Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:36])[CH:7]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1>O.O1CCCC1>[CH2:30]([O:29][CH:7]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:22][CH:23]=2)=[CH:11][CH:10]=1)[C:6]([OH:36])=[O:5])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCOC(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCOC(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97.6 %

Procedure:
Lithium hydroxide hydrate (0.036 g; 0.85 mmole) dissolved in water (2.6 ml) was slowly added at room temperature to a solution of 2-hexyloxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic acid methyl ester (described in Example 16) (0.37 g; 0.77 mmole) in tetrahydrofuran (3.5 ml). The reaction mixture was stirred at room temperature for 3.5 hours and then evaporated to remove tetrahydrofuran. The residue was acidified with potassium hydrogen sulfate (1 M) until pH<2 and then extracted with ethyl acetate. The organic phase was washed with brine and dried. Evaporation to remove the solvent gave 0.349 g (97.5%) of 2-hexyloxy-3-[4-(2-{4-methanesulfonyloxyphenyl}-ethoxy)phenyl]propanoic acid.
Reaction SMILES: [NH2:1][C:2]([C:4]1[N:8]=[C:7]([C@H:9]([CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])[O:6][N:5]=1)=[O:3].FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]([C:4]1[N:8]=[C:7]([C@H:9]([CH2:18][CH2:19][CH2:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)[CH2:10][C:11]([OH:13])=[O:12])[O:6][N:5]=1)=[O:3]
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCc1ccccc1)c1nc(C(N)=O)no1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
A solution of tert-butyl (3R)-3-[3-(aminocarbonyl)-1,2,4-oxadiazol-5-yl]-6-phenylhexanoate (Preparation 5) (250 mg, 0.68 mmol) in dichloromethane (10 ml) was cooled to 0° C. and treated with trifluoroacetic acid (5 ml). The mixture was stirred for 2 hours, being allowed to warm to room temperature over this time. The solvent was removed under reduced pressure and the residue was azeotroped with toluene (×2) then hexane to afford the title compound as a white solid (204 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2>CC(C)=O.FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[CH3:4][C:3]1([CH3:7])[CH:2]=[C:10]([CH3:9])[C:10]2[C:2](=[C:3]3[CH2:4][CH2:5][CH2:6][C:7]3=[CH:8][CH:9]=2)[NH:1]1
Reactant: Nc1cccc2c1CCC2
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: CC(C)=O
Product: CC1=CC(C)(C)Nc2c1ccc1c2CCC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of 4-aminoindane (50 g) in acetone (500 ml) was added scandium(III) trifluoromethanesulfonate (10 g), and the mixture was stirred at room temperature for 5 days.
Reaction SMILES: [CH:1]([N:4]([CH2:25][C@@H:26]1[C@H:30]2[O:31]C(C)(C)[O:33][C@H:29]2[C@H:28]([N:36]2[CH:44]=[N:43][C:42]3[C:37]2=[N:38][CH:39]=[N:40][C:41]=3[NH2:45])[O:27]1)[CH:5]1[CH2:8][CH:7]([CH2:9][CH2:10][C:11]2[NH:15][C:14]3[CH:16]=[CH:17][C:18]([C:20]4([CH3:24])[CH2:23][CH2:22][CH2:21]4)=[CH:19][C:13]=3[N:12]=2)[CH2:6]1)([CH3:3])[CH3:2].FC(F)(F)C(O)=O.O>>[NH2:45][C:41]1[N:40]=[CH:39][N:38]=[C:37]2[C:42]=1[N:43]=[CH:44][N:36]2[C@H:28]1[C@H:29]([OH:33])[C@H:30]([OH:31])[C@@H:26]([CH2:25][N:4]([CH:1]([CH3:3])[CH3:2])[CH:5]2[CH2:6][CH:7]([CH2:9][CH2:10][C:11]3[NH:15][C:14]4[CH:16]=[CH:17][C:18]([C:20]5([CH3:24])[CH2:23][CH2:22][CH2:21]5)=[CH:19][C:13]=4[N:12]=3)[CH2:8]2)[O:27]1
Reactant: CC(C)N(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCc2nc3cc(C4(C)CCC4)ccc3[nH]2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)N(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(CCc2nc3cc(C4(C)CCC4)ccc3[nH]2)C1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 64.9 %

