Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[CH3:9][C:10]1[CH:18]=[C:17]([C:19]([F:28])([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])[CH:16]=[C:15]([CH3:29])[C:11]=1[C:12](Cl)=[O:13]>O1CCCC1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[NH2:7][C:3]1[CH:2]=[C:1]([NH:8][C:12](=[O:13])[C:11]2[C:10]([CH3:9])=[CH:18][C:17]([C:19]([F:28])([C:20]([F:21])([F:22])[F:23])[C:24]([F:25])([F:26])[F:27])=[CH:16][C:15]=2[CH3:29])[CH:6]=[CH:5][CH:4]=1
Reactant: Nc1cccc(N)c1
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1C(=O)Nc1cccc(N)c1
Temperature: 70 °C
Reaction time: 48 h
Yield: 0.1 %

Procedure:
To a solution of benzene-1,3-diamine (4.48 g, 41.4 mmol) in anhydrous tetrahydrofuran (3 ml) under an atmosphere of nitrogen was added 2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-benzoyl chloride (4.40 g, 13.8 mmol) (Example I4) dissolved in anhydrous tetrahydrofuran (3 ml). The reaction mixture was stirred at 70° C. for 48 hours. Then the reaction mixture was diluted with ethyl acetate and aqueous sodium hydrogen carbonate (saturated). The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 3:1) to give N-(3-amino-phenyl)-2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-benzamide (3.4 mg, 61% yield). 1H-NMR (CDCl3, 400 MHz): 7.34 (t, 1H), 7.30 (s, 2H), 7.15 (t, 1H), 6.75 (d, 2H), 6.52 (d, 2H), 2.46 (s, 6H) ppm.
Reaction SMILES: [Na+].[Cl:2][C:3]1[C:4]([F:17])=[CH:5][C:6]([N+:14]([O-])=O)=[C:7]([NH:9][CH2:10][C:11]([O-])=[O:12])[CH:8]=1.O.O.[Sn](Cl)Cl>C(O)C>[Cl:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][C:4]=1[F:17])[NH:14][C:11](=[O:12])[CH2:10][NH:9]2
Reactant: O=C([O-])CNc1cc(Cl)c(F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1CNc2cc(Cl)c(F)cc2N1
Temperature: 25 °C
Yield: 59.4 %

Procedure:
A suspension of N-(5'-chloro-4'-fluoro-2'-nitrophenyl)glycine sodium salt (0.650 g, 2.61 mmol) and tin (II) chloride dihydrate (1.770 g, 7.845 mmol) in ethanol (10.5 mL) was refluxed for 1 h. It was then cooled to room temperature and ~5 mL ethanol was removed under vacuum. The precipitated solid was collected by filtration under vacuum, washed with ethanol (3 mL) and dried to obtain 0.311 g (59%) title compound as an off-white powder; 1H NMR (DMSO-d6) δ 3.69 (s, 2H), 6.08 (s, 1H), 6.65 (d, 1H, J=9.9 Hz), 6.71 (d, 1H, J=7.2 Hz), 10.39 (s, 1H). The solvent from the filtrate was removed under vacuum. The residue was diluted with water (15.0 mL) and the pH was adjusted with 10% Na2CO3 to ~9. The resulting suspension was extracted with ethyl acetate (50 mL). The ethyl acetate was dried over anhydrous Na2SO4 and removed under vacuum to yield further 0.118 g (22%) of pure (1H NMR) title compound for a combined yield of 81%.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:5]=1[OH:14])[CH:2]=[CH2:3].[C:15](Cl)(=[O:21])[CH2:16][CH2:17][CH2:18][C:19]#[CH:20].Cl[Sn](Cl)(Cl)Cl>C(Cl)Cl>[CH2:1]([C:4]1[CH:9]=[C:8]([C:15](=[O:21])[CH2:16][CH2:17][CH2:18][C:19]#[CH:20])[CH:7]=[C:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:5]=1[OH:14])[CH:2]=[CH2:3]
Reactant: C=CCc1cccc(C(C)(C)C)c1O
Reactant: C#CCCCC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: C#CCCCC(=O)c1cc(CC=C)c(O)c(C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
