Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].[CH2:22]([O:29][C@@H:30]1[C@@H:37]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@@H:36](O)[C@@H:35]([CH2:47][O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[O:34][C@@H:31]1[O:32][CH3:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O[C@@H]1[C@@H](OCC2C=CC=CC=2)[C@@H](OC(F)(F)F)[C@@H](C(=S(=O)=O)OCC2C=CC=CC=2)O[C@@H]1OC)C1C=CC=CC=1>C(Cl)Cl>[CH2:22]([O:29][C@@H:30]1[C@@H:37]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C@@H:36]([O:12][S:9]([C:8]([F:21])([F:20])[F:7])(=[O:11])=[O:10])[C@@H:35]([CH2:47][O:48][CH2:49][C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[O:34][C@@H:31]1[O:32][CH3:33])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@H](O)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CO[C@H]1O[C@H](C(OCc2ccccc2)=S(=O)=O)[C@H](OC(F)(F)F)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@H](OS(=O)(=O)C(F)(F)F)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of dry pyridine (0.46 ml) in methylene chloride (17.5 ml) cooled to -15° C. is added trifluoromethane sulfonic anhydride (0.87 ml). The mixture is stirred during 15 min at -10° C., then methyl 2,3,6-tri-O-benzyl-α-D-galacto-pyranoside (1.2 g, 2.58 mmol) in methylene chloride (5 ml) is added (N. Morishima, S. Koto, M. Oshima, A. Sugimoto and S. Zen, Bull. Chem. Soc. Jpn., 56, 2849 (1983)). The mixture is washed with water. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure so as to afford an oil which is the expected trillate methyl 2,3,6-tri-O-benzyl-4-O-trifluoromethyl-sulfonyl-α-D-galactopyranoside.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:14][CH3:15])=[C:7](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)[CH:8]=1)#[N:2].C(N(CC)CC)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:45]([O:52][C:53](=[O:72])[CH2:54][C@@H:55]([NH2:71])[CH2:56][N:57]1[CH2:62][CH2:61][CH:60]([O:63][C:64]2[CH:69]=[CH:68][C:67]([F:70])=[CH:66][CH:65]=2)[CH2:59][CH2:58]1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C(Cl)Cl>[CH2:45]([O:52][C:53](=[O:72])[CH2:54][C@@H:55]([NH:71][C:11](=[O:13])/[CH:10]=[CH:9]/[C:7]1[CH:8]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=1[O:14][CH3:15])[CH2:56][N:57]1[CH2:58][CH2:59][CH:60]([O:63][C:64]2[CH:65]=[CH:66][C:67]([F:70])=[CH:68][CH:69]=2)[CH2:61][CH2:62]1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: N[C@H](CC(=O)OCc1ccccc1)CN1CCC(Oc2ccc(F)cc2)CC1
Reactant: COc1ccc(C#N)cc1/C=C/C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C#N)cc1/C=C/C(=O)N[C@H](CC(=O)OCc1ccccc1)CN1CCC(Oc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (E)-3-(5-cyano-2-methoxy-phenyl)-acrylic acid (0.916 g, 4.51 mmol), triethylamine (1.257 ml, 9.02 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (1.44 g, 4.51 mmol) in DCM (10 ml) is treated with (R)-3-amino-4-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-butyric acid benzyl ester. The reaction mixture is stirred at ambient temperature for 2 hours, then is washed with water, dried over MgSO4 and evaporated. The crude product is purified by flash silica chromatography (elution with 2:1 ethylacetate:hexane) to afford (R)-3-[(E)-3-(5-cyano-2-methoxy-phenyl)-acryloylamino]-4-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-butyric acid benzyl ester. [MH]+ 572.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH:21]2[CH2:26][CH2:25][N:24]([C:27](OC(C)(C)C)=O)[CH2:23][CH2:22]2)[C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:34][C:35]1[CH:42]=[CH:41][C:38](C=O)=[CH:37][CH:36]=1.[BH4-].C(OC(=O)C)(=O)C>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:38]3[CH:41]=[CH:42][C:35]([CH3:34])=[CH:36][CH:37]=3)[CH2:23][CH2:22]2)[C:10](=[O:20])[CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: Cc1ccc(C=O)cc1
Agent: [BH4-]
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(Cc3ccc(C)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The product from example 13 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). 4-Methylbenzaldehyde (0.134 ml, 1.1 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3×6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 22 mg; HRMS (FAB+, NBA) (M+H)+ 457.2853, C30H37N2O2 requires 457.2855; LC-MS: (M+H)+ 457.2, tr 6.97 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([Mg]Br)[CH:29]=[CH:30][CH:31]=1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])([C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([O:25][CH3:24])[CH:31]=2)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2]
Reactant: COc1cccc([Mg]Br)c1
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1=O
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1(O)c1cccc(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
6-Methoxy-1-oxo-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (100 mg, 0.325 mmol) obtained in Example 1 was dissolved in THF and 1.5 equivalents of 3-methoxyphenylmagnesium bromide were added thereto, followed by stirring for 1 hr at 0° C. Then, the reaction mixture washed with saturated saline and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4, and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 122 mg of the titled compound (yield: 90.4%).
