Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[O:5][C:4](=[O:26])[CH:3]=1.[C:27]([C:31]1[CH:36]=[C:35]([CH2:37][OH:38])[C:34]([CH3:39])=[CH:33][C:32]=1[S:40]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:30])([CH3:29])[CH3:28].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:27]([C:31]1[CH:36]=[C:35]([CH2:37][OH:38])[C:34]([CH3:39])=[CH:33][C:32]=1[S:40][C:3]1[C:4](=[O:26])[O:5][C:6]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)[CH2:7][C:2]=1[OH:1])([CH3:30])([CH3:29])[CH3:28]
Reactant: O=C1C=C(O)CC(CCc2ccc(O)cc2)(CCc2ccc(O)cc2)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccc(O)cc3)(CCc3ccc(O)cc3)OC2=O)c(C(C)(C)C)cc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared as described in General Method 9 using 0.14 g (0.39 mmol) of 4-hydroxy-6,6-bis [2-(4-hydroxyphenyl)ethyl]-5,6-dihydro-pyran-2-one (prepared in Example PP), 0.19 g (0.52 mmol) of toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl) ester (prepared in Example FFF), 0.22 g (1.6 mmol) of K2CO3, and 3 mL of DMF. The solution was stirred overnight at room temperature. Purification by silica gel chromatography, eluting with CH2Cl2 :MeOH (100:0 to 90:10), gave the title compound, m.p. 192°-194° C. 1H NMR (DMSO-d6) δ 1.48 (s, 9 H), 1.83 (s, 3 H), 2.02 (m, 4 H), 2.54 (m, 4 H), 2.96 (br s, 2 H), 4.35 (br s, 2 H), 4.94 (br s, 1 H), 6.68 (m, 5 H), 6.99 (dd, 4 H), 7.26 (s, 1 H), 9.16 (s, 2 H).
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])[C:11]([C:24](O)=[O:25])=[CH:10]2)=[O:5].N1C=CC=CC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:59][C:60]1[CH:70]=[CH:69][C:63]([C:64]([N:66]([CH3:68])[CH3:67])=[O:65])=[CH:62][CH:61]=1>CN(C=O)C.O>[CH3:67][N:66]([CH3:68])[C:64]([C:63]1[CH:69]=[CH:70][C:60]([NH:59][C:24]([C:11]2[N:12]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:13]3[C:9]([CH:10]=2)=[CH:8][C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:27])([CH3:1])[CH3:28])=[CH:15][CH:14]=3)=[O:25])=[CH:61][CH:62]=1)=[O:65]
Reactant: CC(C)(C)CC(=O)Nc1ccc2c(c1)cc(C(=O)O)n2Cc1ccccc1F
Reactant: CN(C)C(=O)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: CN(C)C(=O)c1ccc(NC(=O)c2cc3cc(NC(=O)CC(C)(C)C)ccc3n2Cc2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon, 200 mg (0.43 mmol) of 5-[(3,3-dimethylbutanoyl)amino]-1-(2-fluorobenzyl)-1H-indole-2-carboxylic acid (Example XXXIX) are dissolved in 2 ml of DMF, and 4 ml of pyridine are added. 489.2 mg (1.29 mmol) of HATU are added to this solution, 140.8 mg (0.86 mmol) of 4-amino-N,N-dimethylbenzamide are then slowly added dropwise and the reaction mixture is stirred at RT overnight. For work-up, water is added and the mixture is extracted repeatedly with ethyl acetate. The combined organic phases are dried over sodium sulphate and filtered, and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC. This gives 47.4 mg (15% of theory) of product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:13](=[O:16])[CH2:14][CH3:15])[S:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[C:17]([O:25][CH2:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[CH2:35][O:36][C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:30]Br)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:18]1([C:17]([O:25][CH2:26][C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=2[CH2:35][O:36][C:37]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:44])[CH2:30][O:1][C:2]2[CH:3]=[C:4]([C:8]3[CH:9]=[C:10]([C:13](=[O:16])[CH2:14][CH3:15])[S:11][CH:12]=3)[CH:5]=[CH:6][CH:7]=2)=[O:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(OCc1ccc(CBr)cc1COC(=O)c1ccccc1)c1ccccc1