Procedure:
9-((3aR,4R,6R,6aR)-6-((isopropyl(3-(2-(5-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-amine 422 mg, 0.686 mmol) was dissolved in a mixture of Trifluoroacetic Acid (6.3 ml, 82 mmol) and water (0.7 ml, 40 mmol) which had been pre-cooled at 0° C. in an ice bath. The solution was stirred at 0° C. for 30 minutes, upon which the ice bath was removed and the mixture was warmed to RT. The mixture was stirred at RT for 2.5 h upon which the residue was taken up in 12 ml MeOH, concentrated to dryness. This was repeated twice, the resultant glass was placed under high vacuum. The crude residue was diluted with 11 ml MeOH, treated with 600 mg K2CO3 and 0.5 ml H2O and allowed to stir at RT till the solution was basic as determined by pH paper. The mixture was filtered and the solids were washed with 20 ml MeOH. The solution was concentrated to a residue that was placed under high vacuum. The crude material was purified by flash chromatography (SiO2, eluting with 10-12% 7N NH3 in CH3OH/CH2Cl2) to give the desired compound as a stiff foam/glass (256 mg). 1H NMR (400 MHz, MeOD) δH ppm 8.30 (m, 1 H), 8.20 (d, J=1.04 Hz, 1 H), 7.38 (d, J=8.09 Hz, 1 H), 7.22 (br. s., 1 H), 6.98 (dd, J=8.50, 1.66 Hz, 1 H), 5.96 (m, 1 H), 4.74 (t, J=4.87 Hz, 1 H), 4.27 (d. J=3.11 Hz, 1 H), 4.08 (m, 1 H), 3.56 (m, 1 H), 3.13 (m, 1 H), 3.00 (m, 1 H), 2.90 (dd, J=14.51, 4.35 Hz, 1 H), 2.75 (m, 3 H), 2.41 (m, 2 H), 2.12 (m, 5 H), 2.00 (m, 1 H), 1.84 (m, 3 H), 1.58 (m, 1 H), 1.46 (s, 3 H), 1.02 (m, 3 H), 0.95 (d, J=6.63 Hz, 3 H).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].C([S:12][CH:13]1[CH2:18][CH2:17][S+:16]([CH3:19])[CH2:15][CH2:14]1)(=O)C.[OH-].[Na+].Cl>O>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[SH:12][CH:13]1[CH2:18][CH2:17][S+:16]([CH3:19])[CH2:15][CH2:14]1
Reactant: CC(=O)SC1CC[S+](C)CC1
Agent: Cl
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: O
Product: C[S+]1CCC(S)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cooled (5° C.) solution of 4-acetylthio-1-methyltetrahydrothiopyranium trifluoromethanesulfonate (3.35 g, 9.83 mmol) in deoxygenated water (32 mL) was added a solution of 1M NaOH (10.8 mL, 10.8 mmol) dropwise. After stirring for 1 hr at 0° C., the pH was adjusted to 7.5 with 1N HCl. The solution was lyophylized to give the desired thiol plus a mixture of salts. The product was used as such without further purification: 1Hmr (D2O) δ: 2.0-4.0 (m, 11H), 2.90 (s, 3H, SCH3) and 1.9 ppm (s, 3H, CH3CO-).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([OH:17])[CH2:14][CH2:13][CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10]2)[C:6]=1[CH3:7].[H-].[Na+].Br[CH2:21][CH:22]=[CH2:23]>CN(C)C=O.C(OCC)C>[CH2:23]([O:17][C:9]1([CH2:8][N:5]2[C:6]([CH3:7])=[C:2]([Br:1])[CH:3]=[N:4]2)[CH2:14][CH2:13][CH2:12][C:11]([CH3:15])([CH3:16])[CH2:10]1)[CH:22]=[CH2:21]
Reactant: C=CCBr
Reactant: Cc1c(Br)cnn1CC1(O)CCCC(C)(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CCOC1(Cn2ncc(Br)c2C)CCCC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of EXAMPLE 157B (2.73 g) in N,N-dimethylformamide (20 mL) was added NaH (1.45 g) and the reaction mixture was stirred for 30 minutes at room temperature. 3-Bromoprop-1-ene (1.53 mL) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with diethyl ether (75 mL), washed with water (2×50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with a gradient of 1.5% to 15% ethyl acetate/hexanes provided the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([CH:8]([CH2:18][CH2:19][CH3:20])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[N:27][C:28]([CH3:34])=[N:29]2.O>C1(C)C=CC=CC=1.[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([CH:8]([CH2:18][CH2:19][CH3:20])[CH2:9][C:10]([C:13]([F:16])([F:14])[F:15])([OH:17])[CH:11]=[N:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[N:27][C:28]([CH3:34])=[N:29]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ncc2c(N)cccc2n1
