Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[OH:10].O.O=O>Cl[Pd]Cl.Cl[Cu].CCCCCC>[C:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:10])[CH3:1]
Reactant: C=Cc1ccccc1
Reactant: CO
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Agent: O=O
Solvent: O
Solvent: CCCCCC
Product: CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
Wacker-Tsuji oxidation of styrene in a PDMS thimble. A PDMS thimble containing PdCl2 (0.025 g, 0.141 mmol) and CuCl (0.282 g, 2.82 mmol) was placed in a 2-necked Schlenk flask with a stir bar. MeOH (1.98 mL) and H2O (0.28 mL) were added to the inside of the PDMS thimble and the flask was capped with a rubber septum. A balloon filled with O2 was affixed to the septum and the reaction mixture was stirred at room temperature for 1 hour. Styrene (0.323 mL, 2.82 mmol) was added to the reaction mixture and allowed to stir under an O2 atmosphere for 24 hours. The PDMS thimble was swelled with hexane (2×25 mL) for 12 hours with a stir bar on the exterior of the PDMS thimble. The hexane extracts were combined and the solvent was removed in vacuo. A 1H NMR spectrograph was recorded in CDCl3 to determine quantitative conversion of the styrene to the following products: 89% ketone, 1% aldehyde, 8% acetal, and 2% ketal. Acetophenone (0.249 g, 73% yield) was isolated as a clear liquid by column chromatography using hexanes/EtOAc (95/5). NMR spectra matched those reported in the literature.13 1H NMR (300 MHz, CDCl3, δ): 7.94 (m, 2H), 7.54 (m, 1H), 7.45 (m, 2H), 2.58 (s, 3H). 13C NMR (75.48 MHz; CDCl3, δ): 197.9, 137.0, 132.9, 128.4, 128.1 and 26.4.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][NH:15][C:16]([NH:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][N:27]=4)[N:22]=[CH:21][CH:20]=3)=O)[CH:9]=2)[C@H:3]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[N:22]1[C:23]2[C:28](=[N:27][CH:26]=[CH:25][CH:24]=2)[C:19]([NH:18][C:16]2[N:11]3[CH:12]=[CH:13][C:8]([N:4]4[C@@H:3]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:2]([CH3:35])([CH3:1])[O:6][C:5]4=[O:7])=[CH:9][C:10]3=[N:14][N:15]=2)=[CH:20][CH:21]=1
Reactant: CC1(C)OC(=O)N(c2ccnc(NNC(=O)Nc3ccnc4cccnc34)c2)[C@H]1c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC1(C)OC(=O)N(c2ccn3c(Nc4ccnc5cccnc45)nnc3c2)[C@H]1c1ccccc1
Reaction time: 1 h
Yield: 1.7 %

Procedure:
A mixture of (S)-2-(4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)pyridin-2-yl)-N-(1,5-naphthyridin-4-yl)hydrazinecarboxamide (150 mg, 0.319 mmol) and POCl3 (292 μL, 3.19 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.) in toluene (6.390 mL) was heated at 100° C. After stirring for 1 hour, an additional 1.5 mL of POCl3 was added to the reaction solution. After stirring for another 3 hours, the reaction mixture was concentrated under reduced pressure. The residue thus obtained was purified by reverse-phase preparative HPLC using 0.1% TFA in ACN/H2O, gradient 20% to 90% over 20 minutes to provide a material which was further purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 10% MeOH in DCM, to provide (S)-3-(3-((1,5-naphthyridin-4-yl)amino)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-5,5-dimethyl-4-phenyloxazolidin-2-one (2.41 mg, 5.34 μmol, 1.671% yield) as greenish solid. 1H NMR (500 MHz, DMSO-d6) δ 10.06-10.13 (m, 1H), 8.95-9.00 (m, 1H), 8.64 (br. s, 1H), 8.34-8.39 (m, 1H), 8.28 (d, J=6.09 Hz, 1H), 7.81-7.87 (m, 1H), 7.55 (d, J=9.62 Hz, 1H), 7.46-7.51 (m, 1H), 7.38-7.44 (m, 3H), 7.31-7.37 (m, 3H), 5.63 (s, 1H), 1.67 (s, 3H), 0.95 (s, 3H). m/z (ESI) 452.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH2:11][C:10]([C:32]([C:38]([F:41])([F:40])[F:39])([C:34]([F:37])([F:36])[F:35])[OH:33])=[N:9]1.Cl>C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[CH:14]=[CH:15][C:16]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:17][CH:18]=2)[CH2:11][C:10]([C:32]([C:34]([F:36])([F:35])[F:37])([C:38]([F:41])([F:40])[F:39])[OH:33])=[N:9]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: OC(C1=NN(c2ccccc2Cl)C(c2ccc(N3CCNCC3)cc2)C1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 207.1 %

