Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+:8].[Cl:9][P:10]1([Cl:20])[N:15]=[P:14](Cl)(Cl)[N:13]=[P:12](Cl)(Cl)[N:11]=1>C1COCC1>[O:1]([P:14]1([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:15]=[P:10]([Cl:20])([Cl:9])[N:11]=[P:12]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+:8].[Cl-:9]
Reactant: [O-]c1ccccc1
Reactant: ClP1(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=N1
Agent: [Na+]
Solvent: C1CCOC1
Product: ClP1(Cl)=NP(Oc2ccccc2)(Oc2ccccc2)=NP(Oc2ccccc2)(Oc2ccccc2)=N1
Product: [Cl-]

Procedure:
The sodium phenoxide containing solution was added dropwise to a solution of hexachlorocyclotriphosphazene, (NPCl2)3 (17.3 g, 0.05 mole) in THF (200 mL) with stirring, under nitrogen. An exothermic reaction occurred as precipitation of a white solid (NaCl) took place. The reaction mixture was refluxed for about 3 hrs. The resulting mixture could be filtered, giving a THF solution of tetraphenoxy-dichlorocyclotriphosphazene as the filtrate, and NaCl as the filtered residue, or used as is. The weight of NaCl isolated after filtration and washing with THF was essentially quantitative (about 7.4 g in this case).
Reaction SMILES: C[O:2][P:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:16][C:17]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:18]=1[C:19](Cl)=[O:20]>CCOCC>[CH3:16][C:17]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:18]=1[C:19]([P:3](=[O:2])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:20]
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Reactant: COP(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: Cc1cc(C)c(C(=O)P(=O)(c2ccccc2)c2ccccc2)c(C)c1
Reaction time: 4.5 h

Procedure:
648 parts of methoxydiphenylphosphine are added slowly to 547.5 parts of 2,4,6-trimethylbenzoyl chloride at 50°-55° C. in a stirred apparatus equipped with a reflux condenser and dropping funnel. Stirring is continued for 4-5 hours at 50° C., the contents of the flask are dissolved in ether at 30° C., and petroleum ether is added until the mixture begins to turn cloudy. On cooling, 910 parts (87% of theory) of 2,4,6-trimethylbenzoyl-diphenylphosphine oxide crystallize. Melting point: 80°-81° C. The product is in the form of pale yellow crystals.
Reaction SMILES: Cl.[CH3:2][N:3]1C[CH2:6][CH:5]([O:8][C:9]2[C:14]([C:15]([O-:17])=O)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:4]1.[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:38]([Cl:42])(Cl)(Cl)[Cl:39]>C(Cl)(Cl)Cl.C(O)C>[ClH:39].[Cl:42][CH2:38][CH2:6][CH:5]1[CH2:4][N:3]([CH3:2])[C:15](=[O:17])[C:14]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=2[O:8]1
Reactant: CN1CCC(Oc2ncccc2C(=O)[O-])C1
Reactant: ClC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CN1CC(CCCl)Oc2ncccc2C1=O

