Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]NC1C=CC=CC=1.F[P-](F)(F)(F)(F)F.[N:16]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2N=N1.[CH2:36]([O:43][C:44]([N:46]1[CH2:49][CH:48]([C:50]([OH:52])=O)[CH2:47]1)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C>[CH2:36]([O:43][C:44]([N:46]1[CH2:49][CH:48]([C:50](=[O:52])[NH:16][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[I:1])[CH2:47]1)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: INc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1I)C1CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 1.0 g (4.57 mmol) iodoaniline in 30 mL acetonitrile were added 2.22 g (5.02 mmol) BOP, 1.78 g (4.57 mmol) azetidine-1,3-dicarboxylic acid monobenzyl ester (route 13, step a), 0.6 mL (4.57 mmol) triethylamine, and the mixture was stirred at room temperature for 16 hours. 0.6 mL (4.57 mmol) triethylamine was added and the mixture was stirred for 2 hours. 2.22 g (5.02 mmol) BOP was added and the mixture was stirred at room temperature for 16 hours. 30 mL 1 M aqueous Na2CO3 was added and the mixture was extracted with EtOAc (2×30 mL), the organic layers were combined, washed with 30 mL brine then dried with Na2SO4. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, heptane/EtOAc 7:3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14]Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[C:11]([O:10][CH3:9])[CH:12]=2)[CH:3]=1
Reactant: COc1cccc(CCl)c1
Reactant: Oc1ccc(Br)cc1
Product: COc1cccc(Cc2cc(Br)ccc2O)c1

Procedure:
Alkylation of 4-bromophenol with 3-methoxybenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-bromo-2-(3′-methoxybenzyl)phenol. This material was converted to compound 75, mp 97-101.5° C., and compound 76, mp 102-106° C., by the procedure similar to that in Example 18 method B.
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]([CH3:21])[C:10](=[O:20])[C:11]1[CH:16]=[CH:15][C:14](F)=[C:13]([F:18])[C:12]=1F)(C)C.[CH2:24]([N:26]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:46])[C:33]2[CH:38]=[C:37]([O:39][C@@H:40]([CH3:44])[CH2:41][O:42][CH3:43])[CH:36]=[C:35]([OH:45])[CH:34]=2)=[N:27]1)[CH3:25].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[CH2:24]([N:26]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:46])[C:33]2[CH:38]=[C:37]([O:39][C@@H:40]([CH3:44])[CH2:41][O:42][CH3:43])[CH:36]=[C:35]([O:45][C:14]3[CH:15]=[CH:16][C:11]4[C:10](=[O:20])[N:9]([CH3:21])[CH2:8][CH2:7][O:6][C:12]=4[C:13]=3[F:18])[CH:34]=2)=[N:27]1)[CH3:25]
Reactant: CCn1ccc(NC(=O)c2cc(O)cc(O[C@@H](C)COC)c2)n1
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1ccc(F)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCn1ccc(NC(=O)c2cc(Oc3ccc4c(c3F)OCCN(C)C4=O)cc(O[C@@H](C)COC)c2)n1
Temperature: 140 °C
Yield: 68.1 %

