Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[I:18].[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1.O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][O:19]1)[N:13]=[C:12]2[I:18]
Reactant: Fc1cccc(F)c1-c1ccc2[nH]nc(I)c2c1
Reactant: C1=COCCC1
Solvent: C1CCOC1
Solvent: O
Product: Fc1cccc(F)c1-c1ccc2c(c1)c(I)nn2C1CCCCO1
Temperature: 70 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
To a solution of 5-(2,6-difluoro-phenyl)-3-iodo-1H-indazole (45.5 g, 127.76 mmol) and TSA (4.86 g, 25.55 mmol) in THF (383.2 mL) was added 3,4-dihydro-2H-pyran (23.8 mL, 255.53 mmol) at RT. The mixture was stirred at 70° C. for 8 h. The reaction mixture was cooled to RT. Water was added to the reaction mixture and extracted with EtOAc (2×500 mL). The organic layer was washed with brine and dried over Na2SO4. The organic layer was concentrated under reduced pressure. The crude product was purified by column using (100-200 mesh) silica with 0-5% EtOAc in hexane to provide 5-(2,6-difluoro-phenyl)-3-iodo-1-(tetrahydro-pyran-2-yl)-1H-indazole (42.95 g, 78.2% yield). MS (ESI, pos. ion) m/z: 441.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=2)[O:5][C:6]=1[CH3:7].C[Sn](C)(C)[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:27][C@H:26]([CH2:28][C:29](=[O:33])[C:30]([NH2:32])=[O:31])[O:25][CH2:24]2)=[CH:19][C:18]=1[F:34]>>[CH3:1][C:2]1[N:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][C@H:26]([CH2:28][C:29](=[O:33])[C:30]([NH2:32])=[O:31])[O:25][CH2:24]4)=[CH:19][C:18]=3[F:34])=[CH:10][CH:9]=2)[O:5][C:6]=1[CH3:7]
Reactant: C[Sn](C)(C)c1ccc(N2CO[C@@H](CC(=O)C(N)=O)C2)cc1F
Reactant: Cc1nc(-c2ccc(Br)cc2)oc1C
Product: Cc1nc(-c2ccc(-c3ccc(N4CO[C@@H](CC(=O)C(N)=O)C4)cc3F)cc2)oc1C

Procedure:
The same procedure as in Example 1 was conducted, except for adding 4-(4,5-dimethyloxazol-2-yl)-bromobenzene and using (S)-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl acetamide as a starting material, to obtain the title compound.
Reaction SMILES: C([O:4][C:5]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6](=[O:8])[CH3:7])(=O)C.[OH-].[K+].[Cl-].[Na+]>CO>[CH:15]1([C:5]([OH:4])([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:6](=[O:8])[CH3:7])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(=O)OC(C(C)=O)(c1ccccc1)C1CCCCC1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: CC(=O)C(O)(c1ccccc1)C1CCCCC1
Yield: 75.4 %

Procedure:
To a solution of 1-acetoxy-1-cyclohexyl-1-phenylpropan-2-one (16.42 g, 0.06 mole) in 55 ml of a 90% aqueous methanol solution was added 3.2 g of potassium hydroxide. The solution was refluxed for 15 minutes, cooled, and 90 ml of a saturated aqueous sodium chloride solution was added. The reaction mixture was washed twice with ether. The ether washes were combined, dried and evaporated to dryness under vacuum. The crude product was vacuum distilled to afford a clear oil (10.51 g, 75.4%), bp 125°-8° C. (0.1 mm). NMR (CDCl3) δ7.6-7.2(m, 5H), 4.5(s, 1H), 2.1(s, 3H), 2.5-0.9(m, 11H). IR (neat) 3456, 3057, 1705, 1448, 1358, 1209, 1124 cm-1.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1)(=[O:5])=[O:4].Cl>O1CCCC1>[OH:11][CH2:10][C:9]1[CH:8]=[CH:7][C:6]([S:3]([NH:2][CH3:1])(=[O:5])=[O:4])=[CH:14][CH:13]=1
Reactant: CNS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(CO)cc1
Temperature: 80 °C
Yield: 74.9 %

