Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]=[N+]=[N-])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1.N1C=CC=CC=1.O>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=2)=[O:30])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH2:18])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(CN=[N+]=[N-])c2)n1
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Cl)cc2)n(-c2cccc(CN)c2)n1
Reaction time: 3 h
Yield: 103.2 %

Procedure:
To a solution of Example H (1.50 g, 5.55 mmol) in dry THF (10 mL) was added a THF solution (10 mL) of 4-chlorophenyl isocyanate (1.02 g, 6.66 mmol) and pyridine (5.27 g, 66.6 mmol) at RT. The reaction mixture was stirred for 3 h and then H2O (30 mL) was added. The precipitate was filtered and washed with 1N HCl and ether to give 1-{3-tert-butyl-1-[3-(aminomethyl)phenyl}-1H-pyrazol-5yl)-3-(4-chlorophenyl)urea (2.28 g, 97%) as a white solid, which was used for next step without further purification. MS (ESI) m/z: 424 (M+H+).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:25])[C:22](O)=[O:23])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.N.CC#[N:35]>C1(C)C=CC=CC=1.CN(C=O)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:25])[C:22]([NH2:35])=[O:23])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C2CCN(C(=O)C(=O)O)CC2)cc1OC1CCCC1
Reactant: CC#N
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(C2CCN(C(=O)C(N)=O)CC2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a magnetically-stirred suspension of 2-[4-(3-cyclopentyloxy-4-methoxyphenyl) piperidin-1-yl]-2-oxo-acetic acid (2.5 mmol, 0.868 g) in dry toluene (25 mL) at room temperature was added oxalyl chloride (2.0M solution in CH2Cl2 ; 2.75 mmol, 1.38 mL) dropwise over 10 minutes, followed by DMF (4 drops). The resulting homogenous solution was stirred at room temperature for 30 minutes, after which time saturated NH3 /CH3CN (25 mL) was added dropwise over 30 minutes. A white solid precipitated out of solution, and the heterogeneous mixture was stirred for 1 hour at room temperature. The solution was diluted with H2O to dissolve the white precipitate and the volatiles were removed in vacuo. The solid was partitioned between saturated NaHCO3 (150 mL) and EtOAc (150 mL) and the aqueous phase was extracted with EtOAc (3×150 mL). The combined organic layers were washed with H2O (300 mL), dried (Na2SO4) and concentrated in vacuo to yield the title compound as a white foam, mp=66°-66.5° C. (1.8 mmol, 0.640 g, 74% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:17]=[C:16](F)[CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]>>[Br:7][C:8]1[CH:17]=[C:16]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1ccc(F)cc1Br
Reactant: C1CNCCN1
Product: COC(=O)c1ccc(N2CCNCC2)cc1Br

Procedure:
The title compound was prepared by substituting piperazine for EXAMPLE 1B and methyl 2-bromo-4-fluorobenzoate for EXAMPLE 1C in EXAMPLE 1D.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3]1.N1C=CC([NH:13][C:14](N)=[S:15])=N1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:14]([NH2:13])=[S:15])=[N:3]1
Reactant: NC(=S)Nc1cc[nH]n1
Reactant: Cn1ccc(N)n1
Product: Cn1ccc(NC(N)=S)n1

Procedure:
This material is prepared from 1-methyl-1H-pyrazol-3-ylamine following the procedure described for the preparation of (1H-pyrazol-3-yl)-thiourea (35a)
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([CH:26]([F:28])[F:27])[CH:23]=[C:22]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=4)[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:28][CH:26]([F:27])[C:24]1[CH:23]=[C:22]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:36])[F:38])=[CH:31][CH:30]=2)[N:21]=[C:20]([C:16]2[CH:15]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=3)[CH:19]=[CH:18][CH:17]=2)[N:25]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)c2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)c2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 17.8 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-5-{3-[4-difluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide (0.4 g) in dichloromethane (7 ml) was added TFA (7 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by flash-chromatography on silica gel (ethyl acetate/hexane) and crystallization (dichloromethane) yielded the title compound as a white solid (0.064 g, 13%). MS (ISP) 512.3 [(M+H)+]; mp 240.5° C.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].S(Cl)([Cl:13])(=O)=O>C(Cl)Cl>[Cl:13][CH:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(Cl)C(C)=O