Procedure:
Hydrogen chloride gas was bubbled into a suspension of 150 g (0.61 mole) of sodium 2-[(1-methyl-3-pyrrolidinyl)oxy]-3-pyridinecarboxylate in 1 liter of chloroform until a pH of 6 was reached. To the stirred mixture was added 350 g (1.34 mole) of triphenylphosphine and 350 g (2.3 mole) of carbon tetrachloride and the resulting cloudy solution was stirred at reflux for 1.5 hr. About 100 ml of ethanol was added and the heat removed. The solution was stirred for 1 hour while cooling and 200 ml of isooctane was added. The solution was extracted 4 times with a total of 800 ml of dilute hydrochloric acid. The acid extracts were combined, made basic with sodium hydroxide and extracted with chloroform. The chloroform layer was separated and dried over sodium sulfate and concentrated. The residue was dissolved in a mixture of 500 ml each of isopropyl alcohol and isopropyl ether and acidified with ethereal hydrogen chloride. The resulting crystals weighed 82 g (49%), A portion was recrystallized from isopropyl alcohol, m.p. 149°-153° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:32][C@H:33]3[CH2:37][CH2:36][C:35](=[O:38])[CH2:34]3)[C:17]([NH:19][C:20]3[N:25]=[CH:24][C:23]([CH2:26][C:27]([O:29]CC)=[O:28])=[CH:22][CH:21]=3)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1.[OH-].[Na+].C(O)C.[ClH:44]>C1COCC1>[ClH:44].[CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:32][C@H:33]3[CH2:37][CH2:36][C:35](=[O:38])[CH2:34]3)[C:17]([NH:19][C:20]3[N:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:22][CH:21]=3)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:11])=[O:12])[CH2:3][CH2:2]1
Reactant: CCOC(=O)Cc1ccc(NC(=O)[C@H](C[C@H]2CCC(=O)C2)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(NC(=O)[C@H](C[C@H]2CCC(=O)C2)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propionic acid (110 mg) in dichloromethane (3 mL) were added sequentially oxalyl chloride (0.03 mL) and a catalytic amount of DMF under ice-cooling, followed by stirring for 1 hour, and then ethyl (6-aminopyridin-3-yl)acetate (58 mg) and pyridine (0.05 mL) were added thereto under ice-cooling, followed by stirring for 2 hours. To the reaction mixture were added water and ethyl acetate. The organic layer was sequentially washed with water, saturated aqueous sodium bicarbonate, and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain ethyl [6-({(2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanoyl}amino)pyridin-3-yl]acetate (57 mg) as a pale yellow amorphous substance. To a solution of the obtained ethyl [6-({(2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanoyl}amino)pyridin-3-yl]acetate (57 mg) in THF (3 mL) was added 1 M aqueous sodium hydroxide solution (0.22 mL), and further added a drop of ethanol, followed by stirring at room temperature overnight. To the reaction solution was added 1 M hydrochloric acid (0.22 mL) to adjust the pH to 4, followed by dilution with saturated brine and dichloromethane for liquid separation. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated under reduced pressure. To a solution of the residue in ethyl acetate (3 mL) was added a 4 M hydrogen chloride/ethyl acetate solution (0.07 mL) under ice-cooling, followed by stirring for 10 minutes under ice-cooling, and the solvent was then evaporated under reduced pressure. To the residue was added ethyl acetate (3 mL), and the precipitate was collected by filtration and dried under reduced pressure to obtain [6-({(2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanoyl}amino)pyridin-3-yl]acetic acid hydrochloride (30 mg) as a colorless solid.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:28])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:14][C:13]=2[Cl:27])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].[CH3:29][C:30]([OH:34])([C:32]#[CH:33])[CH3:31]>>[Cl:27][C:13]1[CH:14]=[C:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH:16]=[CH:17][C:12]=1[C:10]([C:8]1[CH:9]=[C:4]([N:1]2[CH:33]=[C:32]([C:30]([OH:34])([CH3:31])[CH3:29])[N:3]=[N:2]2)[CH:5]=[CH:6][C:7]=1[CH3:28])=[O:11]
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: C#CC(C)(C)O
Product: Cc1ccc(-n2cc(C(C)(C)O)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 116, using compound 434 (0.125 mmol) and 2-methyl-but-3-yn-2-ol (0.125 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 30:70 to 70:30 as the eluent to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[OH:32])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15](/[CH:18]=[CH:19]\[C:20]4[CH:21]=[N:22][CH:23]=[N:24][CH:25]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:34]([O:40][CH2:41]I)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36].C(OCC)(=O)C>CN(C)C(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[OH:32])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O:28][CH2:41][O:40][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:27])=[C:15](/[CH:18]=[CH:19]\[C:20]4[CH:25]=[N:24][CH:23]=[N:22][CH:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)(C)C(=O)OCI
Reactant: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(/C=C\c4cncnc4)CS[C@H]23)cs1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)C(=O)OCOC(=O)C1=C(/C=C\c2cncnc2)CS[C@@H]2[C@H](NC(=O)/C(=N\O)c3csc(N)n3)C(=O)N12

