Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH:8]([P:13](=[O:16])([OH:15])[OH:14])[P:9](=[O:12])([OH:11])[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C([O-])=O.[Ag+:24]>C(O)C>[O:1]([CH:8]([P:13](=[O:14])([O-:15])[O-:16])[P:9](=[O:10])([O-:11])[O-:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[Ag+:24].[Ag+:24].[Ag+:24].[Ag+:24]
Reactant: O=P(O)(O)C(Oc1ccccc1)P(=O)(O)O
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: CCO
Product: O=P([O-])([O-])C(Oc1ccccc1)P(=O)([O-])[O-]
Yield: 85.8 %

Procedure:
A solution of (phenoxymethylene)-bisphosphonic acid (8.04 g) in absolute ethanol (50 ml) was added to a stirred solution of silver trifluoroacetate (33.15 g) in absolute ethanol (200 ml). The mixture was cooled in ice and filtered. Drying in vacuo gave tetrasilver (phenoxymethylene)-bisphosphonate as a beige powder (17.9 g) which was suspended in acetonitrile (360 ml) and treated with iodomethyl pivalate (31.1 g). After stirring for 30 minutes at room temperature, the mixture was filtered, and the filtrate was evaporated in vacuo to leave a crude oil which was purified by chromatography on silica gel to give the title compound as a colourless oil.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]([O:23]CC)=[O:22])[CH:16]=3)[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:26]=[CH:27][CH:28]=[CH:29][C:4]=2[NH:3]1.C(O)C.[OH-].[Na+].Cl>O>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]([OH:23])=[O:22])[CH:16]=3)[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:26]=[CH:27][CH:28]=[CH:29][C:4]=2[NH:3]1
Reactant: CCOC(=O)c1cc(N2CCC(N3CCc4ccccc4NC3=O)CC2)ncn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(N2CCC(N3CCc4ccccc4NC3=O)CC2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
590 mg (1.49 mmol) ethyl 6-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylate, 20 mL ethanol, 1 mL water and 1 mL (4.0 mmol) of a 4M NaOH solution were stirred for 2 h at RT. The reaction mixture was diluted with water until the precipitate had dissolved. 1 mL of a 4M hydrochloric acid solution were added and the ethanol was eliminated i. vac. The reaction mixture was stirred for 30 min at RT, the precipitate was suction filtered and dried at 50° C. in the CAD.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:13]2[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[N:17]=2)=[C:9]([CH:12]=1)[CH:10]=[O:11])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH2:37](O)[CH2:38][CH2:39][OH:40]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:13]2[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[N:17]=2)=[C:9]([CH:10]2[O:40][CH2:39][CH2:38][CH2:37][O:11]2)[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCCO
Reactant: CC1(C)COC(c2ccc(C(C)(C)C)cc2C=O)=N1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CC1(C)COC(c2ccc(C(C)(C)C)cc2C2OCCCO2)=N1
Temperature: 25 °C
Yield: 21.7 %

Procedure:
A mixture of 101d (60 g, 0.23 mol), pyridinium p-toluenesulfonate (4 g, 0.02 mol) and 1,3-propanediol (60 mL) in toluene (500 mL) was heated to reflux overnight and cooled to room temperature upon the completion of reaction determined by LCMS. The reaction mixture was washed with 200 mL of 50 percent aqueous NaHCO3, 200 mL of water, and 200 mL of brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give a residue which was purified by silica gel chromatography using EtOAc/petroleum ether=1:5 as eluent to provide 101e (16 g, 21.7%) as a clear yellow gum. LCMS (ESI) 318 (M+H)+. 1HNMR (300 MHz, CDCl3) δ 7.79 (s, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.36 (dd, J=1.6, 8.4 Hz, 1H), 6.32 (s, 1H), 4.23 (dd, J=5.2, 11.2 Hz, 2H), 4.06 (s, 2H), 4.04-3.98 (m, 2H), 2.27-2.21 (m, 1H), 1.48-1.38 (m, 1H), 1.38 (s, 6H), 1.32 (s, 9H).
Reaction SMILES: [Na].[CH3:2][S:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[CH3:2][S:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH2:11][C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CSc1ccc(C(C)=O)cc1
Agent: [Na]
Product: CCOC(=O)C(=O)CC(=O)c1ccc(SC)cc1