Procedure:
32.5 g (0.25 mol) of ethyl acetoacetate are dissolved in 64 ml of methylene chloride. 33.74 g (0.25 mol) of sulfuryl chloride are added dropwise to this solution, and the mixture is then (when the evolution of gas is complete) heated at a gentle boil for one hour. After the methylene chloride has been removed by distillation, the residue is distilled at 86°-92° C./12 mmHg. 38.8 g of substance are obtained, 1H NMR: --CH3 1.31 ppm (t, 3H), --CH2 --(ester) 4.28 ppm (q, 2H), --CH3 (acetyl) 2.38 ppm (s, 3H), --CHCl--4.76 ppm (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>CN(C)C=O>[N:14]1([CH2:13][CH2:12][O:8][C:4]2[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: ClCCN1CCOCC1
Reactant: Nc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1cccc(OCCN2CCOCC2)c1
Reaction time: 1 h

Procedure:
To 36.01 g. of m-aminophenol dissolved in 325 ml. of N,N-dimethylformamide, 16.3 g. of 50% sodium hydride in oil was added. The reaction was stirred for 1 hour, until the effervescence stopped; then 57 g. of N-(2-chloroethyl)morpholine, from above, was added. After stirring overnight, the mixture was heated on a steam bath for 1/2 hr., then concentrated under vacuum. The residue was taken up in 300 ml. of 2N hydrochloric acid and washed twice with ether. After basifying with 10N sodium hydroxide, the product was extracted into ether, dried (magnesium sulfate), filtered through hydrous magnesium silicate and evaporated to a brown oil. Distillation gave 34.0 g. of a golden oil, b.p. 165°-180° C./0.45 mm.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:35]2[N:44]=[CH:43][C:42]3[C:37](=[C:38]([F:49])[CH:39]=[C:40]([C:45]([CH3:48])([CH3:47])[CH3:46])[CH:41]=3)[C:36]2=[O:50])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][NH:28][C:29](=[O:32])[CH:30]=[CH2:31])[N:20]=2)[C:15](=[O:33])[N:14]([CH3:34])[CH:13]=1)(=O)C.[Li+].[OH-]>C1COCC1.CC(O)C.O>[C:45]([C:40]1[CH:41]=[C:42]2[C:37](=[C:38]([F:49])[CH:39]=1)[C:36](=[O:50])[N:35]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[N:20]=[C:21]([O:25][CH2:26][CH2:27][NH:28][C:29](=[O:32])[CH:30]=[CH2:31])[CH:22]=[CH:23][CH:24]=4)[C:15](=[O:33])[N:14]([CH3:34])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:44]=[CH:43]2)([CH3:48])([CH3:47])[CH3:46]
Reactant: C=CC(=O)NCCOc1cccc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3COC(C)=O)cn(C)c2=O)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: C=CC(=O)NCCOc1cccc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.4 %

Procedure:
A mixture of 104d (140 mg, 0.21 mmol) and LiOH (44 mg, 1.05 mmol) in THF/i-PrOH/water (2.0 mL/1.2 mL/0.8 mL) was stirred at rt for 1 h. The mixture was extracted with EA. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC to give 104 (10 mg, 10% for two steps) as a light yellow solid. 1H NMR (500 MHz, CDCl3): δ 8.72-8.66 (m, 2H), 8.33 (s, 1H), 7.91 (s, 1H), 7.59-7.47 (m, 6H), 6.51 (s, 1H), 6.44 (d, J=10.0 Hz, 1H), 6.24-6.16 (m, 2H), 5.99-5.94 (m, 1H), 5.50 (d, J=10.0 Hz, 1H), 4.58-4.48 (m, 2H), 4.28-4.21 (m, 2H), 3.99-3.57 (m, 5H), 1.43 (s, 9H). MS-ESI: [M+H]+ 640.3
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.CN(C)C=O.[H-].[Na+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CO.ClCCl>[CH2:36]([O:35][C:33]([CH2:32][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)=[O:34])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)Cn1c(NC2CCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Reaction time: 0.5 h

