Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:45])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:37][NH:38][C:39]([O:41][CH:42]([CH3:44])[CH3:43])=[O:40])(C)(C)C.Cl.O1CCOCC1>>[CH:42]([O:41][C:39]([NH:38][CH2:37][C:10]1[CH:11]=[C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH:31]4[CH2:32][CH2:33][O:34][CH2:35][CH2:36]4)=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])[CH:13]=[CH:14][C:9]=1[CH2:8][CH2:7][C:6]([OH:45])=[O:5])=[O:40])([CH3:44])[CH3:43]
Reactant: Cc1oc(-c2ccc(OC3CCOCC3)cc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CNC(=O)OC(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1oc(-c2ccc(OC3CCOCC3)cc2)nc1CCOc1ccc(CCC(=O)O)c(CNC(=O)OC(C)C)c1
Reaction time: 16 h

Procedure:
A mixture of 3-[4-{2-[2-(4-hydroxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-2-(isopropoxycarbonylamino-methyl)-phenyl]-propionic acid tert-butyl ester (120 mg, 0.223 mmol, Example 406), tetrahydro-pyran-4-ol (22.7 mg, 0.223 mmol), triphenylphosphine (58.4 mg, 0.223 mmol) and toluene (10 mL) was treated dropwise with DIAD (45 mg, 0.223 mmol). The mixture was stirred under N2 at ambient temperature for 16 h and concentrated. The crude product was purified by radial chromatography (10-70% EtOAc/hexanes) to give 3-[2-(isopropoxycarbonylamino-methyl)-4-(2-{5-methyl-2-[4-(tetrahydro-pyran-4-yloxy)-phenyl]-oxazol-4-yl}-ethoxy)-phenyl]-propionic acid tert-butyl ester. The ester product was dissolved 4M HCl/dioxane (5 mL), stirred for 16 h and concentrated to give the title compound: MS [ES] m/z 525 (M+H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[NH:18][CH3:19]>>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[N:18]([CH3:19])[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CNc1ccccc1OC
Product: COc1ccccc1N(C)S(=O)(=O)c1ccc(C(=O)O)cc1

Procedure:
4-(chlorosulfonyl)benzoic acid (500 mg, 2.27 mmol) was treated with 2-methoxy-N-methylaniline (933 mg, 6.8 mmol) using method A to give 4-(N-(2-methoxyphenyl)-N-methylsulfamoyl)benzoic acid as an off white solid. Yield: 515 mg (71%). 1H-NMR: 8.11 (d, J=8.5 Hz, 2H), 7.73 (d, J=8.5 Hz, 2H), 7.33 (ddd, J=8.5, 7.5, 1.5 Hz, 1H), 7.17 (dd, J=7.5, 1.5 Hz, 1H), 7.00-6.92 (m, 2H), 3.33 (s, 3H), 3.14 (s, 3H).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][CH2:2]1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>C(O)C.O.[OH-].[Na+]>[C:11]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][CH2:2]1)(=[O:13])[CH3:12]
Reactant: c1ccc2c(c1)NCCN2
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)N1CCNc2ccccc21

Procedure:
A solution of 0.186 mole (25 g) of 1,2,3,4-tetrahydroquinoxaline was dissolved in 250 ml of ethanol and 17.6 ml of acetic anhydride was added dropwise with stirring. The solution was then diluted with 750 ml of water and basified with 1 N sodium hydroxide. The solution was extracted with chloroform, the organic extracts were dried and then evaporated to provide the solid product, 1-acetyl-1,2,3,4-tetrahydroquinoxaline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:36])=[C:16]([N:18]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)[CH:25]=3)[N:20]=[CH:19]2)[CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([CH3:36])=[C:16]([N:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([N:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)[CH:25]=4)[N:20]=[CH:19]3)[CH:17]=2)=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)c1ccnc(Cl)c1
Reactant: Cc1ccc(N)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O
Yield: 91.5 %

