Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[C:10]([C:28]2[N:32](C(OC(C)(C)C)=O)[C:31]3[CH:40]=[CH:41][CH:42]=[CH:43][C:30]=3[N:29]=2)=[N:11][C:12]([C:15]2[CH2:16][CH2:17][N:18](C(OC(C)(C)C)=O)[CH2:19][CH:20]=2)=[CH:13][N:14]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:29]1[C:30]2[CH:43]=[CH:42][CH:41]=[CH:40][C:31]=2[N:32]=[C:28]1[C:10]1[C:9]([NH2:8])=[N:14][CH:13]=[C:12]([C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH:20]=2)[N:11]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3nc4ccccc4n3C(=O)OC(C)(C)C)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(C2=CCNCC2)nc1-c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48 %

Procedure:
A solution of tert-butyl 2-(3-(bis(tert-butoxycarbonyl)amino)-6-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-yl)-1H-benzo[d]imidazole-1-carboxylate (1.7248 g, 2.490 mmol) in DCM (17.25 mL) was treated with TFA (5 mL, 64.90 mmol) and left to stir at ambient temperature for 4 hours. The reaction mixture was concentrated in vacuo and triturated from MeOH/Toluene and the resultant orange solid was filtered off (622 mg, 48% Yield). 1H NMR (400.0 MHz, DMSO) d 2.90 (2H, m), 3.41 (2H, m), 3.96 (2H, m), 6.80 (1H, m), 7.09-7.30 (4H, m), 7.82 (2H, br s), 8.52 (1H, s) ppm; MS (ES+) 293.03
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[OH:14])[CH:2]=[CH2:3].C(C1C(C(F)(F)F)=CC=CC=1O)C=C.[H][H]>CO.CCOC(C)=O.[Pd]>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:12])([F:13])[F:11])=[CH:6][C:5]=1[OH:14])[CH2:2][CH3:3]
Reactant: C=CCc1ccc(C(F)(F)F)cc1O
Reactant: [H][H]
Agent: [Pd]
Agent: C=CCc1c(O)cccc1C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCc1ccc(C(F)(F)F)cc1O
Yield: 87.5 %

Procedure:
A mixture of 2-allyl-5-trifluoromethyl-phenol (60 mg, 12%) and 2-allyl-3-trifluoromethyl-phenol and 10% Pd/C (20 mg) in methanol (4 ml) was hydrogenated under 50 psi hydrogen atmosphere for 1 hour. The mixture was dissolved in EtOAc, filtered through a celite pad. The filtrate was concentrated under reduced pressure, and dried to give 2-propyl-5-trifluoromethyl-phenol (53 mg, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH3:13][S:14]([N:17]([CH2:36][CH2:37][Cl:38])[N:18]([S:32]([CH3:35])(=[O:34])=[O:33])[C:19](OCC1C=CC=CC=1[N+]([O-])=O)=[O:20])(=[O:16])=[O:15]>>[CH3:13][S:14]([N:17]([CH2:36][CH2:37][Cl:38])[N:18]([S:32]([CH3:35])(=[O:33])=[O:34])[C:19]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11])=[O:20])(=[O:15])=[O:16]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CO
Reactant: CS(=O)(=O)N(CCCl)N(C(=O)OCc1ccccc1[N+](=O)[O-])S(C)(=O)=O
Product: CS(=O)(=O)N(CCCl)N(C(=O)OCc1ccc(Cl)cc1[N+](=O)[O-])S(C)(=O)=O

Procedure:
1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(4-chloro-2-nitrobenzyloxy)carbonyl]hydrazine (compound 13b) was prepared from 4-chloro-2-nitrobenzyl alcohol using a procedure similar to that described for compound 13a. The Mp was about 120-121° C., and the yield was approximately 40.0% by weight after recrystallization from ethanol. 1H NMR (acetone-d6): δ 8.2 and 7.7-8.0 (3H, s, m, aromatic H), 5.8 (2H, d, ArCH2), 3.6-4.1 (4H, m, CH2CH2Cl), 3.5 and 3.2 (6H, 2s, 2 CH3SO2).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: C1COCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Product: O=C([C@@H]1CCCN1C(=O)OCc1ccccc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.5 %