Procedure:
The compound (100 mg) of Example 16 was dissolved in N,N-dimethylacetamide (2 ml), followed by the addition of pivaloyloxymethyl iodide (50 mg). They were reacted for 1 hour. Ethyl acetate (50 ml) was added. The resulting mixture was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. Ether was added to the residue and the resulting solid was collected by filtration, whereby the title compound (80 mg) was obtained.
Reaction SMILES: [N+:1]([C:4]1[C:21]([N+:22]([O-])=O)=[CH:20][C:7]2[O:8][C:9]([CH2:15][C:16]([F:19])([F:18])[F:17])([C:11]([F:14])([F:13])[F:12])[O:10][C:6]=2[CH:5]=1)([O-])=O.[H][H]>O1CCCC1>[NH2:22][C:21]1[C:4]([NH2:1])=[CH:5][C:6]2[O:10][C:9]([CH2:15][C:16]([F:19])([F:18])[F:17])([C:11]([F:12])([F:13])[F:14])[O:8][C:7]=2[CH:20]=1
Reactant: O=[N+]([O-])c1cc2c(cc1[N+](=O)[O-])OC(CC(F)(F)F)(C(F)(F)F)O2
Reactant: [H][H]
Solvent: C1CCOC1
Product: Nc1cc2c(cc1N)OC(CC(F)(F)F)(C(F)(F)F)O2

Procedure:
39 g of the product of Example 29 were dissolved in 2000 ml of tetrahydrofuran, and 20 g of catalyst (palladium-on-charcoal, 5% by weight) were added. The reaction mixture was hydrogenated with hydrogen at 25 to 30 bar for 13 hours at room temperature. It was then filtered and the solvent was stripped off under vacuum to leave a solid. The yield was 274 g (=96% of theory). 19F NMR: -61.2 and -86.6 ppm. 1H NMR: 3.02 ppm.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH:9]2[CH2:11][CH:6]1[C:7](=[O:12])[O:8]2)=[O:4].[NH2:13][C@H:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH2:16][CH3:17].CCN(C(C)C)C(C)C.OC1C=CC=CN=1>C1COCC1>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][C@@H:9]([OH:8])[CH2:11][C@H:6]1[C:7](=[O:12])[NH:13][C@H:14]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:15][CH2:16][CH3:17])=[O:4]
Reactant: CCC[C@H](N)C(=O)OC(C)(C)C
Reactant: COC(=O)C1CC2CC1C(=O)O2
Agent: Oc1ccccn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC[C@H](NC(=O)[C@@H]1C[C@H](O)C[C@H]1C(=O)OC)C(=O)OC(C)(C)C
Yield: 95.8 %

Procedure:
Compound 41 (263 mg, 1.55 mmol) and H-Nva-OtBu (420 mg, 2.42 mmol) were dissolved in dry THF (20 mL). DIEA (530 uL, 3.04 mmol) and 2-hydroxypyridine (260 mg, 2.73 mmol) were added and the mixture was refluxed for five days. The solvent was evaporated and the crude product was purified by flash column chromatography (toluene/EtOAc 1:2) to give 42 (510 mg, 96%).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[CH:3]1[C:9](Cl)=[O:10].C(N(CC)CC)C.CC[O:22]CC>>[Cl:7][C:6]([Cl:8])=[CH:5][CH:4]1[CH:3]([C:9]([OH:22])=[O:10])[C:2]1([CH3:12])[CH3:1]
Reactant: CCOCC
Reactant: CC1(C)C(C=C(Cl)Cl)C1C(=O)Cl
Solvent: CCN(CC)CC
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Temperature: 25 °C