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]2[C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[CH:22]=[CH:21][CH:20]=2)[CH:13]=1.[I-:32].[Cs+].COCCOC.N(OCCC(C)C)=O>CO.[Cu]I>[I:32][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]2[C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[CH:22]=[CH:21][CH:20]=2)[CH:13]=1
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4N)ncn3)cccc2s1
Reactant: [I-]
Agent: [Cu]I
Agent: CC(C)CCON=O
Agent: [Cs+]
Solvent: CO
Solvent: COCCOC
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4I)ncn3)cccc2s1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To N-{4-[6-(2-amino-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide, (Example 151), (0.25 g, 0.56 mmol) was added CsI (0.15 g, 0.56 mmol, Aldrich), 12 (0.071 g, 0.28 mmol, Aldrich), CuI (0.032 g, 0.17 mmol, Aldrich) and ethylene glycol dimethyl ether (6 mL). To the mixture was added isoamyl nitrite (0.45 mL, 3.4 mmol, Aldrich) and the reaction was stirred for 1 h at room temperature, at 65° C. for 3 h, and then at room temperature for 18 h. The reaction mixture was diluted with MeOH (2 M in NH3) and concentrated. The residue was taken up in MeOH and concentrated onto silica gel. Purification by silica gel chromatography (gradient, 0.4 to 1.3% MeOH (2 M in NH3)/CH2Cl2) afforded the title compound as a white solid. Mp: 242-243° C. MS (ESI, pos. ion) m/z: 557.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=2[CH:6]=1.[N+]([O-])([O-])=[O:12].[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>C(O)(=O)C.O.O>[Cl:1][C:2]1[S:3][C:4]2[C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:5]=2[CH:6]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Clc1cc2c(s1)CCCC2
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCCc2cc(Cl)sc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
10.0 g (57.9 mmol) of 2-chloro-4,5,6,7-tetrahydro-1-benzothiophene are dissolved in acetic acid/water (247 ml/82 ml), 127 g (231 mmol) of ammonium cerium (IV) nitrate in water (50 ml) are added and the mixture is stirred at room temperature for 5 h. The reaction mixture is added to ice-water and extracted with dichloromethane. After washing with water, the organic phase is dried over sodium sulphate and concentrated under reduced pressure. This gives 5.60 g of 2-chloro-5,6-dihydro-1-benzothiophen-7(4H)-one.
