Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12]C)[C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C(O)(=O)C.Br.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5]([C:8]([F:9])([F:10])[F:11])=[N:6][CH:7]=1
Reactant: COc1cc(Br)cnc1C(F)(F)F
Agent: Br
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Oc1cc(Br)cnc1C(F)(F)F
Temperature: 110 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A solution of 5-bromo-3-methoxy-2-(trifluoromethyl)pyridine (28) (0.87 g, 3.4 mmol) in a mixture of acetic acid (6 mL) and 33% HBr in acetic acid (12 mL) was stirred at 110° C. in a sealed tube overnight. Then Potassium Sodium tartrate tetrahydrate (7.8 g) was added slowly under 0° C. The mixture was taken up in ethyl acetate after 10 minutes stirring, the organic phase was washed with brine, dried over Na2SO4. The extract was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of Hexane-Ethyl acetate (1:2) as the eluent to give the product (29) 0.65 g as gray solid, Yield: 79%. 1H NMR (CD3OD, 400 MHz): δ 8.18 (s, 1H), 7.58 (s, 1H). 19F NMR (CDCl3, 376 MHz): −68.0.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[C:11]#[N:12].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:19]O.[OH-].[Na+]>C1COCC1.O>[CH2:1]([C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[CH2:11][NH2:12])[CH3:19]
Reactant: CO
Reactant: Cc1cc2[nH]ncc2cc1C#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc2[nH]ncc2cc1CN
Temperature: 25 °C
Yield: 30 %

Procedure:
A solution of 6-methyl-1H-indazole-5-carbonitrile (preparation 32) (230 mg, 1.47 mmol) in THF (10 ml) under nitrogen was treated with a solution of lithium aluminum hydride (1N, 3.66 ml,3.66 mmol) in THF at 0° C. The resultant mixture was stirred for 16 hr warming to room temperature, then treated with MeOH (12 ml), H2O (0.8 ml), NaOH (4N, 2 ml) and H2O (4 ml). The resultant precipitate was removed by filtration, washed with THF and purified by chromatography (SiO2, eluting with 90:10:1 CH2Cl2:MeOH:NH3) to give the desired product (71 mg, 30%). 1H NMR (CD3OD) δ 2.40 (s, 3H), 3.95 (s, 2H), 7.35 (s, 1H), 7.70 (s, 1H), 7.95 (s, 1H). LRMR m/z=162.0 (M+1)+.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54]C(OC(C)(C)C)=O)[S:52][CH:53]=4)=[N:28]\[O:29]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:64][S:65][C:66]2[N:70]([CH3:71])[N:69]=[N:68][N:67]=2)=[S:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1(OC)C=CC=CC=1.[N+](C)([O-])=O.Cl.O>[NH2:54][C:51]1[S:52][CH:53]=[C:49](/[C:27](=[N:28]/[OH:29])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:63])[N:22]3[C:17]([C:15]([OH:14])=[S:16])=[C:18]([CH2:64][S:65][C:66]4[N:70]([CH3:71])[N:69]=[N:68][N:67]=4)[CH2:19][S:20][C@H:21]23)=[O:62])[N:50]=1
Reactant: Cn1nnnc1SCC1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(=O)OC(C)(C)C)n3)[C@H]2SC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: C[N+](=O)[O-]
Solvent: O
Product: Cn1nnnc1SCC1=C(C(O)=S)N2C(=O)[C@@H](NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1
Reaction time: 1 h
Yield: 70.2 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetyl]amino-3-(1-methyl-5-tetrazolyl)thiomethylthio-3-cephem-4-carboxylic acid diphenylmethyl ester (576 mg: 0.555 mMol.) in a mixture of anisole (2 ml) and nitromethane (8 ml) cooling at -30° to -40° C. is added a solution of aluminum chloride (591 mg: 4.44 mMol.) in anisole (2 ml), and the mixture is stirred at -30° to -40° C. for 1 hour. The reaction mixture is diluted with 1N-hydrochloric acid (5 ml) and water and washed with ethyl acetate. The aqueous layer is concentrated under reduced pressure to remove the organic solvents, and purified by styrene-divinylbenzene copolymer chromatography (methanol: water=4:1). The resulting powder is washed with ethyl acetate to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetyl]amino-3-(1-methyl-5-tetrazolyl)thiomethylthio-3-cephem-4-carboxylic acid as yellow powder (200 mg). Yield: 68%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C@@:10]([CH:13]([O:16][CH3:17])[O:14][CH3:15])([CH3:12])[C@H:9]3[O:18][C@H:8]3[C:7]=2[CH:19]=1)#[N:2].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][CH2:28][C:29]2[NH:30][CH:31]=[CH:32][N:33]=2)=[CH:23][CH:22]=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C@@:10]([CH:13]([O:16][CH3:17])[O:14][CH3:15])([CH3:12])[C@@H:9]([OH:18])[C@H:8]([N:27]([C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=3)[CH2:28][C:29]3[NH:30][CH:31]=[CH:32][N:33]=3)[C:7]=2[CH:19]=1)#[N:2]
Reactant: COC(OC)[C@@]1(C)Oc2ccc(C#N)cc2[C@@H]2O[C@@H]21
Reactant: Clc1ccc(NCc2ncc[nH]2)cc1
Product: COC(OC)[C@@]1(C)Oc2ccc(C#N)cc2[C@@H](N(Cc2ncc[nH]2)c2ccc(Cl)cc2)[C@@H]1O
Yield: 28.3 %