Procedure:
1-(2-Chloro-phenyl)-5-[4-(4-BOC-piperazin-1-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (480.0 mg, 0.8 mmol) prepared in Example 311 was added to a saturated solution of hydrochloric acid in ethyl acetate (5.0 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give 450.0 mg of the titled compound as a pale yellow solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:14][C:15]([F:22])([F:21])[C:16](B(O)O)=[CH2:17].[Cl-].[NH4+]>O1CCOCC1>[F:14][C:15]([F:22])([F:21])[C:16]([C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)=[CH2:17]
Reactant: C=C(B(O)O)C(F)(F)F
Reactant: Ic1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1COCCO1
Product: C=C(c1ccncc1)C(F)(F)F
Temperature: 110 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
To 1,4-dioxane were added 3.22 g of 4-iodopyridine, 10.87 g of potassium carbonate, 0.036 g of tetrakis(triphenylphosphinepalladium) and 5.5 g of 1-(trifluoromethyl)vinylboronic acid, and the mixture was stirred at 110° C. for 8 hours. Thereafter, this solution was poured into an aqueous saturated ammonium chloride solution, followed by extraction with diethyl ether three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 2.0 g of 4-[1-(trifluoromethyl)ethenyl]pyridine.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](N)=[O:8])=[CH:5][CH:4]=1)#[N:2].Cl.[CH3:13][OH:14]>CO>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:14][CH3:13])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: CO
Reactant: N#Cc1ccc(C(N)=O)cc1
Agent: Cl
Product: COC(=O)c1ccc(C#N)cc1
Yield: 93.9 %

Procedure:
p-Cyanobenzamide (73.0 g, 0.5 mol) which has a purity of 99% or more and methanol (460.3 g) were placed in a 2 l-separable flask, and the mixture was allowed to react at 64° C. for 12 hours while a 20% hydrochloric acid/methanol solution (162.4 g) prepared in advance was added thereto with stirring. Gas chromatographic analysis revealed that the reaction mixture contained 75.7 g of methyl p-cyanobenzoate (yield 94%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:18])[C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])[CH:3]=1.[NH2:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=1[C:9]([NH:8][C:4]1[N:5]=[CH:6][N:7]=[C:2]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:29][CH:30]=2)[CH:3]=1)=[O:18]
Reactant: O=C(Nc1cc(Cl)ncn1)c1c(Cl)cccc1Cl
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCOC(=O)c1ccc(Nc2cc(NC(=O)c3c(Cl)cccc3Cl)ncn2)cc1
Temperature: 130 °C
Yield: 64.7 %