Procedure:
Combine (1H-benzimidazol-2-yl)(1-(t-butoxycarbonyl)piperidin-4-yl)amine (0.5 g, 1.58 mmol) and dimethylformamide (10 mL). Add portionwise, sodium hydride (0.08 g, 60% in oil, 1.66 mmol). After 30 minutes, add ethyl bromoacetate (0.277 g, 1.66 mmol). After 12 hours, quench by the addition of water and extract the quenched reaction mixture with dichloromethane. Separate the layers and extract the organic layer with five times with water. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 5% methanol/dichloromethane to give (1-(ethoxycarbonylmethyl)-1H-benzimidazol-2-yl)(1-(t-butoxycarbonyl)piperidin-4-yl)amine.
Reaction SMILES: C([C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]([O:30][C:31]([F:48])([F:47])[C:32]([F:46])([F:45])[O:33][C:34]([F:44])([F:43])[C:35]([F:42])([F:41])[O:36][C:37]([F:40])([F:39])[F:38])([F:29])[F:28])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)CCCCCCC.[CH2:49]([O:56]C1C=NC(C2C=CC(O)=CC=2)=NC=1)[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]>CN(C)C=O>[CH2:49]([O:56][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]([O:30][C:31]([F:47])([F:48])[C:32]([F:45])([F:46])[O:33][C:34]([F:44])([F:43])[C:35]([F:42])([F:41])[O:36][C:37]([F:40])([F:38])[F:39])([F:29])[F:28])=[CH:19][CH:20]=2)=[N:13][CH:14]=1)[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]
Reactant: CCCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCCCCCCc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1
Solvent: CN(C)C=O
Product: CCCCCCCOc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
The title compound was prepared essentially as in Example I by combining 3-(2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy) 1-chloropropane (5.5 g, 15.0 mmol, Example 24) with 5-heptyloxy-2-(4-hydroxyphenyl)pyrimidine (3 g, 10.5 mmol) in dimethylformamide and stirring at 120° C. overnight to provide product boiling at 195°-210° C. at 0.3 torr (yield of 5.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[N:22]=[C:21]([C:23]([NH:25][NH2:26])=[O:24])[O:20][N:19]=2)=[CH:4][CH:3]=1.ClC1C=CC(C2N=C3C=CC([F:42])=CN3C=2CC2N=C(C(OCC)=O)ON=2)=CC=1.O.NN>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([F:42])=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[N:22]=[C:21]([C:23]([NH:25][NH2:26])=[O:24])[O:20][N:19]=2)=[CH:6][CH:7]=1
Reactant: NNC(=O)c1nc(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)no1
Reactant: CCOC(=O)c1nc(Cc2c(-c3ccc(Cl)cc3)nc3ccc(F)cn23)no1
Agent: NN
Solvent: O
Product: NNC(=O)c1nc(Cc2c(-c3ccc(Cl)cc3)nc3ccc(F)cn23)no1