Procedure:
2-Chloropyridine-4-carbonyl chloride (0.61 g) was added to a stirred mixture of 3-(5-amino-2-methylphenyl)-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one (1 g), triethylamine (1 g) and methylene chloride (15 ml) and the resultant mixture was stirred at ambient temperature for 18 hours. The mixture was washed with a saturated aqueous sodium bicarbonate solution and the organic phase was evaporated. There was thus obtained the title compound (1.28 g); NMR Spectrum: (DMSOd6) 2.05 (s, 3H), 2.22 (s, 3H), 2.46-2.5 (m, 4H), 3.25-3.28 (m, 4H), 7.42-7.47 (m, 2H), 7.62 (s, 1H), 7.76-7.79 (m, 2H), 7.85 (d, 1H), 7.98 (s, 1H), 8.07 (s, 1H), 8.61 (d, 1H), 10.65 (s, 1H); Mass Spectrum: M+H+ 489 & 491.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]([OH:18])=O)[N:13]=2)=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O[NH:51][C:52](=[NH:54])[CH3:53]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]3[O:18][N:54]=[C:52]([CH3:53])[N:51]=3)[N:13]=2)=[N:6][CH:7]=1
Reactant: CC(=N)NO
Reactant: O=C(O)CCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(CCc2csc(Nc3ncc(Br)cc3Oc3ccccc3)n2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
To a mixture of 3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanoic acid (0.100 g, 0.238 mmol), DIEA (0.0456 mL, 0.262 mmol) in 5 mL DMF at ambient temperature was added N-((dimethylamino)fluoromethylene)-N-methylmethanaminium hexafluorophosphate(V) (0.0628 g, 0.238 mmol). The mixture was stirred for 30 minutes at ambient temperature and then N-hydroxyacetamidine (0.0194 g, 0.262 mmol) was added in one portion and the reaction was heated at 110° C. overnight. The reaction was then cooled to ambient temperature and EtOAc was added and the organic layer washed with water (2×10 mL), dried over Na2SO4 and concentrated to a residue that was purified on silica gel eluting with 25% EtOAc/Hexanes to give 5 the title compound (0.067 g, 61.4% yield). 1H NMR (d6 DMSO) δ 2.29 (s, 3H), 3.04 (t, 7.6 Hz, 2H), 3.26 (t, J=7.6 Hz, 2H), 6.74 (s, 1H), 7.11 (d, J=7.8 Hz, 2H), 7.21 (t, J=7.3 Hz, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.44 (t, J=8.0 Hz, 2H), 8.22 (d, J=2.0 Hz, 1H), 11.00 (s, 1H).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Cl:10][C:11]1[N:12]=[CH:13][C:14]([C:17]([OH:19])=O)=[N:15][CH:16]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[F:44][C:45]([F:51])([F:50])[C:46]1([NH2:49])[CH2:48][CH2:47]1.C([O-])(O)=O.[Na+]>>[Cl:10][C:11]1[N:12]=[CH:13][C:14]([C:17]([NH:49][C:46]2([C:45]([F:51])([F:50])[F:44])[CH2:48][CH2:47]2)=[O:19])=[N:15][CH:16]=1
Reactant: NC1(C(F)(F)F)CC1
Reactant: O=C(O)c1cnc(Cl)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1(C(F)(F)F)CC1)c1cnc(Cl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
N,N-Diisopropylethylamine (1.3 mL, 7.5 mmol) was added to a mixture of 5-chloropyrazine-2-carboxylic acid (0.40 g, 2.5 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1.0 g, 2.8 mmol) and 1-(trifluoromethyl)cyclopropanamine (0.32 g, 2.5 mmol) (Oakwood, Cat. #: 038175) in dichloromethylene (10 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was worked up with saturated aqueous NaHCO3, and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-20%) to afford the desired product (0.41 g, 67%). LCMS (M+H)+: m/z=266.0/267.9.
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([I:15])[CH:12]=[C:11]([F:16])[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH2:19]([O:21][C:22](=[O:35])[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1)[CH3:20].C(OC(=O)C1C=CC(N2CCN(C3C=CC(C(=O)NC4C=CC(C)=C(I)C=4)=CN=3)CC2)=CC=1)C>>[CH2:19]([O:21][C:22](=[O:35])[C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH2:30][CH2:31][N:32]([C:2]3[CH:18]=[CH:17][C:5]([C:6](=[O:7])[NH:8][C:9]4[CH:14]=[C:13]([I:15])[CH:12]=[C:11]([F:16])[CH:10]=4)=[CH:4][N:3]=3)[CH2:33][CH2:34]2)=[CH:27][CH:28]=1)[CH3:20]
Reactant: O=C(Nc1cc(F)cc(I)c1)c1ccc(Cl)nc1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Agent: CCOC(=O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccc(C)c(I)c4)cn3)CC2)cc1
Product: CCOC(=O)c1ccc(N2CCN(c3ccc(C(=O)Nc4cc(F)cc(I)c4)cn3)CC2)cc1