Procedure:
A suspension of N-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-2,3,4-trifluoro-N-methylbenzamide (300 mg, 0.86 mmol), N-(1-ethyl-1H-pyrazol-3-yl)-3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide (290 mg, 0.91 mmol) and potassium carbonate (237 mg, 1.73 mmol) in DMA (20 mL) was heated to 140° C. for 4 hours. The reaction was poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine (50 mL) and dried (MgSO4), filtered and evaporated to give an orange oil. This was purified by column chromatography on alumina, eluting with 30-100% ethyl acetate in isohexane, to give the desired product as a colourless oil (300 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:15][C@H:14]3[N:11]([C:12](=[O:26])[C@@H:13]3[C@H:16]([O:18][Si:19]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:20][CH3:21])[CH3:17])[C:10]=2[C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])[CH:6]=[CH:7][CH:8]=1.C(N(CC)C(C)C)(C)C.[CH3:42][N:43]=[C:44]=[O:45]>ClCCl>[CH3:42][NH:43][C:44]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:15][C@H:14]3[N:11]([C:12](=[O:26])[C@@H:13]3[C@H:16]([O:18][Si:19]([CH2:20][CH3:21])([CH2:24][CH3:25])[CH2:22][CH3:23])[CH3:17])[C:10]=2[C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])[CH:6]=[CH:7][CH:8]=1)=[O:45]
Reactant: CN=C=O
Reactant: C=CCOC(=O)C1=C(c2cccc(CO)c2)C[C@@H]2[C@@H]([C@@H](C)O[Si](CC)(CC)CC)C(=O)N12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)C1=C(c2cccc(COC(=O)NC)c2)C[C@@H]2[C@@H]([C@@H](C)O[Si](CC)(CC)CC)C(=O)N12
Reaction time: 24 h
Yield: 43.4 %

Procedure:
Allyl (5R,6S)-3-[3-(hydroxymethyl)phenyl]-7-oxo-6-{(1R)-1-[(triethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (250 mg) prepared in the above step, was dissolved in dichloromethane (10 ml), and thereto were added N,N-diisopropylethylamine (14 mg) and methyl isocyanate (276 mg). The mixture was stirred for 1 day, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform) to give allyl (5R,6S)-3-[3-({[(methylamino)carbonyl]oxy}methyl)phenyl]-7-oxo-6-{(1R)-1-[(triethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (122 mg).
Reaction SMILES: S(O[C@H:12]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C@@H:14]([CH2:15][CH2:16][C@@H:17]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:38])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C@H:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:13]1)(C1C=CC(C)=CC=1)(=O)=O.[N-:39]=[N+:40]=[N-:41].[Na+]>CN(C)P(=O)(N(C)C)N(C)C>[N:39]([C@@H:12]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C@@H:14]([CH2:15][CH2:16][C@@H:17]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:38])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C@H:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:13]1)=[N+:40]=[N-:41]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CC[C@@]3(C)[C@@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]43)C2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](N=[N+]=[N-])CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C

Procedure:
4 g (7.37 mmol) 3β-tosyloxy-5α-cholestane and 0.99 g (15.23 mmol) NaN3 are heated under stirring in 25 ml hexamethylphosphoric acid triamide (HMPT) for 3 h to 90° C. The reaction mixture is cooled and given into 100 ml ice water, the precipitated raw product subsequently removed by filtration, washed with water and dissolved in 60 ml ether. The organic phase is washed twice with water, dried over Na2SO4 and concentrated. The resulting wax-like product is directly processed further:
Reaction SMILES: C(OC1C=CC2C(=CC=CC=2)C=1C=NO)C1OC1.[OH:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]=1[CH:30]=[O:31].C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45]>CN(C)C=O.O>[CH2:47]([O:46][C:44]([CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][O:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]=1[CH:30]=[O:31])=[O:45])[CH3:48]
Reactant: CCOC(=O)CCCCCBr
Reactant: O=Cc1c(O)ccc2ccccc12
Agent: O=C([O-])[O-]
Agent: ON=Cc1c(OCC2CO2)ccc2ccccc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCOc1ccc2ccccc2c1C=O
Reaction time: 1 h
Yield: 83.9 %

