Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:10]2[CH:11]=[C:12]([CH3:25])[N:13]=[C:14]([C:19](N(OC)C)=[O:20])[C:15]=2[C:16](=[O:18])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][Mg+].[Br-]>C1COCC1>[C:19]([C:14]1[N:13]=[C:12]([CH3:25])[CH:11]=[C:10]2[C:15]=1[C:16](=[O:18])[CH:17]=[C:8]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[N:9]2[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:20])[CH3:32]
Reactant: C[Mg+]
Reactant: CON(C)C(=O)c1nc(C)cc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)c1nc(C)cc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 65.7 %

Procedure:
2-Anilino-N-methoxy-N,7-dimethyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridine-5-carboxamide (60 mg, 0.14 mmol) was suspended in THF (5 mL). To this stirring suspension at 0° C. was added MeMgBr (0.19 mL, 0.56 mmol, 3M in Et2O). The reaction was stirred at room temperature for 6 h and quenched with saturated aqueous NH4Cl, diluted with EtOAc, and washed with brine. The organic layer was collected, dried over Na2SO4, and concentrated in vacuo. The residue was purified by Biotage silica gel chromatography using EtOAc as the eluent to provide 5-acetyl-2-anilino-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one as a light yellow solid (34 mg, 66%): LCMS RT: 2.20 min, MH+: 370.4.
Reaction SMILES: COC([CH:5]1[CH2:10][C:9]([C:26]#[N:27])([C:11]2[C:19]3[C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[O:16][C:15]=3[C:14]([O:24][CH3:25])=[CH:13][CH:12]=2)[CH2:8][CH2:7][C:6]1=[O:28])=O.[Cl-].[Na+]>CS(C)=O.O>[CH3:25][O:24][C:14]1[C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[C:19]=2[C:11]([C:9]2([C:26]#[N:27])[CH2:8][CH2:7][C:6](=[O:28])[CH2:5][CH2:10]2)=[CH:12][CH:13]=1
Reactant: COC(=O)C1CC(C#N)(c2ccc(OC)c3oc4ccccc4c23)CCC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(C2(C#N)CCC(=O)CC2)c2c1oc1ccccc12
Temperature: 135 °C

Procedure:
To a solution of 5-cyano-5-(4-methoxy-dibenzofuran-1-yl)-2-oxo-cyclohexane carboxylic acid methyl ester obtained in example 1 (7 g, 0.0185 mol) in DMSO (140 ml) and water (9 ml) was added sodium chloride (7 g, 0.119 mol) at room temperature. The reaction mass was heated to 130-140° C. for 5 hrs. Once the product is formed, the reaction mass was quenched with water and extracted with ethyl acetate. The organic layer was dried with sodium sulfate and concentrated under vacuum. 1-(4-methoxy-dibenzofuran-1-yl)-4-oxo-cyclohexane carbonitrile was isolated by column chromatography. Yield 4.2 g (71%)
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH:3]1[CH2:8][C:7](=[O:9])[CH2:6][C:5](=[O:10])[CH2:4]1.[O:13](S(C(F)(F)F)(=O)=O)[S:14]([C:17]([F:20])([F:19])[F:18])(=O)=[O:15]>C(Cl)Cl>[F:18][C:17]([F:20])([F:19])[S:14]([O:9][C:7]1[CH2:8][CH:3]([C:2]([F:11])([F:12])[F:1])[CH2:4][C:5](=[O:10])[CH:6]=1)(=[O:15])=[O:13]
Reactant: O=C1CC(=O)CC(C(F)(F)F)C1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=C1C=C(OS(=O)(=O)C(F)(F)F)CC(C(F)(F)F)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of 5-(trifluoromethyl)cyclohexane-1,3-dione (1.0 eq) in DCM (0.23 M) was added TEA (1.2 eq) to give a clear solution. The mixture was cooled to 0° C. And then Tf2O (1.05 eq) in DCM was added dropwise. The reaction mixture was stirred at that temperature for 2 hours. The reaction mixture was diluted with DCM, and washed with water, aq. NaHCO3, brine, and was dried over MgSO4, filtered and concentrated to give 3-oxo-5-(trifluoromethyl)cyclohex-1-enyl trifluoromethanesulfonate, which was used to next step directly. LC/MS (m/z): MH+=313.0, Rt=1.02 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6](=[O:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.OO.[C:14]([OH:17])(=O)[CH3:15].S([O-])([O-])=O>O.C1CCCCC1.O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].C(#N)C>[CH:14]1([O:17][N:3]2[C:4]([CH3:10])([CH3:9])[CH2:5][C:6](=[O:8])[CH2:7][C:2]2([CH3:11])[CH3:1])[CH2:15][CH2:6][CH2:7][CH2:2][CH2:1]1
Reactant: CC(=O)O
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Agent: O=[W](=O)([O-])[O-]
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: O
Solvent: C1CCCCC1
Solvent: CC#N
Product: CC1(C)CC(=O)CC(C)(C)N1OC1CCCCC1
Temperature: 32.5 °C
Yield: 732.4 %

