Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:8]2)=[O:4].[NH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40].C[O-].[Na+]>>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:35])[C:5]([C:3]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:4])=[N:14][C:13]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=[C:9]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:10]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(-c2ccccc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2ccccc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 92.4 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3,8-diphenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (23 mg, 0.050 mmol), β-alanine (444 mg, 5.0 mmol) and NaOMe solution (8 mL, 3.7 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH about 2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-60% EtOAc/hexanes+2% AcOH) to give 24 mg of the title compound as a yellow solid. MS: (+) m/z 520.34 (M+1).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:19])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][Si](C)(C)C)=[CH:9][CH:8]=1)[CH3:6])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[CH2:1]([NH:3][C:4](=[O:19])[CH:5]([C:7]1[CH:8]=[CH:9][C:10]([C:13]#[CH:14])=[CH:11][CH:12]=1)[CH3:6])[CH3:2]
Reactant: CCNC(=O)C(C)c1ccc(C#C[Si](C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1ccc(C(C)C(=O)NCC)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To 9.73 g (35.6 mmol) N-ethyl-2-(4-trimethylsilanylethynyl-phenyl)-propionamide (XVI.1) in 400 mL THF, an aqueous solution of 24.81 g (71.2 mmol) tetra-n-butyl-ammonium fluoride (75%) is added. The mixture is stirred at rt for 45 min. After that time, water is added and the mixture is extracted with EtOAc twice. The combined organic layers are washed with brine and dried over sodium sulphate. The solvent is evaporated and the residue is purified by column chromatography (silicia gel; EtOAc/heptane, gradient 50% to 80%) to yield the desired product.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=[C:11]2[C:31]2[CH:32]=[N:33][C:34]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:35][C:36]=2[O:37][CH2:38][CH3:39])=[O:9])[CH2:4][CH2:3]1.[CH:44]1[CH:49]=[N:48][CH:47]=[C:46]([N:50]=[C:51]=[O:52])[CH:45]=1>>[C:40]([C:34]1[N:33]=[CH:32][C:31]([C:11]2[N:10]([C:8]([N:5]3[CH2:4][CH2:3][CH:2]([NH:1][C:51]([NH:50][C:46]4[CH:47]=[N:48][CH:49]=[CH:44][CH:45]=4)=[O:52])[CH2:7][CH2:6]3)=[O:9])[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=2)=[C:36]([O:37][CH2:38][CH3:39])[CH:35]=1)([CH3:42])([CH3:41])[CH3:43]
Reactant: O=C=Nc1cccnc1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(NC(=O)Nc2cccnc2)CC1

Procedure:
In a manner similar to the method described in example 160, (4-Amino-piperidin-1-yl)-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-methanone (example 204) was reacted with pyridine-3-isocyanate (Oakwood Products) to give the title compound. HR-MS (ES, m/z) calculated for C40H46Cl2N7O3 [(M+H)+] 742.3034, observed 742.3029.
Reaction SMILES: [O:1]=[C:2]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[BH4-].[Na+]>C(O)C>[OH:1][CH:2]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(=O)c1cccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(O)c1cccs1
Temperature: 25 °C
Yield: 91 %

Procedure:
A solution of ethyl 2-oxo-2-(thiophen-2-yl)acetate (5.00 g, 27.1 mmol) in ethanol (50 ml) was cooled at 0° C. with an ice bath. NaBH4 (0.31 g, 8.14 mmol) was added in four portions under stirring. The mixture was stirred at 0° C. for 10 minutes, then allowed to warm at room temperature and stirred for additional 30 minutes. The reaction mixture was concentrated under vacuum and the residue was partitioned between Et2O and ice-cooled water. The organic layer was separated, washed with water and brine, dried over Na2SO4, filtered and evaporated (5.05 g, 91% yield).
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:16][CH2:17][CH2:18][CH2:19]Cl)[C:13]([NH:14][CH3:15])=[C:9]2[C:8](=[O:21])[N:7]([CH2:22][CH2:23][CH3:24])[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4].[H-].[Na+]>CN(C=O)C>[CH2:1]([N:5]1[C:10]2=[N:11][N:12]3[CH2:16][CH2:17][CH2:18][CH2:19][N:14]([CH3:15])[C:13]3=[C:9]2[C:8](=[O:21])[N:7]([CH2:22][CH2:23][CH3:24])[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)n(CCC)c(=O)c2c(NC)n(CCCCCl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(CCC)c(=O)c2c3n(nc21)CCCCN3C
Temperature: 25 °C
Reaction time: 5 h
Yield: 66.6 %

