Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[C:5]([NH:27][C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])([CH2:9][C:10]1[O:14][N:13]=[C:12]([CH:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:11]=1)C(O)=O)[CH3:2].C(OC(=O)C(NC(OCC=C)=O)(CC1ON=C(C2CCCN2C(OC(C)(C)C)=O)C=1)C(OCC)=O)C>O1CCOCC1>[C:23]([O:22][C:20]([N:16]1[CH2:17][CH2:18][CH2:19][CH:15]1[C:12]1[CH:11]=[C:10]([CH2:9][CH:5]([NH:27][C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])[C:4]([O:3][CH2:1][CH3:2])=[O:34])[O:14][N:13]=1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: C=CCOC(=O)NC(Cc1cc(C2CCCN2C(=O)OC(C)(C)C)no1)(C(=O)O)C(=O)OCC
Agent: C=CCOC(=O)NC(Cc1cc(C2CCCN2C(=O)OC(C)(C)C)no1)(C(=O)OCC)C(=O)OCC
Solvent: C1COCCO1
Product: C=CCOC(=O)NC(Cc1cc(C2CCCN2C(=O)OC(C)(C)C)no1)C(=O)OCC
Temperature: 125 °C
Yield: 56 %

Procedure:
A mixture of 2-allyloxycarbonylamino-2-[3-(1-tert-butoxycarbonyl-pyrrolidin-2-yl)-isoxazol-5-ylmethyl]-malonic acid monoethyl ester and 2-allyloxycarbonylamino-2-[3-(1-tert-butoxycarbonyl-pyrrolidin-2-yl)-isoxazol-5-ylmethyl]-malonic acid diethyl ester (10.4 g, 21.5 mmol) was dissolved in dioxane (130 mL) and heated in an oil bath to 125° C. for 3 hours. The dioxane was then removed in vacuo. The residue was dissolved in ethyl acetate, washed with saturated sodium carbonate and brine, dried over magnesium sulfate and concentrated. The crude material was chromatographed on a Biotage Flash 40M column eluting with ethyl acetate/hexanes (1:4) to give the title compound as a clear oil (5.12 g, 56% 2 steps). MS (CI) m/z 338.0 (M-99). 2-Allyloxycarbonylamino-2-[3-(1-tert-butoxycarbonyl-pyrrolidin-2-yl)-isoxazol-5-ylmethyl]-malonic acid diethyl ester was recovered (2.96 g, 27%). MS (CI) m/z 509.9 (M+1), 409.9 (M−99)
Reaction SMILES: [F:1][C:2]([F:6])([CH3:5])[CH2:3][OH:4].[CH3:7][S:8](Cl)(=[O:10])=[O:9].O>C(Cl)Cl>[CH3:7][S:8]([O:4][CH2:3][C:2]([F:6])([F:1])[CH3:5])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)Cl
Reactant: CC(F)(F)CO
Solvent: O
Solvent: ClCCl
Product: CC(F)(F)COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.6 %

Procedure:
To a mixture of 2,2-difluoropropan-1-ol (2.00 g, 20.8 mmol) and TEA (3.16 g, 31.25 mmol) in dry DCM (20 mL) was added methanesulfonyl chloride (2.84 g, 24.96 mmol) at 0° C. The resulting reaction mixture was stirred at rt for 1.5 h. Water was added and the mixture was extracted with DCM (3×100 mL). The combined organic layers were washed with saturated aqueous ammonium chloride solution, brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under vacuum to give the title product (2.70 g, 15.52 mmol, 75% yield), which was used directly in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[CH:3]=1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[F:22][C:23]1[CH:31]=[C:30]2[C:26]([C:27]([CH2:32][CH2:33][NH:34][C:35](=[O:37])[CH3:36])=[CH:28][NH:29]2)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:31]=[C:30]2[C:26]([C:27]([CH2:32][CH2:33][NH:34][C:35](=[O:37])[CH3:36])=[C:28]([CH:14]([C:3]3[C:4](=[O:13])[O:5][CH:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:2]=3[OH:1])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:29]2)=[CH:25][CH:24]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1C=C(O)C(c2ccccc2)O1
Reactant: CC(=O)NCCc1c[nH]c2cc(F)ccc12
Product: CC(=O)NCCc1c(C(C2=C(O)C(c3ccccc3)OC2=O)c2ccccc2)[nH]c2cc(F)ccc12