Procedure:
As shown in Chemical Formula 4, in 20 mL of DMF (N,N-dimethylformamide), 1.09 g (6.33 mmol) of 2-hydroxy-1-naphthoaldehyde (1) and 1.22 g (8.86 mmol) of potassium carbonate were dissolved and the resultant reaction solution was stirred for 1 hour. To the reaction solution, 1.94 g (8.72 mmol) of ethyl 6-bromohexanoate (5) was added and the resultant reaction mixture was stirred at 100° C. for 13 hours to effect the reaction. Then, to the reaction solution, 50 mL of water was added and the reaction mixture was extracted with 50 mL of ethyl acetate. The organic phase was washed with each of 50 mL of pure water and 50 mL of Brine three times and was dried over MgSO4, and the solvent thereof was concentrated under reduced pressure. The resultant green crude product was recrystallized in hexane-AcOEt (hexane-ethyl acetate) to obtain 1.67 g (yield: 84%) of 2-[5-(ethoxycarbonyl)pentyloxy]-1-naphthoaldehyde (6) as a plate-shaped crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:22]=[CH:21][N:20]=[C:19]3[C:11]=2[C:12]2[CH:13]=[CH:14][C:15]4[C:16](=[CH:23][N:24]([CH2:26][CH2:27]OS(C)(=O)=O)[N:25]=4)[C:17]=2[S:18]3)[CH:5]=[CH:6][C:7]=1[F:8].C(N(C(C)C)CC)(C)C.[NH2:42][CH2:43][CH2:44][S:45]([CH3:48])(=[O:47])=[O:46]>CN(C=O)C.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:22]=[CH:21][N:20]=[C:19]3[C:11]=2[C:12]2[CH:13]=[CH:14][C:15]4[C:16](=[CH:23][N:24]([CH2:26][CH2:27][NH:42][CH2:43][CH2:44][S:45]([CH3:48])(=[O:47])=[O:46])[N:25]=4)[C:17]=2[S:18]3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CS(=O)(=O)OCCn1cc2c(ccc3c2sc2ncnc(Nc4ccc(F)c(Cl)c4)c23)n1
Reactant: CS(=O)(=O)CCN
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)CCNCCn1cc2c(ccc3c2sc2ncnc(Nc4ccc(F)c(Cl)c4)c23)n1
Temperature: 80 °C
Yield: 5.1 %

Procedure:
To a stirring solution of methanesulfonic acid 2-[6-(3-chloro-4-fluoro-phenylamino)-10-thia-2,3,7,9-tetraaza-cyclopenta[a]fluoren-2-yl]-ethyl ester (190 mg, 0.39 mmol) in DMF (3 mL) was added diisopropylethylamine (99 mg, 0.77 mmol) and 2-aminoethylmethylsulfone (143 mg, 1.16 mmol). It was heated to 80° C. for overnight. The crude mixture was diluted with methanol (5 mL) and it was separated by prep HPLC. The prep HPLC fractions were collected and solvent was removed by vacuum. The solid was re-dissolved by ethyl acetate (15 mL) and water (10 mL), sat. sodium carbonate solution (3 mL) was added. The organic layer was separated and dried over sodium sulfate. Evaporation of the solvents gave (3-chloro-4-fluoro-phenyl)-{2-[2-(2-methanesulfonyl-ethylamino)-ethyl]-2H-10-thia-2,3,7,9-tetraaza-cyclopenta[a]fluoren-6-yl}-amine as a white solid (10.3 mg, 5.1%) 1H-NMR (DMSO-d6) δ 9.25 (bs, 1H), 8.80 (d, 1H), 8.60 (d, 1H), 8.40 (t, 1H), 7.90 (d, 1H), 7.80 (d, 1H), 7.60 (t, 1H), 7.40 (t, 1H), 4.60 (t, 2H), 3.20 (t, 2H), 2.90 (s, 3H), 2.10 (t, 2H), 2.05 (t, 2H); LCMS RT=2.89 min; [M+H]+=519.2.
Reaction SMILES: [CH2:1]([O:4][S:5]([O-:8])(=[O:7])=[S:6])[CH2:2][CH3:3].[Na+:9].[CH2:10]([SH:16])[C:11]1[O:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+].Br[CH2:20][CH2:21][CH3:22].[S:23]([O-])([O-])(=O)=S.[Na+].[Na+]>O.CO.O>[CH2:1]([O:4][S:5]([O-:8])(=[O:7])=[S:6])[CH2:2][CH3:3].[Na+:9].[CH2:20]([S:23][S:16][CH2:10][C:11]1[O:15][CH:14]=[CH:13][CH:12]=1)[CH2:21][CH3:22]
Reactant: SCc1ccco1
Reactant: O=S([O-])([O-])=S
Reactant: CCCBr
Agent: CCCOS(=O)([O-])=S
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCSSCc1ccco1