Procedure:
To a cooled solution (10°-15° C.) of 2.0 grams (0.009 mole) of cyano(6-phenoxy-2-pyridine)methanol and 2.0 grams (0.009 mole) of 2,2-dimethyl-3-(2,2-dichloroethenyl)cyclopropane carboxylic acid chloride in 25 milliliters of anhydrous ether was added 1 milliliter of triethylamine. A white precipitate separated out immediately. The reaction mixture was stirred at room temperature for one-half (1/2) hour. The mixture was diluted with 50 milliliters of water and extracted thoroughly with ether. The ether extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under vacuo to give 3.4 grams of crude 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropane carboxylic acid:cyano(6-phenoxy-2-pyridinyl)methyl ester product as a thick brown oil. This oil was purified by distillation under reduced pressure to give 1.8 grams of a light brown oil boiling at 190°-200° C. at 0.1-0.2 milliliters of mercury (mm). The oil had a refractive index of n(25/D)=1.5264. The structure of the product was confirmed by its nuclear magnetic resonance spectrum (NMR). Upon analysis, the product was found to have carbon, hydrogen and nitrogen contents of 60.28, 4.47 and 6.62 percent, respectively, as compared with the theoretical contents of 60.44, 4.35 and 6.71 percent respectively, as calculated for the above compound. (Compound No. 1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]([OH:21])=O)=[N:4][C:5]([Cl:18])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1.COC(C1C(Cl)=CC(C2C=CC=C(C(F)(F)F)C=2)=C(Cl)N=1)=O.CC1C(C(O)=O)=NC=C(C2C=CC=C(C(F)(F)F)C=2)C=1.[N:64]1([CH:69]2[CH2:74][CH2:73][NH:72][CH2:71][CH2:70]2)[CH2:68][CH2:67][CH2:66][CH2:65]1>>[Cl:1][C:2]1[C:3]([C:19]([N:72]2[CH2:73][CH2:74][CH:69]([N:64]3[CH2:68][CH2:67][CH2:66][CH2:65]3)[CH2:70][CH2:71]2)=[O:21])=[N:4][C:5]([Cl:18])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:17])[F:16])[CH:9]=2)[CH:7]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: O=C(O)c1nc(Cl)c(-c2cccc(C(F)(F)F)c2)cc1Cl
Agent: COC(=O)c1nc(Cl)c(-c2cccc(C(F)(F)F)c2)cc1Cl
Agent: Cc1cc(-c2cccc(C(F)(F)F)c2)cnc1C(=O)O
Product: O=C(c1nc(Cl)c(-c2cccc(C(F)(F)F)c2)cc1Cl)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of example 1, 3,6-dichloro-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid [prepared from 3,6-dichloro-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid methyl ester (intermediate 11) by saponification in analogy to the procedure described for intermediate 1B] was reacted with 4-pyrrolidin-1-yl-piperidine to give the title compound as light yellow amorphous solid. MS: 472.1 (MH+, 2Cl).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[C:16]([O-:20])(=[O:19])[CH2:17][CH3:18].[Na+]>C(OC(=O)CC)(=O)CC>[CH3:18][C:17](=[CH:12][C:11]1[CH:14]=[CH:15][C:8]([S:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:9][CH:10]=1)[C:16]([OH:20])=[O:19]
Reactant: O=Cc1ccc(Sc2ccccn2)cc1
Reactant: CCC(=O)[O-]
Agent: CCC(=O)OC(=O)CC
Agent: [Na+]
Product: CC(=Cc1ccc(Sc2ccccn2)cc1)C(=O)O
Reaction time: 5 h

