Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:35]1[CH2:38][CH:37]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[CH2:36]1>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:35]4[CH2:38][CH:37]([N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)[CH2:36]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: C1CN(C2CNC2)CCO1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CC(N3CCOCC3)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(3-morpholin-4-ylazetidin-1-yl)-1,3-thiazol-4(5H)-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 4-Azetidin-3-yl-morpholine following General Procedure C.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3]C1C=C2C(C=CN2)=CC=1.[C:14]([C:17]1[C:25]2[C:20](=[CH:21][C:22](F)=[C:23](F)[CH:24]=2)[N:19]([CH2:28][C:29]([OH:31])=[O:30])[CH:18]=1)(=[O:16])[NH2:15]>>[C:14]([C:17]1[C:25]2[C:20](=[CH:21][C:22]([O:3][CH:2]([F:13])[F:1])=[CH:23][CH:24]=2)[N:19]([CH2:28][C:29]([OH:31])=[O:30])[CH:18]=1)(=[O:16])[NH2:15]
Reactant: FC(F)Oc1ccc2cc[nH]c2c1
Reactant: NC(=O)c1cn(CC(=O)O)c2cc(F)c(F)cc12
Product: NC(=O)c1cn(CC(=O)O)c2cc(OC(F)F)ccc12

Procedure:
was prepared from 6-difluoromethoxy-1H-indole [200207-21-2] in a similar manner as described for the preparation of (3-carbamoyl-5,6-difluoro-indol-1-yl)acetic acid. White solid. MS (LC/MS): 285 [M+H]+, 569 [2M+H]+; tR (HPLC conditions k): 2.64 min.
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].N([O-])=[O:21].[Na+].Cl.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>CC#N.O>[OH:21][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11]
Reactant: O=N[O-]
Reactant: Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C1CCC(N2Cc3c(O)cccc3C2=O)C(=O)N1
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
A 250 mL-3N-RBF was charged with 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione and H2O (10 vol) and cooled to 0-5° C. NaNO2 (1.1 eq) and HCl (1.1 eq) were added, and the mixture was stirred for 30 minutes. The mixture was then heated to 75-80° C. for 2 hours. The mixture was cooled to room temperature, filtered and dried in vacuo (18 h, 35-40° C.). The crude product was purified by prep-HPLC (Conditions: C18 Symmetry Column, 90:10 H2O: MeCN isocratic, 60 mL/min flow rate, product retention time ˜30 min) to give an off-white solid (240 mg, 2.4%, 99.5 HPLC AP); mp 296.39° C.; HPLC: Hypersil DBS C85m column, 250×4.6 mm, 35° C.; 99:1 to 85:15 Gradient CH3CN/10 mM aq. KH2PO4, 1.0 mL/min over 20 minutes; 7.60 min, 99.5% AP at 210/240 nm: 1H-NMR (DMSO-d6): 10.97 (1H, br s), 10.11 (1H, br s), 7.34 (1H, t), 7.17 (1H, d), 7.03 (1H, d), 5.09 (1H, dd), 4.25 (2H, dd), 2.97-2.85 (1H, m), 2.62-2.36 (2H, m), 2.03-1.96 (1H, m) ppm; 13C-NMR (DMSO-d6):172.85, 171.04, 168.27, 152.55, 133.41, 129.44, 127.94, 117.97, 113.71, 51.59, 45.09, 31.22, 22.42 ppm; LC-MS ES+ (M+1) 261; CHN-Analysis, calcd for C13H12N2O4: C, 60.00%; H, 4.65%; N, 10.76%. Found: C, 59.54%; H, 4.88%; N, 10.48%.
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:31][C:32]1[CH:37]=[C:36](B(O)O)[CH:35]=[CH:34][N:33]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)(Cl)Cl>[Cl:31][C:32]1[CH:37]=[C:36]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][S:2](=[O:1])(=[O:30])[CH2:3][CH2:4]2)=[O:9])[CH:35]=[CH:34][N:33]=1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Reactant: OB(O)c1ccnc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3-c2ccnc(Cl)c2)CC1
Yield: 10 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), 2-chloropyridine-4-boronic acid, copper(II) acetate, pyridine and using chloroforme instead of dichloromethane as solvent, to give the desired product as a light brown solid (10%).
Reaction SMILES: [Cu][C:2]#[N:3].[CH3:4][O:5][C:6](=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1Br>CN(C)C=O.O.[Fe](Cl)(Cl)Cl>[CH3:4][O:5][C:6](=[O:15])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[C:2]#[N:3]
Reactant: COC(=O)Cc1ccccc1Br
Reactant: N#C[Cu]
Agent: Cl[Fe](Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1C#N
Temperature: 25 °C