Procedure:
Add methyl amine (4.5 mL, 2 M in dichloromethane) to a mixture of 4-chlorosulfonyl benzoic acid (0.5 g) and dichloromethane (20 mL). Stir at room temperature overnight. Quench by pouring the reaction mixture into a mixture of saturated aqueous ammonium chloride and ethyl acetate. Separate the layers, wash the organic phase with water, dry the remaining organic phase over sodium sulfate and then concentrate under reduced pressure to provide (0.40 g, 82%) of an oil. Add borane-tetrahydrofuran complex (7.44 mL, 1 M) to a mixture of 4-methylsulfamoyl-benzoic acid (0.4 g) and tetrahydrofuran (10 mL) at 0° C. Heat at 80° C. for 3 hours. Cool at room temperature and add 1 N aqueous hydrochloric acid (20 mL) and extract with ethyl acetate. Wash with saturated aqueous sodium bicarbonate and dry the remaining organic phase over sodium sulfate and concentrate under reduced pressure to provide (0.28 g, 75%) of an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-])=O)[CH:9]=1)[C:5]#[N:6].O.O.Cl[Sn]Cl>CCO.C1COCC1>[NH2:10][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([Br:1])[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(Br)cc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1cc(N)cc(Br)c1
Temperature: 25 °C
Reaction time: 10.5 h
Yield: 61.8 %

Procedure:
To a stirring solution of 1.8 g of 3-bromo-5-nitrobenzonitrile in 8 mL of EtOH and 8 mL of THF was added 8.8 g (38.6 mmol) of SnCl2.2H2O in several portions. The mixture was allowed to stir at r.t. for 10.5 h and then concentrated. A solution of 2N NaOH (60 mL) was added and stirring continued for 2 h. EtOAc was added, and the layers were separated. The organic layer was washed with H2O and brine. The aqueous layer was reextracted with EtOAc and washed with brine. The combined extracts were dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (35% EtOAc/hexanes) provided 965 mg of 3-amino-5-bromobenzonitrile.
Reaction SMILES: N([O-])=O.[Na+].O.N[C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[OH-].[Na+].[H+].[B-](F)(F)(F)[F:21]>>[F:21][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)c1[nH]cnc1N
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1[nH]cnc1F
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 16 %

Procedure:
Ethyl 4-fluoro-1H-imidazole-5-carboxylate was prepared as described in J. Org. Chem. 1984, 49, 1951. A solution of NaNO2 (76 mg, 2.2 mmol) in minimum amount of H2O was added to a solution of ethyl 4-amino-1H-imidazole-5-carboxylate (310 mg, 2.0 mmol) in 50% HBF4 (7.0 mL) at −10° C. The reaction was stirred for 10 min and then irradiated with medium-pressure mercury vapor lamp (450 W) for 3 h at the same temperature. The mixture was neutralized with NaOH (5N) to Ph=5 while the temperature was maintained at −10° C. The resulting mixture was extracted with EtOAc and the extracts were over sodium sulfate and concentrated. The residue was purified by column chromatography (0-50% EtOAc in Hexane) to give the title compound (50 mg, 16%) as a white solid.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[N:15][C:14]=3[C:24]([OH:26])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C([O:29][C:30](=[O:41])[C:31]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([NH2:40])[CH:35]=1)([CH3:33])[CH3:32])C>>[C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([CH:18]4[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]4)=[N:15][C:14]=3[C:24]([NH:40][C:36]3[CH:35]=[C:34]([C:31]([CH3:33])([CH3:32])[C:30]([OH:41])=[O:29])[CH:39]=[CH:38][CH:37]=3)=[O:26])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: O=C(O)c1nc(C2CCCCC2)[nH]c1CCC12CC3CC(CC(C3)C1)C2
Reactant: CCOC(=O)C(C)(C)c1cccc(N)c1
Product: CC(C)(C(=O)O)c1cccc(NC(=O)c2nc(C3CCCCC3)[nH]c2CCC23CC4CC(CC(C4)C2)C3)c1