Procedure:
A mixture of 0.115 g (1.37 mmol) of sodium bicarbonate and 0.275 g (0.834 mmol) of sodium tungstate dihydrate in 2 mol of water is added to a mixture of 10.00 g (64.4 mmol) of 2,2,6,6-tetramethylpiperidin-4-one and 9 ml of acetonitrile at 300 C. A solution of 11.83 g (174 mmol) of 50% aqueous hydrogen peroxide is added dropwise to the reaction mixture over 4.25 hours while the reaction temperature is maintained at 30-35° C. Approximately 3.25 hours after the peroxide addition is begun, a mixture of 0.056 g of sodium bicarbonate and 0.134 g of sodium tungstate dihydrate in 1 ml of water is added to the reaction mixture. After a total reaction time of 6.5 hours, the reaction mixture is diluted with cyclohexane. The aqueous layer is extracted twice with a mixture of 2:1 cyclohexane-acetonitrile. The total amount of cyclohexane used is 60 ml. Acetonitrile (60 ml) is added to the combined organic layers. The reaction mixture is heated to 45° C. and a solution of 0.334 g (1.24 mmol) of ferrous chloride tetrahydrate and 0.312 g (5.20 mmol) of glacial acetic acid in 5 ml of water is added. A solution of 14.95 g (220 mmol) of 50% aqueous hydrogen peroxide is added dropwise to the reaction mixture over 4.25 hours as the reaction mixture is maintained at the reflux temperature of 60° C. The reaction mixture is cooled, and 10% aqueous sulfite solution is added to decompose excess peroxide. The aqueous layer is extracted with a 2:1 mixture of acetonitrile-cyclohexane and then with ethyl acetate. The combined organic layers are concentrated, and the concentrate is purified by flash chromatography with 100:7.5 heptane-ethyl acetate to afford 9.65 g (59% yield) of the title compound, a white solid, mp 33-37. GC assay is 99%.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(N(CC)CC)C.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](Cl)(=[O:21])=[O:20])#[N:12]>O1CCCC1>[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([N:2]([CH3:3])[CH3:1])(=[O:21])=[O:20])#[N:12]
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Reactant: CNC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1ccccc1C#N
Reaction time: 2 h

Procedure:
(Step 1) To a mixture of dimethylamine (49.6 ml, 2M tetrahydrofuran solution) and triethylamine (3.46 ml) was added a solution of 2-cyanobenzene-1-sulfonyl chloride (5.0 g) in tetrahydrofuran (20 ml) at room temperature. The mixture was stirred at the same temperature for 2 hr, and concentrated under reduced pressure. The residue was suspended in water, and filtered. The filtered solid was dissolved in dichloromethane, the solution was washed with water, and the organic layer was dried over sodium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to give 2-cyano-N,N-dimethylbenzenesulfonamide (5.1 g).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:25][C:26]2[N:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: Nc1ncccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1ncccn1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 67 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared in Example 38, 100 mg, 0.35 mmol) in methylene chloride (1 mL) was treated with 2 drops of dry N,N-dimethylformamide. The reaction mixture was cooled to 0° C. and then treated dropwise with oxalyl chloride (34 mL, 0.39 mmol). The reaction mixture was stirred at 0° C. for 10 min and then stirred at 25° C. for 2 h. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in a small amount of methylene chloride and was slowly added to a cooled (0° C.) solution of 2-aminopyrimidine (67 mg, 0.70 mmol) in methylene chloride (1 mL). The resulting reaction mixture was stirred at 0° C. for 30 min and then stirred at 25° C. for 2 h. The reaction mixture was concentrated in vacuo to remove methylene chloride. The resulting residue was diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyrimidin-2-yl-propionamide (85.4 mg, 67%) as a white solid: mp 103-105° C.; EI-HRMS m/e calcd for C18H19Cl2N3O (M+) 363.0905, found 363.0915.
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:8]([O:10][C:11](=[O:33])[CH:12]([O:30][CH2:31][CH3:32])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:16][CH:15]=1)[CH3:9].CCCCCCC>C1(C)C=CC=CC=1>[CH2:8]([O:10][C:11](=[O:33])[CH:12]([O:30][CH2:31][CH3:32])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][C:6](=[O:7])[NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:27][CH:28]=2)=[CH:16][CH:15]=1)[CH3:9]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(O)cc2)cc1)OCC
Reactant: CC(C)(C)N=C=O
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(OC(=O)NC(C)(C)C)cc2)cc1)OCC
Yield: 20.3 %