Procedure:
The title compound was prepared in the same fashion as that for compound 215 from ethyl 3-((2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxylate and hydrazine hydrate. m/e+=387 (M+H+). 1H NMR (400 MHz, in DMSO-d6): δ 10.75 (1H, D, brs, NH), δ 8.70-8.68 (1H, D, dd, J=4.4, 2.0 Hz, ArH), δ 7.83-7.80 (2H, D, d, J=8.4 Hz, ArH), δ 7.75-7.71 (1H, D, dd, J=10.0, 5.2 Hz, ArH), δ 7.55-7.53 (2H, D, d, J=8.4 Hz, ArH), δ 7.47-7.42 (1H, D, dt, J=8.4, 2.4 Hz, ArH), δ 5.01-4.75 (2H, D, brd, NH2), δ 4.74 (2H, D, s, CH2).
Reaction SMILES: [K].[CH3:2][O:3][C:4]1[CH:25]=[CH:24][C:7]2[NH:8][C:9]([S:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)=[O:12])=[N:10][C:6]=2[CH:5]=1.C(O)(=O)C.CO.O.O.O.O.O.O.[Cl-].[Mg+2:39].[Cl-]>O>[Mg:39].[CH3:2][O:3][C:4]1[CH:25]=[CH:24][C:7]2[NH:8][C:9]([S:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)=[O:12])=[N:10][C:6]=2[CH:5]=1
Reactant: [Mg+2]
Agent: COc1ccc2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Agent: [Cl-]
Agent: [K]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: [Mg]
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole potassium salt (100 g) was taken in water (500 ml) and was stirred at room temperature for 10-15 minutes. The pH was adjusted to 10-11 with acetic acid at and the mixture was stirred for half an hour 20-25° C. Methanol (100 ml) was added. Aqueous solution of magnesium chloride hexahydrate (20.3 g dissolved in 100 ml) was then added to the above mixture at room temperature under stirring. The mixture was stirred for 60 minutes at room temperature. The resulting solid was filtered, washed with methanol and water. The wet material was dried under reduced pressure at 40-45° C. for 8-10 hours.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][N:6]1[C:14](=S)[CH2:15][C:16](=O)[CH3:17])=[O:4].[F:20][C:21]([F:26])([F:25])[CH2:22][NH:23][NH2:24]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][N:6]1[C:14]1[N:23]([CH2:22][C:21]([F:26])([F:25])[F:20])[N:24]=[C:16]([CH3:17])[CH:15]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(C)(=O)=O)CN1C(=S)CC(C)=O
Reactant: NNCC(F)(F)F
Product: COC(=O)[C@@H]1C[C@@H](S(C)(=O)=O)CN1c1cc(C)nn1CC(F)(F)F

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-methanesulfonyl-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester (example 448c) was reacted with 2,2,2-trifluoroethylhydrazine (CAS Reg. No. 5042-30-8) to give the title compound. MS (ESI): m/z=370.4 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[O:20])=[CH:15][CH:14]=2)[C@H:11]([C:21]([O:23][CH3:24])=[O:22])[O:10][C:9]1([CH3:26])[CH3:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=[O:29])C>>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:29])=[O:20])=[CH:15][CH:14]=2)[C@H:11]([C:21]([O:23][CH3:24])=[O:22])[O:10][C:9]1([CH3:26])[CH3:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)O
Reactant: COC(=O)[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1c1ccc(C=O)cc1
Product: COC(=O)[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1c1ccc(C(=O)O)cc1
Temperature: 45 °C

Procedure:
To a solution of 2.1 g of methyl (4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-(4-formylphenyl)-5-oxazolidinecarboxylate in 25 cm3 of acetic acid are added 1.06 g of sodium perborate hydrate. The reaction medium is heated with stirring to a temperature in the region of 45° C., maintained for 10 hours at this temperature and then cooled to a temperature in the region of 20° C. and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residual oil is dissolved in 75 cm3 of ethyl acetate and the solution obtained is washed with 5 times 5 cm3 of distilled water, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. 2.2 g of methyl (4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-(4-carboxyphenyl)-5-oxazolidinecarboxylate are thus obtained in the form of a yellow oil.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:11][C:10]=1[F:21])C1C=CC=CC=1>CO.[Pd]>[F:21][C:10]1[CH:11]=[C:12]([CH2:15][CH2:16][S:17]([CH3:20])(=[O:18])=[O:19])[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: CS(=O)(=O)CCc1ccc(OCc2ccccc2)c(F)c1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)CCc1ccc(O)c(F)c1
Reaction time: 3 h
Yield: 92.3 %

Procedure:
To a solution of 1-benzyloxy-2-fluoro-4-(2-methylsulfonyl-ethyl)-benzene (1.5 g, 4.87 mmol) in MeOH (25 mL) was added Pd/C (50 mg). The reaction was stirred under H2 (1 atm) for 3 hours. The solid material was filtrated off and the filtrate was concentrated under vacuum to afford the desired compound (981 mg, 92.4%) as a yellowish solid. The crude compound was used for the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 9.73 (s, 1H), 7.14˜7.11 (m, 1H), 6.94˜6.87 (m, 2H), 3.43˜3.37 (m, 2H), 2.98 (s, 3H), 2.95˜2.91 (m, 2H). LCMS 228.2 [MH+].
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:14]=[CH2:15])=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])([O-])=O>CCOC(C)=O.CCO.[Pd]>[NH2:1][C:4]1[C:5]([CH2:14][CH3:15])=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: C=Cc1c(C(=O)OC)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCc1c(N)cccc1C(=O)OC
Yield: 97.7 %

