Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C(C(=O)C1CNCCO1)C(O)=O)C1C=CC=CC=1.[CH3:20][O:21][C:22](=[O:34])[CH:23]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:24]([OH:26])=O.C([O:37][C:38]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39])C.[OH-].[Na+]>CO.O>[CH3:20][O:21][C:22]([CH:23]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:24]([N:43]1[CH2:44][CH2:45][CH:40]([C:38]([OH:39])=[O:37])[CH2:41][CH2:42]1)=[O:26])=[O:34]
Reactant: CCOC(=O)C1CCNCC1
Reactant: COC(=O)C(Cc1ccccc1)C(=O)O
Agent: O=C(O)C(Cc1ccccc1)C(=O)C1CNCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)C(Cc1ccccc1)C(=O)N1CCC(C(=O)O)CC1

Procedure:
In a manner analogous to that described for the preparation of α-benzyltetrahydro-β-oxo-4H-1,4-oxazinepropionic acid, benzylmalonic acid monomethyl ester was amidated with piperidine-4-carboxylic acid ethyl ester and the resulting compound [MS: 347 (M)+ ]was saponified with 1N sodium hydroxide solution in a mixture of methanol and water at 0° for 2 hours. The crude product obtained was purified by chromatography on silica gel with a 95:5:2 mixture of chloroform, ethanol and ethyl acetate and recrystallized from a mixture of methanol, methylene chloride and ether, to yield 1-[α-(methoxycarbonyl)hydrocinnamoyl]-4-piperidinecarboxylic acid, melting point 138°.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[N:12]=[CH:11][C:10]([O:13][C@@H:14]3[CH2:18][CH2:17][NH:16][C:15]3=[O:19])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Br[C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][CH2:26][C:27]2=[O:30])=[C:23]([F:31])[CH:22]=1>O1CCOCC1>[CH:1]1([CH2:4][CH2:5][O:6][C:7]2[N:12]=[CH:11][C:10]([O:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:21]4[CH:29]=[C:28]5[C:24](=[C:23]([F:31])[CH:22]=4)[CH2:25][CH2:26][C:27]5=[O:30])[C:15]3=[O:19])=[CH:9][CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=C1CCc2c(F)cc(Br)cc21
Reactant: O=C1NCC[C@H]1Oc1ccc(OCCC2CC2)nc1
Solvent: C1COCCO1
Product: O=C1CCc2c(F)cc(N3CC[C@@H](Oc4ccc(OCCC5CC5)nc4)C3=O)cc21
Temperature: 85 °C

Procedure:
A mixture of (R)-3-[6-(2-cyclopropyl-ethoxy)-pyridin-3-yloxy]-pyrrolidin-2-one (100 mg), 6-bromo-4-fluoro-2,3-dihydro-1H-inden-1-one (87 mg) and 1,4-dioxane (2 mL) was purged with argon. N,N′-Dimethyl-ethylene-diamine (336 mg), cesium carbonate (248 mg) and copper(I) iodide (7 mg) were added. The mixture was heated to 85° C. for 3 hours. After cooling to r.t. the mixture was filtered and the filtrate purified by preparative HPLC to provide Example 1-08. 1H-NMR (400 MHz, DMSO) 67.99 (1H, dd, J=11.3, 1.8 Hz), 7.97 (1H, d, J=3.1 Hz), 7.77 (1H, d, J=1.8 Hz), 7.53 (1H, dd, J=9.0, 3.1 Hz), 6.77 (1H, d, J=9.0 Hz), 5.22 (1H, dd, J=8.3, 8.3 Hz), 4.24 (2H, t, J=6.8 Hz), 3.96 (1H, m), 3.86 (1H, m), 3.10 (2H, m), 2.72 (2H, m), 2.69 (1H, m), 2.14 (1H, m), 1.60 (2H, dt, J=6.8, 6.8 Hz), 0.80 (1H, m), 0.42 (2H, m), 0.10 (2H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[C@@H:25]1[CH2:29][NH:28][CH2:27][C@H:26]1[C:30]([O:32][CH2:33][CH3:34])=[O:31]>ClCCl>[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[C@@H:25]1[CH2:29][N:28]([C:13]([C:9]2[CH:10]=[N:11][O:12][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[O:14])[CH2:27][C@H:26]1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: Cc1ccc(-c2oncc2C(=O)Cl)cc1
Reactant: CCOC(=O)[C@@H]1CNC[C@H]1c1cc2ccccc2o1
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CN(C(=O)c2cnoc2-c2ccc(C)cc2)C[C@H]1c1cc2ccccc2o1
Reaction time: 1 h