Procedure:
Using general procedure C, 4-hydroxy-5-phenyl-5H-furan-2-one (Lit. 14) was reacted with benzaldehyde and N-[2-(6-fluoro-1H-indol-3-yl)-ethyl]-acetamide (Example 18.1.) to give the title compound as pale brown solid. MS: 485.0 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>>[CH3:18][O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:23]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: COc1ccccc1C(=O)Cl
Product: COc1ccccc1C(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Yield: 37.4 %

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.008 mL (0.058 mMol) 2-methoxybenzoyl chloride, 0.006 gm (39%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[C:5]([CH:14]([CH3:16])[CH3:15])[C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:24](#N)[CH3:25]>>[CH:14]1([C:5]2[C:6]([O:12][CH3:13])=[CH:7][CH:8]=[C:9]3[C:4]=2[N:3]=[C:2]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:11]=[CH:10]3)[CH2:16][CH2:25][CH2:24][CH2:15]1
Reactant: CC#N
Reactant: Nc1ccccc1
Reactant: COc1ccc2cnc(Cl)nc2c1C(C)C
Product: COc1ccc2cnc(Nc3ccccc3)nc2c1C1CCCC1
Temperature: 90 °C
Yield: 37 %

Procedure:
A mixture of 2-chloro-7-methoxy-8-(2-propyl)quinazoline (200 mg, 0.76 mmol) and aniline (212 mg, 2.28 mmol) in acetonitrile (3 mL) was heated at 90° C. for 60 hours in a sealed tube. The solvent was removed under reduced pressure, to the residue 5% sodium carbonate solution was added. The product was extracted with ethyl acetate (3×40 mL). The combined organic extract was washed with brine, dried (Na2SO4), and concentrated. The product was purified on a column of silica gel to give the title compound as a yellow solid (90 mg, 37%), mp 187–188° C.; 1H NMR (CDCl3) δ: 1.72–2.30 (complex, 8H, 4×CH2), 3.96 (s, 3H, OCH3), 4.33 (m, 1H, CH), 7.23–7.41 (m, 2H, Ar-H), 7.58 (d, 1H, Ar-H), 7.83 (d, 2H, Ar-H), 8.93 (s, 1H, Ar-H); MS: m/z 319.81, C20H21N3O; Analysis: Calcd.: C, 75.21; H, 6.63; N, 13.16. Found: C, 75.03; H, 6.73; N, 13.05.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][N+:5]([O-:9])=[C:4]([CH3:10])[C:3]=1[CH3:11].[CH3:12][C:13]1([CH3:21])[O:18][CH2:17][CH:16]([CH2:19][OH:20])[CH2:15][O:14]1>C1(C)C=CC=CC=1>[CH3:12][C:13]1([CH3:21])[O:18][CH2:17][CH:16]([CH2:19][O:20][C:2]2[C:7]([CH3:8])=[CH:6][N+:5]([O-:9])=[C:4]([CH3:10])[C:3]=2[CH3:11])[CH2:15][O:14]1
Reactant: Cc1c[n+]([O-])c(C)c(C)c1Cl
Reactant: CC1(C)OCC(CO)CO1
Solvent: Cc1ccccc1
Product: Cc1c[n+]([O-])c(C)c(C)c1OCC1COC(C)(C)OC1
Reaction time: 2.5 h
Yield: 90.6 %

Procedure:
A mixture of 4-chloro-2,3,5-trimethylpyridine 1-oxide (840 g), (2,2-dimethyl-1,3-dioxan-5-yl)methanol (688 g) and toluene (2.52 L) was heated under reflux while removing a water content. While azeotropical dehydration was continued, potassium hydroxide (0.58 kg) was added to the reaction mixture over 3 hours and 45 minutes, and azeotropic dehydration was continued for 2.5 hours. The mixture was cooled to 30° C. or less, and ethyl acetate (2.5 L) and a 17% saline solution (3.5 L) were added to the mixture and then the mixture was allowed to stand for overnight. The ethyl acetate layer was separated and the aqueous layer was extracted with ethyl acetate (1.0 L×3). The ethyl acetate layers were combined, filtrated through celite, and concentrated under reduced pressure to obtain a desired product (1.20 kg).
Reaction SMILES: [CH3:1][O:2][C:3]1([C:9]2[S:13][C:12]([S:14][C:15]3[CH:20]=[CH:19][C:18]([C:21](=O)[CH3:22])=[CH:17][CH:16]=3)=[N:11][CH:10]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.Cl.[NH2:25][OH:26]>>[CH3:1][O:2][C:3]1([C:9]2[S:13][C:12]([S:14][C:15]3[CH:20]=[CH:19][C:18](/[C:21](=[N:25]/[OH:26])/[CH3:22])=[CH:17][CH:16]=3)=[N:11][CH:10]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: COC1(c2cnc(Sc3ccc(C(C)=O)cc3)s2)CCOCC1
Reactant: NO
Agent: Cl
Product: COC1(c2cnc(Sc3ccc(/C(C)=N/O)cc3)s2)CCOCC1
Yield: 80 %