Procedure:
5-(2-Adamantan-1-yl-ethyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid (Example 252) was reacted with 2-(3-amino-phenyl)-2-methyl-propionic acid ethyl ester (prepared from 2-(4-chloro-phenyl)-2-methyl-propionic acid using Mutti's procedure (S. Mutti et al. Synth. Comm. 1997, 27, 425)) according to the procedure of Example 20, step d. The ethyl ester was hydrolysed using the same procedure as in Example 247, step b to afford the title compound. 1H NMR (300 MHz, d6-DMSO) 10.52 (1H, br s), 7.70 (2H, m), 7.32 (1H, m), 7.12 (1H, d), 2.93 (3H, m), 1.98-1.35 (33H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 63.89; H, 8.61; N, 7.77%; C39H60N4O8.1.0 mol H2O requires: C, 64.09; H, 8.55; N, 7.67%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6](OS(C(F)(F)F)(=O)=O)=[C:5]([CH3:20])[CH:4]=1)#[N:2].[CH3:21][S:22]([C:25]1[CH:26]=[C:27]([C:34]([CH3:46])([CH3:45])[CH2:35][C:36]([C:41]([F:44])([F:43])[F:42])([OH:40])[CH2:37][C:38]#[CH:39])[C:28]2[O:32][CH2:31][CH2:30][C:29]=2[CH:33]=1)(=[O:24])=[O:23]>C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:40][C:36]([C:41]([F:43])([F:44])[F:42])([CH2:35][C:34]([C:27]1[C:28]2[O:32][CH2:31][CH2:30][C:29]=2[CH:33]=[C:25]([S:22]([CH3:21])(=[O:24])=[O:23])[CH:26]=1)([CH3:45])[CH3:46])[CH2:37][C:38]#[C:39][C:6]1[C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:20]
Reactant: C#CCC(O)(CC(C)(C)c1cc(S(C)(=O)=O)cc2c1OCC2)C(F)(F)F
Reactant: Cc1cc(C#N)cc([N+](=O)[O-])c1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(C#N)cc([N+](=O)[O-])c1C#CCC(O)(CC(C)(C)c1cc(S(C)(=O)=O)cc2c1OCC2)C(F)(F)F
Temperature: 60 °C
Yield: 42.8 %

Procedure:
A mixture of trifluoromethanesulfonic acid 4-cyano-2-methyl-6-nitrophenyl ester (217 mg, 0.7 mmol), dichlorobis(triphenylphosphine)palladium (II) (24.6 mg, 0.035 mmol), copper (I) iodide (13.3 mg, 0.7 mmol), and 6-(5-methanesulfonyl-2,3-dihydrobenzofuran-7-yl)-6-methyl-4-trifluoromethylhept-1-yn-4-ol (273 mg, 0.7 mmol) in a mixture of 0.8 mL of anhydrous toluene and 0.3 mL of anhydrous triethylamine was heated in a microwave at 60° C. for 10 minutes. The reaction mixture was applied to a column of SiO2 (50% ethyl acetate in hexanes) to give 165 mg of the title product as a light yellow oil (43% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[N:6][OH:7])[CH3:5])[CH3:2].C(O[K])(C)(C)C.[CH2:14]([O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1F)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[N:6][O:7][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]([O:21][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:30])[CH3:5])[CH3:2]
Reactant: O=C(OCc1ccccc1)c1ccccc1F
Reactant: CCOC(C)=NO
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(C)=NOc1ccccc1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 64.4 %

Procedure:
To a stirring solution of ethyl-N-hydroxyacetimidate (2.06 g, 20.0 mmol) in anhydrous DMF (60 mL) under Ar was added tBuOK (2.21 g, 19.7 mmol) all at once. After 30 min benzyl-2-fluorobenzoate 16 (4.13 g, 17.9 mmol) was added as a solution in DMF (20 mL) and the reaction was stirred at room temperature. After 3 h the reaction was diluted with H2O (400 mL), extracted with EtOAc (3×100 mL), and the combined organics were washed with H2O (3×50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated. Flash chromatographic purification over silica (5-10% gradient EtOAc in hexanes) afforded 18 as a clear syrup (3.61 g, 64%). 1H-NMR (500 MHz, CDCl3) δ 1.34 (t, J=7.0 Hz, 3H), 2.00 (s, 3H), 4.18 (q, J=7.0 Hz, 2H), 5.34 (s, 2H), 6.96 (dt, J=1.1, 7.7 Hz, 1H), 7.30-7.35 (m, 1H), 7.35-7.39 (m, 2H), 7.42-7.48 (m, 3H), 7.55 (dd, J=1.1, 8.4 Hz, 1H), 7.90 (dd, J=1.8, 7.7 Hz, 1H); 13C-NMR (125 MHz, CDCl3) δ 14.4, 14.5, 63.1, 66.6, 114.5, 117.0, 120.4, 128.2, 128.4, 128.5, 131.7, 133.8, 136.1, 159.5, 165.8, 166.7; GC-MS 313 m/z[M]+, C18H19NO4 requires 313, 228 m/z [M-85]+, benzyl-2-hydroxybenzoate C14H12O3 requires 228.
Reaction SMILES: [Cl:1][C:2]([Cl:15])([Cl:14])[CH2:3][C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:7])[CH2:5][OH:6].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:6][CH2:5][C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:7])[CH2:3][C:2]([Cl:14])([Cl:15])[Cl:1])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: OCC(O)(CC(Cl)(Cl)Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC(O)(CC(Cl)(Cl)Cl)c1ccccc1

