Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:14]([CH3:31])[C:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)[S:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2].[C@@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(O)(=O)C>CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C@H:14]([CH3:31])[C@:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)[S:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(c1nc(-c2ccc(C#N)cc2)cs1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: CC1(C)C2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H](c1nc(-c2ccc(C#N)cc2)cs1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 70 °C
Yield: 38.4 %

Procedure:
Racemic 3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol (44 g) and (1R)-10-camphorsulfonic acid (20 g) were suspended in methanol (ca. 300 ml), the slurry was stirred intensively, warmed up to ca. 70° C. and a small addition of acetic acid was added to obtain a clear solution. After cooling of the solution to rt and then to 0° C., the mixture was seeded with enantiomerically pure salt and stirred for another 2 hrs. The crystalline solid was collected by filtration, washed with cooled methanol and dried under reduced pressure. The crystals were partitioned between methylenechloride (300 ml) and saturated aqueous sodium bicarbonate solution (200 ml). The organic layer was washed twice with water (50 ml), dried with magnesium sulphate, filtrated and evaporated under reduced pressure to give the title compound (16.9 g, 38% yield, 95% ee). The analytical data were identical with published (U.S. Pat. No. 5,648,372 or Chem. Pharm. Bull. 1998, 46, 623).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:27])(=[N:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])[CH:14]=2)=[CH:5][C:4]=1[N:28]=[CH:29]N(C)C)#[N:2].[NH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1.CCCCCC.ClCCl.CO>CO>[CH2:25]([O:24][C:22]([N:21]=[S:19]([CH3:27])([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][O:11][C:6]2[CH:5]=[C:4]3[C:3]([C:1]([NH:33][C:34]4[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=4)=[N:2][CH:29]=[N:28]3)=[CH:8][C:7]=2[O:9][CH3:10])[CH:14]=1)=[O:20])=[O:23])[CH3:26]
Reactant: Nc1ccncc1
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc(N=CN(C)C)c(C#N)cc2OC)c1
Solvent: CO
Solvent: ClCCl
Solvent: CCCCCC
Product: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc3ncnc(Nc4ccncc4)c3cc2OC)c1
Yield: 34 %

Procedure:
According to GWP 5, the reaction of N′-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzyloxy}-4-methoxyphenyl)-N,N-dimethylformimidamide (78 mg, 0.12 mmol) with 4-aminopyridine (19 mg, 0.20 mmol) and chromatographic purification (silica gel, amino column, hexane, dichloromethane/methanol: 0→5% methanol) gives the desired product in 34% yield (29 mg).
Reaction SMILES: Br[C:2]1[C:3]([OH:14])=[C:4]([CH:7]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=1)[CH:5]=[O:6].[CH3:15][O:16][C:17]1[C:22](B(O)O)=[CH:21][CH:20]=[CH:19][N:18]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:10]([C:8]1[CH:9]=[C:2]([C:22]2[C:17]([O:16][CH3:15])=[N:18][CH:19]=[CH:20][CH:21]=2)[C:3]([OH:14])=[C:4]([CH:7]=1)[CH:5]=[O:6])([CH3:13])([CH3:12])[CH3:11]
Reactant: COc1ncccc1B(O)O
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ncccc1-c1cc(C(C)(C)C)cc(C=O)c1O
Yield: 77.4 %

Procedure:
step 1—A sealed tube containing 3-bromo-5-tert-butyl-2-hydroxy benzaldehyde E-1b (R1═OH, R4=tert-Bu, 858 mg, 3.339 mmol), 37 (766 mg, 5.008 mmol), Pd(PPh3)4 (240 mg, 0.208 mmol), and Na2CO3 (891 mg, 8.406 mmol) in a mixture of MeOH (10 mL) and DCM (2 mL) was irradiated in a microwave reactor at 115° C. for 30 min. The organic volatiles were removed under reduced pressure and the residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (3 to 5% EtOAc) to afford 737 mg (77%) of 5-tert-butyl-2-hydroxy-3-(2-methoxy-pyridin-3-yl)-benzaldehyde (48) as a pale yellow oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]([O:22][CH3:23])[CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[C:24]1(=O)[C:27]2([CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:26](=[O:33])[CH2:25]1>C(Cl)Cl>[O:33]=[C:26]1[C:27]2([CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:24]([NH:1][C@@H:2]([CH2:7][C:8]2[CH:9]=[C:10]([O:22][CH3:23])[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:12]([O:14][CH3:15])[CH:13]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:25]1
Reactant: COC(=O)[C@@H](N)Cc1cc(OC)c(-c2ccccc2)c(OC)c1
Reactant: O=C1CC(=O)C12CCOCC2
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1cc(OC)c(-c2ccccc2)c(OC)c1)NC1=CC(=O)C12CCOCC2
Yield: 84.4 %

