 (dd, J=2.1, 3.6, 2H), 7.09 (dd, J=2.1, 3.6, 2H), 7.13-7.24 (m, 10H), 7.58-7.67 (m, 2H), 7.79-7.87 (m, 2H): 31P (162 MHz, CDCl3) δ 22.28 (d, J=5.3, 1P), 22.37 (d, J=1.9, 1 P), 34.38 (d, J=5.3, 1 P), 34.91 (d, J=1.9, 1 P).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:24]([CH3:25])=[CH:23][C:12]([CH2:13][C@@H:14]([CH2:19][C:20]([O-])=[O:21])[C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=1[O:26][CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH2:40][CH2:39][C:38]3[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=3[NH:36][C:35]2=[O:45])[CH2:30][CH2:29]1.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(#N)C.C1COCC1>[CH2:1]([O:8][C:9]1[C:24]([CH3:25])=[CH:23][C:12]([CH2:13][C@@H:14]([CH2:19][C:20](=[O:21])[N:28]2[CH2:29][CH2:30][CH:31]([N:34]3[CH2:40][CH2:39][C:38]4[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=4[NH:36][C:35]3=[O:45])[CH2:32][CH2:33]2)[C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=1[O:26][CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Reactant: COC(=O)[C@H](CC(=O)[O-])Cc1cc(C)c(OCc2ccccc2)c(OC)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1)Cc1cc(C)c(OCc2ccccc2)c(OC)c1

Procedure:
Prepared analogously to Example 12d from 5.80 g (15.6 mmol) 1-methyl(S)-2-(4-benzyloxy-3-methoxy-5-methyl-benzyl)-succinate and 4.20 g (17.13 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, using 3.43 g (17.9 mmol) (3-dimethylamino-propyl)-ethyl-carbodiimide and 2.38 g (19.5 mmol) 4-dimethylamino-pyridine for the coupling and 130 mL acetonitrile and 50 mL THF as solvent.