Reactant: CCCC(CC(O)(C=O)C(F)(F)F)c1cccc(F)c1OC
Agent: [Ti+4]
Agent: CC[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC(CC(O)(C=Nc1cccc2nc(C)ncc12)C(F)(F)F)c1cccc(F)c1OC
Yield: 86.8 %

Procedure:
300 mg (0.97 mmol) of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)heptanal and 138 mg (0.87 mmol) of 5-amino-2-methylquinazoline are dissolved in 28 ml of toluene and the solution is admixed with 0.48 ml of titanium tetraethoxide. The reaction mixture is heated at 100° for 2 hours, cooled, poured into water and stirred vigorously. The suspension is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. The phases of the filtrate are separated and extraction is carried out again with ethyl acetate. The extracts are washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is removed in vacuo to give 350 mg of crude 4-(3-fluoro-2-methoxyphenyl)-1-[(2-methylquinazolin-5-yl)imino]-2-(trifluoromethyl)heptan-2-ol as a crude product. The crude imine is dissolved in 35 ml of CH2Cl2 and the solution is cooled to −20° C. 5.8 ml (5.8 mmol) of a 1 M BBr3 solution in dichloromethane are added slowly dropwise over 5 minutes and the mixture is allowed to warm to room temperature over 1.5 hours. The reaction solution is poured onto a mixture of saturated NaHCO3 solution and ice. Extraction is carried out repeatedly with ethyl acetate and the extracts are washed with saturated NaCl solution and dried over Na2SO4. Purification by column chromatography on silica gel (hexane/isopropanol 0-15%) and subsequent HPLC separation on chiral stationary phase afford 16 mg of product and 26 mg of the corresponding (5α,6α,8α) compound (Example 62).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][C:21]([OH:23])=O)=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:25]1[C:29](=O)[CH2:28][CH2:27][C:26]1=O.C1(N=C=NC2CCCCC2)CCCCC1.C(N)CCC>C(#N)C.C(OCC)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][C:21]([NH:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:23])=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2ccc(OCC(=O)O)cc2C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Solvent: CCCCN
Solvent: CCOCC
Product: CCCCNC(=O)COc1ccc2c(c1)C[C@@H](NC(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4 g (0.0013 mole) of (2S)-2-tert-butoxycarbonylamino-7-hydroxycarbonylmethoxy-tetralin and 1.66 g (0.0143 mole) of N-hydroxysuccinimide in 40 ml of acetonitrile were stirred at ambient temperature for 3 hours and 2.95 g (0.0143 mole) of DCC (dicyclohexylcarbodiimide) in 15 ml of ethyl ether were added. 1.3 ml (0.0195 mole) of n-butylamine were then added and it was stirred at ambient temperature overnight. The solvent was evaporated off, the residue was taken up in water; it was extracted with ethyl acetate. The organic phase was washed with an aqueous sodium bicarbonate solution, dried and the solvent was evaporated off under reduced pressure. The residue was taken up in a 1:1 ethyl acetate/hexane mixture; the precipitate formed was filtered off and oven dried. The product of the heading was obtained as a white solid.