Procedure:
A mixture of methyl 3-nitro-2-vinylbenzoate (1.1 g, 5.31 mmol), and 5% Pd/C (100 mg) in EtOAc/EtOH 1:1 (50 ml) was hydrogenated at 3 atm over night. The mixture was filtered through Celite, and the filtrate was concentrated to give the title compound 0.93 g (97%) as a colourless oil.
Reaction SMILES: CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.FC(F)(F)C(O)=O.[Cl:38][CH2:39][CH2:40][CH2:41]/[C:42](=[CH:46]\[C:47]1[CH:52]=[CH:51][C:50]([N:53]2[CH:57]=[C:56]([CH3:58])[N:55]=[CH:54]2)=[C:49]([F:59])[CH:48]=1)/[C:43]([OH:45])=O.[F:60][C:61]1[CH:66]=[C:65]([F:67])[CH:64]=[CH:63][C:62]=1[CH:68]([NH2:70])[CH3:69]>CN(C=O)C.C(OCC)(=O)C>[F:60][C:61]1[CH:66]=[C:65]([F:67])[CH:64]=[CH:63][C:62]=1[CH:68]([NH:70][C:43](=[O:45])/[C:42](=[CH:46]/[C:47]1[CH:52]=[CH:51][C:50]([N:53]2[CH:57]=[C:56]([CH3:58])[N:55]=[CH:54]2)=[C:49]([F:59])[CH:48]=1)/[CH2:41][CH2:40][CH2:39][Cl:38])[CH3:69]
Reactant: CC(N)c1ccc(F)cc1F
Reactant: Cc1cn(-c2ccc(/C=C(\CCCCl)C(=O)O)cc2F)cn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cn(-c2ccc(/C=C(\CCCCl)C(=O)NC(C)c3ccc(F)cc3F)cc2F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

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: [F:1][C:2]([C:10]([F:13])([F:12])[F:11])([CH:7](O)[CH3:8])[C:3]([O:5][CH3:6])=[O:4].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.FC(C(F)(F)F)(C(OS(C(F)(F)F)(=O)=O)C)C(OC)=O.N12CCCN=C1CCCCC2>ClCCl.N1C=CC=CC=1>[F:1][C:2]([C:10]([F:11])([F:13])[F:12])([CH:7]=[CH2:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(F)(C(C)O)C(F)(F)F
Agent: COC(=O)C(F)(C(C)OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CC(F)(C(=O)OC)C(F)(F)F
Reaction time: 2 h

Procedure:
Methyl 2-fluoro-2-trifluoromethyl-3-hydroxybutanoate (1 g) and pyridine (440 μl) in dichloromethane (5 ml) were stirred at -10° C. under nitrogen. Trifluoromethanesulphonic anhydride (900 μl) in dichloromethane (5 ml) was added dropwise and the resulting mixture stirred for 2 hours. The solution of methyl 2-fluoro-2-trifluoromethyl-3-trifluoromethylsulphonyloxybutanoate prepared in Step 1 was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (1.5 ml) and heated under reflux for 1 hour. Further DBU (1.5 ml) was added and the mixture left to stand at room temperature overnight. The red solution was washed with 5% aqueous HCl, saturated aqueous sodium bicarbonate (twice), dried (MgSO4) and concentrated at atmospheric pressure to give a red oil which was distilled using a Kugelrohr apparatus. The fraction distilling at 50° C. (air bath temperature) and at 100 mmHg was shown by NMR to be the desired product; 1H NMR (270 MHz; CDCl3) δ 3.92 (3H,s), 5.65(1H,dd), 5.81(1H,d), 6.08(1H,ddd) ppm. ##STR1##