Procedure:
The title compound was prepared in the same manner as for intermediate 66 using sodium metal (0.160 g, 6.95 mmol), 1-[4-(methylthio)phenyl]ethanone (1.05 g, 6.32 mmol) and diethyl ethanedioate (0.856 mL, 6.32 mmol). The product was collected as 1.58 g (59%). LCMS E-S (M+H)=266.9. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29-1.50 (m, 3H), 2.41-2.62 (m, 3H), 4.23-4.49 (m, 2H), 7.15-7.38 (m, 2H), 7.89 (dd, J=8.72, 2.15 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:12])[CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:12])[CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: CCCC(O)c1ccc(Cl)nc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCCC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 101.2 %

Procedure:
To a solution of 1-(6-chloropyridin-3-yl)butan-1-ol (210 mg, 1.13 mmol) in 10 mL dichloromethane was added 2 g of silica gel, followed by pyridinium chlorochromate (488 mg, 2.26 mmol) The mixture was stirred at room temperature 5 h. The mixture was filtered through a plug of silica gel, eluting with 100 mL dichloromethane. The eluent was concentrated to give 1-(6-chloropyridin-3-yl)butan-1-one (210 mg). 1H NMR (400 MHz, CDCl3) δ 8.88-8.96 (m, 1H), 8.14-8.20 (m, 1H), 7.42 (d, J=8.4 Hz, 1H), 2.92 (t, J=7.2 Hz, 2H), 1.70-1.82 (m, 2H), 0.99 (t, J=7.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10](=[O:12])[NH:9][CH2:8][CH2:7][C:6]=2[C:5]([C:13]([O:15]C)=[O:14])=[CH:4][C:3]=1[O:17][CH:18]([CH3:20])[CH3:19].[CH2:21]([O:28][C:29]1[C:34]([CH2:35]Cl)=[C:33]([CH3:37])[CH:32]=[C:31]([CH3:38])[N:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>O1CCOCC1>[CH2:21]([O:28][C:29]1[C:34]([CH2:35][N:9]2[CH2:8][CH2:7][C:6]3[C:5]([C:13]([OH:15])=[O:14])=[CH:4][C:3]([O:17][CH:18]([CH3:20])[CH3:19])=[C:2]([Cl:1])[C:11]=3[C:10]2=[O:12])=[C:33]([CH3:37])[CH:32]=[C:31]([CH3:38])[N:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1cc(OC(C)C)c(Cl)c2c1CCNC2=O
Reactant: Cc1cc(C)c(CCl)c(OCc2ccccc2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cc(C)c(CN2CCc3c(C(=O)O)cc(OC(C)C)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Temperature: 100 °C
Yield: 33 %

Procedure:
To a mixture of methyl 8-chloro-1-oxo-7-(propan-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate (Cpd F, 92.0 mg, 0.310 mmol) and 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (Cpd Z, 97.1 mg, 0.371 mmol) in 1,4-dioxane (3 mL) was added KHMDS (308 mg, 1.54 mmol). The reaction mixture was heated at 100° C. for 1 hour. The solvent was removed under vacuum and the residue diluted with EtOAc (10 mL) and water (10 mL). The pH of the aqueous layer was adjusted to 3-4 using 1N HCl. The aqueous layer was extracted with EtOAc (25 mL) and the organic layer concentrated under vacuum. The residue was purified by column chromatography (silica gel, heptanes/EtOAc) to give 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-1-oxo-7-(propan-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid (90a, 52 mg, 33% yield) as an oil.
Reaction SMILES: [CH:1]1([CH2:4][C@@H:5]([OH:9])[C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)(=O)C>[CH:1]1([CH2:4][C@@H:5]([OH:9])[C:6]([O:8][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: BrCc1ccccc1
Reactant: O=C(O)[C@H](O)CC1CC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)[C@H](O)CC1CC1
Temperature: 25 °C