Procedure:
Furfuryl propyl disulfide was prepared by a Bunte salt reaction. Sodium furfurylthiolate was prepared by reaction of furfuryl mercaptan with sodium hydroxide in water. Sodium propylthiosulfate (Bunte salt) was prepared by reaction of bromopropane with sodium thiosulfate in a mixture of methanol/water. The reaction of the two salts, sodium furfurylthiolate and sodium propylthiosulfate, in water yielded furfuryl propyl disulfide.
Reaction SMILES: C([O:8][C:9]1[CH:34]=[C:33]([CH2:35][CH3:36])[CH:32]=[CH:31][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)(=[O:20])=[O:19])=[CH:14][C:13]=1[F:30])C1C=CC=CC=1.O1CCCC1>C(O)C>[CH2:35]([C:33]1[CH:32]=[CH:31][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)(=[O:20])=[O:19])=[CH:14][C:13]=2[F:30])=[C:9]([OH:8])[CH:34]=1)[CH3:36]
Reactant: CCc1ccc(Oc2ccc(S(=O)(=O)NCCc3ccccn3)cc2F)c(OCc2ccccc2)c1
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1ccc(Oc2ccc(S(=O)(=O)NCCc3ccccn3)cc2F)c(O)c1
Yield: 56 %

Procedure:
According to the procedure of example 20(b) except substituting 4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene for 4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-N-(2-pyridin-2-yl-ethyl)-benzene sulfonamide (150 mg; 0.30 mmol) and tetrahydrofurane for ethanol (3 mL), the title compound (70 mg; 62%) was obtained as a clear oil, after purification via preparative TLC (dichloromethane/ethyl acetate).
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]([N+:22]([O-])=O)[CH:9]=2)=[N:6][NH:5][C:4](=[O:25])[CH2:3]1.[H][H]>C(O)C.C(O)(=O)C.[Pd]>[CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]([NH2:22])[CH:9]=2)=[N:6][NH:5][C:4](=[O:25])[CH2:3]1
Reactant: [H][H]
Reactant: CC1CC(=O)NN=C1c1ccc(NCc2ccccc2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC1CC(=O)NN=C1c1ccc(NCc2ccccc2)c(N)c1

Procedure:
A mixture of 6.75 gm of 5-methyl-6-(3-nitro-4-benzylamino-phenyl)-4,5-dihydro-2H-pyridazine-3-one and 0.7 gm of 10% palladium charcoal in a mixture of 100 ml of ethanol and 20 ml of glacial acetic acid was treated for 3.5 hours at room temperature with hydrogen at 5 bar. The catalyst was filtered off, the filtrate was evaporated, and the residue was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:12])=[C:4](Cl)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[CH2:13]([O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[CH3:14].C(N(CC)CC)C>CCO>[Cl:1][C:2]1[C:3]([Cl:12])=[C:4]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][CH2:13][CH3:14])=[CH:17][CH:18]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1
Reactant: Clc1nn2ccnc2c(Cl)c1Cl
Reactant: CCOc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOc1ccc(Nc2c(Cl)c(Cl)nn3ccnc23)cc1
Temperature: 90 °C
Yield: 86 %

Procedure:
A mixture of 6,7,8-trichloroimidazo[1,2-b]pyridazine (0.04 g, 0.18 mmol) from 1d, p-ethoxyaniline (0.025 g, 0.18 mmol) and triethylamine (0.055 mL, 0.4 mmol) were suspended in EtOH (1.0 mL) and heated to 90° C. for 2.5 hours. The reaction mixture was then cooled to room temperature and concentrated in vacuo to provide crude 6,7-dichloro-N-(4-ethoxyphenyl)imidazo[1,2-b]pyridazin-8-amine (0.05 g, 86%).
Reaction SMILES: P([O-])([O-])([O-])=[O:2].[K+].[K+].[K+].[OH:9][CH2:10][C:11]([C@H:13]([C@@H:15]([C@H:17]([CH2:19][OH:20])[OH:18])[OH:16])[OH:14])=[O:12]>O>[CH2:19]([OH:20])[C@H:17]([OH:18])[C@@H:15]([OH:16])[C@H:13]([OH:14])[C:11]([C:10]([OH:2])=[O:9])=[O:12]
Reactant: O=P([O-])([O-])[O-]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: [K+]
Solvent: O
Product: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Reaction time: 38 h