Procedure:
To 5-(4-methylphenyl)isoxazole-4-carbonyl chloride (10 mg, 0.045 mmol) in dichloromethane (1 mL) was added ethyl (±)-trans-4-(1-benzofuran-2-yl)pyrrolidine-3-carboxylate (13 mg, 0.050 mmol, 1.1 equ.), and the reaction mixture was stirred for 1 h. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC to give the title compound. HRMS (ESI, pos. ion) m/z calcd for C26H24N2O5: 444.1685, found 444.1693.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>C(Cl)Cl>[CH3:20][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:30]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)=[O:31])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1
Reactant: CN(C)CCCOc1ccc(N)cc1-c1ccnn1C
Reactant: COc1ccc(N=C=O)cc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(OCCCN(C)C)c(-c3ccnn3C)c2)cc1
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (38.3 mg, 0.140 mmol) in CH2Cl2 (2 mL) was added 4-methoxyphenyl isocyanate (0.21 μL, 0.162 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH3 in methanol (30 mL). The NH3 containing fractions were dried in vacuo to afford Compound 131 as a colorless solid (53.1 mg, 90%). LCMS m/z (%)=424 (MH+) (100), 1H NMR (400 MHz, DMSO-d6) δ: 8.49 (bs, 1H), 8.43 (bs, 1H), 7.44 (d, J=1.86 Hz, 1H), 7.42 (dd, J=8.92, 2.73 Hz, 1H), 7.36 (d, J=2.71 Hz, 1H), 7.33 (d, J=9.09 Hz, 2H), 7.07 (d, J=8.96 Hz, 1H), 6.85 (d, J=9.09 Hz, 2H), 6.23 (d, J=1.82 Hz, 1H), 3.96 (t, J=6.35 Hz, 2H), 3.71 (s, 3H), 3.65 (s, 3H), 2.18 (t, J=7.05 Hz, 2H), 2.07 (s, 6H), 1.77-1.69 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:14])[C:6]([CH3:13])=[CH:7][C:8]=2[CH3:12])[O:3]1.[Cl:16][S:17](O)(=[O:19])=[O:18]>ClC(Cl)Cl>[S:17]([Cl:16])([C:7]1[C:6]([CH3:13])=[C:5]([CH3:14])[C:4]2[O:3][C:2]([CH3:15])([CH3:1])[CH2:11][CH2:10][C:9]=2[C:8]=1[CH3:12])(=[O:19])=[O:18]
Reactant: Cc1cc(C)c2c(c1C)OC(C)(C)CC2
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: Cc1c(C)c(S(=O)(=O)Cl)c(C)c2c1OC(C)(C)CC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 39.7 %

Procedure:
The starting material for this synthesis was 2,2,5,7,8-pentamethylchroman and 77.55 g, 0.38 mol was dissolved in trichloromethane (1 liter) and cooled to 0° C. Chlorosulphonic acid (176.85 g, 1.52 mol) in a further 800 ml of solvent was added and the mixture stirred for 15 minutes at 0° C. and then for a further hour without cooling. The reaction mixture was poured onto ice and the organic layer separated off. This organic layer was then washed with 5% sodium carbonate solution, with saturated sodium bicarbonate solution and with brine. The aqueous washings were combined and extracted with more solvent. The original organic layer and the organic extract were combined, dried over anhydrous magnesium sulphate, stirred with activated charcoal and filtered through kieselguhr. Most of the trichloromethane was removed in vacuuo and then petroleum ether (40°/60° C.) was added and the remainder of the trichloromethane was removed in vacuuo. This crude product was dissolved in more petroleum ether and the solution cooled to 0° C. and filtered to give 45.96 g of Pmc-Cl (yield 39.7%, melting point 77°-82° C.).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[S:24](Cl)(=[O:26])=[O:25]>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:24]([C:20]2[O:19][CH:23]=[CH:22][CH:21]=2)(=[O:26])=[O:25])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: O=S(=O)(Cl)c1ccco1
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: O=S(=O)(Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F)c1ccco1