Procedure:
A solution of N-benzyloxycarbonyl-L-proline (5 g, 20.06 mmol), morpholine (1.92 ml, 20.06 mmol), and N-hydroxysuccinimide (2.31 g, 20.06 mmol) in N, N-dimethylformamide (100 ml) was added DCC (4.14 g, 20.06 mmol) and the resulting mixture was stirred for 4 h at room temperature. After the precipitation was filtered off, the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate and the resulting precipitation was filtered off. After the filtrate was washed with dilute hydrochloric acid, saturated sodium hydrogencarbonate aq., and water, the organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized from the mixed solvents of ethyl acetate-hexane to give the compound (34) (4.44 g, 69.5%).
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][O:50][CH:51]5[CH2:53][CH2:52]5)=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH2:54][OH:55])[CH2:11][O:12]2)C1C=CC=CC=1.C1COCC1.ClC1C=CC=CC=1Cl>[Pd].CO>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([CH2:54][OH:55])([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][O:50][CH:51]2[CH2:53][CH2:52]2)=[CH:43][CH:42]=1
Reactant: OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCCOC5CC5)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Solvent: Clc1ccccc1Cl
Product: OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCCOC5CC5)cc4)c3)(O1)[C@H](O)[C@@H](O)[C@@H]2O
Reaction time: 3 h
Yield: 97.9 %

Procedure:
[(1S,2S,3S,4R,55)-2,3,4-tribenzyloxy-5-[4-chloro-3-[[4-[2-(cyclopropoxy)ethoxy]phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol 1g (220.3 mg, 0.29 mmol) was dissolved in 10 mL mixed solution (THF and MeOH, v:v=1:1), followed by addition of 1,2-dichlorobenzene (0.34 mL, 3 mmol) and Palladium/carbon (90 mg, 10%). The mixture was exchanged with H2 three times and stirred for 3 hours, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system A to obtain the title compound (1S,2S,3S,4R,5S)-5-[4-chloro-3-[[4-[2-(cyclopropoxy)ethoxy]phenyl]methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol 1 (140 mg, white solid), yield: 100%. MS m/z (ESI): 510.2 [M+18]. 1H NMR (400 MHz, CD3OD): δ 7.45 (d, 1H), 7.36 (m, 2H), 7.10 (d, 2H), 6.82 (m, 2H), 4.14 (d, 1H), 4.05 (m, 4H), 3.83 (m, 3H), 3.78 (m, 1H), 3.66 (m, 2H), 3.57 (m, 2H), 3.40 (m, 1H), 0.56 (m, 2H), 0.48 (m, 2H).
Reaction SMILES: [C:1]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]([CH3:37])[C:20](=[O:36])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[CH2:13][CH2:12]1)=[O:9].[N:44]1([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[C:1]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][N:19]([CH3:37])[C:20](=[O:36])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([N:47]3[CH2:48][CH2:49][N:44]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:45][CH2:46]3)=[O:32])=[CH:29][CH:28]=2)[CH2:15][CH2:16]1)=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 42 %

Procedure:
The compound (200 mg, 0.311 mmol) obtained in Example 15c was dissolved in 1,4-dioxane, a 4 N hydrochloric acid-dioxane solution (4.67 mL, 18.7 mmol) was added, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, toluene was added, and then the solvent was evaporated under reduced pressure to give crude 4-({6-[(2-{4-[(biphenyl-2-ylcarbamoyl)oxy]piperidin-1-yl}ethyl)(methyl)amino]-6-oxohexyl}amino)benzoic acid. The resulting crude carboxylic acid compound and tert-butyl piperazine-1-carboxylate (58 mg, 0.311 mmol) were dissolved in methylene chloride, triethylamine (0.259 mL, 1.87 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (90 mg, 0.467 mmol) were added, and the mixture was stirred at room temperature for 17 hours. The solvent was evaporated under reduced pressure, the resulting residue was dissolved in ethyl acetate, water and saturated aqueous sodium hydrogencarbonate were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate, then the solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:2→0:100, v/v) to give the title compound (98 mg; yield, 42%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)=[CH:11][C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][OH:34]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:32][CH2:33][OH:34])[CH:14]=3)=[CH:11][C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCCBr
Reactant: CCOC(=O)c1cc(-c2cccc(O)c2)n(-c2cccc(Cl)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(-c2cccc(OCCO)c2)n(-c2cccc(Cl)c2)n1

