Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([SH:4])([CH3:3])[CH3:2].[CH3:5][C@H:6]1[CH2:11][O:10][CH2:9][CH2:8][N:7]1[C:12]1[CH:17]=[C:16]([CH2:18]OS(C)(=O)=O)[N:15]=[C:14]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:32])=[CH:26][CH:25]=2)[N:13]=1>C(#N)C.N12CCCN=C1CCCCC2>[CH3:5][C@H:6]1[CH2:11][O:10][CH2:9][CH2:8][N:7]1[C:12]1[CH:17]=[C:16]([CH2:18][S:4][CH:1]([CH3:3])[CH3:2])[N:15]=[C:14]([C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:31]([NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:32])=[CH:28][CH:29]=2)[N:13]=1
Reactant: CC(C)S
Reactant: C[C@H]1COCCN1c1cc(COS(C)(=O)=O)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)SCc1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Isopropyl mercaptan (0.075 mL) was dissolved in acetonitrile (5 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.12 mL). The reaction was allowed to stir at room temperature for 15 minutes then 1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonyloxymethyl)pyrimidin-2-yl]phenyl]-3-phenyl-urea (228 mg) in acetonitrile (5 mL) added. The reaction was stirred for 30 minutes then concentrated in vacuo. The residue was chromatographed on silica, eluting with 2.5% methanol in DCM, to give the desired compound (78 mg) as a gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16]>C(O)C.[Pd]>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])cc1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)cc1NC(=O)OC(C)(C)C
Yield: 91.6 %

Procedure:
A solution of 1,1-dimethylethyl [2-(methyloxy)-5-nitrophenyl]carbamate (6 g, 22 mmol) in absolute ethanol (150 mL) was hydrogenated with 10% Pd/C (˜1.00 g, Lancaster) at 50 psi overnight. The catalyst was removed by vacuum filtration through a celite pad, rinsed with methanol, and filtrate was concentrated under reduced pressure to provide 1,1-dimethylethyl [5-amino-2-(methyloxy)phenyl]carbamate (4.8 g, 90%) as a tan solid. ESIMS (M+H)+=239.
Reaction SMILES: [Mg].[CH:2](Cl)([CH3:4])[CH3:3].[CH3:6][C:7]([CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:8][CH:9]=[O:10]>CCOCC>[CH3:3][CH:2]([CH:9]([OH:10])[CH:8]=[C:7]([CH3:6])[CH2:11][CH:12]([CH3:14])[CH3:13])[CH3:4]
Reactant: CC(=CC=O)CC(C)C
Reactant: CC(C)Cl
Agent: [Mg]
Solvent: CCOCC
Product: CC(=CC(O)C(C)C)CC(C)C
Temperature: 0 °C
Yield: 72.6 %