Procedure:
To a stirring solution of copper (I) cyanide (1.2 eq) in dimethylformamide (2.1 M) at room temperature was added slowly a solution of 2a in dimethylformamide (8.7 M). The reaction was heated to reflux overnight then cooled to room temperature. A solution of iron (III) chloride (1.2 eq) in H2O (0.3 M) was added slowly to the vigorously stirred solution. The resulting solution was extracted with ethyl acetate (3×). The organic phases were combined then washed with brine (1×), dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (15% ethyl acetate/hexanes) to afford the product as a clear oil. (70%) 1H NMR (300 MHz, CDCl3) δ 6.09 (m, 1H), 5.98 (m, 1H), 5.79 (m, 2H), 2.29 (s, 2H), 2.11 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].I[CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24].Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)CCI
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(CCC(F)(F)F)c1cccc(Cl)c1
Temperature: 25 °C

Procedure:
To a stirred solution of m-chlorophenylacetic acid (2.38 g, 14 mmol) in tetrahydrofuran (85 ml) was added at −78° C. lithium diisopropylamide solution (31 ml 1M in THF, 31 mmol). After stirring the mixture for 20 min 1-iodo-3,3,3-trifluoropropane (4.38 g, 20 mmol) was added and the mixture was allowed to warm to room temperature overnight. Water (5 ml) was added followed by 2N hydrochloric acid (10 ml). The reaction mixture was extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4 and evaporated and the residue was purified by column chromatography (SiO2, heptane/EtOAc=9:1) to yield a colourless oil, (1.75 g, 47%); MS (EI): 264.9 (M+.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH:10]([O:12][C:13]1[NH:14][N:15]=[C:16]([CH2:18][CH3:19])[CH:17]=1)[CH3:11].[NH4+].[Cl-].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>ClCCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([CH2:18][CH3:19])[CH:17]=[C:13]2[O:12][C:10]=1[CH3:11]
Reactant: CCc1cc(OC(C)C(=O)c2ccc(Cl)cc2Cl)[nH]n1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCc1cc2oc(C)c(-c3ccc(Cl)cc3Cl)n2n1
Temperature: 80 °C

Procedure:
To a pale yellow solution of 1-(2,4-dichloro-phenyl)-2-(5-ethyl-2H-pyrazol-3-yloxy)-propan-1-one (9.00 g, 28.7 mmol) in 1,2-dichloroethane (125 ml) is slowly added via syringe titanium tetrachloride (3.80 ml, 34.5 mmol) generating a dark red solution. The reaction mixture is heated at 80° C. for 3 hours and allowed to cool to RT. The reaction mixture is poured slowly into NH4Cl (200 ml) and basified (pH 8) using Na2CO3 (200 ml). EtOAc (300 ml) is added and the biphasic solution is filtered through Celite® 521 (filter material) to remove titanium salts. The solution is extracted with EtOAc (3×75 ml) and the combined organics washed with H2O (1×100 ml), and brine (100 ml), dried (Na2SO4), filtered and concentrated in vacuo to yield an amber solid. The residue is crystallized from hot EtOAc/iso-hexane (1:5, 30 ml) to yield white solid: The mother liquor is purified using a Flashmaster (SiO2 150 ml/70 g column) eluting with 3:1 iso-hexane/EtOAc to yield a yellow solid which is crystallized from hot EtOAc/iso-hexane (1:8, 30 ml) to yield the title compound as a pale yellow solid; MS: m/z 295.15 [M+H]+
Reaction SMILES: F[B-](F)(F)F.[F:6][S:7]([F:19])([F:18])([F:17])([F:16])[C:8]1[CH:13]=[CH:12][C:11]([N+:14]#[N:15])=[CH:10][CH:9]=1.[C:20]1([OH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])(=O)C.[Na+]>C(#N)C>[OH:26][C:20]1[CH:25]=[CH:24][C:23](/[N:15]=[N:14]/[C:11]2[CH:12]=[CH:13][C:8]([S:7]([F:16])([F:17])([F:18])([F:19])[F:6])=[CH:9][CH:10]=2)=[CH:22][CH:21]=1
Reactant: N#[N+]c1ccc(S(F)(F)(F)(F)F)cc1
Reactant: Oc1ccccc1
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CC#N
Product: Oc1ccc(/N=N/c2ccc(S(F)(F)(F)(F)F)cc2)cc1
Yield: 61.7 %