Procedure:
100 mg (0.29 mmol) of the compound of Example 44A are provided in 2 ml of dry acetone, 44.4 mg (0.32 mmol) of potassium carbonate and 36.5 mg (0.29 mmol) of 2-bromoethanol are added, and the mixture is heated under reflux overnight. The reaction mixture is subsequently purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with the addition of 0.1% formic acid) and 13.1 mg of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Br)[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].O.[Cl:16][C:17]1[CH:41]=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][C:18]=1[C:19]([NH:21][C:22]1[N:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:25]=[C:24]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:23]=1)=[O:20]>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([C:39]2[CH:40]=[CH:41][C:17]([Cl:16])=[C:18]([CH:38]=2)[C:19]([NH:21][C:22]2[N:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:25]=[C:24]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:23]=2)=[O:20])[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)ccc2Cl)n(-c2ccccc2)n1
Reactant: Nc1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(NC(=O)c2cc(-c3cccc(N)n3)ccc2Cl)n(-c2ccccc2)n1
Temperature: 100 °C
Yield: 51 %

Procedure:
6-amino-2-bromopyridine (835.5 mg, 4.83 mmol), sodium carbonate (1.39 g, 13.2 mmol) and water (0.5 mL) were added to the solution of ethyl 5-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylate in dioxane obtained in Preparation 5. The reaction was degassed with nitrogen for 30 minutes before the addition of Pd(dppf)Cl2 with further degassing for 10 minutes. The reaction was heated to 100° C. for 16 hours. The reaction was cooled and eluted through a pad of silica, eluting with EtOAc (50 mL). The organic solution was washed with water (50 mL) dried over magnesium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 30-50% EtOAc in heptanes to afford the title compound as a pale yellow solid (1.02 g, 51%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:10][CH:9]=1
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
To a stirred suspension of 4-(5-bromo-2-chlorobenzyl)phenol (5.0 g, 16.8 mmol) in N,N-dimethylformamide (20 mL) and cesium carbonate (11.0 g, 33.6 mmol) was added ethyl 2-bromoacetate (2.8 mL, 25.2 mmol). The mixture was stirred overnight at 80° C. The solution was diluted with water, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine prior to drying over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give 5.0 g of white solid (78% yield).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][C:3]=1[Cl:16].[F:17][C:18]1[CH:23]=[C:22](B(O)O)[CH:21]=[CH:20][N:19]=1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.CO.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].COCCOC>[Cl:16][C:3]1[C:2]([C:22]2[CH:21]=[CH:20][N:19]=[C:18]([F:17])[CH:23]=2)=[N:7][C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: Clc1ccc(NCC2CCOCC2)nc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: COCCOC
Solvent: ClCCl
Product: Fc1cc(-c2nc(NCC3CCOCC3)ccc2Cl)ccn1
Temperature: 25 °C
Yield: 77.8 %

Procedure:
A mixture of 6-bromo-5-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (intermediate E) (630 mg, 2.062 mmol), 2-fluoropyridin-4-ylboronic acid (639 mg, 4.54 mmol), PdCl2(dppf).CH2Cl2 adduct (168 mg, 0.206 mmol), DME (9 ml) and 2M sodium carbonate (3.09 ml, 6.18 mmol) was stirred at 105° C. for 2 hours, and the reaction progress was followed by LCMS. The reaction mixture was let cool to room temperature, diluted with 30 ml of ethyl acetate, 10 ml of methanol, filtered and concentrated. The crude material was purified by silica gel chromatography using 40 g column and eluting with 5-45% ethyl acetate in heptane. The desired fractions were concentrated to constant mass giving, 516 mg of the title compound as free base. LCMS (m/z): 332.0 (MH+), retention time=0.88 min
Reaction SMILES: [CH2:1]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[OH:18]O>C(O)(=O)C>[CH2:1]([C:12]1[CH:13]=[N+:14]([O-:18])[CH:15]=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCc1cccnc1
Reactant: OO
Solvent: CC(=O)O
Product: CCCCCCCCCCCc1ccc[n+]([O-])c1
Yield: 86.8 %