Procedure:
26.4 g (1.1 gram atom) of magnesium shavings and 100 ml of anhydrous ether are added to a round flask which is provided with a stirrer, condenser, thermometer and dropping funnel. There is now slowly added thereto a solution of 90.2 g (1.15 mol) of isopropyl chloride in 150 ml of ether. After completion of the addition, the mixture is held at reflux temperature for a further 1 hour. There are now added thereto at a temperature of 10° C. 126.2 g (1 mol) of 3,5-dimethyl-2-hexenal dissolved in 250 ml of anhydrous ether. The mixture is held at reflux temperature for 3 hours, then cooled down to 0° C. and decomposed by the addition of 370 ml of 10% ice-cold hydrochloric acid. The ethereal solution is washed neutral with water and dried, and the solvent is evaporated. There are thus obtained 168 g of crude material, fractional distillation of which yields 123.7 g (72.6%) of 2,5,7-trimethyl-4-octen-3-ol of boiling point 78°-79° C./5 mmHg; nD20 =1.4526.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][C:32](Cl)=[O:33].C(N(CC)CC)C>ClCCl>[CH:23]1[CH:22]=[CH:21][N:13]2[CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:32](=[O:33])[CH2:31][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[CH3:24])=[N:7][CH:6]=3)=[O:9])[CH2:11][C:12]=12
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1
Reactant: Cc1ccccc1CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1CC(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2.0 mmol of 10,11-dihydro-10-(6-amino-3-pyridinylcarbonyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 2.1 mmol of 2-methylbenzeneacetyl chloride and 5 mmol of triethylamine in 10 ml of dichloromethane is stirred under argon at room temperature for 16 hours. The solvent is removed under vacuum and the residue partitioned between 50 ml of ethyl acetate and 25 ml of water. The organic layer is separated, washed with H2O, 1N NaHCO3, brine and dried (Na2SO4). The solvent is removed and the residue chromatographed on silica gel with ethyl acetate-hexane as solvent to give the product as a solid.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:16]=[C:17]2[C:26](=[CH:27][CH:28]=1)[C:25]1[N:21]([CH:22]=[C:23]([C:29]3[N:33]([CH:34]([CH3:36])[CH3:35])[N:32]=[CH:31][N:30]=3)[N:24]=1)[CH2:20][CH2:19][O:18]2)(=[O:8])=[O:7])(C)(C)C>C(O)(C(F)(F)F)=O>[CH:34]([N:33]1[C:29]([C:23]2[N:24]=[C:25]3[C:26]4[CH:27]=[CH:28][C:15]([C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=5[S:6]([NH2:5])(=[O:7])=[O:8])=[CH:16][C:17]=4[O:18][CH2:19][CH2:20][N:21]3[CH:22]=2)=[N:30][CH:31]=[N:32]1)([CH3:36])[CH3:35]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3ccccc3S(=O)(=O)NC(C)(C)C)cc1OCC2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3ccccc3S(N)(=O)=O)cc1OCC2
Temperature: 80 °C
Yield: 33.3 %

Procedure:
A mixture of N-tert-butyl-2-{4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-12-yl}benzene-1-sulphonamide (200 mg, 0.400 mmol) in TFA (5.0 mL) was heated to 80° C. for 3 h. After concentration, the residue was adjusted to pH around 8, extracted with ethyl acetate (3×50 mL). After removal of the solvent, the residue was purified by reverse phase combiflash eluting with a 0-70% gradient of CH3CN in 0.3% NH4HCO3 to give 109 (60 mg, 33% yield) as white solid. LCMS (ESI): RT=5.15 min, m/z: 451.2 [M+H+]. 1H NMR (500 MHz, DMSO-d6): δ 8.44-8.41 (m, 1H), 8.07-8.03 (m, 1H), 7.98 (d, J=7.5 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.64-7.56 (m, 3H), 7.39-7.36 (m, 1H), 7.21-7.19 (m, 2H), 7.09 (d, J=5.5 Hz, 1H), 5.97-5.95 (m, 1H), 4.58-4.55 (m, 4H) 1.52-1.49 (m, 6H)
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13](OC(C)(C)C)=O)[CH2:9][CH2:8]2)[N:3]=[CH:2]1.C(O)(C(F)(F)F)=O.[Br:27][C:28]1C(Cl)=[C:30]([N+:35]([O-:37])=[O:36])[C:31]([NH2:34])=[N:32][CH:33]=1>C(Cl)Cl>[Br:27][C:28]1[C:13]([N:10]2[CH2:9][CH2:8][N:7]([CH2:6][C:4]3[N:3]=[CH:2][S:1][CH:5]=3)[CH2:12][CH2:11]2)=[C:30]([N+:35]([O-:37])=[O:36])[C:31]([NH2:34])=[N:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cscn2)CC1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncc(Br)c(N2CCN(Cc3cscn3)CC2)c1[N+](=O)[O-]
Reaction time: 1 h
Yield: 58.9 %