Procedure:
A mixture of N-(6-chloropyrimidin-4-yl)-2,6-dichlorobenzamide (302 mg, 1.0 mmol), ethyl 4-aminobenzoate (0.33 g, 2.0 mmol), Pd2(dba)3 (0.1 mmole, 92 mg), 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.15 mmol, 87 mg) and cesium carbonate (2.0 mmoles; 652 mg) in a microwave tube was evacuated, back-filled with N2 (2×). 1,4-Dioxane (10 mL) was then added. The tube was sealed, and heated at 130° C. in microwave for 15 min. The mixture was filtered through Celite using EtOAc to rinse. The combined filtrates were concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-50% EtOAc/hexane) to afford ethyl 4-(6-(2,6-dichlorobenzamido)pyrimidin-4-ylamino)benzoate as an off-white solid (0.279 g, yield: 65%). LCMS (ESI) m/z: 431.0 [M+H+].
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([CH2:22][O:23][CH3:24])[CH2:20]O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].ClCCCS([NH:32]CC(OC)CSCCCCCCCCCCCCCCCC)(=O)=O.C1(=O)NC(=O)C2=CC=CC=C12>>[CH2:1]([S:17][CH2:18][CH:19]([CH2:22][O:23][CH3:24])[CH2:20][NH2:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Reactant: CCCCCCCCCCCCCCCCSCC(CO)COC
Agent: O=C1NC(=O)c2ccccc21
Product: CCCCCCCCCCCCCCCCSCC(CN)COC

Procedure:
3-Hexadecylthio-2-methoxymethylpropanol IVk3 is allowed to react and worked up by the same procedure as described in (4). The phthalimide compound m.p. 45° C. The summary of the experimental condition and the physical data of the product are listed in Tables 5 and 6.
Reaction SMILES: Cl.[CH3:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH2:18]([O:22][C:23]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:24]=1[C:25](O)=[O:26])[CH:19]([CH3:21])[CH3:20].C(OCC)(=O)C>C(#N)C>[CH2:18]([O:22][C:23]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:24]=1[C:25]([N:15]1[CH2:14][CH2:13][N:12]([C:9]2[CH:10]=[CH:11][C:5]3[S:4][C:3]([CH3:2])=[N:7][C:6]=3[CH:8]=2)[CH2:17][CH2:16]1)=[O:26])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: Cc1nc2cc(N3CCNCC3)ccc2s1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1nc2cc(N3CCN(C(=O)c4cc(S(C)(=O)=O)ccc4OCC(C)C)CC3)ccc2s1

Procedure:
Prepared in analogy to example 1.1 (b) from 2-methyl-5-piperazin-1-yl-benzothiazole hydrochloride and 2-isobutoxy-5-methanesulfonyl-benzoic acid (example 2.4) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a brownish solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:9][CH:10]1[CH2:15][CH2:14][CH:13](/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][Br:21])[CH2:12][CH2:11]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pt](=O)=O.[Pt]>[C:1]([O:5][C:6](=[O:22])[N:7]([CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Br:21])[CH2:12][CH2:11]1)[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(CC1CCC(/C=C\CCCBr)CC1)C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: [Pt]
Solvent: CCO
Product: CN(C[C@H]1CC[C@H](CCCCCBr)CC1)C(=O)OC(C)(C)C

Procedure:
1.15 g (3.07 mmol) trans-E/Z-[4-(5-bromo-pent-1-enyl)-cyclohexylmethyl]-methyl-carbamic acid tert-butyl ester dissolved in 15 ml of ethanol were added to a suspension of 300 mg platinum dioxide freshly reduced to platinum by hydrogenation immediately prior to use. Hydrogenation was then continued at ambient pressure until 95% of the calculated amount of hydrogen had been consumed. Then, the reaction mixture was filtered over celite and evaporated giving 0.950 g (82%) trans-[4-(5-bromo-pentyl)-cyclohexylmethyl]-methyl-carbamic acid tert-butyl ester as colorless viscous oil, MS: 375 (M+, 1Br).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH:12]([CH3:35])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:31](=[O:32])[C:30]2[N:29]([CH3:33])[CH:28]=[N:27][C:26]=2[N:25]([CH3:34])[C:23]1=[O:24].C(N(CC)CC)C>ClCCl.O>[O:11]=[C:12]([CH3:35])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:31](=[O:32])[C:30]2[N:29]([CH3:33])[CH:28]=[N:27][C:26]=2[N:25]([CH3:34])[C:23]1=[O:24]
Reactant: CC(O)CCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)CCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.2 %