Procedure:
Gluconobacter oxydans L-8 (FERM-P No. 8355) was cultivated in a 30 l jar fermentor in the same manner as described in Example 5. After 38 hours of cultivation, 1.5 l of the culture was harvested to obtain the cells. 10 g of the cells were suspended into 60 ml of 10 mM potassium phosphate buffer (pH, 7.0) and homogenized by a Dyno mill homogenizer (Willy, A. Bachofen Co.) with glass beads at 2000 rpm for 4 minutes at 4° C. The homogenate was centrifuged at 5000 rpm for 10 minutes to remove the intact cells. 2 ml of the supernatant thus obtained was mixed with 1 ml of 0.5M potassium phosphate buffer (pH, 7.0) and 6 ml of water containing 100 mg of L-sorbose and incubated at 30° C. for 4 hours. As a result, 25 mg of 2-keto-L-gulonic acid was formed.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4](=[O:24])[C@@H:5]2[CH:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].[CH3:25][Si:26]([CH3:39])([CH3:38])N1C(=O)C2CCCCC2C1=O.[Br:40]N1C(=O)CCC1=O>ClCCl>[Br:40][CH2:1][C:2]1[CH2:3][S:4](=[O:24])[C@@H:5]2[CH:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([O:10][Si:26]([CH3:39])([CH3:38])[CH3:25])=[O:9]
Reactant: C[Si](C)(C)N1C(=O)C2CCCCC2C1=O
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: C[Si](C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Reaction time: 1 h
Yield: 45 %

Procedure:
To a refluxing suspension of 347 mg (1.00 mmole) of 3-methyl-7-phenylacetamido-3-cephem-4-carboxylic acid-1-oxide in 25 ml of dichloromethane, 340 mg of N-trimethylsilylhexahydrophthalimide (1.5 mmoles) were added and after refluxing for 50 minutes, a second portion of 340 mg of N-trimethylsilylhexahydrophthalimide (1.5 mmoles) was added thereto. The clear solution that was obtained after refluxing for ten minutes was diluted with dichloromethane to approximately 40 ml, was cooled in an ice-bath and then bromination was carried out in one hour using 260 mg (1.46 mmoles) of N-bromosuccinimide as the brominating agent to obtain a 45% yield of of trimethylsilyl 3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31]([OH:33])=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37][CH2:38][CH:39]=[CH2:40]>>[CH2:38]([NH:37][C:31](=[O:33])[C:30]1[CH:34]=[CH:35][CH:36]=[C:28]([S:27][CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:29]=1)[CH:39]=[CH2:40]
Reactant: O=C(O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Reactant: C=CCN
Product: C=CCNC(=O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 89.3 %