A solution of 2-allyl-6-t-butylphenol (0.57 g; 3 mmol) in dry CH2Cl2 (12 ml) is cooled to -78° C., and 5-hexynoyl chloride (0.43 g; 3.3 mmol) is added via syringe, followed by SnCl4 (0.375 ml) added dropwise via syringe, with stirring under Argon. After 30 min the reaction is allowed to warm to 0° C. and is stirred at that temperature for 5 min; it is then quenched with ca 1 ml of 3N HCl. The reaction is poured into 100 ml water and extracted with 3×50 ml portions of ether. The combined ether layers are washed with 150 ml portions of water until the aqueous layer is neutral (pH test). The ether layer is dried (MgSO4), filtered, and concentrated in vacuo to give crude product, which is chromatographed with 20:1 hexane/EtOAc, giving 0.64 g 2-allyl-4-(5-hexynoyl)-6-t-butylphenol (77% yield). The product is recrystallized from hexane at 0° C. to give crystals melting at 62°-63° C.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]=[C:9]([S:11][CH3:12])[S:10][C:6]=2[CH:5]=[C:4]([CH2:13][NH:14][C:15]2[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:3]=1.Br[C:23]1C=C(N)C(NCC2C=CC3N=C(SC)SC=3C=2)=CC=1OC>>[N:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:13][C:4]2[CH:3]=[C:2]([Br:1])[C:7]3[N:8]=[C:9]([S:11][CH3:12])[S:10][C:6]=3[CH:5]=2)[CH:23]=1
Reactant: CSc1nc2c(Br)cc(CNc3ncccc3N)cc2s1
Reactant: COc1cc(NCc2ccc3nc(SC)sc3c2)c(N)cc1Br
Product: CSc1nc2c(Br)cc(Cn3cnc4cccnc43)cc2s1

Procedure:
6-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)-4-bromo-2-(methylthio)benzo[d]thiazole was synthesized as an orange solid (180 mg) using a procedure analogous to that described in Step 3 of Example 41, substituting N2-((4-bromo-2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyridine-2,3-diamine from the previous step for 4-bromo-5-methoxy-N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine used in Example 41. LCMS (ESI) m/z 390, 392 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[S:4].[CH2:6](N(CC)CC)C.C[O:14][C:15](=O)[C:16]([CH:18](OC(=O)C)[C:19]1[S:20][CH:21]=[CH:22][N:23]=1)=C>CCO>[CH3:6][S:4][C:3]1[NH:5][C:15](=[O:14])[C:16]([CH2:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[CH:1][N:2]=1
Reactant: CNC(N)=S
Reactant: C=C(C(=O)OC)C(OC(C)=O)c1nccs1
Reactant: CCN(CC)CC
Solvent: CCO
Product: CSc1ncc(Cc2nccs2)c(=O)[nH]1
Temperature: 70 °C

Procedure:
Methyl thiourea (0.492 g, 2.28 mmol, 1.1 eq) was dissolved in EtOH (dried over mol. sieves) (2 ml) and triethyl amine (0.633 ml, 2.2 eq) was added. Reaction mixture was heated to 70° C. and 2-(acetoxy-thiazol-2-yl-methyl)-acrylic acid methyl ester (0.5 g, 2.07 mmol, 1 eq) dissolved in EtOH (dried over mol. sieves) (2 ml), was added. It was heated at 70° C. for 8 h and then, it was cooled and filtered. Filtrate was evaporated to dryness and purified via Biotage SP 1 Snap 25 g, 25 ml/min; in system MeOH/DCM 1-30% MeOH in 30 CV. Appropriate fractions were combined and evaporated to give 250 mg of brown powder.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=O.COCCO[AlH2-]OCCOC.[Na+].O>O1CCCC1>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH2:7]2
Reactant: O=C1NCCc2c(F)cccc21
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1cccc2c1CCNC2
Reaction time: 18 h

Procedure:
5-Fluoro-3,4-dihydro-2H-isoquinolin-1-one (200 mg, 1.2 mmol) was dissolved in anhydrous tetrahydrofuran (6 ml), and the solution was mixed with Red-Al (Aldrich, 65% toluene solution, 6.1 mmol) and stirred at roar temperature for 18 hours. Water was slowly added to the reaction solution, and celite filtration was carried out when foaming started. The reaction product was extracted from the filtrate with ethyl acetate, and the reaction product was extracted from the extract with dilute hydrochloric acid. The water layer was alkalified with sodium hydroxide aqueous solution, and the reaction product was extracted therefrom with ethyl acetate. The extract was washed with saturated brine and dried with anhydrous magnesium sulfate, and then the solvent was removed by evaporation under a reduced pressure to obtain crude 5-fluoro-3,4-dihydro-2H-isoquinoline. The crude 5-fluoro-3,4-dihyrdro-2H-isoquinoline was dissolved in anhydrous N,N-dimethylformamide (3 ml), and the solution was mixed with 2a-(4-bromobutyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one (370 mg, 1.2 mmol) and potassium carbonate (250 mg, 1.8 mmol) and stirred at room temperature for 18 hours. The reaction solution was mixed with water, the reaction product was extracted with ethyl acetate, and the extract was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was removed by evaporation from the extract under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 55 mg (0.14 mmol, 12% in yield) of the title compound.
Reaction SMILES: Cl.[F:2][C:3]([F:13])([F:12])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[CH2:10][NH2:11].CCN(C(C)C)C(C)C.Cl[C:24]1[N:29]=[C:28]([Cl:30])[C:27]([C:31]#[N:32])=[CH:26][N:25]=1>CN(C=O)C>[Cl:30][C:28]1[C:27]([C:31]#[N:32])=[CH:26][N:25]=[C:24]([NH:11][CH2:10][C:5]2[CH:6]=[N:7][CH:8]=[CH:9][C:4]=2[C:3]([F:12])([F:2])[F:13])[N:29]=1
Reactant: NCc1cnccc1C(F)(F)F
Reactant: N#Cc1cnc(Cl)nc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cnc(NCc2cnccc2C(F)(F)F)nc1Cl
Reaction time: 0.17 h
Yield: 43 %

Procedure:
To (4-(trifluoromethyl)pyridin-3-yl)methanamine hydrochloride (1.0 equiv.) in DMF (1.0 M) was added DIEA (2.5 equiv.). The reaction was cooled to −20° C. (ice/brine bath) then added 2,4-dichloropyrimidine-5-carbonitrile (1.0 equiv.). The reaction mixture was stirred for 10 min, then removed from the ice bath and allowed to stir for 30 min. The reaction mixture was diluted with ethyl acetate and partitioned with water. The organic layer was separated and volatile solvents were removed under reduced pressure. The residue was purified using silica gel chromatography (5-50% ethyl acetate in hexanes). The desired fractions were combined and volatile solvents were removed under reduced pressure. The residue was triturated in 10% ethyl acetate in hexanes, filtered, washed with hexanes, and dried in vacuo to afford 4-chloro-2-(((4-(trifluoromethyl)pyridin-3-yl)methyl)amino)pyrimidine-5-carbonitrile (43.0% yield) as a pale tan solid; MS (ESI) m/z 314.0 [M+1]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[OH:37])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=2[CH2:18]1)=O.[N:38]1([C:46](=O)[CH2:47]Cl)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[N:38]1([CH2:46][CH2:47][O:37][C:36]2[CH:35]=[CH:34][C:4]([CH2:5][CH2:7][NH:8][C:9]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=3[CH:17]3[CH2:26][CH2:25][C:24]4[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=4[CH2:18]3)=[CH:3][C:2]=2[F:1])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: O=C(CCl)N1CCCCCCC1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)c(F)c2)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN3CCCCCCC3)c(F)c2)c1
Yield: 31.9 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 1-azocan-1-yl-2-chloroethanone (15 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (6.9 mg) was obtained.