Procedure:
Using an analogous procedure to that described in Example 15, 4'-[5-(4-methoxytetrahydropyran-4-yl)thiazol-2-ylthio]acetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-[5-(4-methoxytetrahydropyran-4-yl)thiazol-2-ylthio]acetophenone oxime in 80% yield, m.p. 114°-116° C.;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[C:13](=[O:26])[NH:14][C:15]3[C:20]([N:21]=1)=[CH:19][C:18]([C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=3)[CH2:7][CH2:6][CH2:5]2.N1C=CC=CC=1.[O:33](S(C(F)(F)F)(=O)=O)[S:34]([C:37]([F:40])([F:39])[F:38])(=O)=[O:35]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[C:13]([O:26][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:35])=[O:33])=[N:14][C:15]3[C:20]([N:21]=1)=[CH:19][C:18]([C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=3)[CH2:7][CH2:6][CH2:5]2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCCc4cc(F)ccc43)nc2c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCc4cc(F)ccc43)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 131.3 %

Procedure:
To a solution of methyl 3-(6-fluoro-1,2,3,4-tetrahydroquinolin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (150 mg, 0.43 mmol) in dichloromethane (40 mL) was added pyridine (136 mg, 1.72 mmol) and Tf2O (242 mg, 0.86 mmol) with stifling overnight maintained with an inert atmosphere of nitrogen at room temperature. The reaction was then quenched with water (50 mL), extracted with dichloromethane (3×10 mL), the organic layers combined and dried over anhydrous magnesium sulfate, concentrated under vacuum to afford methyl 3-(6-fluoro-1,2,3,4-tetrahydroquinolin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (274 mg, crude), which was used to the next step directly.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23]([O:30][CH2:31][CH2:32]Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(=O)CC>[CH2:23]([O:30][CH2:31][CH2:32][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:16])[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:7]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cc1ccccc1)c1ccc(O)cc1
Reactant: BrCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(Cc1ccccc1)c1ccc(OCCOCc2ccccc2)cc1

Procedure:
1-(4-Hydroxyphenyl)-2-phenyl ethanone (17 g, 0.08 mol) is dissolved in 2-butanone (200 ml) and potassium carbonate (33.1 g, 0.24 mol) and 2-benzyloxyethyl bromide (25.8 g, 0.12 mol) is added to the solution. Mixture is stirred and refluxed for three hours. Then the solution is filtered and the filtrate is evaporated to dryness. The residue is dissolved in toluene, washed with 2 N aqueous sodium hydroxide solution and with water, dried and evaporated to dryness. The product is crystallized from ethanol. Yield 23.2 g, 84%.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:4]([NH:6][C@@H:7]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[CH2:8][CH2:9][C:10](=[O:12])[NH2:11])=[O:5])[CH3:3].Cl.C(OCC)(=O)C.N1C=CC=CC=1CC(O)=O.O>C(O)(=O)C.[Pd]>[NH2:1][C@H:2]([C:4]([NH:6][C@@H:7]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[CH2:8][CH2:9][C:10](=[O:12])[NH2:11])=[O:5])[CH3:3]
Reactant: CCCCOC(=O)[C@@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Agent: O=C(O)Cc1ccccn1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCCOC(=O)[C@@H](CCC(N)=O)NC(=O)[C@H](C)N