Procedure:
tert-Butyl 4-(thiazol-4-ylmethyl)piperazine-1-carboxylate (0.160 g, 0.56 mmol, 1.0 eq) was dissolved in DCM (1.8 mL) and the reaction mixture cooled in a ice-water bath before the dropwise addition of TFA (1.8 mL). Stirring was continued at this temperature for 1 h, the solvents were removed in vacuo. The resulting crude material was azeotroped with toluene and dried. The resulting 4-(piperazin-1-ylmethyl)thiazole (supposedly 0.10 g, 0.56 mmol, 1.1 eq) was suspended in iPrOH (0.55 mL) and DIPEA (0.22 mL). To this solution, 5-bromo-4-chloro-3-nitropyridin-2-amine (0.130 g, 0.51 mmol, 1 eq) was added and the reaction mixture was heated and stirred for 17 h at 65° C. The mixture was filtered, washed with iPrOH (3×3 mL), Et2O (2×3 mL) and dried to give the title compound as a bright yellow powder (0.120 g, 55%); 1H-NMR (500 MHz, DMSO-d6): δ 2.58 (br s, 4H, piperazine N(CH2)2), 3.06 (m, 4H, piperazine N(CH2)2), 3.72 (s, 2H, NCH2), 6.96 (s, 2H, NH2), 7.54 (br d, 1H, J=1.2 Hz, thiazole 5-H), 8.15 (s, 1H, pyridine 6-H), 9.04 (d, 1H, J=1.7 Hz, thiazole 2-H); LC (Method B)-MS (ESI, m/z): Rt=1.83 min—398/400 [(M+H)+, Br isotopic pattern, 100%].
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:32]2[CH2:31][CH2:30][N:29]([CH:28]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:25]3[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=3)[CH2:34][CH2:33]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccc(Cl)cc1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)n1nc(CCCN2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1-c1ccc(Cl)cc1

Procedure:
123 mg (75%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propanal (80 mg, 0.275 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (79 mg, 0.275 mmol), DIPEA (0.072 mL, 0.413 mmol) and NaBH(OAc)3 (175 mg, 0.825 mmol).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][CH:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:9][CH:8]=1)(=O)=O.[CH3:19][O:20][C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:22].C(Cl)Cl.[F-].[Cs+]>O1CCOCC1.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]>[C:13]([CH:10]1[CH2:11][CH2:12][C:7]([C:26]2[CH:27]=[CH:28][C:23]([C:21]([O:20][CH3:19])=[O:22])=[CH:24][CH:25]=2)=[CH:8][CH2:9]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1ccc(C2=CCC(C(C)(C)C)CC2)cc1
Reaction time: 16 h

Procedure:
A mixture of Example 5A (286 mg, 1.0 mmol), (4-methoxycarbonylphenyl)-boronic acid (216 mg, 1.2 mmol), Pd(dppf)Cl2.CH2Cl2 (37 mg, 0.05 mmol), and cesium fluoride (454 mg, 3.0 mmol) in dioxane (5 mL) was heated to 90° C., stirred for 16 hours, filtered through a pad of silica gel (10 g) with diethyl ether (5 mL) and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [O:1]=[C:2]1[C:7]2([CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:22]=1.C(O)(C(F)(F)F)=O>ClCCl>[S:30]([N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([CH2:20][N:3]2[CH2:4][CH2:5][CH2:6][C:7]3([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]3)[C:2]2=[O:1])=[CH:22]1)([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:31])=[O:32]
Reactant: Cc1ccc(S(=O)(=O)n2cc(CN3CCCC4(CCN(C(=O)OC(C)(C)C)CC4)C3=O)c3ccccc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(CN3CCCC4(CCNCC4)C3=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 144.1 %

