Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[C:7]([C:29]#[N:30])=[N:8][C:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][OH:24])=[C:16]([C:25]([F:28])([F:27])[F:26])[CH:15]=2)=[CH:10][C:11]=1[NH:12][CH3:13]>O.Cl.CN1C(=O)CCC1.C(OCC)(=O)C>[OH:24][CH2:23][CH2:22][CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:9]2[N:8]=[C:7]([C:29]#[N:30])[C:6]3[N:5]=[N:1][N:12]([CH3:13])[C:11]=3[CH:10]=2)=[CH:15][C:16]=1[C:25]([F:28])([F:26])[F:27]
Reactant: O=N[O-]
Reactant: CNc1cc(-c2ccc(OCCCO)c(C(F)(F)F)c2)nc(C#N)c1N
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: Cn1nnc2c(C#N)nc(-c3ccc(OCCCO)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.2 %

Procedure:
A solution of sodium nitrite (13.07 g) in water (40 ml) was added to 3-amino-6-(4-(3-hydroxypropoxy)-3-(trifluoromethyl)phenyl)-4-(methylamino)picolinonitrile (49.6 g) in 2M hydrochloric acid (203 ml) and NMP (180 ml). The mixture was stirred at room temperature for 2 hours then diluted with ethyl acetate (50 mml), and the mixture washed with water (300 ml+100 ml×4), the organic layer was dried over magnesium sulphate, solvent removed under reduced pressure. The residue was then columned on silica gel using DCM then DCM-MeOH (199:1) as eluant to give expected product (10.34 g). 1H NMR (CD3OD) δ: 8.55 (s, 1H), 8.39-8.45 (m, 2H), 7.35 (d, 1H), 4.45 (s, 3H), 4.30 (t, 2H), 3.80 (t, 2H), 2.06 (quin, 2H). MS m/z 378 (M+H).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C@H:3]([N:26]1[CH2:30][CH2:29][C@H:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10]/[N:11]=[CH:12]/[C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([O:24][CH3:25])[CH:17]=[C:18]([F:23])[CH:19]=3)[N:14]=2)=[CH:8][CH:9]=1.C(O)(=O)C.C(O)(=O)C.I(C1C=CC=CC=1)=O>C(Cl)Cl>[F:40][C:2]([F:1])([F:39])[C@H:3]([N:26]1[CH2:30][CH2:29][C@H:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])[CH2:27]1)[C:4]1[CH:9]=[CH:8][C:7]2[N:6]([C:12]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[C:16]([O:24][CH3:25])[CH:17]=[C:18]([F:23])[CH:19]=4)[N:14]=3)=[N:11][N:10]=2)[CH:5]=1
Reactant: COc1cc(F)cc2ccc(/C=N/Nc3ccc([C@@H](N4CC[C@H](NC(=O)OC(C)(C)C)C4)C(F)(F)F)cn3)nc12
Agent: O=Ic1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(F)cc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
To tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-((E)-2-((6-fluoro-8-methoxyquinolin-2-yl)methylene)hydrazinyl)pyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (300 mg, 0.533 mmol) in DCM (5 mL) was added iodosobenzene diacetate (206 mg, 0.640 mmol) and the reaction was stirred at ambient temperature for 2 hours. After concentration, the residue was purified by reverse phase chromatography (SP4, 12M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(3-(6-fluoro-8-methoxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (189 mg, 63.2% yield) as a beige solid
Reaction SMILES: Cl.[CH2:2]([N:6]=[C:7]([NH2:19])[NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][S:15][CH2:16][CH2:17][NH2:18])[N:13]=1)[CH2:3][CH2:4][CH3:5].[CH3:20][N:21]=[C:22]=[S:23].C(N(CC)CC)C.CO>O>[CH2:2]([N:6]=[C:7]([NH2:19])[NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][S:15][CH2:16][CH2:17][NH:18][C:22]([NH:21][CH3:20])=[S:23])[N:13]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CN=C=S
Reactant: CCCCN=C(N)Nc1nc(CSCCN)cs1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: CCCCN=C(N)Nc1nc(CSCCNC(=S)NC)cs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-(2-n-butylguanidino)-4-(2-aminoethyl)thiomethylthiazole hydrochloride (1.10 g.), methylisothiocyanate (0.70 g.), triethylamine (0.90 g.) and methanol (5 ml.) was stirred at room temperature for four hours. It was then diluted with water (25 ml.), extracted with ethyl acetate (2×25 ml.) and the combined extracts washed with water (50 ml.). The organic layer was then extracted with 1 N hydrochloric acid (2×25 ml.), the combined aqueous layers washed with ethyl acetate (25 ml.) and then basified by addition of aqueous ammonia. The resulting emulsion was extracted with ethyl acetate and the extract was washed with water and dried over magnesium sulphate. It was filtered and evaporated to dryness to give 2-(2-n-butylguanidino)-4-[2-(3-methylthioureido)ethylthiomethyl]thiazole as a brown gum. The n.m.r. spectrum in d6 dimethyl sulphoxide (DMSO) using tetramethylsilane as internal standard had the following resonances (δ): 0.6- 1.5 (7H, multiplet); 2.5 (2H, multiplet); 2.75 (3H, triplet); 3-3.5 (4H, multiplet); 3.55 (2H, singlet); 6.45 (1H, singlet); 6.7-7.6 (broad multiplet).