Reaction SMILES: [C:1]1([C:7]2[O:8]C3C=C(C(OC)=O)C=CC=3N=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-].O.[ClH:23]>C1COCC1.CO>[C:7]([Cl:23])(=[O:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)oc2c1
Reactant: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of methyl 2-phenyl-benzooxazole-6-carboxylate 1u (0.37 g, 1.46 mmol) and LiOH (0.10 g, 4.2 mmol) in THF (4 mL), MeOH (4 mL), and H2O (4 mL) was stirred at room temperature for 6 h. Aqueous 1N HCl solution was added to the mixture to adjust pH to 3˜4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aq. NaCl, dried over Na2SO4 and concentrated to give 1t (0.34 g).
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=O)[CH2:2]1.[C:9]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)#[N:10].[NH2:19][C:20]1[CH:24]=[CH:23][NH:22][N:21]=1>>[C:9]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]2[C:2]3[C:1](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]=3[NH:19][C:20]3=[CH:24][CH:23]=[N:22][N:21]23)=[CH:13][CH:12]=1)#[N:10]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: Nc1cc[nH]n1
Reactant: O=C1CCCC(=O)C1
Product: N#Cc1ccc(C2C3=C(CCCC3=O)Nc3ccnn32)cc1

Procedure:
1,3-Cyclohexanedione, 4-cyanobenzaldehyde and 3-aminopyrazole were processed as described in General Procedure A to provide the title compound.
Reaction SMILES: [OH:1][C:2]1C(=O)O[CH:5]=[CH:6][CH:7]=1.[CH3:9][O:10][C:11]([CH3:22])([CH3:21])[CH2:12][CH2:13][CH:14]=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].CO.[H][H]>C1(C)C=CC=CC=1.[Pd]>[C:16]([CH:15]1[CH:14]([CH2:13][CH2:12][C:11]([O:10][CH3:9])([CH3:21])[CH3:22])[CH2:5][CH2:6][CH2:7][C:2]1=[O:1])([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C=CCCC(C)(C)OC
Reactant: O=c1occcc1O
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOC(=O)C1C(=O)CCCC1CCC(C)(C)OC
Reaction time: 20 h

Procedure:
A mixture of 3-Hydroxypyrone (obtained by the procedure of R. H. Wiley and C. H. Jorboe, J. Am. Chem. Soc., 78, 2398, (1956), 5.0 g, 0.045 mol) and ethyl 6-methoxy-6-methyl-2-heptenoate (8.9 g, 0.045 mol) were dissolved in toluene (15 mL) and heated in a sealed vessel for 7 hours at 200~C. After cooling 5% Pd/C (1.0 g) and methanol (50 mL) were added and the vessel was pressurized with hydrogen gas (200 psi). After stirring 20 hours the mixture was filtered and concentrated to the residue. The crude product decomposed on distillation. No further purification was attempted. NMR of crude material (CDCl3)δ 1.2(s,6H), 1.3(t,3H), 3.2(s,3H), 3.7(m,1H), 4.2(m,2H); IR (neat) 2600-3800, (broad band), 2990, 2950, 1740, 1720, 1680, 1650, 1620, 1470, 1390, 1370, 1220, 1090 cm-1.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:12][CH:13]=O)=[CH:4][C:5]2[CH2:9][O:8][C:7](=[O:10])[C:6]=2[CH:11]=1.Cl.[N:16]1([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][C:28]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[O:29])=[CH:23][CH:22]=2)[CH:20]=[N:19][N:18]=[N:17]1.C([BH3-])#N.[Na+].CO>C(O)(=O)C>[CH3:1][C:2]1[C:3]([CH2:12][CH2:13][N:33]2[CH2:32][CH2:31][N:30]([C:28](=[O:29])[CH2:27][C:24]3[CH:23]=[CH:22][C:21]([N:16]4[CH:20]=[N:19][N:18]=[N:17]4)=[CH:26][CH:25]=3)[CH2:35][CH2:34]2)=[CH:4][C:5]2[CH2:9][O:8][C:7](=[O:10])[C:6]=2[CH:11]=1