Procedure:
330 mg (0.8 mM) of (II), dissolved in 30 ml of glacial acetic acid, are hydrogenated for 4 hours, in the presence of 330 mg of Pd (5%) on charcoal and of 1 ml (1 mM) of N HCl. It is checked, by thin layer chromatography on silica gel in the system ethyl acetate-pyridine-acetic acid-water (6:2:0.6:1), that the hydrogenation is complete, then the catalyst is filtered off and the solvent concentrated. The residual oil is dried carefully under vacuum (dessicator, with P2O5) and used as such in the following step.
Reaction SMILES: [Zn:1].Cl[Si](C)(C)C.BrCCBr.[I:11][CH:12]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1>CN(C)C(=O)C>[I-:11].[C:19]([O:18][C:16]([N:14]1[CH2:15][CH:12]([Zn+:1])[CH2:13]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: [Zn]
Agent: C[Si](C)(C)Cl
Solvent: CC(=O)N(C)C
Solvent: BrCCBr
Product: CC(C)(C)OC(=O)N1CC([Zn+])C1
Product: [I-]
Reaction time: 0.33 h

Procedure:
Zinc (2.472 g, 0.03780 mol) was stirred in 10 mL of degassed N,N-dimethylacetamide under N2 atmosphere. Chlorotrimethylsilane (0.411 mL, 0.00324 mol) and 1,2-Dibromoethane (0.233 mL, 0.00270 mol) were added and the mixture was stirred for 20 minutes. Tert-butyl 3-iodoazetidine-1-carboxylate (7.644 g, 0.02700 mol) in degassed N,N-dimethylacetamide (60.0 mL) was added slowly and the cloudy reaction was stirred at room temperature for 1.5 hours to give (1-(tert-butoxycarbonyl)azetidin-3-yl)zinc(II) iodide.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[CH2:8][C@@H:7]([C:9]2[O:13][N:12]=[C:11]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:10]=2)[N:6]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)=[O:21])[CH2:5]1.C(N(CC)CC)C.[C:41](Cl)(=[O:43])[CH3:42].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]1[CH2:8][C@@H:7]([C:9]2[O:13][N:12]=[C:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:41](=[O:43])[CH3:42])[CH2:16][CH2:15]3)[N:10]=2)[N:6]([C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)=[O:21])[CH2:5]1
Reactant: CC(=O)Cl
Reactant: CON=C1C[C@@H](c2nc(C3CCNCC3)no2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON=C1C[C@@H](c2nc(C3CCN(C(C)=O)CC3)no2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(4-piperidinyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinone O-methyloxime (Example 12) was dissolved in dry DCM at 0° C. in presence of 1.5 equivalent of triethyl amine and treated with 1 equivalent of acetyl chloride. The reaction mixture was stirred at this temperature for 30 minutes and then hydrolyzed with ice. The reaction was then made basic with a sodium carbonate solution (10%) and extracted with DCM. It was then dried with magnesium sulfate and solvent removal afforded a residue which was purified by flash-chromatography using cyclohexane/ethylacetate (1/1) as eluent to give (3EZ,5S)-5-[3-(1-acetyl-4-piperidinyl)-1,2,4-oxadiazol-5-yl]-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinone O-methyloxime as a mixture of E-/Z-isomers in 95% yield (100% purity by HPLC).
Reaction SMILES: [CH:1](=[N:9][CH:10]1[C:35](=[O:36])[N:12]2[C:13]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[C:14]([CH2:17]Cl)[CH2:15][S:16][C@H:11]12)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:37]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I-].[Na+].C(O)(C)C>CN(C)C=O>[CH:1](=[N:9][CH:10]1[C:35](=[O:36])[N:12]2[C:13]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[C:14]([CH:17]=[CH2:37])[CH2:15][S:16][C@H:11]12)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(CCl)CS[C@@H]2C(N=Cc3ccccc3O)C(=O)N12
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N=Cc3ccccc3O)[C@H]2SC1
Yield: 78.4 %