Procedure:
The title compound (106 mg, 28%) was prepared using (2S,3S,4S)-6-cyano-3,4-dihydro-2-dimethoxymethyl-3,4-epoxy-2-methyl-2H-1-benzopyran (210 mg, 0.8 mmol) and 4-chlorophenyl-1H-imidazol-2-ylmethylamine (167 mg, 0.8 mmol), according to the same procedure used for the preparation of example 1 above.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[CH3:7][O:8][C:9]1[C:10]([N+:19]([O-:21])=[O:20])=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=[O:13]>C(O)(=O)C>[CH3:7][O:8][C:9]1[C:10]([N+:19]([O-:21])=[O:20])=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:12]([OH:2])=[O:13]
Reactant: COc1ccc(C=O)c([N+](=O)[O-])c1OC
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: COc1ccc(C(=O)O)c([N+](=O)[O-])c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
Potassium permanganate (0.6 g, 3.8 mmol, 2.0 eq), is added at room temperature to a stirred solution of 3,4-dimethoxy-2-nitro-benzaldehyde (0.4 g, 1.9 mmol, 1.0 eq) in acetic acid (10 mL). After stirring overnight at room temperature, the reaction mixture is quenched with saturated sodium sulfite aqueous solution and extracted with ethyl acetate (3×20 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford 3,4-dimethoxy-2-nitro-benzoic acid as a white solid (0.35 g, 81% yield).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:18][CH2:17][CH2:16][CH2:15][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1
Reactant: ClCCCBr
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCCOc1ccc(-c2ccccc2)cc1
Yield: 71.1 %