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was reacted with furan-2-sulfonyl chloride to obtain the title compound. 1H NMR (300 MHz, CDCl3): δ 7.53 (br s, D2O exchangeable, 1H), 7.38 (dd, J=1.8 & 10.5 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.21 (d, J=3.0 Hz, 1H), 6.96 (dd, J=8.7 & 16.5 Hz, 1H), 6.87 (ddd, J=1.8, 5.1 & 9.0 Hz, 1H), 6.53 (dd, J=1.8 & 3.6 Hz, 1H), 6.44 (dt, J=5.1, 8.7 & 13.8 Hz, 1H), 6.22 (br s, D2O exchangeable, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.O.[OH-].[Na+].[H][H]>[Pd].C(O)CCC>[Cl:1][N:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Product: Clc1ccccc1N(Cl)Nc1ccccc1
Yield: 78.2 %

Procedure:
630 g o-chloronitrobenzene, 615 g water and 185 g sodium hydroxide (corresponding to a 23.1 wt. % aqueous solution), 0.9 g naphthalenediol-1,4, 535 g n-butanol and 1.0 g palladium on alumina (5% Pd) (the quantitative ratio of palladium metal to o-chloronitrobenzene used being 0.00008:1) are hydrogenated at a hydrogen pressure of 6 bars and at 55° to 65° C. for 4 hours and worked up as described in Example 1. 396 g pure 2,2'-dichlorohydrazobenzene of a purity of better than 98% is obtained in a yield of 78% of theory. In addition, 37 g o-chloroaniline is obtained which after the n-butanol has been drawn off is distillable under vacuum and thus may be recovered pure. When the distillation residue is mixed with 65 g n-butanol of 60° C., a second fraction of 61 g 2,2'-dichlorohydrazobenzene of a purity of from 97 to 98% crystallizes out on cooling. The total hydrazobenzene yield thus is 89.8%. In addition, 7.3 wt. % o-chloroaniline is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH:28][C:29](=[O:31])[CH3:30])[C:19]2=[O:32])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10]C)[CH3:2].I[Si](C)(C)C>C(Cl)Cl.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH:28][C:29](=[O:31])[CH3:30])[C:19]2=[O:32])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[OH:10])[CH3:2]
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Agent: C[Si](C)(C)I
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of (S)—N-{2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide (1 mmol) in anhydrous CH2Cl2, is added iodotrimethylsilane (6 mmol). The mixture is stirred at room temperature for 24 hours. The reaction mixture is diluted with brine and is extracted with CH2Cl2. The CH2Cl2 is removed to give crude (S)—N-{-2-[1-(3-ethoxy-4-hydroxy-phenyl)-2-methanesulfonyl-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide. The product is purified by recrystallization.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Li+].CC([N-]C(C)C)C.[Si:27]([O:44][CH2:45][C:46]1[C:51]([N:52]2[CH2:57][C@H:56]([CH3:58])[O:55][C@H:54]([CH3:59])[CH2:53]2)=[C:50]([Cl:60])[C:49]([F:61])=[CH:48][N:47]=1)([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CON(C)[C:65](=[O:72])[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][N:67]=1>C1COCC1>[Si:27]([O:44][CH2:45][C:46]1[N:47]=[C:48]([C:65]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][N:67]=2)=[O:72])[C:49]([F:61])=[C:50]([Cl:60])[C:51]=1[N:52]1[CH2:57][C@H:56]([CH3:58])[O:55][C@H:54]([CH3:59])[CH2:53]1)([C:40]([CH3:43])([CH3:41])[CH3:42])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CON(C)C(=O)c1ccccn1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ncc(F)c2Cl)C[C@H](C)O1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc(C(=O)c3ccccn3)c(F)c2Cl)C[C@H](C)O1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 67.4 %