Reaction SMILES: [F:1][C:2]([F:24])([CH3:23])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][C:13]3([CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[C:12]2=[O:22])=[CH:7][CH:6]=1)[OH:4].[C:25]([Mg]Br)([CH3:27])=[CH2:26]>>[F:24][C:2]([F:1])([CH3:23])[CH:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:15][CH2:14][C:13]3([CH2:20][CH2:19][C:18]([OH:21])([C:25]([CH3:27])=[CH2:26])[CH2:17][CH2:16]3)[C:12]2=[O:22])=[CH:9][CH:10]=1)[OH:4]
Reactant: C=C(C)[Mg]Br
Reactant: CC(F)(F)C(O)c1ccc(N2CCC3(CCC(=O)CC3)C2=O)cc1
Product: C=C(C)C1(O)CCC2(CCN(c3ccc(C(O)C(C)(F)F)cc3)C2=O)CC1

Procedure:
The title compound was prepared in analogy to example 55 from (2-(4-(2,2-difluoro-1-hydroxypropyl)phenyl)-2-aza-spiro[4.5]decane-1,8-dione by reaction with isopropenylmagnesium bromide (0.5 M in THF) as a white solid. MS (m/e): 379[M+].
Reaction SMILES: C[C:2]1([C:8](O)=O)[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH:18]=C>CC(C)=O>[CH2:8]([CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7])[CH:17]=[CH2:18]
Reactant: C=CCBr
Reactant: CC1(C(=O)O)CCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCC1CCCC1=O
Temperature: 25 °C
Yield: 87.9 %

Procedure:
A stirred solution of methyl 2-carboxycyclopentanone (35.5 g, 250 mmol) in acetone (500 mL) was treated with anhydrous potassium carbonate (138 g, 1.0 mol) and allyl bromide (100 mL, 1.15 mol) and refluxed for 5 h. The mixture was cooled and filtered through Celite® (rinse filter cake with acetone), and the filtrate was concentrated in vacuo. The residual oil was dissolved in methanol (450 mL), treated with 6 N HCl (250 mL), and refluxed for 40 h. The solution was cooled to room temperature, concentrated in vacuo to remove most methanol, and diluted with water (200 mL). The aqueous solution was extracted with dichloromethane (3×250 mL), and the combined organic solution was washed with water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride (200 mL each), dried (Na2SO4), and gently (volatile product) concentrated in vacuo to 75 mL volume. This solution was loaded onto a silica gel column (˜500 cc) and eluted with dichloromethane to afford (after gentile concentration of fractions) 2-allylcyclopentanone (27.3 g, 88%) as a colorless oil. NMR (CDCl3): δ 5.65-5.75 (m, 1 H), 4.90-5.05 (m, 2 H), 2.40-2.50 (m, 1 H), 2.20-2.30 (m, 1 H), 1.85-2.15 (m, 5 H), 1.65-1.75 (m, 1 H), 1.45-1.55 (m, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7](Cl)[S:8][C:4]=2[CH:3]=1.Cl.[F:13][CH2:14][CH2:15][NH2:16]>CO>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH:16][CH2:15][CH2:14][F:13])[S:8][C:4]=2[CH:3]=1
Reactant: Clc1nc2ccc(Br)cc2s1
Reactant: NCCF
Agent: Cl
Solvent: CO
Product: FCCNc1nc2ccc(Br)cc2s1
Temperature: 120 °C
Yield: 54.5 %

Procedure:
A mixture of 6-bromo-2-chlorobenzo[d]thiazole (248 mg, 1 mmol), 2-fluoroethanamine hydrochloride (200 mg, 2 mmol), and TEA (303 mg, 3 mmol) in 3 mL MeOH was heated at 120° C. in a microwave reactor for 20 min. After cooling to rt, the mixture was concentrated and chromatographed (6% to 60% EtOAc in hexane) to afford 6-bromo-N-(2-fluoroethyl)benzo[d]thiazol-2-amine as a white solid (150 mg, 54%). MS (ESI) m/z 276.9 (M+H+).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3[NH:16][C:17]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([C:28]6[CH:33]=[C:32]([F:34])[C:31]([OH:35])=[CH:30][C:29]=6[CH2:36][CH3:37])=[CH:25][CH:26]=5)[NH:21][N:20]=4)=[N:18][C:12]=3[CH2:11]2)=[O:9])=[N:6][CH:7]=1.[N:38]1([CH2:44][CH2:45][NH2:46])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[CH2:36]([C:29]1[CH:30]=[C:31]([OH:35])[C:32]([F:34])=[CH:33][C:28]=1[C:24]1[CH:23]=[C:22]2[C:27]([C:19]([C:17]3[NH:16][C:13]4[CH2:14][CH2:15][N:10]([C:8]([C:5]5[CH:4]=[N:3][C:2]([NH:46][CH2:45][CH2:44][N:38]6[CH2:43][CH2:42][O:41][CH2:40][CH2:39]6)=[CH:7][N:6]=5)=[O:9])[CH2:11][C:12]=4[N:18]=3)=[N:20][NH:21]2)=[CH:26][CH:25]=1)[CH3:37]