Procedure:
Using a similar procedure to that for the preparation the compound of Example 38 from methyl (2S)-2-amino-3-(2,6-dimethoxy[1,1′-biphenyl]-4-yl)propanoate (2.0 g, 6.3 mmol) and 7-oxaspiro[3.5]nonane-1,3-dione (1.1 g, 1.1 eq) in DCM (30 ml) was prepared the title compound as a white foam (2.4 g, 86%). δH (300 MHz, DMSO d6) 8.53 (1H, d, J 8.7 Hz), 7.20–7.30 (3H, m), 7.08 (2H, d, J 8.1 Hz), 6.70 (2H, d, J 8.5 Hz), 4.44 (1H, s), 4.30 (1H, m), 3.72 (3H, s), 3.61 (6H, s), 3.22 (1H, dd, J 13.7, 5.0 Hz), 2.98 (1H, dd, J 13.8, 10.1 Hz), 1.74–1.99 (2H, m), 1.48 (1H, d, J 13.6 Hz), 1.31 (1H, d, J 13.0 Hz); m/z (ES+, 70V) 439 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:7]([C:22]([OH:24])=[O:23])=[CH:6]2>C(O)C.[Pt]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH:7]([C:22]([OH:24])=[O:23])[CH2:6]2
Reactant: COc1ccc(C(=O)n2c(C(=O)O)cc3cc(OC)ccc32)cc1
Agent: O=[Pt]
Solvent: CCO
Product: COc1ccc(C(=O)N2c3ccc(OC)cc3CC2C(=O)O)cc1
Reaction time: 6 h

Procedure:
To a solution of 5-methoxy-1-(4′-methoxybenzoyl)-1H-indole-2-carboxylic acid (7.02 g, 21.57 mmol) in ethanol (200 mL) was added platinum oxide (0.7 g). The mixture was hydrogenated for 6 hours at 32 psi. The reaction mixture was filtered through a pad of Celite. The filter cake was washed with ethanol. The combined filtrate and washings was evaporated in vacuo to dryness. The solid residue was recrystallized from ethanol to yield 5-methoxy-1-(4′-methoxybenzoyl)-2,3-dihydro-1H-indole-2-carboxylic acid, 6.35 g (90%): mp 151-152° C.; 1H NMR (DMSO-d6) δ 3.05 (1H, m, CH), 3.56-3.63 (1H, m, N—CH), 3.70 (3H, s, OMe), 3.81 (3H, s, OMe), 4.97-5.01 (1H, m, CH), 6.67 (1H, br, ArH), 6.86 (2H, m, 2×ArH), 7.00 (2H, d, J=8.6 Hz, 2×H), 7.45 (2H, J=8.6 Hz, 2×ArH), 12.92 (1H, brs, exchangeable, OH). Anal. Calcd. for C18H17NO5.0.1H2O: C, 65.69; H, 5.26; N, 4.25. Found: C, 65.61; H, 5.48; N, 4.17.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].Br[C:17]1[S:18][CH:19]=[C:20]([Br:22])[N:21]=1>>[Br:22][C:20]1[N:21]=[C:17]([O:15][CH:12]2[CH2:11][CH2:10][N:9]([C:7]3[O:6][N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:8]=3)[CH2:14][CH2:13]2)[S:18][CH:19]=1
Reactant: CC(C)c1noc(N2CCC(O)CC2)n1
Reactant: Brc1csc(Br)n1
Product: CC(C)c1noc(N2CCC(Oc3nc(Br)cs3)CC2)n1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-42, using 1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-ol and 2,4-dibromothiazole
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:9]=[C:10]3[N:26]([CH3:27])[CH:25]=[CH:24][C:11]3=[N:12][C:13]=2[C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15])[CH2:3]1.[C:28]1(=[O:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30](=[O:37])[NH:29]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[O:38]=[C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30](=[O:37])[N:29]1[CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:9]=[C:10]3[N:26]([CH3:27])[CH:25]=[CH:24][C:11]3=[N:12][C:13]=2[C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH3:15])[CH2:3]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccn(C)c2cc1N1CCCC(O)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccn(C)c2cc1N1CCCC(N2C(=O)c3ccccc3C2=O)C1
Temperature: 0 °C
Yield: 24.8 %