Procedure:
tert-Butyl isocyanate (0.14 g; 1.4 mmole) was slowly added to a solution of 2-ethoxy-3-{4-[2-(4-hydroxyphenyl)ethoxy]phenyl}propanoic acid ethyl ester (described in Example 26b) (0.5 g; 1.4 mmole) in toluene (5 ml) and thereafter the reaction mixture was stirred over night. The crude mixture was purified by chromatography on silica gel using ethyl acetate:heptane (gradient 1.25-80% ethyl acetate) as eluant to give 0.13 g (yield 20%) of 3-{4-[2-(4-tert-butylcarbamoyloxyphenyl)ethoxy]phenyl}-2-ethoxypropanoic acid ethyl ester.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[F:23])=[C:11]([CH2:24][CH2:25][C:26]#[N:27])[CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:29][CH2:30][CH2:31]Br.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl-].[NH4+]>C1COCC1>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[F:23])=[C:11]([CH2:24][C:25]2([C:26]#[N:27])[CH2:31][CH2:30][CH2:29]2)[CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: BrCCCBr
Reactant: COc1ccc(F)c(-c2ccc(O[Si](C)(C)C(C)(C)C)cc2CCC#N)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(O[Si](C)(C)C(C)(C)C)cc2CC2(C#N)CCC2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(4-((tert-butyl(dimethyl)silyl)oxy)-2′-fluoro-5′-methoxybiphenyl-2-yl)propanenitrile (165 mg) and 1,3-dibromopropane (67 μL) in THF (4 mL) was added a solution (1 M, 1.1 mL) of lithium bis(trimethylsilyl)amide in THF at 0° C., and the mixture was stirred at 0° C. for 1 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (116 mg) as a colorless oil.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:31])[C@@H:7]([O:28][CH2:29][CH3:30])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16]/[CH:17]=[C:18](/[CH3:27])\[C:19]#CC2C=CC=CC=2)=[CH:11][CH:10]=1)C.[CH2:32](O)[CH3:33]>>[C:8]1([C:33]2[CH:32]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=[CH:10][C:19](/[C:18](/[CH3:27])=[CH:17]/[CH2:16][O:15][C:12]2[CH:11]=[CH:10][C:9]([CH2:8][C@H:7]([O:28][CH2:29][CH3:30])[C:6]([OH:5])=[O:31])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCO
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C(/C)C#Cc2ccccc2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccccc3)cc2)cc1)C(=O)O
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
Sodium hydroxide (1N, 1.25 mL, 1.25 mmol) was added to a solution of (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-acid ethyl ester (example 3) (0.246 g, 0.627 mmol) in ethanol (20 mL) and the mixture stirred at 70° C. for 2.5 h. After cooling to room temperature the resulting mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The aqueous phase was collected, acidified with 1N hydrochloric acid (5 mL) and extracted into ethyl acetate (100 mL). The organic phase was washed with brine, dried (Na2SO4) and evaporated to give (E)-(S)-3-[4-(3-biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-ethoxy-propionic acid as an oil; 0.150 g (66%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[S:19]([NH:22][C:23]1[C:32]([C:33]([O:35]C)=[O:34])=[C:31]2[C:26]([CH:27]3[CH2:37][CH:28]3[CH2:29][O:30]2)=[CH:25][CH:24]=1)(=[O:21])=[O:20])=[O:9])[CH3:2].[OH-].[Li+].C(O)=O>O1CCOCC1.O>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[S:19]([NH:22][C:23]1[C:32]([C:33]([OH:35])=[O:34])=[C:31]2[C:26]([CH:27]3[CH2:37][CH:28]3[CH2:29][O:30]2)=[CH:25][CH:24]=1)(=[O:20])=[O:21])=[O:9])[CH3:2]
Reactant: CCN1CCC[C@H]1C(=O)NCc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Agent: [Li+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Solvent: C1COCCO1
Product: CCN1CCC[C@H]1C(=O)NCc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21
Yield: 31 %