Reactant: CCC(=O)c1cc(-c2cccc(O)c2)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCC(=O)c1cc(-c2cccc(OCc3ccc(COC(=O)c4ccccc4)c(COC(=O)c4ccccc4)c3)c2)cs1

Procedure:
In a manner similar to that of Example 1(i), by reaction of 3.8 g (16.3 mmol) of 1-[4-(3-hydroxyphenyl)-2-thiophenyl]-1-propanone with 16.9 g (18 mmol) of 3,4-bis(benzoyloxymethyl)benzyl bromide and 2.36 g (17 mmol) of potassium carbonate, the desired product is obtained in the form of white crystals (m.p.=117° C.; m=9.1 g; Y=95%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16]I)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>C(OCC)(=O)C>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][O:18][C:19]2[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCI)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCCOc2ccc(C=O)cc2)CC1

Procedure:
A solution of 3-(N-Boc-piperidin-4-yl)propyl iodide 1-1 (5.0 g, 14.2 mmol) (preparation described in EP 478,328), 4-hydroxybenzaldehyde 1-2 (1.73 g, 14.2 mmol), Cs2CO3 (9.2 g, 28.4 mmol) and DMF (50 ml) was stirred at ambient temperature for 2.0 hours. The reaction mixture was diluted with ethyl acetate and then washed with H2O, sat. NaHCO3, 10% KHSO4, brine, dried (MgSO4) and concentrated. Flash chromatography (silica, 10% EtOAc/hexane) provided 1-3 as a white solid.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH3:17])[S:15][C:9]=2[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)[C:7]1=[O:33].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH2:16]([C:14]1[S:15][C:9]2[N:8]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)[C:7](=[O:33])[NH:6][C:11](=[O:12])[C:10]=2[CH:13]=1)[CH3:17]
Reactant: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A mixture of 4′-{[3-(2,4-dimethoxybenzyl)-6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (64 g) and trifluoroacetic acid (300 mL) was stirred at 50° C. for 2 hr. To the reaction mixture was added toluene (300 mL), and the mixture was concentrated under reduced pressure. To the obtained residue was added ethyl acetate (150 mL), and the mixture was concentrated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (46.1 g, 100%).
Reaction SMILES: C(O[C:4](=O)[CH:5]([CH3:24])[CH2:6][N:7]([C:14]1[C:19]([N+:20]([O-])=O)=[CH:18][N:17]=[C:16]([Cl:23])[N:15]=1)[CH2:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)C.[C:26](O)(=O)C>[Fe]>[Cl:23][C:16]1[N:17]=[CH:18][C:19]2[NH:20][C:24](=[CH2:26])[CH:5]([CH3:4])[CH2:6][N:7]([CH2:8][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13]3)[C:14]=2[N:15]=1
Reactant: CCOC(=O)C(C)CN(CC1CCCC1)c1nc(Cl)ncc1[N+](=O)[O-]
Reactant: CC(=O)O
Agent: [Fe]
Product: C=C1Nc2cnc(Cl)nc2N(CC2CCCC2)CC1C

Procedure:
To a solution of 2.18 g (0.0059 mole) of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentylmethyl-amino]-2-methyl-propanoic acid ethyl ester in 40 mL of acetic acid was added 2.0 g (0.0358 g-atom) of iron powder. The mixture was heated at 80 degrees for 2.5 hours, and then filtered through Celite while still hot. The filter cake was washed with 100 mL of ethyl acetate. The filtrate was washed successively with 100 mL of water, 100 mL of 7.4 M ammonium hydroxide, 100 mL of water and 100 mL of brine. The aqueous layers were back extracted with 100 mL of ethyl acetate. The ethyl acetate layers were combined, dried, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from dichloromethane—hexanes to give 1.16 g of (rac)-2-chloro-9-cyclopentylmethyl-7-methyl-6-methylene-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepine (VI-55) as light brown crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:11]([CH2:22][C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=3)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CO.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:11]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=3)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)c1ccc(Cn2nc(-c3cc(Cl)cc(Cl)c3)cc2-c2ccc(OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2cc(-c3cc(Cl)cc(Cl)c3)nn2Cc2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the intermediate from step C (Isomer A, 0.99 g, 2.13 mmol) in THF (30 mL) was added methanol (10 mL) followed by sodium hydroxide solution (2N, 2 mL, 4 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to remove the organic solvents. The residue was acidified with 1N HCl until the pH was less than 2. The resulting solution was extracted with ethyl acetate (3×) dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound as a white solid. This material was used in the next step without any further purification. 1H NMR (DMSO, 500 MHz): δ 7.89(d, J=8.2 Hz, 2H), 7.88(d, J=1.8 Hz, 2H), 7.55(d, J=1.9 Hz, 1H), 7.38(d, J=8.7 Hz, 2H), 7.15(d, J=8.3 Hz, 2H), 7.11(s, 1H), 7.04(d, J=8.7 Hz, 2H), 5.5(s, 2H), 3.79(s, 3H). LC-MS: 2.69 min. (M+H)=453.
Reaction SMILES: II.[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:16]I)[C:12]([O:14][CH3:15])=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[C:19]1[CH:20]=[CH:21][C:22]2[S:27](=[O:29])(=[O:28])[N:26]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=3[O:39][CH3:40])[CH2:25][CH2:24][C:23]=2[CH:41]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>CN(C=O)C.[Zn].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]>[C:3]([O:7][C:8]([NH:10][C@H:11]([CH2:16][C:19]1[CH:20]=[CH:21][C:22]2[S:27](=[O:28])(=[O:29])[N:26]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=3[O:39][CH3:40])[CH2:25][CH2:24][C:23]=2[CH:41]=1)[C:12]([O:14][CH3:15])=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: COc1ccc(CN2CCc3cc(Br)ccc3S2(=O)=O)c(OC)c1
Reactant: COC(=O)[C@H](CI)NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: II
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](Cc1ccc2c(c1)CCN(Cc1ccc(OC)cc1OC)S2(=O)=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46 %

Procedure:
Iodine (0.11 g, 0.43 mmol) was added to a mixture of (R)-methyl 2-(tert-butoxycarbonylamino)-3-iodopropanoate (1.30 g, 3.58 mmol) and zinc (0.620 g, 9.75 mmol) in DMF (30 mL). The mixture was stirred for 10 min and another portion of iodine (0.11 g, 0.43 mmol) was added. The mixture was stirred for another 1 h. 6-Bromo-2-(2,4-dimethoxybenzyl)-3,4-dihydro-2H-benzo[e][1,2]thiazine 1,1-dioxide (1.34 g, 3.25 mmol), Pd2(dba)3 (0.08 g, 0.09 mmol) and S—Phos (0.070 g, 0.17 mmol) were added. The reaction mixture was stirred at 50° C. for 4 h and then cooled to ambient temperature. The mixture was filtered and the filtrate was poured into water (50 mL). The resulting mixture was extracted with EtOAc (100 mL×3). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=15:1 to 3:1) to afford (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-(2-(2,4-dimethoxybenzyl)-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2]thiazin-6-yl)propanoate (0.8 g, 46% yield) as a yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH:10]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)[C:11](=[O:28])[N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH2:14][CH2:13]1)(C)(C)C.C(Cl)[Cl:39]>Cl.O1CCOCC1>[ClH:39].[ClH:39].[NH2:7][CH2:8][CH2:9][CH:10]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=1)[C:11]([N:12]1[CH2:13][CH2:14][N:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH2:16][CH2:17]1)=[O:28]
Reactant: ClCCl
Reactant: Cc1ccc(CC(CCNC(=O)OC(C)(C)C)C(=O)N2CCN(c3ncnc4ccccc34)CC2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(CC(CCN)C(=O)N2CCN(c3ncnc4ccccc34)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture containing [3-(4-Methyl-benzyl)-4-oxo-4-(4-quinazolin-4-yl-piperazin-1-yl)-butyl]-carbamic acid tert-butyl ester (0.22 g, 0.44 mmol) in 10 mL of DCM and 5 mL of 4N HCl in dioxane was allowed to stir at room temperature under a nitrogen atmosphere overnight. The reaction was concentrated under reduced pressure. The residue was dissolved in methanol and ether added to precipitate the product. The solids were filtered and dried to afford 4-Amino-2-(4-methylbenzyl)-1-(4-quinazolin-4-yl-piperazin-1-yl)-butan-1-one dihydrochloride (167 mg.) LCMS (APCI+) m/z 404 [M+H]+; Rt: 1.87 min. 1H NMR (D2O, 400 MHz) δ 8.45 (1H, s), 7.87 (2H, t, J 8.1 Hz), 7.65-7.57 (2H, m), 7.01 (4H, s), 4.18-4.12 (1H, m), 3.98-3.92 (1H, m), 3.82-3.71 (2H, m), 3.52-3.37 (3H, m), 3.25-2.76 (6H, m), 2.64-2.54 (1H, m), 2.02 (3H, s), 1.98-1.80 (1H, m.)
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:30]1[N:31]=[C:32]([NH:35]C(=O)C(F)(F)F)[S:33][CH:34]=1)[C:5]([NH:7][CH:8]1[C:28](=[O:29])[N:10]2[C:11]([C:25]([OH:27])=[O:26])=[C:12]([CH2:15][O:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][S:14][C@H:9]12)=[O:6].O.O.O.C([O-])(=O)C.[Na+]>CC(C)=O.O>[CH3:1][O:2][N:3]=[C:4]([C:30]1[N:31]=[C:32]([NH2:35])[S:33][CH:34]=1)[C:5]([NH:7][CH:8]1[C:28](=[O:29])[N:10]2[C:11]([C:25]([OH:27])=[O:26])=[C:12]([CH2:15][O:16][C:17](=[O:24])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(=O)c3ccccc3)CS[C@H]12)c1csc(NC(=O)C(F)(F)F)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(=O)c3ccccc3)CS[C@H]12)c1csc(N)n1
Reaction time: 72 h
Yield: 66.8 %

Procedure:
A solution of 7-[2-methoxyimino-2-{-2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]-3-benzoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) (1.1 g) in acetone (4 ml) was added at ambient temperature to a solution of sodium acetate trihydrate (2.4 g) in water (10 ml), and the mixture was allowed to stand for 3 days at ambient temperature. Acetone was distilled off under reduced pressure and water (10 ml) was added thereto. The resulting mixture was adjusted to pH 2.5 with 10% hydrochloric acid under ice-cooling. Precipitates were collected by filtration, washed with water and dried under reduced pressure to give 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-benzoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) (0.62 g).