Procedure:
A solution of 11.0 g (47 mmol) of 3-n-undecylpyridine and 8 ml of an aqueous 35% hydrogen peroxide dissolved in 30 ml of glacial acetic acid was heated at 70° to 80° C. for 3 hours, and then further heated with an additional 3 ml of hydrogen peroxide at the same temperature for 9 hours. After cooling, the mixture was concentrated under a reduced pressure to about a half amount, and 50 ml of water was added, followed by a concentration to a half amount (repeated twice). The residue was extracted with diethyl ether and washed with sodium hydrogen carbonate. After drying over anhydrous sodium sulfate, the product was concentrated under a reduced pressure, and the residue was purified by separation according to silica gel column chromatography (ethyl acetate→methanol:ethyl acetate=15:85) to obtain 10.2 g of the desired product (yield 86.8%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:11]1([NH:22][C:23](=[O:28])[CH2:24][CH2:25][CH2:26][CH3:27])[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21].C(N(CC)CC)C.[C:36](Cl)(=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38]>C(Cl)Cl>[O:21]=[C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19](=[O:20])[C:11]1([C:3]1[CH:4]=[CH:5][C:6]([CH:8]([CH3:10])[CH3:9])=[CH:7][C:2]=1[O:1][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[NH:22][C:23](=[O:28])[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCCCC(=O)NC1(c2ccc(C(C)C)cc2O)C(=O)c2ccccc2C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)NC1(c2ccc(C(C)C)cc2OC(=O)C(C)(C)C)C(=O)c2ccccc2C1=O
Reaction time: 2 h
Yield: 91.3 %

Procedure:
A solution of pentanoic acid [2-(2-hydroxy-4-isopropyl-phenyl)-1,3-dioxo-indan-2-yl]-amide (0.10 g, 0.26 mmol) in anhydrous methylene chloride (10 ml) was added triethylamine (0.03 g, 0.31 mmol) and pivaloyl chloride (0.047 g, 0.39 mmol) and then stirred for 2 hrs. The reaction mixture was concented and extracted with ethylacetate. The concentrated organic layer was purified using silica gel column chromatography (ethylacetate:hexane=1:4) to afford the title compound (0.11 g, 91%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:17]O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5]([O:7][CH3:17])=[O:6]
Reactant: O=C(O)c1cc(Br)cc(I)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)cc(I)c1
Temperature: 25 °C
Yield: 96 %