Procedure:
4-{4-[5-(3-Fluoro-5-iodo-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid ethyl ester was prepared from 6-chloro-N-(3-fluoro-5-Iodo-phenyl)-nicotinamide and 4-(piperazin-1-yl)-benzoic acid ethyl ester following a method similar to the one described in the synthesis of 4-{4-[5-(3-iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid ethyl ester above. The product was isolated after suspension in small volume of EtOAc filtration and a wash with CH3CN. HRMS m/z calcd for C25H24N4O3FI [M+H]+: 575.0950. Found: 575.0947.
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[C:5]([F:25])=[C:6]([CH:20]=[C:21]([F:24])[C:22]=1[F:23])[C:7]([CH:9](C(OCC)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)(O)[O-].[Na+]>O1CCOCC1>[F:26][CH:2]([F:1])[O:3][C:4]1[C:5]([F:25])=[C:6]([CH:20]=[C:21]([F:24])[C:22]=1[F:23])[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)c(OC(F)F)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CC(=O)c1cc(F)c(F)c(OC(F)F)c1F

Procedure:
The whole of the diethyl 3-difluoromethoxy-2,4,5-trifluorobenzoylmalonate [(XIV), R1 =--OCHF2, R3' =H, R17 =C2H5, X=X'=F] [prepared as described in step (a) above] was dissolved in 200 ml of dioxane, and then 4.52 g (0.0238 moles) of p-toluenesulfonic acid monohydrate were added to the resulting solution. The mixture was then heated under reflux for 6 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure. 100 ml of water and 2.52 g (0.03 moles) of sodium bicarbonate were added to the residue, and the mixture was extracted with ethyl acetate. The extract was Washed with water and dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to give 5.66 g of ethyl 3-difluoromethoxy-2,4,5-trifluorobenzoylacetate as a reddish brown liquid.
Reaction SMILES: C([Li])CCC.[C:6]1([CH:12]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:13][CH2:14][P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:29][S:30]SC.O>O1CCCC1>[C:6]1([CH:12]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:13][CH:14]([P:15](=[O:22])([O:16][CH2:17][CH3:18])[O:19][CH2:20][CH3:21])[S:30][CH3:29])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCOP(=O)(CCC(c1ccccc1)c1ccccc1)OCC
Reactant: CSSC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(CC(c1ccccc1)c1ccccc1)SC
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
A solution of n-butyl lithium (2.5M in n-hexane, 132 ml, 33 mmol) was added dropwise over 10 minutes to a stirred solution of diethyl 3,3-diphenylpropylphosphonate (9.96 g, 30 mmol) in dry tetrahydrofuran (100 ml) cooled to -60° C. under nitrogen atmosphere. After 20 minutes at -60° C. a solution of dimethyl disulphide (2.96 ml, 33 mmol) in dry tetrahydrofuran (5 ml) was added in one portion turning the solution colour from orange to pale yellow immediately. After 30 minutes at -60° C., water (200 ml) was added and the mixture extracted with diethyl ether (2×100 ml). The ether extracts were washed with saturated aqueous sodium bicarbonate (2×100 ml), brine solution (100 ml), dried, filtered and evaporated to a yellow oil (13 g). Chromatography on flash silica eluting with diethyl ether gave the title product as a colourless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])(=[O:21])=[O:20])[O:13][C:14]=1[CH2:15][OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1C=O)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])(=[O:21])=[O:20])[O:13][C:14]=1[CH:15]=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(CNS(=O)(=O)c2ccccc2Cl)oc(CO)c1OCc1ccccc1
Agent: O=Cc1oc(CNS(=O)(=O)c2ccccc2)cc(=O)c1OCc1ccccc1
Product: O=Cc1oc(CNS(=O)(=O)c2ccccc2Cl)cc(=O)c1OCc1ccccc1
Yield: 85.1 %