Procedure:
Diisopropylamine (0.925 mL, 6.55 mmol) was added dropwise to a stirring solution of 2.5M n-butyllithium in hexane (2.495 mL, 6.24 mmol) in THF (10 mL) at −78° C. Allowed solution to warm to 0° C. for 10 minutes then cooled again to −78° C. Cannulated the prepared LDA at −78° C. into (2R,6S)-4-(2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine (Intermediate 45, 1.6 g, 3.12 mmol) in THF (10 mL) at −78° C. Allowed the dark solution to stir for 20 minutes and then cannulated into a stirring solution of N-methoxy-N-methylpicolinamide (1.05 g, 6.24 mmol) in THF (10 mL) at −78° C. Allowed the solution to warm to −50° C. and then quenched with saturated ammonium chloride solution. Extracted mixture with ethyl acetate and washed resulting organics with brine. Dried organics over sodium sulfate, filtered, and evacuated filtrate under vacuum to give crude yellow oil. The crude oil was purified on silica using 10-30% acetone in n-hexane as eluant to give 1.3 g (67%) of the title compound as oil.
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=[CH:23][C:16]=23)[CH:12]=[N:11]1)([CH3:9])[CH2:3][C:4](OCC)=[O:5].C1COCC1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl.O>[CH3:9][C:2]([N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])[CH:22]=[CH:23][C:16]=23)[CH:12]=[N:11]1)([CH3:1])[CH2:3][CH2:4][OH:5]
Reactant: CCOC(=O)CC(C)(C)n1cc(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(CCO)n1cc(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: -10 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To a solution of ethyl 3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]-pyridin-4-yl)-1H-pyrazol-1-yl]butanoate (213 mg, 0.000481 mol) in THF (5 mL, 0.0616 mol) at −78° C. was added diisobutylaluminum hydride in DCM (1.00 M, 1.1 mL) dropwise. The reaction mixture was stirred for 3 hours during which time the reaction slowly warmed to −10° C. To the mixture at −10° C. was carefully added K/Na tartrate tetrahydrate in water. The mixture was stirred for 2 hours, then was extracted with three portions of ethyl acetate. The combined organic extracts were washed with two portions of water and one portion of brine, then dried over sodium sulfate, filtered and concentrated to afford 3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]-pyridin-4-yl)-1H-pyrazol-1-yl]butan-1-ol (185 mg, 96%), which was used without further purification. A portion of the alcohol so obtained (15 mg, 0.000037 mol) was stirred in TFA (1 mL) for 2 hours. The TFA was removed in vacuo and the residue was stirred with 2 mL MeOH containing 0.5 mL NH4OH for 16 hours. Volatiles were removed and the product was purified by preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA) to afford 3-methyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butan-1-ol as the trifluoroacetate salt (8.0 mg, 57%). 1H NMR (300 MHz, d6-DMSO): δ 12.17 (s, 1H), 8.58 (br s, 1H), 8.32-8.22 (br m, 2H), 7.62 (br s, 1H), 7.53 (br d, 1H), 7.03 (br s, 1H), 3.25 (t, 2H), 2.07 (t, 2H), 1.62 (s, 6H); MS(ES): 271 (M+1).
Reaction SMILES: BrC1SC2C(=NC=CC=2OC2C=CC([N+]([O-])=O)=CC=2)C=1.F[C:22]1[CH:44]=[C:43]([N+:45]([O-:47])=[O:46])[CH:42]=[CH:41][C:23]=1[O:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]2[CH:31]=[C:32]([C:34]3[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=3)[S:33][C:26]=12>>[N+:45]([C:43]1[CH:42]=[CH:41][C:23]([O:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27]3[CH:31]=[C:32]([C:34]4[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=4)[S:33][C:26]=23)=[CH:22][CH:44]=1)([O-:47])=[O:46]
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(O)cc4)sc23)c(F)c1
Agent: O=[N+]([O-])c1ccc(Oc2ccnc3cc(Br)sc23)cc1
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(O)cc4)sc23)cc1
Yield: 81 %