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH3:18].[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([OH:32])=[C:26]([CH:31]=1)[C:27]([O:29]C)=[O:28].Cl.C(N=C=NCCCN(C)C)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[OH:32][C:25]1[CH:24]=[CH:23][C:22]([NH:21][C:1](=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH3:18])=[CH:31][C:26]=1[C:27]([OH:29])=[O:28]
Reactant: COC(=O)c1cc(N)ccc1O
Reactant: CC/C=C\C/C=C\C/C=C\CCCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: CC/C=C\C/C=C\C/C=C\CCCCCCCC(=O)Nc1ccc(O)c(C(=O)O)c1
Reaction time: 14 h

Procedure:
To a solution of (9Z,12Z,15Z)-octadeca-9,12,15-trienoic acid (1.66 g, 5.98 mmol) and methyl 5-amino-2-hydroxybenzoate (1 g, 5.98 mmol) in methylene chloride (100 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.16 g, 6.0 mmol) and dimethylaminopyridine (100 mg). The mixture was stirred under N2 (14 h) and then diluted with methylene chloride (100 mL) and washed successively with 3N HCl, sat sodium bicarbonate solution and sat sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give the corresponding amide, 2.0 grams.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])[CH2:9][C@H:8]1[CH2:31][CH2:32][N:33]1[CH:37]=[CH:36][CH:35]=[N:34]1)=[O:6])[CH:2]=[CH2:3].[F:38][S:39]([O:42][CH3:43])(=[O:41])=[O:40]>ClCCl>[F:38][S:39]([O-:42])(=[O:41])=[O:40].[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])[CH2:9][C@H:8]1[CH2:31][CH2:32][N+:33]1[N:34]([CH3:43])[CH:35]=[CH:36][CH:37]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CCn3cccn3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: COS(=O)(=O)F
Solvent: ClCCl
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CC[n+]3cccn3C)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: O=S(=O)([O-])F

Procedure:
To a solution of allyl (4R,5S,6S)-3-[(2R,4S)-1-allyloxycarbonyl-2-{2-(pyrazol-1-yl)ethyl}pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (10.49 g) in dichloromethane (150 ml) was added methyl fluorosulfonate (2.33 ml) with stirring under ice-cooling. The mixture was stirred for 1.5 hours at the same temperature. The mixture was evaporated in vacuo to give allyl (4R,5S,6S)-3-[(2R,4S)-1-allyloxycarbonyl-2-{2-(2-methyl-1-pyrazolio)ethyl}pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate fluorosulfonate (12.75 g). This compound was immediately used as the starting compound for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1.C[N:18]([CH:20]=O)C.Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][N:36]([CH2:39][CH3:40])[CH2:37][CH3:38])=[CH:28][CH:27]=1)=O>O.CCOC(C)=O>[CH2:15]([C:20]1[N:9]([C:8]2[CH:7]=[CH:6][C:5]([O:4][C:3]3[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:2]=3[Cl:1])=[CH:11][CH:10]=2)[CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][N:36]([CH2:39][CH3:40])[CH2:37][CH3:38])=[CH:28][CH:27]=2)[N:18]=1)[CH2:2][CH2:3][CH3:12]
Reactant: CCN(CC)CCCOc1ccc(C(=O)CBr)cc1
Reactant: Nc1ccc(Oc2ccc(Cl)cc2Cl)cc1
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCc1nc(-c2ccc(OCCCN(CC)CC)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-(2,4-dichloro-phenoxy)aniline described above (1.2 eq., 5.2 mmol) in anhydrous DMF (20 mL) DIEA (3 eq. 15 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (4.4 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold H2O and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product obtained from 2-4% MeOH/DCM (yield˜5%).