Procedure:
A mixture of 34 g (0.2 mole) of 4-phenylphenol, 63 g (0.4 mole) of 1-bromo-3-chloropropane and 82.9 g (0.6 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 17 hr. The mixture was cooled, filtered, and the filtrate concentrated under reduced pressure. The residue was triturated with petroleum ether (30°-60° C.) and a solid crystallized. The solid was collected by filtration and was subjected to flash chromatography on 400 g of silica gel on a 10-cm diameter column to remove starting phenol. The column was eluted with a 1:2 mixture of benzene and cyclohexane, and fractions containing title compound were combined and concentrated to give a solid residue. The solid was triturated with petroleum ether (30°-60° C.), collected by filtration, and dried to yield 35.1 g (71%) of title compound as a white solid. An analytical sample was recrystallized from petroleum ether (60°-110° C.), mp 65°-66° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[N:2]1.[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1F.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1[N:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[N:2]1
Reactant: c1ccc(-c2cc[nH]n2)nc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-n2ccc(-c3ccccn3)n2)c(F)c1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
Compound 17a (1 g, 6.9 mmol) obtained from the aforesaid process and 3,4-difluoro-nitrobenzene (0.74 mL) were dissolved in N,N-dimethylformamide (20 mL), and then anhydrous potassium carbonate (1.9 g) was added thereto. The mixture was reacted at 100° C. for 4 hours. After completion of the reaction, the reactant mixture was cooled to room temperature. Water was added to the mixture, resulting in a substantial amount of precipitate. Then, the precipitate was suction-filtered, and the filter cake was recrystallized with acetone to get the product 18a as a white powder (1.7 g), with a yield of 93.4%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH2:13][CH2:14][OH:15])[CH2:12][CH2:11][NH:10][CH2:9]1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[C:21](Cl)=[O:22]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH2:13][CH2:14][OH:15])[CH2:12][CH2:11][N:10]([C:21](=[O:22])[C:20]2[CH:19]=[C:18]([O:17][CH3:16])[C:26]([O:27][CH3:28])=[C:25]([O:29][CH3:30])[CH:24]=2)[CH2:9]1
Reactant: OCCC1(c2ccccc2F)CCNC1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Product: COc1cc(C(=O)N2CCC(CCO)(c3ccccc3F)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.1 using 2-[3-(2-fluoro-phenyl)-pyrrolidin-3-yl]-ethanol (23 mmol) and 3,4,5-trimethoxy-benzoyl chloride (23 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=1
Reactant: CO
Reactant: CC(C)Oc1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(OC(C)C)cc1
Yield: 67 %

Procedure:
3.0 g of 4-isopropoxy-benzoic acid (16.7 mmol, 1.0 eq) were dissolved in MeOH (20 mL) and a catalytic quantity of sulfuric acid was added; the mixture was heated at reflux for 2 days. The solvent was then evaporated and the residue was dissolved in DCM and washed with 10% NaOH. The organic phases were dried and evaporated to give 2.2 g of title product (yield 67%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8]=1[S:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]([CH2:28][CH3:29])[CH2:25][CH:24]([C:30](OCC)=[O:31])[CH2:23]2.[OH-].[Na+]>O1CCCC1.O>[N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8]=1[S:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]([CH2:28][CH3:29])[CH2:25][CH:24]([CH2:30][OH:31])[CH2:23]2
Reactant: CCOC(=O)C1Cc2cccc(CSc3nc4ccccc4[nH]3)c2N(CC)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCN1CC(CO)Cc2cccc(CSc3nc4ccccc4[nH]3)c21
Yield: 78.3 %

Procedure:
To a suspension of lithium aluminium hydride (0.3 g) in tetrahydrofuran (50 ml) was added dropwise a solution of 8-(2-benzimidazolyl)thiomethyl-1-ethyl-3-ethoxycarbonyl-1,2,3,4-tetrahydroquinoline (1.0 g) in tetrahydrofuran (10 ml) with stirring under ice-cooling. The mixture was stirred for 3 hours at the same temperature. To the reaction mixture were added water (0.3 ml) and a solution of sodium hydroxide (0.3 g) in water (1.5 ml). After filtering off the precipitate, the filtrate was dried over anhydrous magnesium sulfate. After distilling off tetrahydrofuran, the resulting residue was recrystallized from ethanol to give 8-(2-benzimidazolyl)thiomethyl-1-ethyl-3-hydroxymethyl-1,2,3,4-tetrahydroquinoline (0.7 g).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[C:16]([F:17])=[CH:15][C:14]([Br:18])=[C:13]([F:19])[C:12]=2[F:20])[N:8]=[C:7]([C:21]([O:23]C)=[O:22])[C:6]=1[Cl:25])(=O)C.[OH-].[Na+].Cl>C1COCC1.CO.O>[NH2:4][C:5]1[CH:10]=[C:9]([C:11]2[C:16]([F:17])=[CH:15][C:14]([Br:18])=[C:13]([F:19])[C:12]=2[F:20])[N:8]=[C:7]([C:21]([OH:23])=[O:22])[C:6]=1[Cl:25]
Reactant: COC(=O)c1nc(-c2c(F)cc(Br)c(F)c2F)cc(NC(C)=O)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc(-c2c(F)cc(Br)c(F)c2F)nc(C(=O)O)c1Cl
Yield: 64.5 %