Reaction SMILES: C([O-])(=O)C.[NH4+].[F:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([O:15][CH2:16][CH2:17][CH3:18])[CH:14]=1)[CH:10]=O.[N+:19]([CH3:22])([O-:21])=[O:20].O>C(O)(=O)C>[F:6][C:7]1[CH:14]=[C:13]([O:15][CH2:16][CH2:17][CH3:18])[CH:12]=[C:9](/[CH:10]=[CH:22]/[N+:19]([O-:21])=[O:20])[CH:8]=1
Reactant: C[N+](=O)[O-]
Reactant: CCCOc1cc(F)cc(C=O)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: CCCOc1cc(F)cc(/C=C/[N+](=O)[O-])c1
Temperature: 140 °C
Yield: 69.7 %

Procedure:
Add ammonium acetate (2.63 g, 34.08 mmol) to 3-fluoro-5-propoxy-benzaldehyde (2.25 g, 12.35 mmol) and nitromethane (3.09 g, 50.63 mmol) in acetic acid (41 mL) at room temperature and heat in 140° C. oil bath for 3 hours. Cool to room temperature and pour into water. Extract with ethyl acetate, dry over magnesium sulfate, filter and concentrate to afford 1.94 g (69.8%) of the desired compound as an oil.
Reaction SMILES: CO[CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][C:5]1=[O:15].[OH:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[OH:24])[NH2:20]>CN(C)C=O>[OH:16][C:17]1[CH:18]=[C:19]([NH:20][CH:3]=[C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:14])[NH:6][C:5]2=[O:15])[CH:21]=[CH:22][C:23]=1[OH:24]
Reactant: Nc1ccc(O)c(O)c1
Reactant: COC=C1C(=O)NC(=O)c2ccccc21
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccccc2C1=CNc1ccc(O)c(O)c1
Temperature: 115 °C
Reaction time: 1.5 h
Yield: 26.3 %

Procedure:
To a suspension of 4-Methoxymethylene-4H-isoquinoline-1,3-dione (40.6 mg, 0.2 mmol) in N,N-dimethylformamide (0.5 mL) is added 3,4-dihydroxyaniline (25 mg, 0.2 mmol). The reaction mixture is shaken at 115° C. for 1.5 hours. The reaction mixture is diluted to 2 mL with N,N-dimethylformamide and purified by C18 reverse phase HPLC. The pure fractions were combined and concentrated to yield the title compound (15.6 mg).
Reaction SMILES: [C:1]1([S:7]([NH:10][CH2:11][CH2:12][S:13][C:14]2[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)Cl>[C:1]1([S:7]([NH:10][CH2:11][CH2:12][S:13]([C:14]2[CH:15]=[CH:16][C:17]([O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=2)=[O:35])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)COc1ccc(SCCNS(=O)(=O)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(S(=O)CCNS(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a solution of ethyl 4-[2-(phenylsulfonylamino)ethylthio]phenoxyacetate (2 g) obtained in Example 3 in methylene chloride (30 ml) was added dropwise under ice cooling a solution of m-chloroperbenzoic acid (0.87 g) in methylene chloride (20 ml). The reaction mixture was stirred at room temperature for an hour, washed with an aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure gave a residue, which was then chromatographed on silica gel column (eluent; ethyl acetate) and recrystallized from ethyl acetate to give ethyl 4-[2-(phenylsulfonylamino)ethylsulfinyl]phenoxyacetate (Compound No. 38) (1.76 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11]([NH:24][C:25](OC(C)(C)C)=O)[C:12]([NH:14][C@H:15](C(=O)NC)C(C)(C)C)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=C1[C@@H](NC(=O)[C@H](N2C=[CH:61][C:60]([C:63]3[CH:68]=[CH:67][C:66]([C:69]4[CH:74]=[CH:73][N:72]=[CH:71][CH:70]=4)=[CH:65][CH:64]=3)=[CH:59]2)CC(O)=O)CC2=CN(C3C2=CC=CC=3)CCOCCN1.CN.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11]([N:24]1[CH:25]=[CH:59][C:60]([C:63]2[CH:68]=[CH:67][C:66]([C:69]3[CH:74]=[CH:73][N:72]=[CH:71][CH:70]=3)=[CH:65][CH:64]=2)=[CH:61]1)[C:12]([NH:14][CH3:15])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Reactant: O=C(O)C[C@H](C(=O)N[C@H]1Cc2cn(c3ccccc23)CCOCCNC1=O)n1ccc(-c2ccc(-c3ccncc3)cc2)c1