Procedure:
Starting from the compound 197 and following the procedure described above for the synthesis of compound 153 (scheme 28), title compound 198 was obtained in 81% yield. LRMS (M+1) 365.0 (100%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:18]=[CH:17][C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)=O)=[CH:6][CH:5]=1.[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20]>C1COCC1.Cl>[CH2:23]([O:22][C:19](=[O:21])[CH:20]=[C:8]([C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)[C:7]1[CH:17]=[CH:18][C:4]([Br:3])=[CH:5][CH:6]=1)[CH3:24]
Reactant: O=C(c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C(c1ccc(Br)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99 %

Procedure:
A solution of triethyl phosphonoacetate (26.8 g, 120.0 mmol) in dry THF (100 mL) was added at 0° C. over a period of 25 min. to a stirred suspension of sodium hydride (60% in oil, 4.8 g, 120.0 mmol) in dry THF (100 ml). After stirring at 0° C. for 30 min. a solution of 4,4′-dibromobenzophenone (20.4 g, 60.0 mmol) in dry THF (200 ml) was added and the mixture slowly warmed to room temperature, and stirring continued for 48 h. The reaction mixture was diluted with 1N hydrochloric acid (400 ml) and ethyl acetate (100 ml). The organic phase was separated, and the aqueous phase further extracted with ethyl acetate (2×300 ml). The combined organic phases were washed with water (300 ml×3), dried (MgSO4), filtered and concentrated in vacuo. The product was purified by column chromatography on silica gel (15% ethyl acetate in n-heptane eluent) to give 24.5 g (99%) 3,3-bis-(4-bromophenyl)-acrylic acid ethyl ester as an off-white amorphous solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([OH:14])=[O:13])=[CH:5]2.S(=O)(=O)(O)O.[C:20](=O)(O)[O-].[Na+]>CO>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14][CH3:20])=[O:13])=[CH:5]2
Reactant: O=C([O-])O
Reactant: O=C(O)c1cnc2ccc(O)cc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cnc2ccc(O)cc2c1
Temperature: 70 °C

Procedure:
6-Hydroxyquinoline-3-carboxylic acid (Int-15, 1 g, 5.29 mmol) was suspended in methanol (25 mL) to which sulfuric acid (0.3 mL, 5 mmol) was carefully added. The reaction was heated at 70° C. under an atmosphere of nitrogen for 48 h. The reaction was cooled to room temperature and saturated sodium bicarbonate solution (2 mL) was added. The solvent was removed under reduced pressure and the crude residue was co-evaporated with toluene twice. The dried residue was purified by silica gel chromatography (methylene chloride to 95/5 methylene chloride/methanol gradient) to afford Int-16 (0.89 g, 83%). LC-MS: (FA) ES+ 204; 1H NMR (400 MHz, d6-DMSO) δ ppm 9.23 (d, J=1.7 Hz, 1H), 9.09 (s, 1H), 8.05 (d, J=9.1 Hz, 1H), 7.59 (dd, J=9.1, 2.5 Hz, 1H), 7.50 (d, J=2.5 Hz, 1H), 3.96 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]([C:19]2[C:20]3[N:21]([N:26]=[CH:27][N:28]=3)[C:22](Br)=[CH:23][N:24]=2)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:6]=1)[CH3:2].CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][NH:41][CH:42]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH2:1]([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:19]2[C:20]3[N:21]([N:26]=[CH:27][N:28]=3)[C:22]([C:38]3[CH:39]=[N:40][NH:41][CH:42]=3)=[CH:23][N:24]=2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(N(C(=O)OC(C)(C)C)c2ncc(Br)n3ncnc23)c1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc(N(C(=O)OC(C)(C)C)c2ncc(-c3cn[nH]c3)n3ncnc23)c1
Temperature: 115 °C
Yield: 108.6 %