Procedure:
A mixture of tert-butyl ((1S)-1-(6-(3-hydroxypiperidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)carbamate (300 mg, 0.802 mmol), isoindoline-1,3-dione (165 mg, 1.12 mmol) and PPh3 (377 g, 1.44 mmol) in THF (2 mL) was stirred at 0° C. Next, diethyl azodicarboxylate (251 mg, 1.44 mmol) was added dropwise at 0° C., and the mixture was stirred at 20° C. for 16 hours. The solvent was evaporated in vacuo, and the residue was purified by preparative TLC to give the title compound as a white solid (100 mg, 35.2%). ESI-MS m/z [M+H]+ calc'd for C28H33N5O4, 504. found 504.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][N:14]=2)[N:10]([C:21]2[CH:22]=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[N:9]=1)=[O:7])C.Cl>CO.O1CCCC1>[CH3:28][O:27][C:24]1[N:23]=[CH:22][C:21]([N:10]2[C:11]([C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][N:14]=3)=[CH:12][C:8]([C:6]([OH:7])=[O:5])=[N:9]2)=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cc(-c2cc(OC)ccn2)n(-c2ccc(OC)nc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccnc(-c2cc(C(=O)O)nn2-c2ccc(OC)nc2)c1
Reaction time: 5 h

Procedure:
1N Aqueous solution of sodium hydroxide (2.23 mL) was added to 1-(6-Methoxy-3-pyridyl)-5-(4-methoxy-2-pyridyl)pyrazole-3-carboxylic acid ethyl ester (0.416 g) obtained from Referential Example 18 in a mixture of methanol (6.3 mL) and tetrahydrofuran (6.3 mL) at room temperature, followed by stirring for 5 hours. The reaction mixture was neutralized with 1N aqueous solution of hydrochloric acid (2.23 mL), and then partitioned between water and chloroform. Subsequently, the aqueous layer was extracted with chloroform twice. The organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure, to thereby give the title compound as a solid substance (0.353 g, 92%).
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[CH2:6]([C:8]([CH3:10])=O)[CH3:7].N1CCCC1>CO.CCOCC.O>[CH3:7][C:6]([CH2:8][CH3:10])=[C:2]1[CH:1]=[CH:5][CH:4]=[CH:3]1
Reactant: C1=CCC=C1
Reactant: CCC(C)=O
Solvent: CO
Solvent: CCOCC
Solvent: C1CCNC1
Product: CCC(C)=C1C=CC=C1
Temperature: 25 °C
Yield: 50.6 %

Procedure:
To a solution of 10.00 g (151.3 mmol) of cyclopentadiene in 30 ml of methanol, 13.6 ml (151.8 mmol) of methyl ethyl ketone and 12.8 ml (153.3 mmol) of pyrrolidine were added with ice cooling, followed by stirring at room temperature for one night. After the reaction solution was diluted with 200 ml of ether, 100 ml of water was added. The organic phase was separated, washed with water and a saturated saline solution, then dried over anhydrous magnesium sulfate and filtered. From the filtrate, the solvent was removed under reduced pressure to obtain a liquid. The liquid was subjected to vacuum distillation (75-82° C./20 mmHg) to obtain 9.20 g (76.55 mmol) of a yellow liquid (yield: 51%). The analyzed values are given below.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:11][CH:12]([CH3:14])[CH3:13])[CH2:10][CH2:9]2)=[C:4]([CH2:15][CH3:16])[CH:3]=1.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:12]([O:11][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])=[CH:3][C:4]=2[CH2:15][CH3:16])[CH2:10][CH2:9]1)([CH3:14])[CH3:13]
Reactant: CCc1cc(Br)ccc1C1(OC(C)C)CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCc1cc(C#C[Si](C)(C)C)ccc1C1(OC(C)C)CC1
Yield: 99.5 %