Agent: CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: CNC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccncc3)cc2)c1
Yield: 51 %

Procedure:
According to the procedure described in Example 1(b) for the preparation of 3(R)-t-butyloxycarbonylamino-N-(2,2-dimethyl-1(S)-(methylcarbarnoyl)propyl)succinamic acid benzyl ester, 2(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinic 4-benzyl ester hydrochloride (prepared as described in Example 7(a)) and excess 40% aqueousueous methylamine were coupled with TBTU. The solid that precipitated from the reaction mixture was washed with water and, after drying, with ethyl acetate to give 51% of N-methyl-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid benzyl ester as a yellow solid: 1HNMR (DMSO-d6): δ—8.58 (d, 2H, J=4.4 Hz), 7.84 (br s, 1H), 7.76-7.70 (m, 4H), 7.60 (d, 2H, J=8.5 Hz), 7.29-7.25 (m, 6H), 6.76 (s, 1H), 6.40 (s, 1H), 5.03 (s, 2H), 4.67 (t, 1H, J=6.2 Hz), 3.20 (dd, 1H, J=15.8, 6.2 Hz), 2.86 (dd, 1H, J=16.0, 8.6 Hz), 2.32 (s, 3H); Anal. Calculated for C27H25N3O3•1.3 H2O: C, 70.05; H, 6.01; N, 9.08. Found: C, 69.98, 69.97; H, 5.98, 6.00; N, 9.01, 9.00.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[OH:20][C:21]1[C:30]2[C:25](=[N:26][C:27]([CH3:31])=[CH:28][CH:29]=2)[N:24]=[CH:23][C:22]=1[C:32](O)=[O:33]>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:32]([C:22]1[CH:23]=[N:24][C:25]2[C:30]([C:21]=1[OH:20])=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=2)=[O:33]
Reactant: Cc1ccc2c(O)c(C(=O)O)cnc2n1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1ccc2c(O)c(C(=O)Nc3ccc(N4CCC(N5CCCC5C)C4)cc3C)cnc2n1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 4-hydroxy-7-methyl-[1,8]naphthyridine-3-carboxylic acid. MS: 446.5 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[N:24]1[N:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]2=[C:26]([C:33](O)=[O:34])[CH:25]=1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:26]2[CH:25]=[N:24][N:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=23)=[O:34])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1cnn2ccccc12
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cnn3ccccc23)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with Pyrazolo[1,5-a]pyridine-3-carboxylic acid. LC-MS (basic): tR=0.83 min; [M+H]+=472.3.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([S:11]([CH2:14][C:15]2[C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([O:25]C)[C:18]([Br:27])=[CH:17][CH:16]=2)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CN(C)C1C=CC=CC=1>C(Cl)Cl>[C:5]1([S:11]([CH2:14][C:15]2[C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([OH:25])[C:18]([Br:27])=[CH:17][CH:16]=2)(=[O:13])=[O:12])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1O
Temperature: 0 °C
Yield: 88.2 %

Procedure:
Aluminium chloride (2.16 g) was added to a stirred solution of methyl 6-(benzenesulfonylmethyl)-3-bromo-2-methoxybenzoate (Intermediate 41, 2.15 g) and N,N-dimethylaniline (3.26 g) in DCM (35 mL) and the resultant mixture was stirred for 50 minutes. Ice water and DCM were added and the organic layer was separated, washed with 1M HCl, dried (Na2SO4), filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with DCM to give methyl 6-(benzenesulfonylmethyl)-3-bromo-2-hydroxybenzoate (1.83 g) as a white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]([C:10]1([F:16])[CH2:14][CH2:13][CH2:12][CH:11]1[OH:15])=[O:9]>N1C=CC=CC=1>[CH3:6][O:7][C:8]([C:10]1([F:16])[CH2:14][CH2:13][CH2:12][CH:11]1[O:15][S:2]([CH3:1])(=[O:4])=[O:3])=[O:9]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C1(F)CCCC1O