Procedure:
Diazonium salt 1 (11.6 mg, 0.0365 mmol), phenol (9.5 mg, 0.10 mmol), and sodium acetate (10.2 mg, 0.124 mmol) were dissolved in 0.21 g of acetonitrile. After 1 month, the solution was filtered through Celite 545. Evaporation of the solvent gave a red oil, which was purified by SiO2 column chromatography (9:1 hexane/ethyl acetate) and following preparative TLC (SiO2, CH2Cl2) afforded 27d as yellow-orange crystals (7.3 mg, 62%); m.p. 110.0-111.0° C. IR (ATR): {tilde over (v)}=3261, 1593, 1505, 1467, 1436, 1402, 1271, 1235, 1142, 1094, 829 cm−1. MS (GC, EI): m/z=324 [M+], 305 [M+-F], 197, 121, 93, 65. 1H NMR (500 MHz, CDCl3): δ=7.92-7.88 (m, 6H), 6.97 (d, J=8.8 Hz, 2H), 5.50 (br. s, 1H) ppm. 13C NMR (125 MHz, CDCl3): δ=159.1 (C), 154.4 (C), 153.7 (C), 147.0 (C), 127.0 (2CH), 125.6 (2CH), 122.5 (2CH), 116.0 (2CH) ppm. 19F NMR (470 MHz, CDCl3): δ=84.1 (quint, J=150 Hz, 1 F), 63.2 (d, J=150 Hz, 4 F) ppm.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.[H-].[Na+].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[S:19][C:18]([S:20]([NH:23][C:24]3[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=3)[C:27](OC)=[O:28])(=[O:22])=[O:21])=[C:17]([CH3:34])[C:16]=2[CH:35]=1>C1COCC1>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[S:19][C:18]([S:20]([NH:23][C:24]3[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=3)[C:27]([O:8][CH2:7][CH2:6][N:1]3[CH:5]=[CH:4][CH:3]=[CH:2]3)=[O:28])(=[O:22])=[O:21])=[C:17]([CH3:34])[C:16]=2[CH:35]=1
Reactant: COC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)c1
Reactant: OCCn1cccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(S(=O)(=O)Nc2cccc(C(=O)OCCn3cccc3)c2)sc2ccc(Cl)cc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
A mixture of 2-pyrrol-1-yl-ethanol (17 mg, 0.15 mmol) and NaH (5 mg, 60% dispersion in mineral oil, 0.13 mmol) in THF (200 μL) was stirred at 0° C. for 15 min. A solution of methyl 3-{[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoate (Example 74) (20 mg, 0.05 mmol) in THF (100 μL) was added, and the reaction mixture was stirred at 0° C. for another 6 h. The reaction was quenched by addition of cold MeOH and 4:1 water/HOAc (50 μL) before purified by preparative HPLC. The title compound was obtained in 53% yield (12.5 mg). MS (ESI+) m/z 475 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:15]=[C:14]([CH:16]2[CH2:18][CH2:17]2)[NH:13][N:12]=1.C(N(CC)CC)C>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Clc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Yield: 69 %

Procedure:
A solution of 2,4,5-trichloropyrimidine (533 mg, 2.93 mmol), 3-amino-5-cyclopropyl-1H-pyrazole (360 mg, 2.93 mmol) and triethylamine (0.49 ml) in EtOH (5 ml) was stirred at room temperature for 10 hours. Solvent was removed and EtOAc was added. The solution was washed with water and dried over anhydrous sodium sulfate and was concentrated to give title compound as a white solid (546 mg, 69%). The compound was carried to the next step without further purification. 1H NMR δ 0.92 (m, 2H), 1.20 (m, 2H), 2.18 (m, 1H), 6.40 (s, 1H), 8.60 (s, 1H), 9.90 (s, 1H), 12.60 (s, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)nc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-n2cncn2)nc1
Reaction time: 0.5 h