Procedure:
To a cooled solution of benzhydryl 7-salicylideneamino-3-chloromethyl-3-cephem-4-carboxylate (4 g) in dimethylformamide (10 ml) were added triphenylphosphine (2.2 g) and sodium iodide with stirring. After stirring for 2 hours at ambient temperature, the reaction mixture was poured into isopropyl alcohol (250 ml), and the precipitated solids (6.7 g) were collected by filtration. To a stirred solution of the above solids in methylene chloride (10 ml) and water (5 ml) was added 36% formaldehyde solution (17.4 ml). Then the reaction mixture was adjusted to pH 9.0 with a saturated aqueous sodium bicarbonate. After stirring for an hour at ambient temperature, the separated organic layer was washed with water and an aqueous sodium chloride, followed by drying over magnesium sulfate. The solution was evaporated under reduced pressure to give benzhydryl 7-salicylideneamino-3-vinyl-3-cephem-4-carboxylate (3 g).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.C([Li])CCC.CON(C)[C:15]([C:17]1[O:21][CH:20]=[N:19][C:18]=1[CH3:22])=[O:16].[Cl-].[Na+]>C(OCC)C.C(O)C>[CH3:22][C:18]1[N:19]=[CH:20][O:21][C:17]=1[C:15]([C:2]1[CH:6]=[CH:5][O:4][CH:3]=1)=[O:16]
Reactant: Brc1ccoc1
Reactant: CON(C)C(=O)c1ocnc1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: Cc1ncoc1C(=O)c1ccoc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
3-Bromofuran (2.5 g) in dry diethylether was stirred and cooled to -70° C. under an atmosphere of dry nitrogen and n-butyllithium (2.5M solution in hexane, 6.8 ml) was added dropwise. After 30 minutes, N-methoxy-N-methyl-4-methyl-5-oxazolecarboxamide (2.89 g) in dry diethylether was added dropwise. After a further 30 minutes the mixture was allowed to warm to room temperature. Ethanol (5 ml) was added followed by saturated aqueous sodium chloride. The mixture was extracted with dichloromethane and the material thus obtained was purified by flash chromatography to give the title compound. M.p. 82°-83.5° C.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([C@@H:10]([C:18]2[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=2)N)[CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:46][CH:45]1[OH:53].CCOC(/[N:59]=N/C(OCC)=O)=O>C1COCC1.C(OCC)(=O)C>[CH2:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:46][CH:45]1[O:53][C:2]1[CH:3]=[C:4]([C@@H:10]([C:18]2[CH:19]=[CH:20][C:22]([NH2:59])=[CH:23][CH:24]=2)[CH2:11][C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: OC1Cc2ccccc2C1
Reactant: COc1ccc([C@H](Cc2ccncc2)c2cccc(N)c2)cc1O
Reactant: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc([C@H](Cc2ccncc2)c2ccc(N)cc2)cc1OC1Cc2ccccc2C1
Reaction time: 0.17 h
Yield: 63 %