Procedure:
A solution of methyl 4-acetamido-6-(4-bromo-2,3,6-trifluorophenyl)-3-chloropicolinate (50 mg, 0.122 mmol, 1.0 eq) and sodium hydroxide (14 mg, 0.366 mmol, 3.0 eq) in THF:MeOH:H2O (1:1:0.5, 2.5 mL) was stirred at 20° C. for 2 h. The reaction mixture was acidified to pH 4-5 using 1.5 N HCl and extracted with EtOAc (2×). The combined organic extract was dried over anhydrous Na2SO4 and evaporated to dryness under reduced pressure to provide the title compound as a pale brown solid (30 mg, 65%).
Reaction SMILES: C([O:3][C:4](=[O:38])[C:5]([CH3:37])([C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:29])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:28])([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[C:16]([O:18]CC)=[O:17])C.[OH-].[K+]>O.C(O)C>[CH3:28][C:15]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)([CH2:14][CH2:13][CH2:12][CH2:11][C:10](=[O:29])[CH2:9][CH2:8][CH2:7][CH2:6][C:5]([CH3:37])([C:30]1[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=1)[C:4]([OH:38])=[O:3])[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)C(C)(CCCCC(=O)CCCCC(C)(C(=O)OCC)c1ccc(C)cc1)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(C)(CCCCC(=O)CCCCC(C)(C(=O)O)c2ccc(C)cc2)C(=O)O)cc1
Yield: 38.6 %

Procedure:
According to the procedure given for 210f, 209e (9.0 g, 17.2 mmol) was hydrolyzed with KOH (85%, 4.0 g, 60.6 mmol) in water (10 mL) and ethanol (30 mL) at reflux for 6 h. After the usual extractive workup, the crude material was purified by flash chromatography (silica gel; ethyl acetate/hexanes=1/10, 1/6, 1/2) to give 210e (3.1 g, 39%) as a white solid. Mp 48-50° C. 1H NMR (CDCl3): δ 10.8-8.8 (br., 2H), 7.22 (d, 4H, J=8.1), 7.12 (d, 4H, J=8.1), 2.36 (t, 4H, J=7.5), 2.31 (s, 6H), 1.98-1.80 (m, 4H), 1.56-1.44 (m, 4H), 1.51 (s, 6H), 1.24-1.15 (m, 4H). 13C NMR (CDCl3): δ 211.63, 183.07, 140.40, 137.00, 129.58, 126.43, 50.02, 42.82, 39.10, 24.74, 24.50, 22.82, 21.39. HRMS (LSIMS, gly): Calcd for C29H39O5 (MH+): 467.2797, found: 467.2785. HPLC: 92.4% pure. Anal. (C29H38O5) C, H.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:19])([CH3:18])[CH2:10]/[CH:11]=[CH:12]/[C:13]([O:15]CC)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCOCC1.O>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:19])([CH3:18])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.1 %

Procedure:
Ethyl (2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoate (1.233 g, 4.54 mmol) was dissolved in dioxane (20 ml). Lithium hydroxide (0.120 g, 5.00 mmol) was added as a solid. Water (10 ml) was added, until a clear solution was reached. The solution was stirred 16 h at room temperature. The solution was diluted with water (70 ml) and was extracted with tert-butyl methyl ether (2×100 ml). The aqueous phase was acidified with 1N sodium hydrogensulfate solution (pH=1) and was extracted with tert-butylmethylether (3×70 ml). The organic phases were combined and dried over magnesium sulfate. The solvent was removed in vacuo to give 1.05 g of (2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoic acid. The crude product was used for further syntheses.
Reaction SMILES: CO[C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:7][N:6]=1)=[O:4].[NH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:30])[CH3:29].CC(O)=O.O>CCO.CCOC(C)=O>[C:28]([NH:27][CH2:26][CH2:25][NH:24][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:7][N:6]=1)=[O:4])(=[O:30])[CH3:29]
Reactant: CC(=O)NCCN
Reactant: COC(=O)c1ncc2ccc(=O)n(Cc3ccccc3)c2c1O
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)NCCNC(=O)c1ncc2ccc(=O)n(Cc3ccccc3)c2c1O
Temperature: 25 °C
Yield: 64.7 %