Reaction SMILES: [OH2:1].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([CH:18]=O)=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:20][CH:21]([NH2:33])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1>CS(C)=O>[CH3:20][CH:21]([N:33]=[C:10]([O:9][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:15]([C:14]1[CH:13]=[CH:12][CH:11]=[CH:16][CH:18]=1)=[O:1])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1
Reactant: O=CC(=O)c1ccccc1OCc1ccccc1
Reactant: COc1ccc(CC(C)N)cc1OC
Reactant: O
Solvent: CS(C)=O
Product: COc1ccc(CC(C)N=C(OCc2ccccc2)C(=O)c2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.3 g of 2-benzyloxyphenylglyoxal hydrate (crude oil) are dissolved in 6 ml of dimethylsulfoxide, and 2 g of α-methyl-3,4-dimethoxyphenethylamine are added thereto. The mixture is stirred at room temperature for 30 minutes, whereby a solution of α-(α-methyl-3,4-dimethoxyphenethylimino)-2-benzyloxyacetophenone in dimethylsulfoxide is obtained.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][Br:8])[C:3](Br)=[O:4].[C:9]([O:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10].[NH4+].[Cl-]>ClCCl>[Br:1][CH:2]([CH2:6][CH2:7][Br:8])[C:3]([NH:23][C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])=[CH:22][CH:21]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: O=C(Br)C(Br)CCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(NC(=O)C(Br)CCBr)cc1
Reaction time: 0.17 h
Yield: 80.3 %

Procedure:
To the derivative 2,4- dibromobutyryl bromide (3.1 g) in dry dichloromethane (60 ml) pyridine (3.2 ml) was added, the mixture was kept at 0° C. under a nitrogen atmosphere for 10 minutes and then the N-t-butoxy carbonyl-1,4 phenylene diamine (2.08 g) was dropped. After 1 hour the mixture was poured into a saturated solution of NH4Cl (200 ml) extracted with EA (3×150 ml) and the organic phase washed with brine (200 ml), dried and concentrated in vacuum, the crude was purified by flash chromatography (eluting with CH/EA 80:20) to give of the title compound as a yellow foam (3.5 g ). T.I.c. CH/EA 8:2, Rf=0.53.