Procedure:
Dimethylsulphoxide (102 mg; 1.3 mmol) was added dropwise to a solution of oxalyl chloride (91.7 mg; 0.72 mmol) in 5 ml of dry dichloromethane at -78° C. A solution of 1-(10-hydroxyundecanyl)-3,7-dimethylxanthine (0.23 g; 0.66 mmol) in 5 ml of dichloromethane was added and the resulting mixture stirred for 15 minutes. Triethylamine (0.332 mg; 3.29 mmol) was then added and the reaction warmed to room temperature. After stirring the reaction for an hour, the mixture was poured into 25 ml of water and extracted with 3×25 ml of dichloromethane. The combined organic extracts were successively washed with 1% hydrogen chloride (20 ml), saturated sodium bicarbonate solution (20 ml) and brine (20 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel using a 20% hexane/ethyl acetate eluant, resulting in 150 mg of 1-(10-oxoundecanyl)-3,7-dimethylxanthine (65.8% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]([O:17]C)=[O:16])=[CH:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]([OH:17])=[O:16])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(=O)n(-c2ccc(F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(=O)n(-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A 100 mL round-bottomed flask was charged with methyl 1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (2.3 g, 9.1 mmol) and 20 mL of EtOH. To this was added NaOH (1.10 g, 27.0 mmol). This solution was stirred at rt for 20 h then concentrated. The mixture was acidified to pH 1 with conc HCl. The resulting precipitate was filtered and dried to give 1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid as an off-white solid.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][N:10]([CH2:12][C:13]3[N:14]=[CH:15][N:16](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:17]=3)[C:9](=[O:37])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:38]C#N>>[CH3:38][N:14]1[C:13]([CH2:12][N:10]2[CH2:11][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][C:9]2=[O:37])=[CH:17][N:16]=[CH:15]1
Reactant: O=C1CC(c2ccccc2)CN1Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC#N
Product: Cn1cncc1CN1CC(c2ccccc2)CC1=O
Temperature: 25 °C

Procedure:
In a 50 ml, three-necked flask fitted with a magnetic stirrer, under inert atmosphere, 4-phenyl-1-[(1-trityl-1H-imidazol-4-yl)methyl]pyrrolidin-2-one x44 (2 g, 4.1 mmol) is dissolved in CH3CN (20 ml) and Mel (283 μL, 4.5 mmol) is added. The mixture is stirred at room temperature and two additional portions of Mel (283 μl and 500 μl) are added after 40 h and 46 h. After stirring for 16 h at room temperature, the mixture is concentrated and dissolved in a 1/1 mixture of AcOH and water. After stirring at room temperature for 48 h, the mixture is filtered and evaporated to dryness (by azeotropic distillation with toluene). The residue is dissolved in a solution of HCl at pH 1 (25 ml) and extracted with CH2Cl2 (3×50 ml). The aqueous phase is brought at pH 10 by adding solid K2CO3 and extracted again with CH2Cl2 (3×50 ml). Combined organic phases are dried over MgSO4, filtered and concentrated to give 1 g of crude product which is purified by chromatography on silicagel (60 g of SiO2, CH2Cl2/EtOH/NH4OH: 94/5.4/0.6 (v/v/v)) to give 0.5 g of 1-[(1-methyl-1H-imidazol-5-yl)methyl]-4-phenylpyrrolidin-2-one. This free base is treated with a 3.6 M solution of HCl (5 ml), and the resulting solid is recrystallized in CH3CN to lead to 1-[(1-methyl-1H-imidazol-5-yl)methyl]-4-phenylpyrrolidin-2-one hydrochloride 119.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([CH:19]2[NH:23][C:22](=[O:24])[CH2:21][CH2:20]2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C>[CH2:27]([N:23]1[CH:19]([C:17]([N:14]2[CH2:13][CH2:12][N:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:16][CH2:15]2)=[O:18])[CH2:20][CH2:21][C:22]1=[O:24])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C2CCC(=O)N2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)C2CCC(=O)N2Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
To a stirring solution of 5-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}pyrrolidin-2-one obtained in Example 62 (0.30 g, 0.91 mmol) in DMF (5 mL) was added sodium hydride (40 mg, 60% in mineral oil, 1.00 mmol) and the mixture was stirred at room temperature for 30 min. After this time, to the mixture was added benzyl bromide (0.17 g, 1.00 mmol) and the mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated ammonium chloride solution, and the mixture was partitioned between ethyl acetate and water, and the organic layer was washed with water, saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was triturated with hexane-diisopropyl ether solution to give the title compound (0.30 g, 79%) as a white solid, mp 164° C.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[C:12]([C:13]([NH:15][CH:16]4[C:21]([CH3:23])([CH3:22])[CH2:20][CH2:19][N:18]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:17]4)=[O:14])=[CH:11][N:10](COCC[Si](C)(C)C)[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.C(N)CN>C(Cl)Cl>[CH3:27][S:24]([N:18]1[CH2:19][CH2:20][C:21]([CH3:23])([CH3:22])[CH:16]([NH:15][C:13]([C:12]2[C:6]3[C:7](=[N:8][CH:9]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[N:5]=3)[NH:10][CH:11]=2)=[O:14])[CH2:17]1)(=[O:26])=[O:25]
Reactant: CC1(C)CCN(S(C)(=O)=O)CC1NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(C3CC3)nc12
Solvent: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CCN(S(C)(=O)=O)CC1NC(=O)c1c[nH]c2ncc(C3CC3)nc12
Reaction time: 3 h
Yield: 62.4 %