Procedure:
To a solution of Intermediate 1 (1.0 g, 3.1 mmol) in THF (25 ml) at RT was added PPh3 (820 mg, 1 eq), 2-indanol (419 mg, 1 eq) and the solution stirred for 10 min prior to the addition of DEAD (492 μl, 1 eq). The reaction mixture was stirred at this temperature for 65 h before the further addition of 2-indanol (419 mg), PPh3 (820 mg) and DEAD (492 μl ). The mixture was stirred for an additional 1.5 h then quenched by the addition of water (10 ml). The mixture was diluted with ethyl acetate (100 ml), washed with water (4×50 ml), brine (50 ml), dried (MgSO4), filtered and concentrated in vacuo to give a brown foam. The crude product was redissolved in ethyl acetate (50 ml) and extracted into hydrochloric acid (2×50 ml, 10% aq). The aqueous extract was basified (NaOH to pH>10) then extracted with ethyl acetate (2×100 ml). The extract was washed with water (2×50 ml), brine (50 ml), dried (MgSO4), filtered and concentrated in vacuo to give a white foam. This was subjected to column chromatography (SiO2 ; ethylacetate) to afford the title compound (856 mg, 63%) as a white foam. δH (CDCl3) 3.05-3.35 (6H, m), 3.77 (3H, s), 4.06 (1H, t, J 8.0 Hz), 5.08 (1H, m), 6.52 (2H, d, J 7.8 Hz), 6.63 (1H, d, J 7.6 Hz), 6.70 (1H, s), 6.76 (2H, s), 6.95 (2H, d, J 6.0 Hz), 7.07 (1H, t, J 7.7 Hz), 7.18 (4H, m), and 8.41 (2H, d, J 5.9 Hz). m/z (ESI) 437 (MH+, 100%), 459 (MNa+, 2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].[OH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.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>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:25]2[CH:26]=[CH:27][C:22]([CH2:21][OH:20])=[CH:23][CH:24]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6]
Reactant: OCc1ccc(B(O)O)cc1
Reactant: COC(=O)C(NS(=O)(=O)c1ccc(Br)cc1)C(C)C
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: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)C(NS(=O)(=O)c1ccc(-c2ccc(CO)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
Step 1B [Intermediate 2: 2-(4-Bromo-benzenesulfonylamino)-3-methyl-butyric acid methyl ester (3.4 g, 9.71 mmol), 4-hydroxymethyl phenyl boronic acid (1.48 g, 9.71 mmol, 1 equiv.), Pd(PPh3)4 (561mg, 0.48 mmol, 0.05 equiv.) were dissolved in ethylene glycol dimethyl ether (90 mL) under N2 atmosphere and stirred at room temperature for 30 min. Then K2CO3 (2.68 g, 19.4 mmol, 2 equiv.) in H2O (30 mL) was introduced to the reaction mixture and heat to reflux overnight. After TLC confirmation of reaction completion, solvent was removed by rotovap, residue partitioned between EtOAc and brine, organic layer dried over MgSO4, solvent removed, crude residue was triturated with EtOAc to give 2-(4′-Hydroxymethyl-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester in 67% yield (2.46 g).
Reaction SMILES: CC1(C)C2C=C(C#C[C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)C=CC=2C(=O)CC1.[C:27]([C:29]1[CH:38]=[C:37]2[C:32]([C:33]([CH3:41])([CH3:40])[CH2:34][CH2:35][C:36]2=[O:39])=[CH:31][CH:30]=1)#[CH:28]>>[CH3:40][C:33]1([CH3:41])[C:32]2[CH:31]=[CH:30][C:29]([C:27]#[C:28][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:38][C:37]=2[C:36](=[O:39])[CH2:35][CH2:34]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1
Reactant: C#Cc1ccc2c(c1)C(=O)CCC2(C)C
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound 1), 4 g (21.7 mmol) of 7-ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound L) was converted into the title compound using 6 g (21.7 mmol) of ethyl 4-iodobenzoate, 5 g (7.2 mmol) of bis(triphenylphosphine)palladium(II) chloride and 1.4 g (7.2 mmol) of cuprous iodide.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([P:26](=[O:28])=[O:27])[N:3]([C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([O:22][CH2:23][CH2:24][NH2:25])[CH:16]=1)[S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])(=[O:6])=[O:5].[Cl:30][C:31]1[N:32]=[N:33][CH:34]=[C:35](Cl)[C:36]=1[Cl:37].C(N(CC)CC)C>O1CCCC1>[CH3:1][C:2]([CH3:29])([P:26](=[O:28])=[O:27])[N:3]([C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([O:22][CH2:23][CH2:24][NH:25][C:35]2[C:36]([Cl:37])=[C:31]([Cl:30])[N:32]=[N:33][CH:34]=2)[CH:16]=1)[S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])(=[O:5])=[O:6]
Reactant: COc1ccccc1S(=O)(=O)N(c1cc(C)cc(OCCN)c1)C(C)(C)P(=O)=O
Reactant: Clc1cnnc(Cl)c1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccccc1S(=O)(=O)N(c1cc(C)cc(OCCNc2cnnc(Cl)c2Cl)c1)C(C)(C)P(=O)=O

Procedure:
940 mg N-(dimethyloxophosphinyl-methyl)-N-[3-(2-amino-ethoxy)-5-methyl-phenyl]-2-methoxy-benzene sulfonamide, 400 mg (2.2 mmol) 3,4,5-trichloropyridazine and 0.31 ml (2.2 mmol) triethylamine in 20 ml dry tetrahydrofuran were stirred for 2 h at 80° C., the solvent was removed in a vacuum, the residue was stirred with water, extracted three times with ethyl acetate, dried over sodium sulfate, filtered, the solvent was removed in a vacuum and 1.26 g (quant.) of a mixture of N-(dimethyloxophosphinyl-methyl)-N-{3-[2-(3,5-dichloropyridazin-4-ylamino)-ethoxy]-5-methylphenyl-}-2-methoxy-benzenesulfonamide and N-(dimethyloxophosphinyl-methyl)-N-{3-[2-(3,4-dichloropyridazin-5-ylamino)-ethoxy]-5-methylphenyl}-2-methoxy-benzenesulfonamide was obtained as an oil. MS (m/e)=573.