Procedure:
A mixture of 1-benzyl-8-hydroxy-2-oxo-1,2-dihydro-[1,6]naphthyridine-7-carboxylic acid methyl ester (20 mg, 0.065 mmol) and N-(2-amino-ethyl)-acetamide (20 mg, 0.19 mmol) in EtOH (3 mL) was refluxed for 16 h. After cooling to r.t., AcOH (0.1 mL), water (15 mL) and EtOAc (20 mL) were added. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4, and concentrated. The crude product was purified by silica gel chromatography (0-7% MeOH/CH2Cl2) to give 16 mg of the title compound as a light yellow solid. MS: (+) m/z 381.34 (M+1).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[SH:19][C:20]1[N:25]2[N:26]=[CH:27][CH:28]=[C:24]2[N:23]=[C:22]([C:29]2[CH:30]=[C:31]([OH:36])[C:32](=[CH:34][CH:35]=2)[OH:33])[CH:21]=1.B(F)(F)F.CCOCC.O>S1(CCCC1)(=O)=O.ClCCl>[NH2:13][C@@H:10]1[C:11](=[O:12])[N:8]2[C@@H:9]1[S:14][CH2:15][C:6]([CH2:5][S:19][C:20]1[N:25]3[N:26]=[CH:27][CH:28]=[C:24]3[N:23]=[C:22]([C:29]3[CH:35]=[CH:34][C:32]([OH:33])=[C:31]([OH:36])[CH:30]=3)[CH:21]=1)=[C:7]2[C:16]([OH:18])=[O:17]
Reactant: Oc1ccc(-c2cc(S)n3nccc3n2)cc1O
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3cc(-c4ccc(O)c(O)c4)nc4ccnn34)CS[C@H]12
Temperature: 25 °C
Reaction time: 5 h
Yield: 74.3 %

Procedure:
7-Aminocephalosporanic acid (272 mg) and 272 mg of the above 4-(7-mercaptopyrazolo[1,5-a]pyrimidin-5-yl)pyrocatechol are suspended in a mixture of 2 ml of sulpholane and 2 ml of dichloromethane. 0.75 ml of boron trifluoride etherate is added thereto and the mixture is stirred at 25° C. for 5 hours. Thereafter, it is treated with 20 ml of water, the aqueous phase is separated, its pH is adjusted to 3.5 using concentrated aqueous amonia solution and the precipitated product is filtered off under suction, washed with water, methanol and finally with diethyl ether and dried at 0.1 mmHg and 40° C. There are obtained 350 mg of (6R,7R)-7-amino-3-[[[5-(3,4-dihydroxyphenyl)pyrazolo[1,5-a]pyrimidin-7yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH:6]([S:9]([CH2:12][C:13](=[O:15])[CH3:14])(=[O:11])=[O:10])([CH3:8])[CH3:7]>CC(O)=O.C(Cl)Cl>[Cl:4][CH:12]([S:9]([CH:6]([CH3:8])[CH3:7])(=[O:11])=[O:10])[C:13](=[O:15])[CH3:14]
Reactant: CC(=O)CS(=O)(=O)C(C)C
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)C(Cl)S(=O)(=O)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 157.9 %