Procedure:
N-(5-Benzyloxy-6-formyl-4-oxo-4H-pyran-2-ylmethyl)-2-chloro-benzenesulfonamide (11-03) (2.8 g, 85.07%) was synthesized as a brown sticky solid from N-(5-benzyloxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-2-chloro-benzenesulfonamide (10-03) (3.3 g, 7.58 mmol) following the procedure described for N-(5-benzyloxy-6-formyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (11-01).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][CH:12]1[CH:17]2[CH:13]1[CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16]2>Cl.O1CCOCC1>[CH:13]12[CH:12]([NH:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)[CH:17]1[CH2:16][NH:15][CH2:14]2
Reactant: CC(C)(C)OC(=O)N1CC2C(C1)C2Nc1ccc2ccccc2n1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc2nc(NC3C4CNCC43)ccc2c1

Procedure:
tert-Butyl 6-(quinolin-2-ylamino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (320 mg, 0.98 mmol) was stirred in 4M HCl in dioxane (2 ml) at r.t. under N2 for 15 min. The solvent was then removed in vacuo and the residue dried under high-vacuum and used in the next step without further purification. LCMS purity 91%, m/z 226 [M+H]+.
Reaction SMILES: [CH:1]1([O:4][N:5]=[C:6]([C:37]2[N:38]=[C:39]([NH:42][CH:43]=[O:44])[S:40][CH:41]=2)[C:7]([NH:9][C@@H:10]2[C:35](=[O:36])[N:12]3[C:13]([C:19]([O:21][CH:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])=[C:14]([CH2:17][Cl:18])[CH2:15][S:16][C@H:11]23)=[O:8])[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:53])C=1>C(Cl)Cl>[CH:1]1([O:4][N:5]=[C:6]([C:37]2[N:38]=[C:39]([NH:42][CH:43]=[O:44])[S:40][CH:41]=2)[C:7]([NH:9][C@@H:10]2[C:35](=[O:36])[N:12]3[C:13]([C:19]([O:21][CH:22]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])=[C:14]([CH2:17][Cl:18])[CH2:15][S:16](=[O:53])[C@H:11]23)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=CNc1nc(C(=NOC2CC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS[C@H]23)cs1
Solvent: ClCCl
Product: O=CNc1nc(C(=NOC2CC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS(=O)[C@H]23)cs1
Reaction time: 1.5 h

Procedure:
To a solution of benzhydryl 7β-[2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate (syn isomer) (3 g) in methylene chloride (300 ml) was dropwise added a solution of m-chloroperbenzoic acid (0.79 g, 80% purity) in methylene chloride (10 ml) below 5° C. The mixture was stirred for 1.5 hours below 5° C. to give precipitates. The precipitates were collected, washed with methylene chloride, and dried over phosphorus pentoxide to give benzhydryl 7β-[2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate 1-oxide (syn isomar) as a solid.
Reaction SMILES: ClC1C=C(C(OO)=[O:9])C=CC=1.[CH2:12]([N:15]1[C:39](=[O:40])[C:18]2=[N:19][N:20]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([N:34]4[CH:38]=[CH:37][CH:36]=[N:35]4)=[CH:30][CH:29]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[C:17]2=[N:16]1)[CH:13]=[CH2:14].C(=O)(O)[O-].[Na+]>ClCCl.[Cl-].[Na+].O>[O:9]1[CH2:14][CH:13]1[CH2:12][N:15]1[C:39](=[O:40])[C:18]2=[N:19][N:20]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([N:34]4[CH:38]=[CH:37][CH:36]=[N:35]4)=[CH:30][CH:29]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[C:17]2=[N:16]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCn1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)nc-2c1=O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=c1c2nn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1CC1CO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3-chlorobenzenecarboperoxoic acid (29 mg, 0.17 mmol, 1.3 equiv) in dichloromethane (3 mL) was cooled to 0° C. and treated with a dichloromethane (1 mL) solution of 2-allyl-5-[4-(1H-pyrazol-1-yl)benzyl]-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one [(Example 10), 50 mg, 0.13 mmol]. After stirring for 1 hour at 0° C., the mixture was warmed to ambient temperature and stirred for an additional 14 hours. The mixture was treated with additional 3-chlorobenzenecarboperoxoic acid (50.0 mg, 0.29 mmol, 2.2 equiv) and after three hours, the mixture was cooled to 0° C., treated with sodium bicarbonate (3 mL, saturated aqueous), diluted with brine (10 mL) and extracted with dichloromethane (3×30 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel gradient chromatography (0:100 to 100:0; hexanes:ethyl acetate), providing the titled compound as a dark red solid: 1H-NMR (400 MHz, CDCl3) δ 8.31-8.28 (1H, m), 7.89 (1H, d, J=2.5 Hz), 7.71 (1H, d, J=1.4 Hz), 7.68 (2H, d, J=8.7 Hz), 7.57-7.51 (3H, m), 7.38 (2H, d, J=8.7 Hz), 6.46 (1H, dd, J=2.4, 1.8 Hz), 5.85 (2H, s), 4.32 (1H, dd, J=14.5, 4.5 Hz), 4.22 (1H, dd, J=14.5, 5.5 Hz), 3.43-3.38 (1H, m), 2.88 (1H, dd, J=4.7, 4.1 Hz), 2.79 (1H, dd, J=4.8, 2.6 Hz) ppm. high resolution mass spectrometry (ES+) m/z 399.1563 [(M+H)+; calculated for C22H18N6O2: 399.1564].
Reaction SMILES: C([O:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[C:8]=2[C@H:7]([CH3:27])[CH2:6]1)(=O)C.[Li+].[OH-].O.CO>C1COCC1>[OH:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[C:8]=2[C@H:7]([CH3:27])[CH2:6]1
Reactant: CC(=O)OC1C[C@@H](C)c2c1ncnc2N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C[C@@H]1CC(O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 15 h
Yield: 54 %