Procedure:
A mixture of methyl (1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-2-yl)cabonylaminomethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 101, 0.212 g) and lithium hydroxide (0.05 g) in dioxane (5.5 mL) and water (2.5 mL) was irradiated in the microwave at 150° C. for 30 minutes. After cooling, the mixture was diluted with water, acidified with formic acid to pH5 and extracted with ethyl acetate. The organic layer was washed with water, dried (MgSO4) and filtered. The filtrate was evaporate to dryness and the residue was purified by HPLC (C18) eluting with a mixture of methanol and water, containing 0.1% formic acid, with a gradient of 35-75% to give (1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-2-yl)cabonylaminomethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (0.064 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].Cl[Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(N(CC)CC)C>ClCCl>[Si:13]([O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH2:1])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cc([N+](=O)[O-])ccc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.2 %

Procedure:
To a magnetically stirred solution of 2-amino-5-nitrophenol (5.62 g, 36.5 mmol) and chloro-t-butyldimethylsilane (5.00 g, 33.2 mmol) in dry dichloromethane (66 mL) was added triethylamine (5.55 mL, 39.8 mmol) at 25° C. The reaction mixture was stirred at ambient temperature for 4 hours and partitioned between diethyl ether (200 mL) and saturated ammonium chloride. The aqueous layer was separated and the ether layer washed (saturated ammonium chloride, 1x; water, 1x; brine, 1x), dried (MgSO4), filtered, and evaporated in vacuo. Crystallization from ethyl acetate/hexanes gave 7.5 g (84%) of O-t-butyldimethylsilyl-2-amino-5-nitrophenol
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([NH:31]C(=O)OC(C)(C)C)([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[N:21]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH3:30])=[CH:24][CH:23]=5)[O:19][N:18]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:4][O:3]1.ClC1C=C(C2ON=C(C3C=CC4OC(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)=CC=4C=3)N=2)C=CC=1OCCC>>[NH2:31][C:5]([C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[N:21]=[C:20]([C:22]4[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][CH3:30])=[CH:26][CH:27]=4)[O:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)([CH2:6][OH:7])[CH2:4][OH:3]
Reactant: CCCc1ccc(-c2nc(-c3ccc4oc(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)cc4c3)no2)cc1
Agent: CCCOc1ccc(-c2nc(-c3ccc4oc(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)cc4c3)no2)cc1Cl
Product: CCCc1ccc(-c2nc(-c3ccc4oc(C(N)(CO)CO)cc4c3)no2)cc1
Yield: 28 %

Procedure:
When the product of Step C was substituted for tert-butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 36, Step E, the similar procedure afforded the title compound in 28% yield, as creamy solid. 1H-NMR (DMSO-d6) 8.30 (s, 1H); 8.08 (d, 2H, J=6.6 Hz); 7.94 (d, 1H, J=7.5 Hz); 7.68 (d, 1H, J=7.5 Hz); 7.46 (d, 2H, J=7.5 Hz); 6.92 (s, 1H); 3.67 (b, 2H); 3.59 (b, 2H); 2.65 (b, 2H); 1.63-1.6 (m, 2H); 0.88 (t, 2H, J=6.3 Hz).
Reaction SMILES: BrN1C(=[O:7])CCC1=O.[CH3:9][C:10]1([CH3:33])[CH:15]=[CH:14][C:13]2[CH:16]=[C:17]([S:20]([N:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:18]=[CH:19][C:12]=2[O:11]1.O.[OH-].[Na+]>CS(C)=O.O1CCOCC1.O>[CH3:9][C:10]1([CH3:33])[CH:15]2[O:7][CH:14]2[C:13]2[CH:16]=[C:17]([S:20]([N:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:18]=[CH:19][C:12]=2[O:11]1
Reactant: CC1(C)C=Cc2cc(S(=O)(=O)N3CCCc4ccccc43)ccc2O1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: CC1(C)Oc2ccc(S(=O)(=O)N3CCCc4ccccc43)cc2C2OC21
Reaction time: 2 h