Procedure:
A stirred, cloudy solution of 3-bromo-5-iodobenzoic acid (10 g, 30.59 mmol) and concentrated sulfuric acid (0.60 mL) in MeOH (65 mL) was heated under reflux for 15 h. The resulting clear, light yellow solution was then allowed to cool to room temperature and was concentrated under vacuum. The residual yellow solid was dissolved in ethyl acetate (100 mL), washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (10 g, 96% yield) as a light yellow solid: 1H NMR (CD3OD, 500 MHz) δ ppm 3.93 (3H, s), 8.12 (1H, m), 8.15 (1H, m), 8.29 (1H, m). HPLC retention time: 2.335 min (method A). MS (ESI) (M+H)+ 340.00.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:33]=[CH:32][C:6]([CH:7]=[N:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C@@:19]([OH:31])([CH3:30])[CH2:20][N:21]3[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[N:23]=[C:22]3Cl)=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[Na+]>CN(C=O)C>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:33]=[CH:32][C:6]([CH:7]=[N:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C@:19]3([CH3:30])[O:31][C:22]4=[N:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][N:21]4[CH2:20]3)=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: C[C@](O)(COC(=O)N1CCN(N=Cc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]1(COC(=O)N2CCN(N=Cc3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To the solution of (R)-3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl 4-(4-trifluoromethylbenzylideneamino)piperazine-1-carboxylate prepared in Example 103 (4.03 g, 7.77 mmol) in DMF (20 ml), sodium hydride (0.37 g, 9.32 mmol) was added followed by stirring for 1 hour with cooling on ice-bath. To the reaction mixture, ice water was added, and the precipitates were filtered off, washed with water and recrystallized from acetonitrile-isopropanol to afford (R)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl 4-(4-trifluoromethylbenzylideneamino)piperazine-1-carboxylate (2.60 g, yield 69%) as a white solid. Melting point 176-178° C.
Reaction SMILES: Br[C:2]1[O:23][C:5]2[N:6]([CH3:22])[CH:7]=[C:8]([C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[O:12])[C:9](=[O:10])[C:4]=2[CH:3]=1.[CH2:24]([OH:28])[CH2:25][C:26]#[CH:27]>C(N(CC)CC)C.CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][NH:13][C:11]([C:8]2[C:9](=[O:10])[C:4]3[CH:3]=[C:2]([C:27]#[C:26][CH2:25][CH2:24][OH:28])[O:23][C:5]=3[N:6]([CH3:22])[CH:7]=2)=[O:12])=[CH:16][CH:17]=1
Reactant: C#CCCO
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(Br)oc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCCO)oc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Bromo-N-(4-chlorobenzyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]-pyridine-5-carboxamide (Example 79, 0.100 g) was suspended in a mixture of triethylamine (2.5 mL) and DMF (0.5 mL). CuI (0.006 g), Pd(PPh3)2Cl2 (0.017 g), and then 3-butyn-1-ol (0.038 mL) were added. The mixture was stirred at room temperature for 30 min and then was partitioned between CH2Cl2 (10 mL) and water (10 mL). The aqueous layer was separated and was extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with a sat. aq. ammonium chloride solution (10 mL), dried (MgSO4), filtered, and concentrated in vacuo. The resulting solid was purified by column chromatography (CH2Cl2/methanol; 99/1, 98/2) followed by recrystallization from ethyl acetate to yield 0.035 g of the title compound as a pale yellow solid. Physical characteristics. M.p. 242-243° C. (dec); 1H NMR (400 MHz, DMSO-d6) δ 10.51, 8.59, 7.41-7.32, 7.21, 5.01, 4.55, 3.92, 3.61, 2.67; MS (ESI+) m/z 385 (,M+H)+.
Reaction SMILES: [C:1]([NH:11][C@@H:12]1[C:24](=[O:25])[N:14]2[C:15]([C:21]([O-:23])=[O:22])=[C:16]([CH2:19][OH:20])[CH2:17][S:18][C@H:13]12)(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[Na+].OP(O)(O)=O>CN(C)C=O>[C:1]([NH:11][C@@H:12]1[C:24](=[O:25])[N:14]2[C:15]([C:21]([OH:23])=[O:22])=[C:16]([CH2:19][O:20][C:1](=[O:10])[CH:2]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[OH:3])[CH2:17][S:18][C@H:13]12)(=[O:10])[CH:2]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[OH:3]
Reactant: O=C([O-])C1=C(CO)CS[C@@H]2[C@H](NC(=O)C(O)c3ccccc3)C(=O)N12
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)C1=C(COC(=O)C(O)c2ccccc2)CS[C@@H]2[C@H](NC(=O)C(O)c3ccccc3)C(=O)N12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 147.8 %

Procedure:
In dimethylformamide (40 ml) was dissolved sodium 7β-mandelamido-3-hydroxymethyl-3-cephem-4-carboxylate (3.86 g), followed by addition of O-carboxymandelic anhydride (2.67 g). The mixture was stirred at room temperature for 30 minutes, after which 2% H3PO4 (150 ml) was added. The mixture was extracted with ethyl acetate (250 ml) and the ethyl acetate layer was rinsed with water (150 ml×2), dried (over magnesium sulfate) and concentrated under reduced pressure. Then, upon addition of ether, there was obtained a powder. This powder was recovered by filtration, washed with ether and dried under reduced pressure over phosphorus pentoxide. The procedure provided 7β-mandelamido-3-mandelyloxymethyl-3-cephem-4-carboxylic acid (3.68 g).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9].[Br:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1>O>[Br:12][C:13]1[S:14][C:15]([C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])=[CH:16][CH:17]=1
Reactant: Brc1cccs1
Reactant: CCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CCCCC(=O)c1ccc(Br)s1
Temperature: 2.5 °C

Procedure:
Charged aluminum chloride (183 mmoles), pentanoyl chloride (147 mmoles) and bromothiophene (122 mmoles) to the RB flask fitted with thermo well, stirred the reaction for 2 hours at 25-30° C. After completion of reaction, cooled the RM to 0-5° C. and added Water (100 ml). Extracted the reaction mass with ethyl acetate (2×200 ml), separated the organic layer and dried with sodium sulphate, distilled off the solvent under reduced pressure to the residue. Residue was high vacuum distilled to get the pure compound (XXI).