Procedure:
To a solution of (R)-tert-butyl 4-(7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (1.16 g, 3.08 mmol) in 12 mL THF was added 3M LiOH (2.57 mL, 7.70 mmol) and 3 mL H2O. The reaction mixture was stirred at room temperature for 15 hours, after which H2O was added, and the mixture was extracted with 3×75 mL EtOAc. The combined extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The crude was purified on silica gel (Biotage 40S) first with 1:1 to 1:6 DCM:EtOAC gradient, followed by 20:1 DCM:MeOH to give (R)-tert-butyl 4-(7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.556 g, 54.0% yield) as a 1:1 mixture of diastereomers as a brown foam. MS (APCI+) m/z 335 [M+H]+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[O:41]1[CH:45]=[CH:44][C:43]([S:46](Cl)(=[O:48])=[O:47])=[CH:42]1>O1CCCC1.O>[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6][N:7]([S:46]([C:43]2[CH:44]=[CH:45][O:41][CH:42]=2)(=[O:48])=[O:47])[C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccoc1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)c2ccoc2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
To a suspension of sodium hydride (60% in oil, 48 mg) in tetrahydrofuran (2 mL) were added dropwise a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (259 mg) in tetrahydrofuran (1 mL), 15-crown-5 (266 mg) and furan-3-sulfonyl chloride (147 mg) under ice-cooling and the mixture was stirred for 30 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→3:2) to give the title compound as a pale-yellow oil (yield 335 mg, 92%).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:23][N:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25](Cl)=[O:26].CO>C(#N)C.ClCCl>[CH3:23][N:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25](=[O:26])[O:14][C:11]1[CH:12]=[CH:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9](=[O:15])[CH:10]=1
Reactant: O=c1cc(O)ccn1Cc1ccccc1
Reactant: CN(C(=O)Cl)c1ccccc1
Solvent: CC#N
Solvent: ClCCl
Solvent: CO
Product: CN(C(=O)Oc1ccn(Cc2ccccc2)c(=O)c1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a chilled solution of 1-benzyl-4-hydroxypyridin-2(1H)-one (0.375 g, 1.86 mmol) in anhydrous acetonitrile (10 mL) was added triethylamine (0.206 g, 2.04 mmol) followed by N-methyl-N-phenylcarbamoyl chloride (0.379 g, 2.24 mmol). The reaction mixture was stirred under nitrogen atmosphere at 0° C. for 30 minutes then at room temperature for 1 hour. The reaction was monitored by TLC (5% methanol in dichloromethane). The solvent was removed under reduced pressure and the residue was washed with 10% citric acid and extracted with ethyl acetate. The organic extracts were combined, washed with water and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to afford a yellow syrup. The residue was purified by flash chromatography (silica gel) using 5% MeOH in CH2Cl2 to give the desired product (0.3829, 61%) as a white semisolid. 1H-NMR (d6-DMSO, 400 MHz) δ7.8 (d, 1H, J=7.2 Hz), 7.39 (m, 10H), 6.19 (s, 2H), 5.03 (s, 2H), 3.29 (s, 3H); ES-HRMS m/z 335.1396 (M+H calculated for C20H19N2O3 requires 335.1418).