Procedure:
N-Bromosuccinimide (3.65 g, 20.5 mmol) is added to a stirred solution of Intermediate 1a (6.80 g, 19.1 mmol) in dimethylsulphoxide (70 mL) and water (0.89 g, 0.50 mmol) at 15° C. The mixture is stirred for 2 hours and then treated with a solution of sodium hydroxide (4.0 g, 100 mmol) in dioxan-water and stirred at 20° C. for 30 minutes. The mixture is concentrated to 25% volume by evaporation under reduced pressure, treated with saturated aqueous ammonium chloride solution (300 mL) and extracted with ethyl acetate (2×200 mL). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by column chromatography (silica gel, 10% acetone in hexane) to give the title compound as a yellow oil, having the following physical characteristics:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:17][C:18]1[CH:23]=[C:22]([CH2:24]Cl)[CH:21]=[C:20]([Cl:26])[CH:19]=1.Cl>CN(C)C=O.C(OCC)C>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:10][O:11][CH2:24][C:22]1[CH:23]=[C:18]([Cl:17])[CH:19]=[C:20]([Cl:26])[CH:21]=1)[C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(=O)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(COCc1cc(Cl)cc(Cl)c1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N-t-butoxycarbonyl-D-serine (10.0 g, 48.7 mol) in N,N-dimethylformamide (150 mL) at about 0 ° C. was added sodium hydride (4.0 g, 60% dispersion in mineral oil, 99.84 mmol) portionwise. The mixture was stirred for about 30 minutes, and then a solution of 1,3-dichloro-5-chloromethyl-benzene (9.5 mL, 48.7 mmol) in ethyl ether (40 mL) was added. The reaction was allowed to slowly warm to room temperature overnight. The reaction was then quenched with 1N NaOH, the mixture extracted three times with dichloromethane. The combined organic layers were then washed three times with water, 1N HCl, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give crude product. The original basic aqueous layer was then acidified to about pH 4 with 1N HCl, and the mixture was extracted three times with dichloromethane. These three organic layers were combined and washed three times each with water and brine then dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give an additional 620 mg of crude product. Both product fractions were combined and purified by silica gel chromatography using 5% methanol/chloroform as eluent and yielded the title compound of part 1-E (12.39 g, 70%): −APcl MS (M−1)− 363, (M−3)− 361; 1H NMR=400 MHz (CDCl3) 67 : 7.13 (arom, s, 3H), 5.42 (NH, d, 1H), 4.50 (CHCO2H, m, 1H), 4.45 (PhCH2O, s, 2H), 3.82 (CH2OBz, d of d, 2H), 1.43 (BOC, s, 9H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][NH:24][CH2:25]2>CN(C=O)C>[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][N:24]([C:11]1[CH:12]=[C:13]3[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=1[F:15])[CH2:25]2
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: Fc1cccc2c1CNC2
Solvent: CN(C)C=O
Product: O=C(O)c1cn(C2CC2)c2cc(N3Cc4cccc(F)c4C3)c(F)cc2c1=O
Temperature: 110 °C
Yield: 43.4 %

Procedure:
A mixture of 136 mg of 1-cyclopropyl-6,7-difluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 206 mg of 4-fluoroisoindoline, and 1.5 ml of anhydrous DMF was heated at 110° C. for 1.5 hours while stirring. The resulting reaction mixture was evaporated under reduced pressure to dryness. 20 ml of chloroform and 10 ml of 5% acetic acid were added to the residue thus obtained, and the mixture was stirred. The deposited crystals were collected by filtration and washed with water and then ethanol. The chloroform layer was separated, washed with water, dried over anhydrous sodium sulfate, and condensed. The residue was crystallized by the addition of hot ethanol. After cooling the mixture, the crystals were collected by filtration. These crystals, combined with the crystals obtained above, were recrystallized from a mixed solvent of chloroform, methanol, and ethanol to obtain 85 mg of the target compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.6 %

Procedure:
5 g tert-butyl 4-hydroxypiperidine-1-carboxylate are placed in 15 ml of pyridine, then 4.7 g p-toluenesulphonyl chloride are added batchwise. The reaction mixture is stirred at ambient temperature, after 12 hours it is poured onto ice water and the mixture obtained is stirred for a further hour at ambient temperature. The precipitated solid is suction filtered and dried. 7.5 g product are obtained.