Procedure:
To a solution of tert-butyl 1-oxo-2-((1-tosyl-1H-indol-3-yl)methyl)-2,9-diazaspiro[5.5]undecane-9-carboxylate (5.3 g, 8.45 mmol) in dichloromethane (30 mL) was added TFA (4.93 mL, 63.4 mmol). The solution was stirred for 70 min at rt. After completion of the reaction the mixture was evaporated to dryness. The residue was crystallized in THF/heptane 3:1 to yield the title compound as white crystals (5.5 g, quant.). [1H NMR (400 MHz, DMSO-d6) ♀ ppm 8.43 (br. s, 2H), 7.89 (d, J=8.28 Hz, 1H), 7.82 (d, J=8.28 Hz, 2H), 7.78 (s, 1H), 7.56 (d, J=7.78 Hz, 1H), 7.38-7.31 (m, 3H), 7.24-7.20 (m, 1H), 4.59 (s, 2H), 3.29-3.19 (m, 2H), 3.12 (t, J=5.77 Hz, 2H), 3.07-2.95 (m, 2H), 2.30 (s, 3H), 2.10 (ddd, J=14.24, 10.35, 4.02 Hz, 2H), 1.75-1.59 (m, 4H), 1.58-1.48 (m, 2H); LCMS RtA=0.88 min, [M+H]+=452.3].
Reaction SMILES: [CH:1]1([S:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8](O)=[O:9])[CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=[N:21]C=2C=1.O.C(Cl)CCl.[OH-].[NH4+]>CN(C=O)C.C(OCC)(=O)C.C1COCC1>[CH:1]1([S:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([NH2:21])=[O:9])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccccc1SC1CCC1
Reactant: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: NC(=O)c1ccccc1SC1CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2B (6.30 g, 26.2 mmol) in DMF (52.5 mL) was added HOBT.H2O (4.9 g, 32.0 mmol) and EDC (5.98 g, 31.3 mmol). After stirring 1 h at rt, the reaction was cooled to 0° C. and 25% ammonium hydroxide was added. The reaction was stirred for 1.5 h and was then diluted with ethyl acetate/THF and washed with 1N HCl (2×) and 1 N NaOH (2×). The aqueous layer was back-extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated to provide 2C (5 g) as a yellow solid. LC-MS: 240.08 (M+H)+.
Reaction SMILES: [CH2:1]([C:21]1[C:26]([OH:27])=[C:25]([CH3:28])[C:24]([CH3:29])=[C:23]([OH:30])[C:22]=1[CH3:31])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH2:7][C@@H:8]([CH2:10][CH2:11][CH2:12][C@@H:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])\[CH3:4].[C:32]([O:35]C(=O)C)(=[O:34])[CH3:33]>N1C=CC=CC=1>[C:32]([OH:35])(=[O:34])[CH3:33].[C:32]([OH:35])(=[O:34])[CH3:33].[CH2:1]([C:21]1[C:26]([OH:27])=[C:25]([CH3:28])[C:24]([CH3:29])=[C:23]([OH:30])[C:22]=1[CH3:31])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH2:7][C@@H:8]([CH2:10][CH2:11][CH2:12][C@@H:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:19])[CH3:20])[CH3:14])[CH3:9])\[CH3:4]
Reactant: CC(=O)OC(C)=O
Agent: C/C(=C\Cc1c(C)c(O)c(C)c(C)c1O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Solvent: c1ccncc1
Product: CC(=O)O
Reaction time: 10 h

Procedure:
The crude phytyltrimethylhydroquinone (31, 9 g, 20.1 mmol) was dissolved in dry pyridine (90 g) and acetic anhydride (90 g). After storage for 10 h at room temperature, the mixture was poured onto ice (200 mL) and extracted with ether (2×100 mL). The ether solution was washed with 3N sulfuric acid (2×100 mL), 10% sodium bicarbonate solution (2×100 mL), and again water (2×100 mL), dried (Na2SO4), and evaporated to yield 10.2 g (95%) of diacetate (32) as a light yellow oil. The oil was used in the next step without further purification.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:7][CH:6]([CH2:8][CH2:9][C:10]([O:12]CC(C)C)=O)[NH:5][CH2:4]1.C(=O)([O-])O.[Na+]>O>[O:2]=[C:3]1[CH2:4][N:5]2[C:10](=[O:12])[CH2:9][CH2:8][CH:6]2[NH:7]1
Reactant: CC(C)COC(=O)CCC1NCC(=O)N1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C1CN2C(=O)CCC2N1
Temperature: 100 °C
Yield: 37.2 %