Reaction SMILES: CC(C([O:6][CH2:7]CN(C)C)=O)=C.CC1C=CC([S:19](C)(=[O:21])=[O:20])=CC=1.[C:23]1([CH3:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[S:19]([C:26]1[CH:27]=[CH:28][C:23]([CH3:29])=[CH:24][CH:25]=1)([O:6][CH3:7])(=[O:21])=[O:20]
Reactant: Cc1ccccc1
Reactant: Cc1ccc(S(C)(=O)=O)cc1
Reactant: C=C(C)C(=O)OCCN(C)C
Product: COS(=O)(=O)c1ccc(C)cc1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
To a 500 milliliter 4 neck round bottom flask equipped with a mechanical stirrer, an argon inlet and outlet on top of a water condenser, and a thermometer was charged 204.1 grams of the AB diblock copolymer toluene solution, prepared as described in Example I, and 110 grams of additional toluene solvent. This solution contains about 100 grams (49 weight percent of solids) of block copolymer of which 19.15 grams (0.1218 mole) are DMAEMA repeat units as determined by 1H-NMR. To this vigorously stirred solution at ambient temperature, about 25° C. throughout, unless otherwise noted, and under a gentle argon flow were added in one portion 20.4 grams (0.1096 mole) of methyl p-toluene sulfonate. The charged mole percent ratio of methyl p-toluene sulfonate to DMAEMA repeat units is 90 percent, thus nearly all of the DMAEMA repeat units have been targeted for conversion to the methyl p-toluene sulfonate quaternary ammonium AB diblock charge director. After about 1 hour, the internal temperature gently exothermed from 20° C. to 27° C. and then began to drop. After about 2 hours after the addition of the methyl p-toluene sulfonate, a heating mantle (set at 25 volts) was applied to the reaction vessel. An internal temperature of about 55° C. was maintained for the next 24 hours. A small aliquot (2.20 grams) of the methyl p-toluene sulfonate quaternary ammonium AB diblock charge director toluene solution was concentrated in the vacuum oven (50° to 55° C. for 28 hours at about 0.5 millimeter Hg) giving 0.78 gram of solid and establishing the solids level at 35.45 weight percent. To 6.79 grams of the 35.45 weight percent of methyl p-toluene sulfonate quaternary ammonium AB diblock charge director solution was added 198 grams of NORPAR 15™ and the mixture was rotoevaporated for about 1 hour at 50° to 60° C. at 40 to 60 millimeters Hg to remove the toluene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[NH:8][CH:9]=[N:10]2)=[C:5]([O:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:4]=1.O=P(Cl)(Cl)[Cl:23].C(N(CC)C(C)C)(C)C>C(Cl)CCl>[Cl:23][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[O:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:10]=[CH:9][N:8]=1
Reactant: COc1cc(OC2CCOCC2)c2c(=O)[nH]cnc2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC2CCOCC2)c2c(Cl)ncnc2c1
Temperature: 100 °C

Procedure:
A mixture of 7-methoxy-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4(3H)-one (0.60 g, 2.17 mmol), POCl3 (0.5 mL), and N,N-diisopropylethylamine (1.5 mL) in ClCH2CH2Cl (6 mL) was heated at 100° C. for 4 hours. After the solvent and reagents were evaporated under reduced pressure, toluene was added to the residue, and the solution was evaporated under reduced pressure. The residue was dried under vacuum to afford 4-chloro-7-methoxy-5-(tetrahydro-2H-pyran-4-yloxy)quinazoline as a brown solid. LC-MS (ESI) m/z 295 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[NH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27]([NH:35][N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:33])=[CH:18][CH:17]=1
Reactant: NN1CCCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)NN4CCCCC4)cc3)c2cc1OC
Yield: 66 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (50 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-aminopiperidine (50 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to the reaction solution to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (47 mg, yield 66%).
Reaction SMILES: [O:1]1[CH2:5]/[C:4](=[N:6]\O)/[C:3](=[N:8]/[OH:9])/[C:2]1=[O:10].S(Cl)(Cl)=O>O1CCOCC1>[N:6]1[O:9][N:8]=[C:3]2[C:2](=[O:10])[O:1][CH2:5][C:4]=12
Reactant: O=C1OCC(=N\O)/C1=N/O
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: O=C1OCc2nonc21
Reaction time: 8 h

Procedure:
4H,6H-Furo[3,4-c][1,2,5]oxadiazol-4-one was synthesized according to literature procedures (Pollet, et al., Synthesis Communications, 1979, 977-979.) To a stirred solution of (3Z,4Z)-furan-2,3,4(5H)-trione 3,4-dioxime (3.0 g, 0.021 mol) in 1,4-dioxane (21 mL) under nitrogen, thionyl chloride (2.1 mL, 0.029 mol) was added dropwise. The resulting yellow solution was stirred overnight and then concentrated in vacuo. The resultant crystalline material was recrystallized once from a minimum amount of ethanol (EtOH) to give the desired compound as an off-white powder. The filtrate was concentrated down and recrystallized again. Combined solids yielded the desired product (2.0 g, 76%). 1H NMR (400 MHz, DMSO-d6) δ: 5.67 (s, 2H). MF═C4H2N2O3; LCMS calculated for C4H3N2O3(M+H)+: m/z=127.014.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9]C2CCCCO2)[CH:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]([CH2:22][CH2:23][C@@:24]([CH3:39])([S:35]([CH3:38])(=[O:37])=[O:36])[C:25]([NH:27][O:28]C2CCCCO2)=[O:26])[C:18](=[O:40])[CH:17]=1.Cl.O>O1CCOCC1.CO>[F:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]([CH2:22][CH2:23][C@@:24]([CH3:39])([S:35]([CH3:38])(=[O:36])=[O:37])[C:25]([NH:27][OH:28])=[O:26])[C:18](=[O:40])[CH:17]=1
Reactant: Cc1c(OC2CCCCO2)ccc(-c2ccn(CC[C@](C)(C(=O)NOC3CCCCO3)S(C)(=O)=O)c(=O)c2)c1F
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: Cc1c(O)ccc(-c2ccn(CC[C@](C)(C(=O)NO)S(C)(=O)=O)c(=O)c2)c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 5.6 %

Procedure:
(2R)-4-{-4-[2-fluoro-3-methyl-4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (335 mg, 0.58 mmol) was dissolved in 3 mL of dioxane. To this solution was added 1 mL of 4M HCl in dioxane 1 mL of water. The resulting solution was stirred at RT for 10 minutes. The material was diluted up with methanol and concentrated (3×). Dichloromethane was added and the mixture was stirred for 18 h. The solution retained color and a fine particulate was suspended. The mixture was filtered leaving 13.3 mg (6%) of white solid. LCMS m/z 413.6 (M+1) 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.71 (s, 3H) 2.14 (d, J=1.56 Hz, 3H) 2.33-2.46 (m, 1H) 2.54-2.68 (m, 1H) 3.10 (s, 3H) 3.91-4.05 (m, 1H) 4.24-4.40 (m, 1H) 6.70 (d, J=8.59 Hz, 1H) 6.75-6.86 (m, 2H) 7.23 (t, J=8.68 Hz, 1H) 7.75 (d, J=6.83 Hz, 1H)
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:38](=[O:39])[N:13]3[C:14]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)=[O:27])=[C:15](OS(C(F)(F)F)(=O)=O)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Sn](CCCC)(CCCC)[C:45]1[O:46][CH2:47][CH2:48][CH:49]=1)CCC.CCCCCC>CN1CCCC1=O.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[O:46]1[CH2:47][CH2:48][CH:49]=[C:45]1[C:15]1[CH2:16][S:17][C@@H:12]2[C@H:11]([NH:10][C:8](=[O:9])[CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:38](=[O:39])[N:13]2[C:14]=1[C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)=[O:27]
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCO1
Reactant: COc1ccc(COC(=O)C2=C(OS(=O)(=O)C(F)(F)F)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN1CCCC1=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(COC(=O)C2=C(C3=CCCO3)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1

Procedure:
4-Methoxybenzyl (6R,7R)-7-phenylacetamido-3-trifluoromethane-sulphonyloxyceph-3-em-4-carboxylate (0.10 g), bis(dibenzylideneacetone)-palladium (0) (0.003 g) and tri-n-butyl(4,5-dihydrofuran-2-yl)stannane (0.122 g, 0.108 ml ) in dry N-methylpyrrolidinone (0.5 ml) were stirred together for 0.25 h. T.l.c. analysis (50% ethyl acetate--hexane) showed no starting material. The mixture was diluted with ethyl acetate, washed three times with water and with brine and then dried. The solution was concentrated to a small volume and then added dropwise to vigorously stirred hexane (50 ml). The suspension was centrifuged and the clear hexane decanted. The precipitate was washed with hexane and dried in vacuo, to give the title compound as a buff coloured, amorphous solid (0.08 g, 93%); δH (250 MHz, CDCl3) 2.60 (2H, dt, J 9.8, 2.9 Hz), 3.38 and 3.47 (2H, ABq, J 18.1 Hz), 3.60 and 3.96 (2H, ABq, J 16.2 Hz), 3.80 (3H, s), 4.07 (1H, dt, J 18.6, 9.8 Hz), 4.21 (1H, dt, J 17.9, 8.5 Hz), 4.94 (1H, d, J 4.9 Hz), 5.02 (1H, t, 2.9 Hz), 5.17 and 5.23 (2H, ABq, J 12.0 Hz), 5.82 (1H, dd, J 9.1, 4.8 Hz), 6.01 (1H, d, J9.1 Hz), 6.88 (2H, d, J 8.7 Hz) and 7.25-7.41 (7H, m).