Procedure:
4,4,4-Trichloro-2-phenyl-2-hydroxybutanol (160 grams; 0.60 mole) was mixed with about 2000 milliliters (ml.) of methylene chloride and triethylamine (63.6 grams; 0.63 mole) was added thereto. The resulting mixture was cooled in an ice-methanol bath to a temperature of about -6 to about -8° C. Methanesulfonyl chloride (69 grams; 0.60 mole) in about 250 ml. of methylene chloride was added dropwise to the stirred reaction mixture over a period of about 45 minutes. The reaction mixture temperature was maintained below about 0° C. during the addition and, following the completion of the methanesulfonyl chloride solution; the reaction mixture temperature was allowed to come to room temperature. Thereafter, the reaction mixture was washed with water (four - 700 ml. portions), then with 700 ml. of a 10% sodium carbonate solution, and finally with another 700 ml. portion of water. An additional 600 ml. of methylene chloride was added to the organic product layer which was then dried over sodium sulfate. The volume of the organic product mixture was reduced to about 400 ml. by evaporation of the carrier medium in vacuo. The resulting white product precipitate was obtained by filtration. As a result of such operations, the desired 4,4,4-trichloro-2-phenyl-2-hydroxybutyl 1-methanesulfonate product was obtained as a white crystalline solid having a melting point of 128°-130° C.
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]([C:21]3[NH:25][N:24]=[N:23][N:22]=3)[C:9]=2[CH3:26])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:34][CH2:35][CH3:36]>CN(C)C=O>[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]([C:21]3[N:25]([CH2:34][CH2:35][CH3:36])[N:24]=[N:23][N:22]=3)[C:9]=2[CH3:26])=[CH:4][CH:3]=1
Reactant: Cc1c(-c2nnn[nH]2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1nnnc1-c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1C
Reaction time: 5 h
Yield: 36.8 %

Procedure:
5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)-1H-tetrazole (150 mg, 0.37 mmol) obtained in Step 1 was dissolved in dimethylformamide (1 ml), and potassium carbonate (250 mg, 1.85 mmol) and 1-iodopropane (0.07 ml, 1.1 mmol) were added thereto at room temperature. After stirring for 5 hours, the resulting solution was quenched with water (1 ml) and the mixture was three time extracted with 5 ml portion of ethyl acetate. The solvent of the extracted organic layer was evaporated under a reduced pressure and the residue was subjected to silica gel column chromatography (hexane/ethyl acetate=1/7 to hexane/ethyl acetate=1/5), to obtain two compounds, one of which was the title compound (61 mg, 37%) in the form of white solid.
Reaction SMILES: [C:1]([O:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([CH3:17])[C:11]([CH3:19])([CH3:18])[CH2:10]1)(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=[O:5].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].C(N(CC)CC)C>>[C:4]([O:6][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21])(=[O:5])[CH2:3][CH2:2][C:1]([O:8][CH:9]1[CH2:14][C:13]([CH3:15])([CH3:16])[N:12]([CH3:17])[C:11]([CH3:19])([CH3:18])[CH2:10]1)=[O:7]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: CN1C(C)(C)CC(OC(=O)CCC(=O)[O-])CC1(C)C
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCC(=O)OC1CC(C)(C)N(C)C(C)(C)C1