Procedure:
A solution of isobutyl 5-oxo-2-imidazolidinepropanoate hydrochloride (1.4 g, 5.76 mmol) in water (100 ml) was treated with sodium hydrogen carbonate (0.54 g, 6.4 mmol) and heated at 100° C. for 20 hours. The solution was evaporated and the residue was chromatographed over silica gel (ethyl acetate-acetone-methanol 6:3:1) to afford 300 mg (37%) of the title compound, m.p. 155°-157° C.
Reaction SMILES: [Na+].[C:2]([C:5]1[N:6]=[C:7]([N:10]2[CH2:13][CH:12]([S:14][C:15]3[C@H:16]([CH3:29])[C@@H:17]4[C@@H:24]([C@H:25]([OH:27])[CH3:26])[C:23](=[O:28])[N:18]4[C:19]=3[C:20]([O-:22])=[O:21])[CH2:11]2)[S:8][CH:9]=1)(=[O:4])[NH2:3].Cl.[C:31]1(O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CN(C1C=CC=CN=1)C.Cl.C(N=C=NCCCN(C)C)C>O.O1CCCC1.C(#N)C.C(OCC)(=O)C>[C:2]([C:5]1[N:6]=[C:7]([N:10]2[CH2:13][CH:12]([S:14][C:15]3[C@H:16]([CH3:29])[C@@H:17]4[C@@H:24]([C@H:25]([OH:27])[CH3:26])[C:23](=[O:28])[N:18]4[C:19]=3[C:20]([O:22][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:21])[CH2:11]2)[S:8][CH:9]=1)(=[O:4])[NH2:3]
Reactant: Oc1ccccc1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(SC3CN(c4nc(C(N)=O)cs4)C3)[C@H](C)[C@H]12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)Oc3ccccc3)=C(SC3CN(c4nc(C(N)=O)cs4)C3)[C@H](C)[C@H]12
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
To a solution of (1R,5S,6S)-2-[1-(4-carbamoyl-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid sodium salt (162 mg, 0.36 mmol) (obtained as described in Example 3) in a mixture of water (1-ml) and tetrahydrofuran (1 ml) was added 1 M hydrochloric acid (0.33 ml, 0.36 mmol) at 0° C. The mixture was concentrated under reduced pressure. To a solution of the residue in acetonitrile (10 ml) were added phenol (102 mg, 1.1 mmol), dimethylaminopyridine (22 mg, 0.18 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (139 mg, 0.73 mmol) at room temperature. After stirring the mixture for 30 minutes, further 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (139 mg, 0.73 mmol) was added thereto and the resulting mixture was stirred for 30 minutes. At the end of this time, to the reaction mixture was added ethyl acetate and the organic layer was washed sequentially with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate—20% acetonitrile; ethyl acetate—40% acetonitrile; ethyl acetate—60% acetonitrile and ethyl acetate to afford phenyl (1R,5S,6S)-2-[1-(4-carbamoyl-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (66 mg, yield 36%) as a colorless powder.
Reaction SMILES: [C:1]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[B-](F)(F)F.C([O+](CC)CC)C.[N+](=[CH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N-]>C(Cl)Cl>[CH2:28]([O:27][C:25]([CH:24]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:1]1=[O:9])=[O:26])[CH3:29]
Reactant: O=C1CCCCCCC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1CCCCCCCC1=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Cyclooctanone (25 g, 198 mmol) is dissolved in methylene chloride (500 mL) and the solution is cooled to 0° C. Triethyloxonium tetrafluoroborate (121.6 g, 640 mmol) is added. Ethyl diazoacetate (41.61 g, 365 mmol) is then added dropwise over 25 minutes, and the reaction is stirred at 0° C. for 4 hours. The reaction is quenched by pouring into a solution of sodium bicarbonate (160 g) in water (1.6 L) and stirring overnight. The reaction mixture is then extracted several times with methylene chloride, the combined organic layers are dried (Na2SO4), and the solvent is evaporated. The product is purified by vacuum distillation (0.2-1.0 mm Hg) and the fraction boiling between 100°-125° C. is collected to give 2-ethoxycarbonyl-cyclononanone.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[C:10](=[O:15])[CH2:11][CH2:12][C:13]=1[CH3:14].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=2[C:9]2[C:10](=[O:15])[CH2:11][CH2:12][C:13]=2[CH3:14])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: CC1=C(c2cc(C)ccc2N)C(=O)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC1=C(c2cc(C)ccc2NS(=O)(=O)c2ccc(C)cc2)C(=O)CC1