Procedure:
To a stirred solution of 7-butyl-2-(4-chlorobutyl)-3-methylamino-5-propyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione(2.0 g) in DMF(30 ml) was added sodium hydride(60% oil, 0.65 g) in portions under ice-cooling. The mixture was stirred at room temperature for further 5 hours. The reaction mixture was concentrated to dryness and was added to ice-water, followed by neutralizing with 1N-HCl and extraction with chloroform. The chloroform layer was washed with water, dried and concentrated to dryness to give a syrupy product. The product was purified by flash chromatography(silica gel, chloroform) to give crystals, which recrystallized from isopropyl ether/hexane to afford colorless crystals(1.2 g, 67%), m.p. 63°-65° C.
Reaction SMILES: [C:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]2[CH:15]=[N:16][C:17]([C:18](OCC)=[O:19])=[C:7]2[C:6]1=[O:23])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27].[H-].[Na+].C(O)(=O)C>O1CCCC1>[C:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]2[CH:15]=[N:16][C:17]([C:18](=[O:19])[CH2:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[C:7]2[C:6]1=[O:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)C(C)(C)C
Reactant: CCOC(=O)c1ncn2c1c(=O)n(C(C)(C)C)c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)CC(=O)c1ncn2c1c(=O)n(C(C)(C)C)c1ccccc12

Procedure:
To a stirred mixture of ethyl 5-tert-butyl-4,5-dihydro-4-oxo-imidazo[1,5-a]quinoxaline-3-carboxylate (1.6 g, 5 mmol) and pinacolone (1.25 ml, 10 mmol) in dry tetrahydrofuran (THF) (30 ml) was added sodium hydride (200 mg, 80% in mineral oil, 6.9 mmol). The mixture was brought to reflux for 2 h, then cooled to room temperature and neutralized with acetic acid. After evaporation of the solvent the residue was partitioned between sat. aqueous NaHCO3 (10 ml) and methylene chloride (30 ml). The organic phase was dried over Na2SO4 and evaporated to give the title compound as yellow crystals. M.p. 190°-191 ° C. (Compound 1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[CH3:10][NH2:11]>CO>[Cl:1][C:2]1[N:7]=[C:6]([NH:11][CH3:10])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CN
Solvent: CO
Product: CNc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a cooled (0° C.) solution of 2,4,5-trichloropyrimidine (2.0 g, 11 mmol) in methanol (30 mL) was added dropwise a 2 M solution of methylamine in methanol (6.3 mL). The reaction was allowed to warm to room temperature and stirred overnight. The reaction was then concentrated and redissolved in DCM. The solution was washed with sat. NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (0-40% EtOAc in heptane) to give 2,5-dichloro-N-methylpyrimidin-4-amine (0.9 g, 50%). 1H-NMR (DMSO): δ 8.13 (s, 1H), 7.89 (s, 1H), 2.86 (d, J=4.5, 3H).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:21].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](Cl)=[O:31])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([NH:1][N:2]2[N:11]=[C:10]([S:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:21])=[O:31])=[CH:25][CH:24]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: Nn1nc(S(=O)(=O)c2ccccc2)c2ccccc2c1=O
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(S(=O)(=O)c2ccccc2)c2ccccc2c1=O

Procedure:
The product from Example 68B and (4-chlorophenyl)acetyl chloride were processed using a method similar to that described in Example 4C to afford the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 8.67-8.69 (m, 1H), 8.43 (d, J=8.0 Hz, 1H), 8.22-8.24 (bs, 1H), 8.00-8.04 (m, 2H), 7.90-7.97 (m, 1H), 7.82-7.87 (m, 1H), 7.66-7.70 (m, 1H), 7.54-7.58 (m, 2H), 7.33-7.36 (m, 2H), 7.24-7.30 (m, 2H), 3.71-3.74 (bs, 2H); MS (APCI+) M/Z 454 (M+H)+.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:20]1([C:26]2[S:27][C:28]([C:31]#[N:32])=[CH:29][N:30]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:8]=2[C:9]([N:23]2[CH2:24][CH2:25][N:20]([C:26]3[S:27][C:28]([C:31]#[N:32])=[CH:29][N:30]=3)[CH2:21][CH2:22]2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N#Cc1cnc(N2CCNCC2)s1
Reactant: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)N2CCN(c3ncc(C#N)s3)CC2)c1
Yield: 64 %