Reactant: NCCN1CCOCC1
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(Cl)cn3)C4)n[nH]c2c1
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(NCCN5CCOCC5)cn3)C4)n[nH]c2c1
Yield: 23.7 %

Procedure:
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (100 mg, 193 μmol) and 2-morpholin-4-yl-ethylamine, (30 mg, 347 μmol) using the method of Example 32. The crude material was purified by HPLC Method F to afford (28 mg, 28%) of the title compound as off-white solid.
Reaction SMILES: ClC1C=CC([N+](=NC2C=CC(Cl)=CC=2)[O-:9])=CC=1.Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.C(OC1C=CC(N=NC2C=CC(OCC)=CC=2)=CC=1)C>>[CH:21]1[C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=[C:19]([OH:9])[CH:20]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: [O-][N+](=Nc1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: CCOc1ccc(N=Nc2ccc(OCC)cc2)cc1
Product: O=[N+]([O-])c1ccc(O)cc1
Yield: 95 %

Procedure:
It has now been found that p-nitrophenetole is obtained with excellent purity and high yields by reaction of p-chloronitrobenzene with ethanol and alkali metal hydroxide in the presence of a phase transfer catalyst, when the reaction is carried out at a temperature in the range of from 60° to 80° C. Thus, a product having a melting point of 58°-59.5° C. and being free from 4,4'-dichloroazoxybenzene, p-chloronitrobenzene, 4,4'-diethoxyazobenzene and p-nitrophenol is obtained with a yield of about 95%.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:9])[O:4][N:3]=1.C(N(CC)CC)C.[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(OCC)(=O)C>[C:31]1([S:37]([O:1][C:2]2[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[O:4][N:3]=2)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cc1cc(O)no1)OC(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)Cc1cc(OS(=O)(=O)c2ccccc2)no1
Reaction time: 1 h

Procedure:
To a solution of 1.55 g (5 mmoles) of benzhydryl 3-hydroxyisoxazol-5-ylacetate in 20 ml of ethyl acetate were added 0.71 ml (5.1 mmoles) of triethylamine and 0.65 ml (5.05 mmoles) of benzenesulphonyl chloride. After stirring the mixture for 1 hour, it was washed with water and then dried. The solvent was distilled off to give the benzhydryl ester of the title compound quantitatively. The ester was then treated in the same manner as described in Preparation 5, affording 1.30 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:21][C:22]2[CH:23]=[C:24]([C:28]3[C:33]([CH3:34])=[CH:32][C:31]([OH:35])=[CH:30][C:29]=3[CH3:36])[CH:25]=[CH:26][CH:27]=2)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[CH2:37][CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].[CH2:46]([S:48][CH2:49][CH2:50]O)[CH3:47].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(OCC)C>[CH2:46]([S:48][CH2:49][CH2:50][O:35][C:31]1[CH:32]=[C:33]([CH3:34])[C:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][N:8]([S:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N+:18]([O-:20])=[O:19])(=[O:10])=[O:11])[C:6]3[CH:5]=[CH:4][C:3]([CH2:37][CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[C:2]([F:1])[CH:7]=3)[CH:23]=2)=[C:29]([CH3:36])[CH:30]=1)[CH3:47]