Procedure:
0.600 g (2.79 mmol) of 2-(2-amino-5-methylphenyl)-3-methyl-2-cyclopenten-1-one, 0.243 g (3.07 mmol) f pyridine, 0.858 g (3.07 mmol) of p-toluenesulfonyl chloride, and 3 mL of M.C were loaded to a 20 mL vial, and then reacted for 12 hours. The work-up was the same as in Example 7 (0.800 g, 78%).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[NH2:32]>>[C:33]1([C:31]2[N:32]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[O:28][N:30]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: NC(=NO)c1ccccc1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3ccccc3)no2)C1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 30 mg (0.22 mmol, 1.1 eq.) of N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 10 mg (10% of theory)
Reaction SMILES: [N:1]1([CH:16]2[CH2:22][CH:21]3[N:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:18]([CH2:19][CH2:20]3)[CH2:17]2)[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][NH:8][CH2:7]2)[CH2:3][CH2:2]1.[C:29](Cl)(=[O:31])[CH3:30].C(N(CC)CC)C.Cl>ClCCl.CCOC(C)=O>[C:29]([N:8]1[CH2:7][C:4]2([CH2:5][CH2:6][N:1]([CH:16]3[CH2:17][CH:18]4[N:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:21]([CH2:20][CH2:19]4)[CH2:22]3)[CH2:2][CH2:3]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)N1C2CCC1CC(N1CCC3(CC1)CNCc1ccccc13)C2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1C2CCC1CC(N1CCC3(CC1)CN(C(C)=O)Cc1ccccc13)C2

Procedure:
Crude ethyl 3-(2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate 5c (1.00 g, 2.6 mmol) was dissolved in anhydrous dichloromethane (12 mL), cooled in an ice/H2O bath and treated dropwise with a solution of acetyl chloride (214 mg, 2.73 mmol) in anhydrous dichloromethane (2 mL). The reaction was then treated dropwise with a solution of 1.1 eq triethylamine (289 mg, 2.86 mmol) in anhydrous dichloromethane (2 mL) and stirred in the ice/H2O bath for 30 min. The reaction was diluted with EtOAc (50 mL) and washed with 50% saturated NaHCO3 (3×20 mL), saturated brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 1.063 g crude product as a pale yellow oil. The crude product was purified by reverse-phase HPLC (2-99% CH3CN—H2O gradient with 0.03% TFA, 15 min). The combined pure fractions were concentrated under reduced pressure and treated with 1 N NaOH (25 mL). The product was extracted with dichloromethane (2×50 mL) and the combined extracts washed with saturated brine, dried (Na2SO4) and filtered and concentrated. The free base was dissolved in anhydrous diethyl ether (˜10 mL) and treated with 1.0 eq HCl (500 μL 2 N ethereal HCl). The suspension was cooled in an ice/H2O bath, filtered, rinsed with Et2O (3×10 mL) and dried to provide ethyl 3-(2-acetyl-2,3-dihydro-1H -spiro[isoquinoline-4,4′-piperidine]-1′-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate. LC/MS m/z [M+H]+ 426.2 retention time 1.89 min (10-99% CH3CN—H2O gradient, with 0.05% TFA, 5 min). 1H-NMR (400 MHz, DMSO-d6) δ 10.88 (br s, 1H), 7.46 (d, J=7.5 Hz, 1H), 7.23 (m, 3H), 4.70 (s, 2H), 4.25 (br s, 2H), 4.05 (br q, 2H), 3.81 (s, 2H), 3.78 (m, 1H), 3.46 (m, 3H), 3.12 (br m, 2H), 2.46 (br m, 1H), 2.13 (s, 3H), 2.12 (br s, 2H), 1.87 (br m, 4H), 1.69 (br m, 4H), 1.21 (t, J=7.1 Hz, 3H).