Procedure:
Using General Procedure D; 4-bromo-1-(1-isopropoxycyclopropyl)-2-ethyl-benzene (Intermediate 93, 300.0 mg, 1.07 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (20.0 mg, 0.11 mmol) and then sparged with argon for 5 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (75.0 mg, 0.11 mmol). The resulting reaction mixture was heated to 70° C. for 5d. The title compound (320.0 mg, 99%) was isolated by chromatography (0-2% EtOAc-hexanes) as an orange oil.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[C:11]3[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:4][C:3]=2[O:2]1>CCO.[Pd]>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:11]3[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1c1ccc2c(c1)OCO2
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1C(c2ccccc2)c2ccccc2C1c1ccc2c(c1)OCO2
Reaction time: 8 h
Yield: 64.7 %

Procedure:
To a solution of ethyl(RS)-1-(3,4-methylenedioxyphenyl)-3-phenylindene-2-carboxylate (1.00 g, 2.60 mmol) in EtOH (25 ml) was added 10% palladium on activated carbon (30 mg). The resulting suspension was stirred under an atmosphere of H2 overnight. Thin layer chromatographic analysis indicated that the reaction was incomplete, so additional 10% palladium on activated carbon (30 mg) was added, and the mixture was shaken on a Parr hydrogenator at 30 psi H2 for 2 d. At this time, thin layer chromatographic analysis again indicated that the reaction was incomplete. The reaction mixture was filtered through a pad of Celite, and 10% palladium on activated carbon (250 mg) was added. The reaction mixture was shaken on a Parr hydrogenator at 60 psi H2 overnight. Filtration and repetition of the latter hydrogenation conditions led to complete consumption of starting material. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to afford the title compound (650 mg, 65%), which was used without further purification.
Reaction SMILES: C([Li])CCC.[CH:6]1[CH:7]=[CH:8][C:9]2[S:14][CH:13]=[CH:12][C:10]=2[CH:11]=1.[CH3:15][C:16]1[CH:17]=[C:18]([CH:22]=[O:23])[O:19][C:20]=1[CH3:21]>C1COCC1>[S:14]1[C:13]([CH:22]([C:18]2[O:19][C:20]([CH3:21])=[C:16]([CH3:15])[CH:17]=2)[OH:23])=[CH:12][C:10]2[CH:11]=[CH:6][CH:7]=[CH:8][C:9]1=2
Reactant: Cc1cc(C=O)oc1C
Reactant: c1ccc2sccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C(O)c2cc3ccccc3s2)oc1C
Reaction time: 0.25 h
Yield: 102.2 %

Procedure:
n-Butyl lithium (2.5 N in hexanes, 32.2 mL, 80.5 mmol) was added to a stirred solution of thianaphthene (10.6 g, 78.9 mmol) in THF (290 mL) at −78 ° C. After 15 min., a solution of 4,5-dimethyl-2-furaldehyde (9.79 g, 78.9 mmol) in THF (10 mL was added. After additional 1 hour, the reaction mixture was quenched with 10% aqueous ammonium chloride (150 mL) and further diluted with water (150 mL). Aqueous mixture was extracted with dichloromethane. The combined dichloromethane extracts were washed with water, dried with brine and anhydrous Na2SO4, and concentrated to provide the title compound as an yellow oil (20.84 g, 100%): NMR (DMSO-d6); δ7.89 (d, J=8 Hz, 1H), 7.76 (d, J=8, Hz, 1H), 7.35-7.26 (m, 2H), 7.25 (s, 1H), 6.36 (s, 1H), 6.08 (s, 1H), 5.92 (s, 1H), 2.13 (s, 3H), 1.86 (s, 3H); MS (EI): [M+], 258.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]([CH2:20][OH:21])=[CH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)[CH2:10][CH2:9]1.C1C=CC=CC=1>N1C=CC=CC=1>[C:1]([O:21][CH2:20][C:6]([F:5])=[CH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)[CH2:9][CH2:10]1)(=[O:3])[CH3:2]
Reactant: OCC(F)=CC1(c2ccc3c(c2)OCO3)CC1
Reactant: CC(=O)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OCC(F)=CC1(c2ccc3c(c2)OCO3)CC1
Yield: 93 %