Reactant: O=C(Cc1ccc(-n2cnnn2)cc1)N1CCNCC1
Reactant: Cc1cc2c(cc1CC=O)COC2=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc2c(cc1CCN1CCN(C(=O)Cc3ccc(-n4cnnn4)cc3)CC1)COC2=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a flask charged with (6-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (100 mg, 0.53 mmol) was added 1-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}piperazine hydrochloride (162 mg, 0.53 mmol), sodium cyanoborohydride (165 mg, 2.6 mmol), methanol (10 mL), and a drop of acetic acid. The mixture was allowed to stir at RT for 16 hours. LC showed formation of the desired product. The solvent was removed under reduced pressure. The residue was redissolved in DMSO-water, and purified by mass-directed HPLC. LC/MS: (1E, m/z) (M+1)+=447.3;
Reaction SMILES: [N:1]#[C:2][CH:3]=[CH:4][C:5]1[C:10]2[O:11][C@@H:12]([CH2:15][O:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:13][O:14][C:9]=2[CH:8]=[CH:7][C:6]=1[N+:27]([O-])=O.O.O.[Sn](Cl)Cl>C(OCC)(=O)C>[CH3:26][C:23]1[CH:24]=[CH:25][C:20]([S:17]([O:16][CH2:15][CH:12]2[O:11][C:10]3=[C:5]4[C:6](=[CH:7][CH:8]=[C:9]3[O:14][CH2:13]2)[N:27]=[C:2]([NH2:1])[CH:3]=[CH:4]4)(=[O:19])=[O:18])=[CH:21][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc([N+](=O)[O-])c(C=CC#N)c3O2)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4nc(N)ccc4c3O2)cc1

Procedure:
To a solution of 2.5 g (6.0 mmole) of toluene-4-sulfonic acid (2R)-8-(3-nitrilo-propenyl)-7-nitro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester in 200 mL of ethyl acetate was added 6.8 g (30 mmole) of tin (II) chloride dihydrate and the mixture was refluxed under nitrogen for 5 hours. The solvent was then removed in vacuum and replaced with 250 mL of methanol. Concentrated HCl (5 mL) was added and the mixture was refluxed under a nitrogen atmosphere for 15 hours. The solvent was again removed in vacuum and 500 mL of saturated aqueous sodium bicarbonate added. This was extracted twice with 250 mL portions of ethyl acetate and the combined organics washed with 400 mL portions of water and saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel with 5% methanol in chloroform as eluant to give 0.80 g of the (R)-enantiomer of the title compound as a yellow solid. 1H-NMR (CDCl3): doublet 8.0 δ (1 H); doublet 7.8 δ (2 H); doublet 7.3 δ (2 H); doublet 7.2 δ (1 H); doublet 7.1 δ (1 H); doublet 6.7 δ (1 H); multiplet 4.5 δ (1 H); multiplet 4.3 δ (3 H); doublet of doublets 4.1 δ (1 H); singlet 2.4 δ (3 H).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.[F:24][C:25]1[CH:26]=[C:27]([CH:33]2[CH2:35][CH:34]2[C:36]([O:38]CC)=[O:37])[CH:28]=[C:29]([F:32])[C:30]=1O>>[CH2:22]([C:19]1[CH:20]=[CH:21][C:16]([C:8]2[C:7]([CH2:6][O:5][C:30]3[C:29]([F:32])=[CH:28][C:27]([CH:33]4[CH2:35][CH:34]4[C:36]([OH:38])=[O:37])=[CH:26][C:25]=3[F:24])=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=2)=[CH:17][CH:18]=1)[CH3:23]