Procedure:
To a solution of 2-cyclopropyl-N-(4,4-dimethyl-1-(methylsulfonyl)piperidin-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (143 mg, 0.27 mmol) in CH2Cl2 (5 mL) was added TFA (2.0 mL, 26.0 mmol). The yellow reaction mixture was stirred for 3 h then concentrated The residue was redissolved in CH2Cl2 (5 mL) and ethylenediamine (0.5 mL, 7.4 mmol) was added. The reaction mixture was stirred at for 1 h then concentrated. The residue was purified by SiO2 chromatography (50% to 100% EtOAc/hexanes to 5% MeOH/EtOAc) to isolate 66 mg (62%) of 2-cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-methanesulfonyl-4,4-dimethyl-piperidin-3-yl)-amide as a white solid. MS: (M+H)+=392.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[C:9]([O:23][CH2:24][CH3:25])=[N:10][CH:11]=[CH:12][C:13]=1[C:14]([N:16](C(C)C)C(C)C)=[O:15].NC1C=CN=CC=1C1C(OCC)=CC=CC=1C(OC)=O>>[CH2:24]([O:23][C:9]1[C:8]2[C:3]3[C:2](=[CH:7][CH:6]=[N:5][CH:4]=3)[N:16]=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11][N:10]=1)[CH3:25]
Reactant: CCOc1nccc(C(=O)N(C(C)C)C(C)C)c1-c1cnccc1N
Agent: CCOc1cccc(C(=O)OC)c1-c1cnccc1N
Product: CCOc1nccc2c(O)nc3ccncc3c12