Procedure:
Nitrogen is bubbled through a mixture of 3-[(5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-tert-butoxycarbonyl-amino]benzoic acid ethyl ester (0.58 g, 1.25 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.49 g, 2.50 mmol), K2CO3 (0.35 g, 2.50 mmol) and Pd(dppf)Cl2DCM (102 mg, 0.125 mmol) in dioxane (37.5 mL) and water (9.6 mL). A condenser is fitted to the flask, the system is evacuated and purged with N2 (g) and then heated at 115° C. for 25 min. The heating bath is removed and CO2 (s) is added to cool and buffer the system. The solvent is removed under reduced pressure and the residue is purified by silica chromatography, eluting with 10% to 50% ethyl acetate in DCM, to afford the title compound as an orange oil (0.61 g, >100%) which is used without further purification.
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]([CH:9]([NH2:11])[CH3:10])[CH:6]=[CH:5][CH:4]=1.[BrH:12]>>[BrH:12].[NH2:11][CH:9]([C:7]1[NH:8][C:3](=[O:2])[CH:4]=[CH:5][CH:6]=1)[CH3:10]
Reactant: COc1cccc(C(C)N)n1
Agent: Br
Product: CC(N)c1cccc(=O)[nH]1
Temperature: 80 °C
Reaction time: 60 h

Procedure:
To 1.6 g of 1-(6-methoxypyridin-2-yl)ethanamine was added 23.7 ml of a 47% aqueous hydrobromic acid solution, followed by stirring at 80° C. for 60 hours. After evaporating the solvent under reduced pressure, the residue was washed with diethyl ether to obtain 2.95 g of 6-(1-aminoethyl)pyridin-2(1H)-one hydrobromide as a pale brown solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:13]([NH:14][C:15](=[O:25])[C:16](=[N:22][O:23][CH3:24])[C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[C:12](=[O:26])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10].P([O-])([O-])([O:29][C:30](=O)[NH2:31])=O.P(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.[Cl-].[Mg+2].[Cl-].[OH-].[K+].Cl>[Cl-].[Mn+2].[Cl-].C(O)(=O)C>[C:30]([O:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:13]([NH:14][C:15](=[O:25])[C:16](=[N:22][O:23][CH3:24])[C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[C:12](=[O:26])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10])(=[O:29])[NH2:31]
Reactant: NC(=O)OP(=O)([O-])[O-]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1ccco1
Agent: [Mn+2]
Agent: Cl
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Solvent: CC(=O)O
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1

Procedure:
Concentrated enzyme (0.5 ml) was incubated at 28° in a final volume of 1.0 ml water containing (6R,7R)-3-hydroxymethyl-7-[2-methoxyimino-2-(fur-2-yl) acetamido]-ceph-3-em-4-carboxylic acid (syn-isomer) (0.1 μmole), carbamoyl phosphate (3 μmoles), ATP (1 μmole), magnesium chloride (1 μmole), manganese chloride (1 μmole) & pipes buffer (50 μmoles) adjusted to pH 6.0 with potassium hydroxide. After 2 hr the reaction was stopped by the addition of acetic acid (20 μl). The pH was then adjusted to 2.0 with M hydrochloric acid and the precipitated protein was centrifuged off. The supernatant was extracted with ethylacetate (2.5 ml). The organic phase was collected and evaporated to dryness. The cephalosporins it contained were then separated by hplc [100 mm × 5 mm diam. column Partisil 5 eluted at 1500 psi with chloroform:methanol: 90% formic acid (25:2:1 v/v) saturated with water] and were detected by their absorption at 270 nm. Their retention time was compared with standard samples. The size of the U.V. absorbing peaks showed that 20% of the cephalosporin starting material had been converted to title compound.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[CH2:8]2.[Br:22][C:23]([CH3:28])([CH3:27])[C:24](Br)=[O:25]>>[Br:22][C:23]([CH3:28])([CH3:27])[C:24]([N:11]([CH:2]1[CH:3]2[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]1[CH2:8]3)[CH2:4]2)[NH:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:25]
Reactant: O=[N+]([O-])c1ccc(NNC2C3CC4CC(C3)CC2C4)cc1
Reactant: CC(C)(Br)C(=O)Br
Product: CC(C)(Br)C(=O)N(Nc1ccc([N+](=O)[O-])cc1)C1C2CC3CC(C2)CC1C3

Procedure:
1-(Adamantan-2-yl)-2-(4-nitrophenyl)hydrazine and 2-bromoisobutyrylbromide were used for a similar reaction and treatment as Process 3 of Example 1, and 2-bromo-N-(adamantan-2-yl)-2-methyl-N′-(4-nitrophenyl)propane hydrazide was obtained as a yellow oil.