Reactant: Cc1cc(O)cc(C)c1-c1cccc(CN(c2ccc(CCC(=O)OC(C)(C)C)c(F)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Reactant: CCSCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCSCCOc1cc(C)c(-c2cccc(CN(c3ccc(CCC(=O)OC(C)(C)C)c(F)c3)S(=O)(=O)c3ccccc3[N+](=O)[O-])c2)c(C)c1
Temperature: 25 °C
Yield: 86.1 %

Procedure:
To a solution of tert-butyl 3-(2-fluoro-4-{[(4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methyl][(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (2.0 g, 3.15 mmol), 2-(ethylthio)ethanol (0.37 mL, 3.47 mmol) and tributylphosphine (1.18 mL, 4.73 mmol) in tetrahydrofuran (40 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.19 g, 4.73 mmol) under stirring at room temperature, and the mixture was stirred for 16 hr. To the reaction mixture were added reagents (2-(ethylthio)ethanol, tributylphosphine and 1,1′-(azodicarbonyl)dipiperidine) in a half amount as above, and the mixture was further stirred for 8 hr. The reaction mixture was diluted with diethyl ether, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=2/1) to give the title compound (1.96 g, yield 86%) as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH2:13][O:12][CH2:11][CH2:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].ClC1C=CC=C(C(OO)=[O:22])C=1>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]2[CH2:13][O:12][CH2:11][CH2:10][C:7]2=[N+:8]([O-:22])[CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=[N+]([O-])c1cnc2c(c1)COCC2
Solvent: ClCCl
Product: O=[N+]([O-])c1cc2c([n+]([O-])c1)CCOC2
Yield: 83.6 %

Procedure:
To a solution of 2.00 g of 3-nitro-7,8-dihydro-5H-pyrano[4,3-b]pyridine [prepared according to the method as described in Bull. Chem. Soc. Jpn. Vol. 63 (1990), 2820] in 40 ml of methylene chloride is added 2.63 g of m-chloroperbenzoic acid, and the resultant mixture is stirred overnight. The reaction mixture is washed with aqueous potassium carbonate, dried over anhydrous magnesium sulfate and the solvent is evaporated. The crude product is recrystallized from ethanol-chloroform to give 1.82 g of 3-nitro-7,8-dihydro-5H-pyrano[4,3-b]pyridine-1-oxide as colorless crystals. Yield: 84%. To a solution of 1.47 g of the product in 75 ml of methanol-dimethylformamide (1:1) is added 100 mg of 10% palladium carbon, and the resultant mixture is hydrogenated at ordinary temperature under atmospheric pressure. After the reduction is completed in about 3 hours, the catalyst is filtered off. The resultant crude crystals are washed with ethanol to give 1.08 g of 3-amino-1-oxide as colorless crystals. Yield: 86%. To a solution of 690 mg of 3-isoxazolylcarbonyl chloride in 20 ml of dimethylformamide is added 414 mg of pyridine under ice cooling, and then 830 mg of 3-amino-1-oxide as crystals is added. The resultant mixture is stirred under ice cooling for 30 minutes and at room temperature for 1 hour, chilled again with ice, and mixed with 4 ml of water. The suspension is neutralized with sodium bicarbonate. The precipitated solid is filtered, washed with water and ethanol in this order and dried to give 1.13 g of the titled compound as colorless crystals. Yield: 86%. ml.: 260° to 265° C. (dec.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[CH:11][C:12]([C:19]([F:22])([F:21])[F:20])=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:25])=O>O1CCOCC1>[Cl:25][C:16]1[C:15]2[C:10](=[CH:11][C:12]([C:19]([F:22])([F:21])[F:20])=[CH:13][CH:14]=2)[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(-c2ccc(Cl)cc2)nc2cc(C(F)(F)F)ccc12
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc2c(Cl)nc(-c3ccc(Cl)cc3)nc2c1