Procedure:
A solution of 3.95 g of 3-cyclopropyl-2(R)-hydroxypropionic acid in 50 ml of ethyl acetate was treated with 5.32 ml of triethylamine and 3.8 ml of benzyl bromide. The mixture was stirred and heated under reflux for 3 hours, then allowed to cool to room temperature overnight. The suspension was washed with 2M hydrochloric acid, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate the solvent was evaporated. The residue was purified by flash chromatography on silica gel using hexane/ethyl acetate (2:1) for the elution to give 3.36 g of benzyl 3-cyclopropyl-2(R)-hydroxypropionate in the form of a yellow oil.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([C:10]1[CH:15]=[C:14]([CH2:16][CH3:17])[CH:13]=[C:12]([CH2:18][CH3:19])[C:11]=1[N:20]=[C:21]=[S:22])[CH3:9].Cl>>[CH2:8]([C:10]1[CH:15]=[C:14]([CH2:16][CH3:17])[CH:13]=[C:12]([CH2:18][CH3:19])[C:11]=1[NH:20][C:21]([NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[S:22])[CH3:9]
Reactant: NC1CCCCC1
Reactant: CCc1cc(CC)c(N=C=S)c(CC)c1
Agent: Cl
Product: CCc1cc(CC)c(NC(=S)NC2CCCCC2)c(CC)c1
Reaction time: 12 h

Procedure:
20.0 g of cyclohexylamine are taken and 15.0 g of 2,4,6-triethyl-phenyl isothiocyanate are introduced whilst stirring. The reaction takes place with slight evolution of heat. The mixture is left to stand for 12 hours and is then stirred with dilute hydrochloric acid and filtered. The crystalline reaction product is triturated with dilute methanol filtered off, washed and dried; yield 22.0 g; melting point 97°-99° C. The elementary analysis and NMR- and IR-spectrum agree with the assumed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([O:6][C:7]2[CH:31]=[CH:30][C:10]([CH2:11][O:12][C:13]3[CH:14]=[C:15]4[N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20][N:16]4[C:17](=[O:19])[N:18]=3)=[CH:9][C:8]=2[C:32]#[N:33])=[CH:4][C:3]=1[C:36]([F:39])([F:38])[F:37].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:35]=[CH:34][C:5]([O:6][C:7]2[CH:31]=[CH:30][C:10]([CH2:11][O:12][C:13]3[CH:14]=[C:15]4[NH:22][CH2:21][CH2:20][N:16]4[C:17](=[O:19])[N:18]=3)=[CH:9][C:8]=2[C:32]#[N:33])=[CH:4][C:3]=1[C:36]([F:39])([F:38])[F:37]
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)c(C#N)c1)nc2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(COc2cc3n(c(=O)n2)CCN3)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
Prepared in a manner similar to that described for E60 using tert-butyl 7-((4-(4-chloro-3-(trifluoromethyl)phenoxy)-3-cyanobenzyl)oxy)-5-oxo-2,3-dihydroimidazo[1,2-c]pyri-midine-1(5H)-carboxylate (150 mg, 0.266 mmol) and TFA (5 ml, 64.9 mmol) in DCM (5 mL).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([C:22]#[N:23])=[CH:12]1)[CH3:10].[I:24]I>C1COCC1>[CH2:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([C:22]#[N:23])=[C:12]1[I:24])[CH3:10]
Reactant: II
Reactant: CCn1cc(C#N)c2ccc(OC)cc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCn1c(I)c(C#N)c2ccc(OC)cc21
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
A 2M solution of lithium diisopropyl amide in THF/hexanes (Acros) (3.9 mL, 7.8 mmol) was diluted with THF (5 mL) in a flame-dried flask. After cooling the reaction to −30° C., a solution of 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (1.30 g, 6.5 mmol) in THF (10 mL) was added dropwise during 10 min, maintaining the temperature at −30° C. After stirring for an additional 30 min at this temperature, a solution of iodine (2.31 g, 9.1 mmol) in THF (5 mL) was added during 10 min. After the addition, the reaction was warmed to ambient temperature during 1 h. The reaction was then diluted with ice-H2O and extracted with EtOAc (2×). The combined organic phases were washed with 1M sodium thiosulfate and saturated NaCl and then concentrated to a brown solid. Chromatography (CH2Cl2/hexanes, 1/1) over silica gel gave 1.31 g (62%) of 1-ethyl-2-iodo-6-methoxy-1H-indole-3-carbonitrile as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]#[C:14][C:15]1[CH:16]=[N:17][C:18]([NH:21][C:22]2[C:27]([N+:28]([O-])=O)=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:31])=[N:19][CH:20]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]#[C:14][C:15]1[CH:20]=[N:19][C:18]([NH:21][C:22]2[C:27]([NH2:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:31])=[N:17][CH:16]=1
Reactant: COc1cc(OC)c(Cl)c(C#Cc2cnc(Nc3c(C)cccc3[N+](=O)[O-])nc2)c1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(OC)c(Cl)c(C#Cc2cnc(Nc3c(C)cccc3N)nc2)c1Cl
Temperature: 85 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
A mixture of 5-((2,6-dichloro-3,5-dimethoxyphenyl)ethynyl)-N-(2-methyl-6-nitrophenyl)pyrimidin-2-amine (150 mg, 0.33 mmol), Iron (147 mg, 2.64 mmol) and ammonium chloride (214 mg, 3.96 mmol) in ethanol (20 mL) and water (2 mL) was stirred at 85° C. for 1 h. LCMS showed the reaction was completed. The reaction was cooled to RT, and the solid was filtered off. The filtrate was concentrated, and the residue was purified by Prep-HPLC to afford the title compound as a white solid (58 mg, 35%). MS (ES+) C21H18Cl2N4O2 requires: 429, 431. found: 430, 432 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.90 (s, 1H), 8.55-8.44 (br, 2H), 6.97 (s, 1H), 6.89-6.86 (m, 1H), 6.57 (d, 1H, J=7.6 Hz), 6.44 (d, 1H, J=7.6 Hz), 4.75 (s, 2H), 3.94 (s, 6H), 2.01 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[C:20]1([N:26]2[CH:30]=[C:29]([CH:31]=O)[CH:28]=[N:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:31][C:29]2[CH:28]=[N:27][N:26]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:30]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cnn(-c2ccccc2)c1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cnn(-c2ccccc2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 1-phenyl-1H-pyrazole-4-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.80 min.; [M+H]+: 392.36 g/mol.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[NH:11][N:10]=2)[CH2:2]1.[OH:23][C:24]1([C:31]2[CH:32]=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1>>[OH:23][C:24]1([C:31]2[CH:32]=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[CH2:25][CH2:26][CH:27]([N:1]2[CH2:2][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:20])([F:19])[F:21])[CH:16]=4)[NH:11][N:10]=3)[CH2:4]2)[CH2:28][CH2:29]1
Reactant: COc1ccc(C2(O)CCC(=O)CC2)cn1
Reactant: O=C(CNc1n[nH]c2ccc(C(F)(F)F)cc12)NC1CNC1
Product: COc1ccc(C2(O)CCC(N3CC(NC(=O)CNc4n[nH]c5ccc(C(F)(F)F)cc45)C3)CC2)cn1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide (as prepared in Example 41, Step A) and 4-hydroxy-4-(6-methoxy-pyridin-3-yl)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>CC(C)=O>[CH2:19]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCC1(C(=O)OCC)CCCC1=O
Yield: 87.3 %