Procedure:
The product is prepared as described in Example 4b by reacting 27.1 g (0.1 mol) of mono(1,2,2,6,6-pentamethyl-4-piperidyl) succinate with 33.3 g (0.1 mol) of 1-bromooctadecane in the presence of 10.1 g (0.1 mol) of triethylamine. The product obtained has a melting point of 38°-40° C. after crystallization from acetonitrile.
Reaction SMILES: [O:1]=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.OP([O-])(O)=O.[K+].[CH3:19][CH2:20][C@@H:21]([C:23]([O:25][C@@H:26]1[C@@H:31]2[C@@H:32]([CH2:37][CH2:38][C@@H:39]([OH:47])[CH2:40][C@@H:41]([OH:46])[CH2:42][C:43]([OH:45])=[O:44])[C@@H:33]([CH3:36])[CH:34]=[CH:35][C:30]2=[CH:29][CH2:28][CH2:27]1)=[O:24])[CH3:22]>>[CH3:19][CH2:20][C@@H:21]([C:23]([O:25][C@@H:26]1[C@@H:31]2[C@@H:32]([CH2:37][CH2:38][C@@H:39]([OH:47])[CH2:40][C@@H:41]([OH:46])[CH2:42][C:43]([OH:45])=[O:44])[C@@H:33]([CH3:36])[CH:34]=[CH:35][C:30]2=[CH:29][C@@H:28]([OH:1])[CH2:27]1)=[O:24])[CH3:22]
Reactant: CC[C@H](C)C(=O)O[C@H]1CCC=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)O)[C@H]21
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])(O)O
Agent: [K+]
Product: CC[C@H](C)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)O)[C@H]21
Reaction time: 36 h

Procedure:
1 ml of a spore suspension of YS-44442 (or YS-45494) stored in GL(10_glycerol—5_lactose) at −80_was opened in laminar flower and added into a 300 ml shake flask containing 20 ml of the seed medium (for every liter: glucose 10 g, peptone 2 g, soy protein 4 g and KH2PO4 1 g, pH 7.0÷0.2). The seed culture was incubated at 27_ for 24 to 48 hrs in a rotary shaker at 200 to 220 rpm (growth phase). Afterward, 1.5 to 2 ml of the seed culture was incubated into a 300 ml shake flask containing 20 ml of the fermentation medium (per liter: glucose 15 g, peptone 5 g, corn steep powder (C.S.P.) 5 g and soybean meal 4 g, KH2PO4 1 g, pH 7.0±0.2). The shake flask was incubated at 27±0.5_ for 18 to 24 hrs in a rotary shaker at 200 rpm (growth phase). The fermentation broth was added with compactin prepared as above into the fermentation broth at a final concentration of 1500 to 2000 mg/L and the incubation was continued for 16 to 24 hrs.
Reaction SMILES: OCCC1C=C(C=CC=1)[C:7]([NH:9][C:10]1[S:11][C:12]2[CH2:39][CH2:38][CH2:37][CH2:36][C:13]=2[C:14]=1[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)=[O:16])=[O:8].CC(OI1(OC(C)=O)(OC(C)=O)O[C:54](=O)[C:53]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]1=2)=O>>[CH3:20][CH2:19][CH:18]([NH:17][CH2:15][CH2:54][C:53]1[CH:48]=[C:49]([CH:50]=[CH:51][CH:52]=1)[C:7]([NH:9][C:10]1[S:11][C:12]2[CH2:39][CH2:38][CH2:37][CH2:36][C:13]=2[C:14]=1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:34][CH:35]=2)=[CH:22][CH:23]=1)=[O:16])=[O:8])[CH2:23][CH3:22]
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(CCO)c4)sc4c3CCCC4)cc2)cc1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Product: CCC(CC)NCCc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Yield: 185.9 %

Procedure:
By using 250 mg of methyl 4-[2-(4-{[(2-{[3-(2-hydroxyethyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate and 450 mg of Dess-Martin Periodinane, the reaction similar to Preparation Example 2 was performed, and then the reaction similar to Preparation Example 14 was performed, thereby obtaining 260 mg of methyl 4-{2-[4-({[2-({3-[2-(pentan-3-ylamino)ethyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[Cl:17][CH2:18][CH2:19]OS(C1C=CC(C)=CC=1)(=O)=O>CC(=O)CC>[Cl:17][CH2:18][CH2:19][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1cccc(OCCCl)c1
Temperature: 25 °C