Procedure:
4′-Amino-2-ethoxy-N,N-diisopropyl-3,3′-bipyridine-4-carboxamide was converted to methyl 2-(4-aminopyridin-3-yl)-3-ethoxybenzoate using the same procedure as shown in (Example 3, Step 2). The product was triturated with diethyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:13]([CH2:22][CH2:23][CH2:24][OH:25])=[N:12][C:11]=2[CH:26]([CH3:28])[CH3:27])[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClC(Cl)(Cl)[C:31]([N:33]=C=O)=[O:32].C(N(CC)CC)C>O1CCCC1.O>[C:31]([O:25][CH2:24][CH2:23][CH2:22][C:13]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:26]([CH3:28])[CH3:27])[N:12]=1)(=[O:32])[NH2:33]
Reactant: CC(C)c1nc(CCCO)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)c1nc(CCCOC(N)=O)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
In 7 ml of dry tetrahydrofuran was dissolved 700 mg (1.6 mmol) of the alcohol (137c), and after the solution was cooled to -40° C., 450 mg (2.4 mmol) of trichloroacetyl isocyanate was added and the temperature was elevated gradually to room temperature. After stirring for 30 minutes, 2 ml of water and 1 ml of triethylamine were added and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% methanol-ethyl acetate) and recrystallized from ethyl acetate-n-hexane to provide 610 mg (yield 79%) of Compound I-150 as crystals. mp 114-115° C.
Reaction SMILES: C([O:5][C:6](=[O:56])[CH:7]([NH:18][C:19](=[O:55])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26][S:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34](=[O:54])[NH:35][CH:36]([C:47]([O:49]C(C)(C)C)=[O:48])[CH2:37][CH2:38][CH2:39][C:40]([O:42]C(C)(C)C)=[O:41])[CH2:8][CH2:9][CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])(C)(C)C.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>ClCCl>[CH:31]1[CH:30]=[C:29]([C:34]([NH:35][C@H:36]([C:47]([OH:49])=[O:48])[CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:54])[C:28]([S:27][S:26][C:21]2[C:20]([C:19]([NH:18][C@H:7]([C:6]([OH:56])=[O:5])[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:55])=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)CCCC(NC(=O)c1ccccc1SSc1ccccc1C(=O)NC(CCCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCC[C@H](NC(=O)c1ccccc1SSc1ccccc1C(=O)N[C@@H](CCCC(=O)O)C(=O)O)C(=O)O
Yield: 72.3 %

Procedure:
This compound was prepared according to the procedure described in Example 50 using [S-(R*,R*)]-2-{2-[2-(1,4-bis-tert-butoxycarbonyl-butylcarbamoyl)-phenyldisulfanyl]-benzoylamino}-hexanedioic acid di-tert-butyl ester (1.1 g, 1.4 mmol) from Example 37, 10 mL dichloromethane, 10 mL trifluoroacetic acid, and 1 mL anisole. The crude product was recrystallized from methanol/dimethylformamide/water to afford 0.6 g of the title compound, mp 259-260° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[C:15](=[O:23])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=O)C.C(=O)([O-])O.[Na+].O.O.[Cl-].[Ca+2].[Cl-].O>CO.C(OCC)(=O)C>[C:18]([NH:17][CH:16]1[C:15](=[O:23])[N:10]2[C:11]([C:12]([OH:14])=[O:13])=[C:6]([CH2:5][O:4][CH3:1])[CH2:7][S:8][C@H:9]12)(=[O:22])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(C)C)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(C)C)[C@H]2SC1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 43.6 %

Procedure:
2 g of 3-acetoxymethyl-7-isobutyrylamino-3-cephem-4-carboxylic acid and 490 mg of sodium hydrogen carbonate were dissolved in 21 ml of 66% v/v aqueous methanol, and 30 g of calcium chloride dihydrate were added. The resulting mixture was stirred at 70° C. for 90 minutes, after which it was cooled and 40 ml of water and 50 ml of ethyl acetate were added. The aqueous phase was adjusted to a pH value of 7-8 and separated, after which it was acidified with hydrochloric acid and extracted three times, each time with 50 ml of ethyl acetate. The extracts were combined, and the combined extracts were washed with an aqueous solution of sodium chloride, dehydrated over anhydrous magnesium sulphate and concentrated by evaporation under reduced pressure. The residue was dissolved in a small volume of ethyl acetate, and insolubles were filtered off. Diisopropyl ether was added to the filtrate, and the resulting precipitates were collected by filtration and dried, giving 800 mg (yield 43.5%) of the title compound.