Reaction SMILES: Br[C:2](=[CH2:23])[CH2:3][CH2:4][O:5][Si:6]([C:19]([CH3:22])([CH3:21])[CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[Cl:31]>C1(C)C=CC=CC=1>[Cl:24][C:25]1[CH:26]=[C:27]([C:2](=[CH2:23])[CH2:3][CH2:4][O:5][Si:6]([C:19]([CH3:22])([CH3:21])[CH3:20])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: C=C(Br)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Product: C=C(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 64.7 %

Procedure:
[(3-Bromo-3-buten-1-yl)oxy](1,1-dimethylethyl)diphenylsilane (P12, 3.50 g) and (3,4-dichlorophenyl)boronic acid (2.06 g) were dissolved in toluene (45 mL), the stirred solution was degassed, then tetrakis(triphenylphosphine)palladium(0) (0.363 g) and ethanol (33 mL) were added and the mixture was degassed again. A 2N aqueous solution of Na2CO3 (24 mL) was added and the mixture was heated to 80° C. and stirred under nitrogen atmosphere for 3 h at this temperature. After cooling to RT, the reaction mixture was extracted with ethyl ether, the organic phase was washed with brine, dried over Na2SO4 and the solvent removed under reduced pressure. The crude product was purified by flash chromatography (eluting with cy/EA from 100/0 to 95/5) to give the title compound (2.65 g) as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([NH:19][S:20]([C:23]3[CH:24]=[N:25][C:26](Cl)=[CH:27][CH:28]=3)(=[O:22])=[O:21])[CH2:15][CH2:14]2)=[O:12])[CH3:9])=[CH:4][CH:3]=1.[NH:30]1[CH:34]=[CH:33][CH:32]=[N:31]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(O)(C)(C)C.C(Cl)Cl.CC#N.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]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([NH:19][S:20]([C:23]3[CH:24]=[N:25][C:26]([N:30]4[CH:34]=[CH:33][CH:32]=[N:31]4)=[CH:27][CH:28]=3)(=[O:22])=[O:21])[CH2:15][CH2:14]2)=[O:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](NC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc(Cl)nc2)CC1)c1ccc(F)cc1
Reactant: c1cn[nH]c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Solvent: CC#N
Product: C[C@@H](NC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc(-n3cccn3)nc2)CC1)c1ccc(F)cc1

Procedure:
Trans-4-(6-Chloro-pyridine-3-sulfonylamino)-cyclohexanecarboxylic acid [(R)-1-(4-fluoro-phenyl)-ethyl]-amide (Example 114, 100 mg, 0.225 mmol), pyrazole (70 mg, 0.91 mmol), Pd2(dba)3 (25 mg, 0.025 mmol), Xantphos (20 mg, 0.05 mmol), sodium tert-butoxide (108 mg, 1.125 mmol) were dissolved in toluene (1 ml) and tert-butanol (3 ml). The reaction mixture was microwaved at 160° C. for 5 min., after which LCMS indicated that the reaction was complete. The reaction was diluted with DCM and MeCN and filtered through a syringe, the concentrated in vacuo to a yellow oil. The crude material was purified via reverse phase chromatography and lyophilized to yield the title compound as a white solid (15 mg, 14%). [M+H]=472.08
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:20]=[C:21](/[CH:23]=[CH:24]/[C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]=4)[N:22]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>N1C=CC=CC=1>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:20]=[C:21](/[CH:23]=[CH:24]/[C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]=4)[N:22]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([NH:19][S:36]([CH3:35])(=[O:38])=[O:37])=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(-c2cnc(N3CCOCC3)c3nc(/C=C/c4ccc5ccccc5n4)cn23)cn1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(-c2cnc(N3CCOCC3)c3nc(/C=C/c4ccc5ccccc5n4)cn23)cn1
Yield: 11.3 %

Procedure:
To a solution of compound 8a (200 mg, 0.450 mmol) in pyridine (4 mL) was added methanesulfonyl chloride (150 mg, 1.32 mmol). The resulting solution was stirred in a 10 mL sealed tube at 30° C. for 8 h. The reaction was quenched with H2O (10 mL). The resulting solids were collected by filtration. The crude material was purified by flash column chromatography on silica gel, eluting with DCM/MeOH (100:1 v/v) to obtain compound 8b as a light yellow solid (26.8 mg, 11% yield). 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 10.91 (s, 1H), 8.55 (s, 1H), 8.35 (d, J=8.4 Hz, 1H), 8.23 (s, 1H), 8.12 (d, J=2.4 Hz, 1H), 8.10-7.93 (m, 2H), 7.87 (d, J=4.8 Hz, 1H), 7.83 (d, J=2.7 Hz, 1H), 7.78-7.73 (m, 1H), 7.68-7.54 (m, 2H), 7.44 (s, 1H), 7.17 (d, J=8.7 Hz, 1H), 4.40-4.20 (m, 4H), 3.85-3.75 (m, 4H), 3.39 (s, 3H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C27H25N7O3S: 528.2 (M+H). Found 528.0.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([C:24]([O:26]C)=[O:25])[C:9]2[CH2:10][CH2:11][N:12]([CH:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[C:13](=[O:16])[C:14]=2[CH:15]=1)(=[O:4])=[O:3].[OH-].[Na+].Cl.ClCCl>O1CCOCC1>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([C:24]([OH:26])=[O:25])[C:9]2[CH2:10][CH2:11][N:12]([CH:17]([CH2:18][CH2:19][CH3:20])[CH2:21][CH2:22][CH3:23])[C:13](=[O:16])[C:14]=2[CH:15]=1)(=[O:3])=[O:4]
Reactant: CCCC(CCC)N1CCc2c(C(=O)OC)cc(NS(C)(=O)=O)cc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCC(CCC)N1CCc2c(C(=O)O)cc(NS(C)(=O)=O)cc2C1=O
Reaction time: 1 h
Yield: 85.4 %

Procedure:
0.51 g of methyl 7-[(methylsulfonyl)amino]-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate is dissolved in 10.5 cm3 of dioxane at a temperature close to 20° C. 3.2 cm3 of a 1N aqueous solution of sodium hydroxide are added, then the reaction mixture is heated at a temperature close to 60° C. for 30 min. The dioxane contained in the reaction mixture is concentrated to dryness under reduced pressure (5 kPa). 20 cm3 of ethyl ether and 20 cm3 of water are added to the residue obtained. After decantation, the aqueous phase is acidified with 2 cm3 of a 2N aqueous solution of hydrochloric acid. 50 cm3 of dichloromethane are added to the mixture, which is stirred for 1 h at a temperature close to 20° C. The precipitate is filtered, washed with two lots of 10 cm3 of water then two lots of 10 cm3 of dichloromethane and dried under vacuum. 0.42 g of 7-[(methylsulfonyl)amino]-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid is obtained in the form of a powder.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:27][CH3:28])[C:12]2[CH:13]=[C:14]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:15]3[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=3[CH:22]=2)=[CH:7][CH:6]=1)C.[OH-].[K+]>C(O)C>[CH2:27]([N:11]([C:12]1[CH:13]=[C:14]([C:23]([CH3:24])([CH3:26])[CH3:25])[C:15]2[O:19][CH2:18][C:17]([CH3:20])([CH3:21])[C:16]=2[CH:22]=1)[C:8]1[CH:7]=[CH:6][C:5]([C:4]([OH:29])=[O:3])=[CH:10][CH:9]=1)[CH3:28]
Reactant: CCOC(=O)c1ccc(N(CC)c2cc(C(C)(C)C)c3c(c2)C(C)(C)CO3)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCN(c1ccc(C(=O)O)cc1)c1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2
Yield: 77.9 %

Procedure:
Following general procedure H and using 4-[ethyl-(7-t-butyl-3,3-dimethyl-2,3-dihydro-benzofuran-5-yl)-amino]-benzoic acid ethyl ester (Compound 25, 0.09 g, 0.227 mmol) and 2.5 mL of 4M potassium hydroxide solution in 4 mL of ethanol, the title compound (0.065 g, 78%) was obtained as a pale yellow solid. 1H NMR (300 MHz, CDCl3): δ 7.89 (d, 2H, J=9.0 Hz), 6.87 (d, 1H, J=2.1 Hz), 6.78 (d, 1H, J=2.1 Hz), 6.58 (d, 2H, J=9.2 Hz), 4.28 (s, 2H), 3.74 (q, 2H, J=7.1 Hz), 1.36 (s, 9H), 1.33(s, 6H), 1.27 (t, 3H, J=7.1 Hz).