Procedure:
2-fluoro-5-nitropyridine (0.5 g, 3.38 mmol), 1,2,4-triazole (0.22 g, 3.22 mmol) were added in DMF (6.4 mL), then cesium carbonate (3.14 g, 9.65 mmol) was added. The reaction was run at room temperature for 30 minutes. Water (50 mL) was added and product fell out of the solution. The solution was filtered and the solid was rinsed with ethyl acetate/water (1:1, 20 mL×2), hot hexane (20 mL) to give the title compound as a white solid.
Reaction SMILES: CN(C1C=CC=C(N(C)C)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1)C.Br[C:33]1[CH:34]=[CH:35][C:36]([O:59][CH3:60])=[C:37]([N:39]2[C:48]3[C:43](=[CH:44][C:45]([S:49]([NH:52][C:53]4[CH:57]=[CH:56][O:55][N:54]=4)(=[O:51])=[O:50])=[CH:46][CH:47]=3)[CH:42]=[CH:41][C:40]2=[O:58])[CH:38]=1.[I-].[O:62]1[CH2:67][CH2:66][CH:65]([Zn+])[CH2:64][CH2:63]1>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:55]1[CH:56]=[CH:57][C:53]([NH:52][S:49]([C:45]2[CH:44]=[C:43]3[C:48](=[CH:47][CH:46]=2)[N:39]([C:37]2[CH:38]=[C:33]([CH:65]4[CH2:66][CH2:67][O:62][CH2:63][CH2:64]4)[CH:34]=[CH:35][C:36]=2[O:59][CH3:60])[C:40](=[O:58])[CH:41]=[CH:42]3)(=[O:51])=[O:50])=[N:54]1
Reactant: [Zn+]C1CCOCC1
Reactant: COc1ccc(Br)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1cccc(N(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Product: COc1ccc(C2CCOCC2)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 38.6 %

Procedure:
A vial was charged with palladium(ii) acetate (2.83 mg, 0.013 mmol), CPhos (0.011 g, 0.025 mmol) and 1-(5-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.100 g, 0.210 mmol). (Tetrahydro-2H-pyran-4-yl)zinc(II) iodide (0.26M in TI-IF) (2.423 ml, 0.630 mmol) was added and the reaction was stirred at 50° C. for 1 h. The reaction was diluted with ethyl acetate and washed (×2) with 1N HCl solution. The organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by reverse-phase preparative HPLC using an XBridge Prep C18 column, 10 micron OBD, 19×100 mm, 0.1% TFA in CH3CN/H2O, gradient 25% to 95% over 12 min to provide N-(isoxazol-3-yl)-1-(2-methoxy-5-(tetrahydro-2H-pyran-4-yl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.039 g, 0.081 mmol, 38.6% yield) as a white solid. m/z (ESI) 482.2 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[C:14]([O:15]C(=O)C)=[C:13]2[C:8]([C:9](OC)=[C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:11][O:12]2)=[CH:7][CH:6]=1)(=O)C.N1C=CN=C1.[O:32]1C2C(=CC=C(O)C=2O)C=C(C2C=CC(O)=CC=2)[CH2:33]1>C(O)C>[CH3:33][O:32][C:22]1[CH:21]=[CH:20][C:19]([C:10]2[CH2:11][O:12][C:13]3[C:8]([CH:9]=2)=[CH:7][CH:6]=[C:5]([OH:4])[C:14]=3[OH:15])=[CH:24][CH:23]=1
Reactant: COC1=C(c2ccccc2)COc2c1ccc(OC(C)=O)c2OC(C)=O
Reactant: Oc1ccc(C2=Cc3ccc(O)c(O)c3OC2)cc1
Agent: c1c[nH]cn1
Solvent: CCO
Product: COc1ccc(C2=Cc3ccc(O)c(O)c3OC2)cc1