Procedure:
The method of Example 17 was repeated using acetyl chloride (1.4 ml), 1-(2-fluoro-3-hydroxyprop-1-enyl)-1-(3,4-methylenedioxyphenyl)cyclopropane (Example 14) (0.68 g), benzene (40 ml) and pyridine (0.26 ml) to yield the title compound (0.73 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:50]=[CH:51][CH:52]=1)[O:5][CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C@H:13]([CH3:49])[CH2:14][O:15][C:16]2[CH:48]=[CH:47][C:19]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[N:23](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:22]3=[O:46])=[CH:18][CH:17]=2)[CH2:8]1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:50]=[CH:51][CH:52]=1)[O:5][CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C@H:13]([CH3:49])[CH2:14][O:15][C:16]2[CH:48]=[CH:47][C:19]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[NH:23][C:22]3=[O:46])=[CH:18][CH:17]=2)[CH2:8]1
Reactant: C[C@H](COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)N1C[C@H](COc2cccc(Cl)c2)OC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](COc1ccc(CC2SC(=O)NC2=O)cc1)N1C[C@H](COc2cccc(Cl)c2)OC1=O
Yield: 73.4 %

Procedure:
A procedure similar to that described in Example 1 was repeated, except that 0.57 g of 5-[4-{2(R)-[5(R)-(3-chlorophenoxymethyl)-2-oxooxazolidin-3-yl]-propoxy}benzyl]-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 45), 2 ml of trifluoroacetic acid and 2 ml of methylene chloride were used, to give 280 mg of the title compound, melting at 52° C. to 53° C. and having [α]D =-39.7° (methanol, c=0.965).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=O)=[CH:22][CH:21]=2)[C:10]1=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O>[C:1]([O:5][C:6](=[O:7])[CH2:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27](=[O:29])[NH:31][CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:22][CH:21]=2)[C:10]1=[O:30])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)Cn1c(=O)n(-c2ccc(CC(=O)O)cc2)c(=O)c2ccccc21
Reactant: NCCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Cn1c(=O)n(-c2ccc(CC(=O)NCCc3ccccc3)cc2)c(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A stirred suspension of [4-(1-tert-butoxycarbonylmethyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-acetic acid (Intermediate F) (932 mg, 2.27 mmol), 2-(aminoethyl)benzene (1.2 eq, 344 mg, 2.72 mmol) and HATU (1.2 eq, 1.035 g. 2.72 mmol) in DCM (8 ml) is treated with DIPEA (2 eq, 711 μL, 4.54 mmol). The reaction mixture is stirred at RT for 48 hours. The mixture is diluted with distilled water (5 ml) followed by 0.1 M HCl (5 ml) and extracted with EtOAc (2×15 ml). The combined organic portions are washed with aqueous saturated aqueous NaHCO3, dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:19][C:20]#[C:21][CH3:22].O>O1CCCC1.CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([O:15][CH2:19][C:20]#[C:21][CH3:22])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: CC#CCBr
Reactant: CCOC(=O)c1cc2ccc(O)cc2o1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1ccc2cc(C(=O)OCC)oc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a mixed solution of 6-hydroxy-benzofuran-2-carboxylic acid ethyl ester (250 mg, 1.21 mmol) in tetrahydrofuran (5 mL) and N,N-dimethylformamide (5 mL) were added sodium hydride (58 mg, 2.42 mmol) and 1-bromo-2-butyne (127 μL) at room temperature, which was stirred at room temperature for 1 hour. Water was added to the reaction solution followed by extraction with ethyl acetate. The organic layer was washed with water and sat. NaCl followed by drying over anhydrous magnesium sulfate and filtering. The filtrate was concentrated under a reduced pressure and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=5:1) to obtain the title compound (254 mg, 81%) as a white solid.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([CH3:14])[CH:8]=1)=[O:5])#[N:2].CO/[CH:17]=[CH:18]/[C:19](=O)[CH3:20].N12CCN(CC1)CC2.C(OCC)(=O)C>COCCOCCO.O>[F:13][C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:19]([CH3:20])=[CH:18][CH:17]=[C:3]([C:1]#[N:2])[C:4]2=[O:5])=[CH:8][C:9]=1[CH3:14]
Reactant: CO/C=C/C(C)=O
Reactant: Cc1cc(NC(=O)CC#N)ccc1F
Agent: C1CN2CCN1CC2
Solvent: COCCOCCO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(-n2c(C)ccc(C#N)c2=O)ccc1F
Temperature: 25 °C
Yield: 34.8 %