Procedure:
Prepared in analogy to example 1 (b) from 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (Example A4) and 2-piperazin-1-yl-thiazole-5-carbonitrile (Example 6(a)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as an off-white crystalline solid (yield 64%). MS (m/e): 461.3 (M+H+, 100%).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([I:9])[CH:5]=[CH:4][N:3]=1.O.[NH2:11][NH2:12].[NH4+].[OH-]>O1CCOCC1.CCO>[Cl:8][C:7]1[C:2]([NH:11][NH2:12])=[N:3][CH:4]=[CH:5][C:6]=1[I:9]
Reactant: NN
Reactant: Clc1nccc(I)c1Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: NNc1nccc(I)c1Cl
Temperature: 80 °C
Yield: 33.9 %

Procedure:
To a solution of intermediate compound D6 (8 g, 29.21 mmol) in 1,4-dioxane (450 ml), was added hydrazine monohydrate (14.169 ml, 175.255 mmol). The reaction mixture was heated in a sealed tube at 80° C. for 16 h. After cooling, NH4OH (32% aqueous solution) was added to the reaction mixture, which was then concentrated in vacuo. The white solid residue thus obtained was taken up in EtOH and heated. The suspension thus obtained was allowed to cool down and the precipitate obtained was filtered off, washed with EtOH and dried in the desiccator to yield intermediate compound D7 (2.67 g, 52%) as a white solid
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2].I(O)(=O)(=O)=[O:14].C(Cl)Cl.O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.[Fe](Cl)(Cl)Cl>[CH2:1]([S:3]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=[O:14])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])O
Reactant: CCSc1ccc([N+](=O)[O-])cc1
Agent: Cl[Fe](Cl)Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: CCS(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
428 mg (2.64 mmol) of iron(III) chloride was added to a mixture of 16.86 g (92.02 mmol) of 1-ethylsulfanyl-4-nitrobenzene in 75 ml acetonitrile and it was stirred for 10 minutes at room temperature. Then 22.44 g (98.44 mmol) of periodic acid was added in portions, so that the temperature did not exceed 30° C. The mixture was stirred for 50 minutes and was then added, with stirring, to a mixture of 170 ml DCM, 500 ml ice water and 100 g sodium thiosulfate pentahydrate. It was extracted with DCM (2×). The combined organic phases were dried (Na2SO4), filtered and concentrated by evaporation. The residue obtained was recrystallized from ethyl acetate/hexane. 12.49 g (62.69 mmol; yield: 68%) of the product was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([N+:15]([O-])=O)[C:13]=2[NH2:14])[CH:5]=[N:6][CH:7]=1>CCO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([NH2:15])[C:13]=2[NH2:14])[CH:5]=[N:6][CH:7]=1
Reactant: Nc1c(-c2cncc(F)c2)cncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1cncc(-c2cncc(F)c2)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 5′-fluoro-5-nitro-3,3′-bipyridin-4-amine (LXXI) (621 mg, 2.65 mmol) in EtOH (18 mL) was added 10% Pd/C (93 mg, 15% by wt). The solution was purged with hydrogen and stirred for overnight at room temperature under hydrogen. The suspension was filtered through Celite and concentrated under vacuum. The crude product was purified through a silica gel column (100% CHCl3→3:97MeOH[7N NH3]:CHCl3) to produce 5′-fluoro-3,3′-bipyridine-4,5-diamine (LXII) as an off-white solid (542 mg, 2.65 mmol, 100% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 4.78 (brs, 2H), 5.28 (brs, 2H), 7.46 (s, 1H), 7.70 (s, 1H), 7.73-7.76 (m, 1H), 8.44-8.45 (m, 1H), 8.56 (d, J=2.8 Hz, 1H); ESIMS found C10H9FN4 m/z 205 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:43]/[OH:44])/[C:8]([NH:10][C@@H:11]2[C:41](=[O:42])[N:13]3[C:14]([C:25]([O:27]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:26])=[C:15]([S:18][CH2:19][C:20]4[CH:21]=[N:22][NH:23][CH:24]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.FC(F)(F)C(O)=O>ClCCl.C1(OC)C=CC=CC=1>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:43]/[OH:44])/[C:8]([NH:10][C@@H:11]2[C:41](=[O:42])[N:13]3[C:14]([C:25]([OH:27])=[O:26])=[C:15]([S:18][CH2:19][C:20]4[CH:21]=[N:22][NH:23][CH:24]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(SCc4cn[nH]c4)CS[C@H]23)cs1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(SCc4cn[nH]c4)CS[C@H]23)cs1
Reaction time: 0.42 h
Yield: 39 %