Procedure:
4′-Methoxyisoflav-3-ene-7,8-diol was prepared from 7,8-diacetoxy-4-methoxyisoflav-3-ene (0.15 g, 0.4 mmol) and imidazole (0.4 g) in ethanol (1.6 ml) as described for isoflav-3-ene-4′,7-8-triol. Yield: (0.73 g, 61%). 1H NMR (CDCl3+d6-DMSO): δ 3.83 (s, 3H, OCH3), 5.15 (s, 2H, H2), 6.51 (d, 1H, J 8.3 Hz, H6), 6.58 (d, 1H, J 8.3 Hz, H5), 6.68 (bs, 1H, H4), 6.92 (d, 1H, J 8.7 Hz, ArH), 7.35 (d, 2H, J 8.7 Hz, ArH). Mass spectrum: m/z 270 (M, 5%); 256 (100); 255 (70); 239 (20); 181 (25).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][CH2:18][CH2:19][CH:20]([N:27]1[C:35]2[C:30](=[CH:31][C:32](/[C:36](/[CH3:41])=[CH:37]/[C:38](O)=[O:39])=[CH:33][CH:34]=2)[CH:29]=[CH:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:17][CH2:18][CH2:19][CH:20]([N:27]1[C:35]2[C:30](=[CH:31][C:32](/[C:36](/[CH3:41])=[CH:37]/[C:38]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:39])=[CH:33][CH:34]=2)[CH:29]=[CH:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: CCCC(c1ccccc1)n1ccc2cc(/C(C)=C/C(=O)O)ccc21
Product: CCCC(c1ccccc1)n1ccc2cc(/C(C)=C/C(=O)Nc3ccccc3OCCCC(=O)O)ccc21

Procedure:
73 mg of compound 44 was obtained in a similar manner to those described in the Examples 1 and 2 using 135 mg of ethyl 4-(2-aminophenoxy)butyrate and 101 mg of 3-[1-[α-(2-methylethyl)benzyl]indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [F:1][C:2]1[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.C(N(CC)CC)C.[Cl:26][CH2:27][C:28](Cl)=[O:29]>ClCCl>[Cl:26][CH2:27][C:28]([N:8]1[CH2:9][CH2:10][CH:5]([O:4][C:3]2[C:11]([F:18])=[C:12]([F:17])[C:13]([F:16])=[C:14]([F:15])[C:2]=2[F:1])[CH2:6][CH2:7]1)=[O:29]
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCC(Oc2c(F)c(F)c(F)c(F)c2F)CC1

Procedure:
A chilled (ice bath temperature) solution of 10.0 g of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine and 5.72 ml of triethylamine in 100 ml of dichloromethane was treated, dropwise, with a solution of 3.26 ml of chloroacetyl chloride in 40 ml of dichloromethane, and then stirred at room temperature for four hours. The reaction mixture was then washed with water followed by a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated to afford 13.35 g of 1-(2-chloroacetyl)-4-(2,3,4,5,6-pentafluorophenoxy)piperidine as an oil.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:18][N:6]2[CH2:7][CH2:8][CH2:9][CH:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:5]2[C:4]1=[O:19].[C:20]([O-:23])(=[S:22])[CH3:21].[K+]>CC(C)=O>[C:20]([S:22][CH2:2][CH:3]1[CH2:18][N:6]2[CH2:7][CH2:8][CH2:9][CH:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:5]2[C:4]1=[O:19])(=[O:23])[CH3:21]
Reactant: CC(C)(C)OC(=O)C1CCCN2CC(CBr)C(=O)N12
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)SCC1CN2CCCC(C(=O)OC(C)(C)C)N2C1=O
Yield: 76.5 %