Solvent: c1ccncc1
Product: COC(=O)C1(F)CCCC1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 5 h
Yield: 81.9 %

Procedure:
0.36 g (3 mmol) of methanesulfonyl chloride was added under ice cooling to a mixture of 0.5 g (3 mmol) of 1-fluoro-2-hydroxy-1-cyclopentanecarboxylic acid methyl ester in cis form (compound number 2a) synthesized in Example 1 and 2 ml of pyridine, and the mixture was stirred at 0° C. for 5 hours. The reaction solution was poured into a ice water and extracted with ether, and the ether layer was washed with cold water. The ether layer was dried over anhydrous magnesium sulfate and the solvent was distilled away to obtain 0.59 g (yield: 80%) of the desired 2-methanesulfonyloxy-1-fluoro-1-cyclopentanecarboxylic acid methyl ester in cis form (compound number 5a).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+].C(NCC)C>CN(C)C=O>[CH2:24]([O:23][C:21]([CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(-c2ccc(C(=O)OCC)cc2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
A mixture of ethyl 4′-hydroxybiphenyl-4-carboxylate (2.262 g), ethyl bromoacetate (1.871 g) and potassium carbonate (1.940 g) in N,N-dimethylformamide (50 mL) was stirred at 60° C. for 1 hr. Diethylamine (6.820 g) was added to the reaction mixture. After being stirred at room temperature for 30 minutes, the mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford ethyl 4′-ethoxycarbonylmethoxybiphenyl-4-carboxylate (3.06 g) as a crude product. A mixture of the crude ethyl 4′-ethoxycarbonylmethoxybiphenyl-4-carboxylate, sodium borohydride (0.706 g), tetrahydrofuran (40 mL) and ethanol (10 mL) was stirred at 60° C. for 1 hr. Methanol (10 mL) was added to the reaction mixture, and stirred at room temperature for additional 30 minutes. The solvent was evaporated under reduced pressure, and the residue was partitioned between ethyl acetate and 1 mol/L hydrochloric acid. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford the title compound (3.000 g)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[C:33]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:32])/[C:4](=[CH:39]\[C:36]1[CH:37]=[CH:38][C:33]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:34][CH:35]=1)/[CH2:5][C:6]([O:8][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:7]
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)C(CC(=O)OC(C)(C)C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)/C(=C\c1ccc(-c2ccccc2)cc1)CC(=O)OC(C)(C)C

Procedure:
Next, a mixture of 2-(triphenylphosphanylidene)-succinic acid 4-tert-butyl ester 1-methyl ester (700 mg, 1.561 mmol) and biphenyl-4-carboxaldehyde (278 mg, 1.419 mmol) in toluene (20 mL) is refluxed for 4 days. The solvent is removed under reduced pressure and the residue is purified by column chromatography using a gradient of 0-30% heptane/EtOAc to give 2-[1-biphenyl-4-yl-meth-(Z)-ylidene]-succinic acid 4-tert-butyl ester 1-methyl ester as an oil, 1H-NMR (400 MHz, CDCl3); δ ppm 1.47 (s, 9H), 3.52 (s, 2H), 3.84 (s, 3H), 7.37 (t, 1H), 7.46 (t, 4H), 7.62 (t, 4H), 7.89 (s, 1H).