Procedure:
A mixture of 6 g of 4-(2-pyridylthio)benzaldehyde, 6 g of sodium propionate and 30 ml of propionic anhydride was stirred for 5 hours at a temperature of 150° to 155° C. and then concentrated under reduced pressure. Water was added to the mixture which was then heated. The mixture was allowed to stand to precipitate crystals and the resulting crystals were separated by filtration, washed with water and dried to obtain 2-methyl-3-[4-(2-pyridylthio)phenyl]propenoic acid. The product was dissolved in 30 ml of methanol, and a small amount of methanolic hydrogen chloride was added to the solution, followed by refluxing for 1 hour. The solvent was distilled off and the resulting crystals were recrystallized from a mixture of methanol and ethyl acetate to obtain 2.6 g (30% yield) of methyl 2-methyl-3-[4-(2-pyridylthio)phenyl]propenoate hydrochloride as colorless needles having a melting point of 130°-133° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([NH2:31])[CH2:6][C:7]1[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[C:10]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:9][CH:8]=1)[CH3:2].BrCC1C2SC=CC=2C(OCCC2N=C(C3C=CC=CC=3)OC=2C)=CC=1.C(OC(=O)CN=C(C1C=CC=CC=1)C1C=CC=CC=1)C.[C:79]([CH2:87][C:88](=O)[CH3:89])(=[O:86])[C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1.C(N(CC)CC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([NH:31]/[C:88](/[CH3:89])=[CH:87]\[C:79](=[O:86])[C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1)[CH2:6][C:7]1[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[C:10]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: CCOC(=O)C(N)Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12
Agent: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CBr)c2sccc12
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)N/C(C)=C\C(=O)c1ccccc1
Yield: 85.2 %

Procedure:
0.334 g (0.75 mmol) [rac]-2-Amino-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid ethyl ester (prepared from 4-[2-(7-bromomethyl-benzo[b]thiophen-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole [PCT Int. Appl. (2001) WO01/79202] and N-(diphenylmethylene)glycine ethyl ester in analogy to the sequence described in examples 15 a] and 15 b]) and 0.161 g (0.97 mmol) benzoylacetone were dissolved in 25 ml of toluene. Then, 0.21 ml (1.5 mmol) triethylamine and 0.026 g (0.15 mmol) 4-toluene sulfonic acid were added and the reaction mixture was heated at reflux for 2 hours. After removing the solvent under reduced pressure, the residue was diluted in water/sodium hydrogen carbonate solution and the reaction mixture was extracted with dichloromethane. The combined organic phases were dried over MgSO4 and evaporated. Purification of the residue by flash-chromatography (silica gel, eluent: gradient of hexane and ethyl acetate) gave 0.38 g (85%) [rac]-2-[1-methyl-3-oxo-3-phenyl-(Z)-propenylamino]-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid ethyl ester as light yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[CH3:23])=[C:13]([C:24]([OH:26])=O)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].[CH3:27][C:28]1([CH3:42])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:30]2([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[O:29]1>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:14]2[N:9]3[N:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:10]3[N:11]=[CH:12][C:13]=2[C:24]([N:33]2[CH2:34][CH2:35][C:30]3([C:36]4[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:28]([CH3:42])([CH3:27])[O:29]3)[CH2:31][CH2:32]2)=[O:26])=[C:17]([CH3:23])[CH:18]=1
Reactant: CC1(C)OC2(CCNCC2)c2ccccc21
Reactant: CCOC(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)O)cnc12
Product: CCOC(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)N3CCC4(CC3)OC(C)(C)c3ccccc34)cnc12
Yield: 78.2 %

Procedure:
In the same manner as in Example 21, step 5 and using 3-ethoxycarbonyl-7-(4-fluoro-2-methylphenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.14 g, 0.39 mmol) obtained in Example 139, step 2 and 3,3-dimethyl-3H-spiro[isobenzofuran-1,4′-piperidine] (WO2005/092895, 0.12 g, 0.47 mmol), the title compound (0.17 g, 77%) was obtained.
Reaction SMILES: [Cl:1][CH2:2][C@@H:3]([OH:15])[CH2:4][C:5](=[O:14])[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[OH-].[Na+]>>[Cl:1][CH2:2][C@@H:3]([OH:15])[CH2:4][C@@H:5]([OH:14])[CH2:6][C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8]
Reactant: CC(C)(C)OC(=O)CC(=O)C[C@H](O)CCl
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)C[C@H](O)C[C@H](O)CCl
Reaction time: 24 h