Procedure:
Sulfuryl chloride (0.248 mL, 3.05 mmol) was added dropwise to a solution of 1-(isopropylsulfonyl)propan-2-one (418 mg, 2.55 mmol) in 1:1 AcOH/DCM (16 ml) at 0° C. The reaction was stirred at rt for 4 h. The solvent was removed in vacuo, then diluted with dichloromethane. The organic layer was washed (2×) with saturated NaHCO3 solution, dried over Na2SO4, filtered, and concentrated to leave 800 mg of a colorless oil. The material was used without further purification.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH:4]([CH3:6])[CH3:5].[Li]CCCC.[C:31]([N:38]1[C@@H:43]([CH:44]=O)[CH2:42][CH2:41][CH2:40][C@@H:39]1[CH3:46])([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].CCOC(C)=O.CCCCCC>C1COCC1.O>[C:31]([N:38]1[C@@H:39]([CH3:46])[CH2:40][CH2:41][CH2:42][C@@H:43]1[CH:44]=[CH:2][CH2:3][CH:4]([CH3:6])[CH3:5])([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]
Reactant: CC(C)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@H]1CCC[C@H](C=O)N1C(=O)OC(C)(C)C
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)CC=C[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
A suspension of isoamyltriphenylphosphonium bromide (10.95 g, 26.5 mmol) in 42 mL of THF was cooled to −30° C. and treated with n-BuLi (11.9 mL, 26.88 mmol) dropwise. The deep red solution was slowly warmed to 0° C., stirred for 30 min, and then cooled to −78° C. The ylide was treated with a solution of trans-N-Boc-2-Methyl-6-Piperidinecarboxaldehyde (4.00 g, 18.93 mmol) in 6 mL of THF, and the mixture was slowly warmed to room temperature. The mixture was diluted with water, and the organic layer was separated. The aqueous layer was extracted with ether and the combined extracts were dried over K2CO3 and then concentrated to give a crude product as an oil. Chromatography on silica with 5% EtOAc/hexane afforded 2.8 g (56%) of the product which was homogeneous by TLC analysis. 1H NMR (250 MHz) δ 5.53-5.32 (m, 2H), 4.56-4.51 (m, 1H), 4.04-4.02 (m, 1H), 1.99-1.37 (m, 18H), 1.23-1.18 (d, 3H), 0.91-0.84 (d, 6H); 13C NMR (62.7 MHz) 155.5 (s), 132.8 (s), 128.2 (s), 78.9 (s), 49.1 (s), 47.6 (s), 36.4 (s), 28.6 (s), 28.5 (s), 28.0 (s), 27.9 (s), 26.3 (s), 25.6 (s), 22.5 (s), 22.4 (s), 20.7 (s), 20.2 (s), 15.2 (s), 13.6 (s) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:27](=[CH:28][CH:29]=1)[C:8]1[NH:9][C:10]([C@@H:12]3[CH2:16][C@H:15]([CH2:17][O:18][CH3:19])[CH2:14][N:13]3[C:20](OC(C)(C)C)=[O:21])=[N:11][C:7]=1[CH:6]=[CH:5]2.Cl.[CH3:31][O:32][C:33]([NH:35][CH:36]([CH:40]([CH3:42])[CH3:41])C(O)=O)=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:27](=[CH:28][CH:29]=1)[C:8]1[NH:9][C:10]([C@@H:12]3[CH2:16][C@H:15]([CH2:17][O:18][CH3:19])[CH2:14][N:13]3[C:20](=[O:21])[C@@H:36]([NH:35][C:33](=[O:34])[O:32][CH3:31])[CH:40]([CH3:42])[CH3:41])=[N:11][C:7]=1[CH:6]=[CH:5]2
Reactant: COC[C@H]1C[C@@H](c2nc3ccc4cc(Br)ccc4c3[nH]2)N(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)NC(C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
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: COC[C@H]1C[C@@H](c2nc3ccc4cc(Br)ccc4c3[nH]2)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
(2S,4S)-tert-butyl 2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (526 mg, 1.14 mmol) was dissolved in DCM (15 mL) and HCl (4 M in dioxane, 3 mL, 12 mmol) was added. The reaction mixture was stirred for 2 h and then concentrated under reduced pressure. The crude residue was treated with (methoxycarbonylamino)-3-methylbutanoic acid (220 mg, 1.25 mmol), HATU (433 mg, 1.14 mmol) and DMF (11 mL), then cooled to 0° C. DIPEA (0.99 mL, 5.7 mmol) was added dropwise and the reaction mixture was immediately warmed to RT. After 45 min at RT, the mixture was diluted with EtOAc (100 mL) and washed successively with saturated aqueous NaHCO3, water and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (0% to 33% MeOH/EtOAc) to afford methyl (S)-1-((2S,4S)-2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (584 mg, 99%).