Reactant: CCOC(=O)C1CC1c1cc(F)c(O)c(F)c1
Reactant: CCc1ccc(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)cc1
Product: CCc1ccc(-c2nsc(C(F)(F)F)c2COc2c(F)cc(C3CC3C(=O)O)cc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 1 following Steps 5 and 6 by coupling [3-(4-ethylphenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methyl methanesulfonate and ethyl 2-(3,5-difluoro-4-hydroxyphenyl)cyclopropane-1-carboxylate followed by hydrolysis to afford the desired product as an off-white solid. 1HNMR (300 MHz, CDCl3) δ 7.75 (d, J=8.1 Hz, 2H), 7.32 (d, J=8.1 Hz, 2H), 6.63-6.71 (m, 2H), 5.16 (s, 2H), 2.69-2.77 (m, 2H), 2.49-2.55 (m, 2H), 1.64-1.89 (m, 2H), 1.29-1.37 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C23H18F5NO3S, 482.1[M−H]. found 482.1.
Reaction SMILES: [O:1]1[CH:6]([C:7]([OH:9])=[O:8])[CH:2]1[C:3]([OH:5])=[O:4].[CH2:10]([K])[CH3:11].C(Cl)(=O)C([Cl:16])=O>C(OCC)C>[Cl-:16].[CH2:10]([O:8][C:7](=[O:9])[CH:6]1[O:1][CH:2]1[C:3]([OH:5])=[O:4])[CH3:11]
Reactant: O=C(O)C1OC1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC[K]
Solvent: CCOCC
Product: CCOC(=O)C1OC1C(=O)O
Product: [Cl-]

Procedure:
To a solution of 1.98 g of ethyl potassium epoxysuccinate (i.e. ethyl potassium oxirane 2,3-dicarboxylate) in 50 ml of ethyl ether, a solution of 1.4 g of oxalyl chloride in 30 ml of ethyl ether was added dropwise while being stirred and cooled by ice for 30 min. After the mixture had been stirred additionally at room temperature for 2 hours, the formed precipitate was filtered. The filtrate was concentrated by evaporation under reduced pressure to give epoxysuccinic acid monoethyl ester chloride as an oil. Then, the acid chloride was dissolved in 30 ml of ethyl ether and the solution thus obtained was added dropwise to a solution of 1.6 g of L-leucine ethyl ester and 1.1 g of triethylamine dissolved in 50 ml of ethyl ether while being stirred and cooled by ice for 30 min. After the mixture had been stirred additionally at room temperature for three hours, the formed precipitate was filtered. The filtrate was evaporated under reduced pressure to give an oil. The oil thus obtained was further purified by silica gel column chromatography using chloroform-acetone (100:5) mixture as solvent to give N-(3-ethoxycarbonyloxirane-2-carbonyl)-L-leucine ethyl ester(EP-146) as a colorless oil. Yield 1.9 g (63%). Mass: m/e 301 (M+). IRνfilm (cm-1): 3370 (amine), 1748 (ester), 1680, 1545 (amide), 895 (epoxide). NMR(CDCl3)δ: 0.95 (6H, d, J=5 Hz), 1.26 (3H, t, J=7 Hz), 1.29 (3H, t, J=7 Hz), 1.64 (3H, m), 3.42 (0.5 H, d, J=2 Hz), 3.51 (0.5 H, d, J=2 Hz), 3.67 (1H, d, J=2 Hz), 4.20 (4H, q, J=2 Hz), 4.6 (1H, m), 6.35 (1H, b.).