Procedure:
Under vigorously agitation, 31.2 g of ethyl 2-oxocyclopentane carboxylate was added to 84.5 g purity of 98%) of ground anhydrous potassium carbonate, and after stirring for several minutes, to the mixture was added 100 ml Of acetone. The reaction mixture was further stirred for about 15 minutes, then thereto was dropwise added 57.54 ml (purity of 98%) of 1-bromo-n-hexane. Upon the completion of the addition, the reaction mixture was heated for reflux for 5 hours. The reaction mixture was filtered under the reduced pressure, and the filter cake was washed with diethyl ether until its color was purely white. Pale yellow filtrate was collected and dried over anhydrous magnesium sulfate, then the solvent was removed. The residue was distilled under reduced pressure, and 41.89 g of colorless liquid as a distillate cut of 156-160° C./23 mmHg was collected. Yield: 87.3%. MS: m/e 240(M+′), 212(M+′—CH2CH2), 195(M+′—OCH2CH3), 167(M+′—CO2CH2CH3), 156(base), 155, 127, 111.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[C:13]([Cl:19])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[K+]>C(O)C.O>[Cl:19][C:13]1[CH:12]=[C:11]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([OH:20])=[O:2])[CH:16]=[CH:15][C:14]=1[S:17][CH3:18]
Reactant: COC(=O)C(CC1CCCC1)c1ccc(SC)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 0.1 %