Procedure:
Under nitrogen atmosphere, diphenylmethyl 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(hydroxyimino)acetamido]-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylate (33.5 g) was suspended in dichloromethane (100 ml) and anisole (35 ml). Trifluoroacetic acid (80 ml) added dropwise below 5° C. for 40 minutes. After stirring below 5° C. for 25 minutes, the reaction mixture was poured into IPE (1.8 l). Resulting precipitate was collected by filtration and dried under reduced pressure. The powder was poured into pH 6.86 buffer (550 ml). The suspension was adjusted to pH 6.9 with 2N-potassium hydroxide, then was stirred at 15° C. until insoluble material disappeared. The solution was subjected to column chromatography on HP-20 (700 ml). The column was washed with water (1.4 l) and the object compound was eluted with 25% aqueous 2-propanol. The active fractions were collected, and adjusted to pH 3.5 with 3N-hydrochloric acid. After stirring at 30° C. for 2 hours, resulting precipitate was filtered and washed with water (50 ml) two times. The precipitate was suspended in water (150 ml), and adjusted to pH 2.0 with 1N-hydrochloric acid. After stirring at room temperature for one hour, the precipitate was collected and washed with water (20 ml). The precipitate was suspended in water (150 ml) again, and then adjusted to pH 2.0 with 1N hydrochloric acid. After stirring at room temperature for one hour, it was adjusted to pH 2.8 with 2N potassium hydroxide. After stirring at the same temperature for 30 minutes, the precipitate was collected, washed with water (20 ml), and dried under reduced pressure to afford 3.75 hydrates of 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(hydroxyimino)acetamido]-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylic acid as crystal (9.7 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[O:6][C@H:5]2[C@H:7]([NH:12][C:13]3[N:18]4[N:19]=[C:20](B5OC(C)(C)C(C)(C)O5)[CH:21]=[C:17]4[N:16]=[CH:15][CH:14]=3)[CH2:8][C@H:9]([CH2:10][OH:11])[C@H:4]2[O:3]1.[Cl:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36](I)=[CH:35][CH:34]=1.ClCCl.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]([C:20]2[CH:21]=[C:17]3[N:16]=[CH:15][CH:14]=[C:13]([NH:12][C@H:7]4[C@@H:5]5[O:6][C:2]([CH3:1])([CH3:31])[O:3][C@@H:4]5[C@@H:9]([CH2:10][OH:11])[CH2:8]4)[N:18]3[N:19]=2)=[CH:35][CH:34]=1
Reactant: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](Nc3ccnc4cc(B5OC(C)(C)C(C)(C)O5)nn34)[C@@H]2O1
Reactant: Clc1ccc(I)c2ccccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](Nc3ccnc4cc(-c5ccc(Cl)c6ccccc56)nn34)[C@@H]2O1
Temperature: 110 °C
Yield: 166.9 %