Procedure:
1.42 g of tert.butyl 2-bromomethyl-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate (diastereomer A) and 0.58 g of potassium thioacetate were stirred at room temperature in 20 ml of acetone for 17 hours. The solvent was removed by evaporation, the residue was diluted with 100 ml of ethyl acetate, the mixture was washed three times with sodium chloride solution, dried over magnesium sulfate and evaporated. After recrystallization of the residue from ethyl acetate/hexane, there were obtained 1.07 g of tert.-butyl 2-acetylthiomethyl-hexahydro-3-oxo-1H-pyrazolo[1,2-a]-pyridazine-5-carboxylate (diastereomer A) having a melting point of 92°-93° C. (from ethyl acetate/hexane).
Reaction SMILES: [C:1]([C:5]1[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8]([OH:18])=[CH:7][N:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)([O:3][CH3:4])=[O:2].[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[C:1]([C:5]1[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8]([O:18][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=2)(=[O:27])=[O:26])=[CH:7][N:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ncc(O)c2c1[nH]c1ccccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1ncc(OS(=O)(=O)c2ccc(C)cc2)c2c1[nH]c1ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.6 %

Procedure:
In 10 ml of dioxane were dissolved 24.2 mg of the product of Example 2, followed by addition of 19.0 mg of p-toluenesulfonyl chloride and 10 mg of sodium carbonate. The mixture was stirred at room temperature for 4 hours and the resultant crystals were recovered by filtration and recrystallized from methanol to yield 35 mg of the title compound as colorless needles, m.p. 230°-231° C. Yield 89.7%.
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]([N:9]1[CH2:13][CH2:12][O:11][C:10]1=[O:14])=[O:8])=[O:4].[CH3:15][S:16][C:17]#[CH:18].P([O-])([O-])([O-])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C@H:5]1[C@H:6]([C:7]([N:9]2[CH2:13][CH2:12][O:11][C:10]2=[O:14])=[O:8])[C:17]([S:16][CH3:15])=[CH:18]1)=[O:4]
Reactant: C#CSC
Reactant: COC(=O)/C=C/C(=O)N1CCOC1=O
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1C=C(SC)[C@H]1C(=O)N1CCOC1=O
Temperature: 0 °C
Reaction time: 24 h
Yield: 83 %

Procedure:
To 200 mg of powdery Molecular Sieves 4A, which had been dried by heating, were added 0.41 ml (0.050 mmol) of the toluene solution obtained above, 1.5 ml of toluene and 2 ml of petroleum ether (boiling point: ca. 80° C.) in an argon atmosphere. Further, 100.15 mg (0.502 mmol) of 3-[(E)-3-(methoxycarbonyl)propenoyl]-oxazolidin-2-one was added thereto and the mixture was cooled to 0° C. To the obtained suspension was added 135 mg (1.88 mmol) of 1-methylthioacetylene dissolved in 1.5 ml of petroleum ether. Next, the mixture was stirred at the same temperature for 24 hours. Then a 0.2M phosphate buffer solution (pH 7.0) was added to the reaction mixture to thereby cease the reaction. After filtering off inorganic matters with Celite, organic matters were extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of common salt and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by thin layer chromatography (ethyl acetate:hexane=1:1, v/v). Thus 113 mg (83%) of (-)-(3R,4R)-3-methoxycarbonyl- 1-methylthio-4-(oxazolidin-2-on-3-yl)carbonyl-1-cyclobutene was obtained. The optical purity of this compound determined by the method as will be described in Referential Example exceeded 98% ee.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].[CH:12](OCC)=[O:13]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[CH:12][OH:13])[C:10]#[N:11]
Reactant: CCOC=O
Reactant: N#CCc1ccc(Cl)cc1Cl
Product: N#CC(=CO)c1ccc(Cl)cc1Cl
Temperature: 70 °C
Reaction time: 24 h
Yield: 74.1 %

Procedure:
0.6 g of metal sodium was added to dry ethanol to obtain an ethanol solution of sodium ethoxide. Then, a mixed liquid comprising 37.2 g of 2,4-dichlorophenyl acetonitrile and 22.2 g of ethyl formate, was added thereto under heating to 70° C. After the addition, the mixture was further heated and refluxed for 2 hours and then, left to stand for 1 day. The reaction solution was cooled to 0° C. and then subjected to filtration. After washing with diethyl ether, the sodium salt collected by filtration was added to 130 ml of distilled water, and 9 ml of acetic acid was dropwise added thereto under cooling at 0° C. After the dropwise addition, the mixture was stirred at room temperature for about 30 minutes. Then, the formed precipitate was collected by filtration and washed with water. It was dried to obtain 31.7 g (yield: 74%) of the desired product. Melting point: 162-163° C.