Reaction SMILES: C[N:2]([CH2:10][C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:13][CH:12]=1)[C:3](=O)OC(C)(C)C.[H-].[Na+].[S:24]1[CH:28]=[CH:27][C:26]([S:29]([Cl:32])(=[O:31])=[O:30])=[CH:25]1>>[ClH:32].[CH3:3][NH:2][CH2:10][C:11]1[CH:15]=[C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:13]([S:29]([C:26]2[CH:27]=[CH:28][S:24][CH:25]=2)(=[O:31])=[O:30])[CH:12]=1
Reactant: CN(Cc1c[nH]c(-c2ccccc2)c1)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccsc1
Agent: [H-]
Agent: [Na+]
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2ccsc2)c1
Product: Cl
Yield: 35.4 %

Procedure:
Using tert-butyl methyl[(5-phenyl-1H-pyrrol-3-yl)methyl]carbamate (250 mg), sodium hydride (60% in oil, 140 mg) and thiophene-3-sulfonyl chloride (340 mg), a procedure as in Example 36 was performed to give the title compound as pale-purple crystals (yield 114 mg, 35%).
Reaction SMILES: CC([O-])(C)C.[K+].[CH3:7][N:8]([CH3:40])[C:9]1[S:10][C@H:11]2[O:17][C@H:16]([CH:18]=O)[C@@H:15]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C@H:14]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[C@H:12]2[N:13]=1.C1[CH2:45][O:44][CH2:43]C1>>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:20][C@@H:15]2[C@@H:16](/[CH:18]=[CH:43]/[O:44][CH3:45])[O:17][C@H:11]3[C@H:12]([N:13]=[C:9]([N:8]([CH3:40])[CH3:7])[S:10]3)[C@H:14]2[O:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)=[CH:23][CH:24]=1
Reactant: COc1ccc(CO[C@@H]2[C@H]3N=C(N(C)C)S[C@H]3O[C@H](C=O)[C@H]2OCc2ccc(OC)cc2)cc1
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CO/C=C/[C@H]1O[C@@H]2SC(N(C)C)=N[C@@H]2[C@@H](OCc2ccc(OC)cc2)[C@@H]1OCc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 14 %

Procedure:
A solution of Ph3PCH2OCH3Br (2.0 g, 5.90 mmol) in THF (30 mL) was treated with t-BuOK (645 mg, 5.76 mmol) at −10° C. for 30 min, and followed by addition of (3aR,5S,6S,7R,7aR)-2-(dimethylamino)-6,7-bis(4-methoxybenzyloxy)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-5-carbaldehyde (700 mg, 1.37 mmol). After stirred for 3 h at 0° C., the resulting solution was quenched with ice-water (20 mL), and extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated to give a residue, which was purified by a silica gel column, eluted with 10-50% ethyl acetate in petroleum ether to give the product 37 as a yellow oil (100 mg, 14%). (ES, m/z) [M+H]+ 515.0; 1H NMR (300 MHz, CDCl3) δ 7.15-7.35 (m, 4H), 6.84-6.98 (m, 4H), 6.45 (d, J=7.8 Hz, 1H), 6.28 (d, J=6.3 Hz, 1H), 5.21 (m, 1H), 4.45-4.89 (m, 4H), 4.18 (t, J=5.7 Hz, 1H), 3.94 (t, J=4.8 Hz, 1H), 3.87-3.91 (m, 1H), 3.78 (s, 6H), 3.56-3.65 (m, 1H), 3.52 (s, 3H), 2.92 (s, 6H).