Procedure:
A solution (30 mL) of 2-cyano-N-(4-fluoro-3-methylphenyl)acetamide (3.60 g, 19.0 mmol), (3E)-4-methoxybut-3-en-2-one (2.80 g, 28.0 mmol) and 1,4-diazabicyclo[2.2.2]octane (3.20 g, 28.0 mmol) in 2-(2-methoxyethoxy)ethanol was stirred at 120° C. for 12 hr. After cooling to room temperature, the reaction solution was divided into two layers with ethyl acetate and water and subjected to extraction (3 times) with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the obtained residue was washed with ethyl acetate and collected by filtration to give the title compound (1.60 g, 34%) as a brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[CH:3]=1.N1C(C)=CC=CC=1C.[O:21](S(C(F)(F)F)(=O)=O)[S:22]([C:25]([F:28])([F:27])[F:26])(=O)=[O:23].C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.C(Cl)Cl.C1COCC1>[F:26][C:25]([F:28])([F:27])[S:22]([O:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][S:22]([C:25]([F:26])([F:27])[F:28])(=[O:21])=[O:23])=[CH:7][CH:8]=2)[CH:3]=1)(=[O:23])=[O:21]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1ccc2ccc(O)cc2c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=S(=O)(Oc1ccc2ccc(OS(=O)(=O)C(F)(F)F)cc2c1)C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
A mixture of 2,7-dihydroxynaphthalene (3.00 g, 18.73 mmol), DMAP (0.42 g, 3.75 mmol) and 2,6-lutidine (4.41 g, 41.18 mmol) was suspended in anhydrous DCM (30 ml) and anhydrous THF (30 ml) in the presence of molecular sieves under an Ar2 atmosphere at −78° C. Tf2O (11.10 g, 39.33 mmol) was added dropwise to this stirred mixture over 15 minutes and the reaction was stirred at −78° C. for 2 hours, then for 5 hours at 0° C. After that time, the reaction was carefully neutralised with saturated aqueous NaHCO3 solution (70 ml), extracted with DMC (6×120 ml), dried (MgSO4), filtered and the solvent removed in vacuo. The orange oil thus obtained was purified by flash column chromatography (petroleum ether:EtOAc, 95:5) to give compound 1 as a white solid (4.94 g, 62%); Rf 0.27 [5% EtOAc in petroleum ether]; mp 60-62° C.; δH (CDCl3, 400 MHz) 7.92 (2H, d, J=9.2 Hz, 2×ArH), 7.73 (2H, d, J=2.4 Hz, 2×ArH), 7.40 (2H, dd, J1=8.8 Hz, J2=2.4 Hz, 2×ArH); δC (CDCl3, 100 MHz) 148.26 (2×Ar—C), 133.62 (Ar—C), 131.27 (Ar—C), 130.80 (2×Ar—CH), 121.13 (2×Ar—CH), 119.48 (2×Ar—CH), 118.77 (2×CF3); HRMS m/z calc. C12H6F6O2S2Na [M+Na]+446.9408. found [M+Na]+446.9424; anal.CHN calcd. C12H6F6O2S2 C, 34.0%; H, 1.4%. found C, 34.2%; H, 1.2%. Spectroscopic data are in accordance with those reported in literature (Yao et al., 1998).