Temperature: 25 °C

Procedure:
To a stirred suspension of 2-(4-chlorophenyl)-7-trifluoromethyl-3H-quinazolin-4-one (50 g, 0.15 mol) in dioxane (400 mL) was added dropwise phosphorus oxychloride (43 mL, 0.46 mol). The suspension was then heated at reflux for 2 h then allowed to cool to room temperature and evaporated under reduced pressure. The remaining solid was dissolved in dioxane (1 L) and an aqueous solution of sodium hydroxide (50 mL, 10% weight/weight (w/w)) was added dropwise maintaining the internal temperature≦10° C.). Water (1 L) was then added to the resultant suspension followed by the dropwise addition of a further quantity of aqueous sodium hydroxide (90 mL, 10% w/w). The precipitate was isolated by vacuum filtration washing with water (3×500 mL) and dried under vacuum (10 mbar, 50° C.). Yield=49 g, 93%; LC-MS: 4.7 min, 343 (M+); 1H NMR (dimethylsulfoxide (DMSO)-d6) δ 7.68 (d, 2 H, J=8.9 Hz), 8.12 (dd, 1 H, J=8.9, 1.8 Hz), 8.48-8.54 (m, 4 H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([S:9][CH:10]1[N:13]([CH:14](O)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C:12](=[O:29])[CH2:11]1)=[O:8].S(Cl)([Cl:32])=O>>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([S:9][CH:10]1[N:13]([CH:14]([Cl:32])[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C:12](=[O:29])[CH2:11]1)=[O:8]
Reactant: O=S(Cl)Cl
Reactant: COCCOCC(=O)SC1CC(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Product: COCCOCC(=O)SC1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
To 800 mg. of p-nitrobenzyl 2-[4-(2-methoxyethoxyacetylthio)-2-oxo-1-azetidinyl]-2-hydroxyacetate was added (all at once) at 0° under N2 atmosphere, thionyl chloride (3 ml.) and the mixture was stirred at room temperature under N2 for 1 hour. The excess of thionyl chloride was removed in vacuo and the residue dissolved in dry benzene (10 ml.) and evaporated to dryness. There was obtained the title product (791 mg.) as a yellowish oil. nmr (CDCl3): δppm 2.9-3.9 (2H, m, H-3), 4.10 (3H, s, --OCH3), 3.5-3.9 (4H, m, --OCH2CH2O--), 4.24 (2H, s, O=C--CH2O--), 5.35-5.45 (2H, m, --CH2 --Ar), 5.70 (1H, m, H-4), 6.12 (1H, s, --CHCl), 7.52, 7.67, 8.21, 5.39 (4H, A2 ' B2 ', aromatic --H); ir (neat): 1780 cm-1 (broad, γc=o, β-lactam and ester), 1695 (γc=o, thioester), 1525 (γNO2).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[C:23](/[CH:25]=[CH:26]/[C:27]1([CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:31][CH2:30][CH2:29][CH2:28]1)#[N:24].C(/C=C\C1(CNC(=O)OC(C)(C)C)CCCC1)#N.C1CCN2C(=NCCC2)CC1>C(#N)C>[C:23]([CH2:25][CH:26]([C:27]1([CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH2:31][CH2:30][CH2:29][CH2:28]1)[N:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1)#[N:24]
Reactant: CC(C)(C)OC(=O)NCC1(/C=C/C#N)CCCC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Agent: CC(C)(C)OC(=O)NCC1(/C=C\C#N)CCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCC1(C(CC#N)n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (355 mg, 1.12 mmol) and tert-butyl (1-[(E)-2-cyanovinyl]cyclopentylmethyl)carbamate and tert-butyl (1-[(Z)-2-cyanovinyl]cyclopentylmethyl)carbamate as a mixture of isomers (329 mg, 1.31 mmol) in ACN (10 mL) was added DBU (0.168 mL, 1.12 mmol). The resulting mixture was stirred at ambient temperature for 3 hours followed by heating to 60° C. for 2.5 hours. The ACN was removed in vacuo and the resulting residue was purified by flash column chromatography (eluting with 0-55% ethyl acetate in hexanes) to afford the product (350 mg, 55%).