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and 3-aminopropene (17 mg, 0.30 mmol, 0.6M in DMF) were combined to give 48 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 538 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.[NH2:12][CH2:13][CH2:14][CH2:15][OH:16].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClC(Cl)C>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][NH:12][CH2:13][CH2:14][CH2:15][OH:16]
Reactant: COc1ccc(Br)c(C=O)c1
Reactant: NCCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1ccc(Br)c(CNCCCO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-bromo-5-methoxybenzaldehyde (1 eq) in dichloroethane was added 3-aminopropanol (1.5 eq) followed by NaBH(OAc)3 (2 eq) and acetic acid (4 eq) and the resulting mixture was stirred at RT under nitrogen for 8 h. The reaction mixture was quenched by careful addition of 2M Na2CO3 solution and stirred 1 h. The mixture was concentrated in vacuo and poured into diethyl ether. The phases were separated and the organic phase washed with 1N HCl solution. The aqueous phase was then washed with diethyl ether and subsequently basified with 1N NaOH solution. The aqueous phase was extracted with diethyl ether, dried over Na2SO4 and concentrated in vacuo to give 3-(((2-bromo-5-methoxyphenyl)methyl) amino)propan-1-ol as a clear oil. EI-MS m/z 274, 276 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:30]1[CH:31]=[CH:32][C:33]([NH:36][C:37]2[CH:38]=[N:39][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:41][CH:42]=2)=[N:34][CH:35]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:30]3[CH:35]=[N:34][C:33]([NH:36][C:37]4[CH:38]=[N:39][C:40]([C:43]([F:45])([F:46])[F:44])=[CH:41][CH:42]=4)=[CH:32][CH:31]=3)=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: FC(F)(F)c1ccc(Nc2ccc(Br)cn2)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nc3)cc2)CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-piperidine-1 carboxylic acid tert-butyl ester (1.56 g, 4.1 mmol) and (5-Bromo-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-yl)-amine (1.28 g, 4.0 mmol) were dissolved in DME (8 mL) in a pressure vessel, and to the solution was added PdCl2dppf (100 mg, 0.12 mmol) and Na2CO3 (2.0M, 4.0 mL, 8.1 mmol). The mixture was sparged with nitrogen for 10 minutes, then the vessel was sealed and stirred at 80° C. for 18 hours. The mixture was partitioned between EtOAc and saturated aqueous NH4Cl, washed with brine, dried with magnesium sulfate, filtered, and concentrated via rotary evaporation. The crude material was purified via column chromatography on silica gel, eluting with a gradient of EtOAc/hexanes (10-50%) to obtain the target compound as a solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (br. s., 2H) 1.42 (s, 9H) 1.52 (qd, J=12.63, 4.55 Hz, 2H) 1.77 (m, 2H) 2.66-2.76 (m, 1H) 4.09 (m, 2H) 7.03 (d, J=8.59 Hz, 1H) 7.34 (d, J=8.34 Hz, 2H) 7.60 (d, J=8.08 Hz, 2H) 7.79 (d, J=8.84 Hz, 1H) 7.99 (dd, J=8.72, 2.65 Hz, 1H) 8.56 (d, J=2.53 Hz, 1H) 8.91 (d, J=2.53 Hz, 1H) 9.87 (s, 1H); MS (M+H)+499.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:16][CH:17]=2)=[CH:11][C:10]([C:28](O)=[O:29])=[N:9]1.C(N1C=CN=C1)([N:33]1[CH:37]=[CH:36]N=C1)=O.C(N)C.C1COCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:16][CH:17]=2)=[CH:11][C:10]([C:28]([NH:33][CH2:37][CH3:36])=[O:29])=[N:9]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(=O)O)nn3-c3ccccc3Cl)s2)c1
Agent: CCN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCNC(=O)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2Cl)n1
Reaction time: 2 h
Yield: 86.4 %

Procedure:
To a suspension of 1-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazole-3-carboxylic acid (92 mg, 0.2 mmol) in DCM (2 mL) was added carbonyldiimidazole (39 mg, 1.2 equiv) and stirring was continued for 2 h at 20° C. A solution of ethylamine in THF (1.8 M, 0.17 mL, 1.5 equiv) was added and the mixture was stirred overnight at 20° C. Evaporation of solvent gave a crude, which was purified by column chromatography on silica gel eluting with MeOH-DCM (1:19) to afford 1-(2-chlorophenyl)-N-ethyl-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazole-3-carboxamide (84 mg). 1H-NMR (CDCl3): δ 8.03 (m, 1H), 7.83 (m, 1H), 7.74 (m, 1H), 7.62-7.45 (m, 5H), 7.22 (m, 1H), 7.19 (s, 1H), 6.91 (m, 1H), 6.82 (d, 1H), 3.55-3.43 (m, 2H), 3.07 (3 s, H), 1.25 (s, 3H). MS(ES): 486 [M+H]+.