Procedure:
A 5-L mini-jar fermenter containing 3 L of medium A was inoculated with Candida magnoliae IFO0705and incubated at 30° C. with 0.5 vvm aeration and stirring at 500 rpm for 24 hours. After completion of cultivation, 30 g of tert-butyl (5S)-6-chloro-5-hydroxy-3-oxohexanoate (synthesized by the process described in Example 1) and 60 g of glucose were added and the reaction was carried out, with the pH maintained at 6.5 with sodium hydroxide, for 18 hours. After completion of the reaction, the cells were removed centrifugally and the supernatant was extracted twice using 1.5 L of ethyl acetate each. The organic phase was separated and dehydrated over anhydrous sodium sulfate and the solvent was distilled off by heating under reduced pressure to recover 24 g of tert-butyl (3R,5S)-6-chloro-3,5-dihydroxyhexanoate as a solid. As analyzed by the method described in Example 4, the diastereomer ratio of this product was (3R,5S)/(3S,5S)=100/0.
Reaction SMILES: [C:1]12([C:11]([NH:13][CH:14]([C:18]3[CH:28]=[CH:27][C:21]([C:22]([O:24]CC)=O)=[CH:20][CH:19]=3)[CH:15]([CH3:17])[CH3:16])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH-:29].[K+].Cl.[NH2:32]O.CO>C(O)(=O)C>[OH:29][NH:32][C:22]([C:21]1[CH:20]=[CH:19][C:18]([CH:14]([NH:13][C:11]([C:1]23[CH2:10][CH:5]4[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]4)[CH2:8]2)[CH2:2]3)=[O:12])[CH:15]([CH3:16])[CH3:17])=[CH:28][CH:27]=1)=[O:24]
Reactant: CCOC(=O)c1ccc(C(NC(=O)C23CC4CC(CC(C4)C2)C3)C(C)C)cc1
Reactant: [OH-]
Reactant: NO
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)C(NC(=O)C12CC3CC(CC(C3)C1)C2)c1ccc(C(=O)NO)cc1
Temperature: 80 °C
Yield: 15 %

Procedure:
To the crude ethyl 4-{1-[(adamantan-1-ylcarbonyl)amino]-2-methylpropyl}benzoate in a vial was added potassium hydroxide (0.11 g, 1.87 mmol), hydroxylamine hydrochloride (0.047 g, 0.68 mmol), and methanol (2 mL). The reaction was capped and heated at 80° C. for 1 h. After cooled to rt, acetic acid (0.097 mL, 1.7 mmol was added to neutralize the excess base. The solvent was then completely evaporated. To the solid was added DMSO (1.3 mL). The solution was then filtered and purified by prep-HPLC purification to give the title compound (0.009 g, 15%) as a white solid. LC-MS: (FA) ES+ 371.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10](=[O:33])[CH2:11][C@H:12]1[C:16]2[CH:17]=[CH:18][C:19]([O:21][C@H:22]3[C:30]4[C:25](=[C:26]([OH:32])[CH:27]=[CH:28][C:29]=4[F:31])[CH2:24][CH2:23]3)=[CH:20][C:15]=2[O:14][CH2:13]1.[C:34]1(B(O)O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH3:8][O:9][C:10](=[O:33])[CH2:11][C@H:12]1[C:16]2[CH:17]=[CH:18][C:19]([O:21][C@H:22]3[C:30]4[C:25](=[C:26]([O:32][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH:27]=[CH:28][C:29]=4[F:31])[CH2:24][CH2:23]3)=[CH:20][C:15]=2[O:14][CH2:13]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccccc5)ccc(F)c43)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Triethylamine (0.4 mL) is added to a mixture of {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (0.15 g), phenylboronic acid (0.10 g), freshly activated molecular sieves 4A (1.0 g), copper(II) acetate (78 mg) and dichloromethane (8 mL) at room temperature. The flask is purged with O2 and sealed. The mixture is stirred under O2 atmosphere (1 bar) at room temperature for 16 h. The mixture is diluted with dichloromethane, filtered and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→80:20) to give the title compound. LC (method 3): tR=0.81 min; Mass spectrum (ESI+): m/z=435 [m+H]+.