Procedure:
A mixture of 6.96 g. of m-nitrophenol, 100 ml. of 2-butanone, 6.9 g. of potassium carbonate, and 11.74 g. of 2 chloroethyl-tosylate was stirred and heated under reflux for 24 hours. After cooling to room temperature, the salts were filtered off and the filtrate concentrated under vacuum. The residue crystallized on seeding and was recrystallized from carbon tetrachloride to give 8.3 g. of product, m.p. 54.5°-57° C.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:12]([O:20][CH2:21][CH2:22]Br)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[C:12]([O:20][CH2:21][CH2:22][O:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: O=C(OCCBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=NOCCOC(=O)c1ccccc1)C(C)=O
Yield: 92.4 %

Procedure:
A mixture of ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 15.7 g.), 2-bromoethyl benzoate (27.5 g.), potassium carbonate (20.7 g.), N,N-dimethylformamide (25 ml.) and ethyl acetate (25 ml.) was treated in a similar manner to that of Example A-(1) to give ethyl 2-(2-benzoyloxyethoxyimino)-3-oxobutyrate (syn isomer, 28 g.).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:9][O:10][CH2:11][CH2:12]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[NH:42]1[CH2:47][CH2:46][CH2:45][C@@H:44]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:43]1>C1COCC1.O>[CH2:51]([O:50][C:48]([C@@H:44]1[CH2:45][CH2:46][CH2:47][N:42]([CH2:12][CH2:11][O:10][CH2:9][CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:43]1)=[O:49])[CH3:52]
Reactant: OCCOCCC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)[C@@H]1CCCNC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@@H]1CCCN(CCOCCC(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(3,3-diphenyl-1-propyloxy)ethanol (2.5 g, 0.010 mol) in dry THF (20 ml) was placed on an ice-bath and a solution of n-butyllithium in hexanes (4.0 ml, 2.5 M) was added dropwise under an atmosphere of nitrogen. When addition was complete the reaction mixture was stirred at room temperature for 0.5 h and then heated at reflux temperature for 1 h. The mixture was cooled to room temperature and p-toluenesulphonyl chloride (2.1 g, 0.011 mol) was added. The mixture was stirred at room temperature for 0.5 h and then heated at reflux temperature for 1 h. To the cooled reaction mixture was added dry potassium carbonate (2.0 g, 0.015 mol) and ethyl (R)-3-piperidinecarboxylate (2.0 g, 0.0125 mol) and the mixture was heated at reflux temperature for 3 h. The cooled reaction mixture was poured into water (200 ml) and extracted with ethyl acetate (2×200 ml). The combined organic extracts was dried over sodium sulphate and the solvent evaporated in vacuo. The residue was submitted to flash chromatography on silica gel (150 g) using a mixture of n-heptane and THF (4:1) as eluent. This provided 0.9 g (11% calculated from 3,3-diphenyl-1-propanol) of the title compound as an oil. TLC: rf=0.24 (SiO2 ; n-heptane/THF=7:3). 1H NMR δ (CDCl3) 4.10 (t, 1H).
Reaction SMILES: C[O-].[Na+].F[C:5]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:6]=1[CH:7]=[O:8].[C:17](O)(=[O:19])C>>[CH3:17][O:19][C:5]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(C(F)(F)F)cc1C=O

Procedure:
To a stirred and ice-cooled solution of NaOMe (904 mg, 4.68 mmol) was added 2-fluoro-5-(trifluoromethyl)benzaldehyde (500 mg, 2.60 mmol) portionwise. The dropping funnel employed was washed with THF. The resultant suspension was stirred at room temperature for 5 hr. The reaction mixture was neutralizing for acetic acid (0.3ml, 5.0 mmol), the solvent was removed. To the solid residue was added water and the mixture was extracted with CH2Cl2. The combined CH2Cl2 extracts were washed with sat. NaHCO3 aq., dried with MgSO4, and concentrated to give crude Compound 4 as a white solid. This was purified with preparative TLC to give pure Compound 4 as a white crystalline (363 mg, 68.4%).