Procedure:
A solution of 2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (4.85 g, 15.50 mol) in ethanol (108 mL) was treated with a solution of potassium hydroxide (4.35 g, 77.50 mmol) in water (25.2 mL). The reaction mixture was stirred at 25° C. for 3 h. The reaction mixture was then concentrated in vacuo to remove ethanol. The resulting aqueous residue was acidified to pH=2 with a 1N aqueous hydrochloric acid solution and then extracted with methylene chloride (3×15 mL). The combined organic layers were then dried over sodium sulfate, filtered, and concentrated in vacuo to afford 2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid (4.14 g, 89.4%) as a white solid which was used without further purification.
Reaction SMILES: C1(C[O:8][C:9]2[CH:19]=[CH:18][C:12]3[C:13](=[O:17])[CH:14]=[CH:15][O:16][C:11]=3[C:10]=2[CH2:20]/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)C=CC=CC=1.CO.[H][H]>[Pd].C(OCC)(=O)C>[OH:8][C:9]1[CH:19]=[CH:18][C:12]2[C:13](=[O:17])[CH2:14][CH2:15][O:16][C:11]=2[C:10]=1[CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: [H][H]
Reactant: O=c1ccoc2c(C/C=C/c3ccccc3)c(OCc3ccccc3)ccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1CCOc2c1ccc(O)c2CCCc1ccccc1
Yield: 228.9 %

Procedure:
A mixture of 6.1 g (16.6 mmol) of (E)-7-(phenylmethoxy)-8-(3-phenyl-2-propenyl)-4H-1-benzopyran-4-one from the preceding example, 1 g of 10% palladium on carbon, 100 mL of methanol, and 300 mL of ethyl acetate was stirred at room temperature, in an atmosphere of hydrogen until approximately one third of the theoretical volume of hydrogen gas was taken up. The catalyst was filtered with suction and the filtrate concentrated in vacuo. The residue was dissolved in 150 mL of methanol and 0.5 g of Raney nickel was added. The hydrogenation was continued with careful monitoring by TLC analysis. When the reduction was essentially complete, the catalyst was filtered with suction and the filtrate concentrated in vacuo. The solid residue (4.75 g) was combined with 6.4 g from another experiment (23.9 mmol scale) and chromatographed on silica gel. Elution with hexane-ethyl acetate mixtures afforded 10.73 g (93.9%) of the title compound as a colorless solid, mp 110°-112° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH2:19]=C1CCN(C2C=CC=CC=2)CC1>>[CH2:19]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: C=C1CCN(c2ccccc2)CC1
Reactant: CCOC(=O)c1ccc(N2CCC(=O)CC2)cc1
Product: C=C1CCN(c2ccc(C(=O)OCC)cc2)CC1

Procedure:
Using ethyl 4-(4-oxopiperidin-1-yl)benzoate 390B (0.575 g, 2.325 mmol), Wittig olefination was carried out as described for 389A. The title compound was obtained as an off-white crystalline solid (0.338 g, 59.3% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21-1.38 (m, 3H) 2.18-2.30 (m, 4H) 3.37-3.50 (m, 4H) 4.23 (q, J=7.16 Hz, 2H) 4.78 (s, 2H) 6.95-7.04 (m, 2H) 7.72-7.82 (m, 2H). ESI-MS: m/z 246.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=O)=O)=[CH:6][C:5]([C:12]2[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)=[C:4]([F:24])[CH:3]=1.II.[C:27](O)(=[O:29])[CH3:28]>>[C:27]([S:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:24])=[C:5]([C:12]2[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[CH:6]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)O
Reactant: Cn1c(C(F)(F)F)ccc(-c2cc(S(=O)(=O)Cl)c(Cl)cc2F)c1=O
Agent: II
Product: CC(=O)Sc1cc(-c2ccc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Yield: 98 %

Procedure:
To 50 ml of acetic acid, 3.1 g (7.7 mmol) of 3-(4-chloro-5-chlorosulfonyl-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone, 1.2 g (38 mmol) of red phosphorus and 0.12 g (0.47 mmol) of iodine were added, followed by heating and refluxing for 1 hour. After cooling, insoluble substances were filtered off, and majority of acetic acid was distilled off. Then, the obtained residue was poured into water and extracted with ethyl acetate. After washing with water and a saturated sodium hydrogencarbonate aqueous solution, the organic layer was washed with anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 2.8 g (yield: 98%) of the desired product. Melting point: 91-92° C.