Reaction SMILES: [C:1]12([C:11]3[C:12]([O:21][CH3:22])=[CH:13][C:14]([OH:20])=[C:15]([CH:19]=3)[C:16](O)=[O:17])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1>>[C:1]12([C:11]3[C:12]([O:21][CH3:22])=[CH:13][C:14]([OH:20])=[C:15]([CH:19]=3)[C:16]([NH:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)=[O:17])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COc1cc(O)c(C(=O)O)cc1C12CC3CC(CC(C3)C1)C2
Reactant: NCCc1ccc(O)cc1
Product: COc1cc(O)c(C(=O)NCCc2ccc(O)cc2)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
0.15 g of the target compound is obtained as solid of a light color in substantially the same manner as in (2) of Example 1, except for using 5-adamantan-1-yl-2-hydroxy-4-methoxybenzoic acid instead of 5-adamantan-1-yl-2,4-dihydroxybenzoic acid and using tyramine instead of dopamine.
Reaction SMILES: C([O:7][C:8]1[CH:9]=[C:10]([CH2:14][C@H:15]([O:20][CH:21]([CH3:23])[CH3:22])[C:16]([O:18][CH3:19])=[O:17])[CH:11]=[CH:12][CH:13]=1)(=O)C(C)(C)C.S(=O)(=O)(O)O.C1(C)C=CC=CC=1.O>CO>[OH:7][C:8]1[CH:9]=[C:10]([CH2:14][C@H:15]([O:20][CH:21]([CH3:23])[CH3:22])[C:16]([O:18][CH3:19])=[O:17])[CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)[C@H](Cc1cccc(OC(=O)C(C)(C)C)c1)OC(C)C
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)[C@H](Cc1cccc(O)c1)OC(C)C
Temperature: 60 °C
Reaction time: 19 h
Yield: 98.6 %

Procedure:
Methyl (2S)-3-(3-pivaloyloxyphenyl)-2-isopropoxypropionate (12.1 kg, 37.5 mol) was dissolved in methanol (49 L) and then cooled, followed by adding dropwise concentrated sulfuric acid (3 L) to the reaction mixture at an internal temperature of 8.8° C. After stirring the reaction mixture at 60° C. for 19 hours, toluene (121 L) and water (61 L) were added to the mixture for separating. The aqueous layer was again extracted with toluene (121 L). The organic layers were then combined. The resultant organic layer was washed with a 5% sodium bicarbonate aqueous solution (57 L) and with water (61 L) and then dried with anhydrous magnesium sulfate, followed by vacuum concentration to obtain 8.81 kg of the title compound in the form of oily matter (yield: 99%).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[C:7]1([CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1)[CH2:6]2.[CH2:19]([OH:22])[CH2:20][OH:21].[C:23]1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:19]1[O:22][C:6]2([C:5]3[C:9](=[CH:10][CH:23]=[C:3]([CH3:11])[CH:4]=3)[CH2:8][C:7]32[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]3)[O:21][CH2:20]1
Reactant: COc1ccc2c(c1)CC1(CCC(=O)CC1)C2=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCCO
Solvent: c1ccccc1
Product: Cc1ccc2c(c1)C1(OCCO1)C1(CCC(=O)CC1)C2
Yield: 91 %

Procedure:
A mixture of 7.3 g. (0.032 M) of 6'-methylspiro(cyclohexane-1,2'-indan)-1',4-dione [8] (prepared in Example 14B), 2.15 g. (1.95 ml.) of ethylene glycol and 0.5 g. of p-toluenesulfonic acid in 200 ml. of benzene is heated at reflux under a Dean-Stark trap for about 5 hours. The mixture is allowed to cool, washed successively with aqueous sodium bicarbonate solution, water and brine and evaporated to dryness. The residual solid is recrystallized from methylene chloride: Skellysolve B to give 7.94 g. (91% yield) of 6'-methylspiro(cyclohexane-1,2'-indan)-1',4-dione 4-ethylene ketal [9] melting at 116° to 118° C.