Procedure:
A microwave vial is charged with ((3aR,4R,6R,6aS)-2,2-dimethyl-6-{[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol (0.25 g, 0.58 mmol), 1-chloro-4-iodo-naphthalene (0.38 g, 1.30 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (29 mg, 0.036 mmol), cesium carbonate (0.70 g, 2.2 mmol) 1,4-dioxane (4.0 mL, 50 mmol) and water (0.60 mL, 30 mmol). The reaction mixture is heated in the microwave at 110° C. for 30 minutes and then cooled to room temperature. The reaction mixture is diluted with ethyl acetate and was washed successively with water, saturated sodium bicarbonate solution and brine. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The crude material is purified by column chromatography (0-80% ethyl actate/hexanes) to provide (s.e.)-[(3aR,4R,6R,6aS)-6-{[2-(4-chloro-1-naphthyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methanol (0.450 g, yield 167%). LCMS: (AA) M+1 465.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20]I)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26]CC)=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[F:35][C:36]1[CH:37]=[CH:38][C:39]([O:44][C@H:45]([CH2:47][CH:48]=[CH2:49])[CH3:46])=[C:40]([CH2:42][OH:43])[CH:41]=1.[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:4][C:5]1([CH3:34])[CH2:6][CH2:7][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:43][CH2:42][C:40]4[CH:41]=[C:36]([F:35])[CH:37]=[CH:38][C:39]=4[O:44][C@H:45]([CH2:47][CH:48]=[CH2:49])[CH3:46])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[C:24]([OH:26])=[O:25])[CH2:9][CH2:10]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Reactant: C=CC[C@H](C)Oc1ccc(F)cc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)O)c(C)nc3cc(COCc4cc(F)ccc4O[C@@H](C)CC=C)nn23)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 36 %

Procedure:
To a solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.05 g, 0.086 mmol) and (S)-(5-fluoro-2-(pent-4-en-2-yloxy)phenyl)methanol (0.022 g, 0.103 mmol) in DMF (1 ml) was added sodium hydride (5.13 mg, 0.128 mmol) and the resulting yellow mixture was stirred at rt. After 5 h, the mixture was diluted with EtOAc and washed with 1N HCl followed by water and brine. The organic phase was dried (Na2SO4), filtered and concentrated. The oil was purified by flash chromatography (Biotage; 0%-10% MeOH/DCM; 10 CV) to give (S)-2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((5-fluoro-2-((S)-pent-4-en-2-yloxy)benzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetic acid (20 mg, 0.031 mmol, 36.6% yield) was obtained as an amber oil. 1H NMR (400 MHz, CDCl3) δ 7.22 (dd, J=9.0, 2.9 Hz, 1H), 6.89 (dd, J=8.1, 3.2 Hz, 1H), 6.84-6.75 (m, 1H), 6.60 (s, 1H), 6.10-5.95 (m, 1H), 5.89-5.75 (m, 1H), 5.52-5.38 (m, 1H), 5.23-4.99 (m, 4H), 4.80 (s, 2H), 4.66 (s, 2H), 4.45-4.28 (m, 1H), 4.06-3.93 (m, 2H), 2.71-2.54 (m, 3H), 2.47 (d, J=5.9 Hz, 1H), 2.40-2.30 (m, 1H), 2.08-1.56 (m, 4H), 1.49-1.01 (m, 15H). LCMS (M+H) calcd for C35H48FN4O6: 639.35. found: 639.2.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:14][C@@H:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12](=[O:22])[O:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:23][CH2:24][CH:25]1[CH2:29][O:28][C:27]([CH3:31])([CH3:30])[O:26]1>C1(C)C=CC=CC=1>[CH3:30][C:27]1([CH3:31])[O:26][CH:25]([CH2:24][O:23][C:9]([C@H:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:14][C@@H:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([OH:11])=[O:22])=[O:10])[CH2:29][O:28]1
Reactant: CC1(C)OCC(CO)O1
Reactant: O=C1OC(=O)[C@H](Cc2ccccc2)C[C@H]1Cc1ccccc1
Solvent: Cc1ccccc1
Product: CC1(C)OCC(COC(=O)[C@H](Cc2ccccc2)C[C@@H](Cc2ccccc2)C(=O)O)O1

Procedure:
A solution of 1.0 g of (S,S)-2,4-dibenzylglutaric anhydride and 0.54 g of 4-hydroxymethyl-2,2-dimethyl-1,3-dioxolane in 10 ml of toluene is refluxed overnight. The solution is washed with water, dried (Na2SO4), filtered and concentrated to give 4-[(2,2-dimethyl-1,3-dioxolan-4-yl)-methoxycarbonyl]-(S,S)-2,4-dibenzylbutyric acid as a viscous oil.