Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:58])/[C:29](=[N:55]\[O:56][CH3:57])/[C:30]3[N:31]=[C:32]([NH:35][C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[S:33][CH:34]=3)[C:25](=[O:59])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].ClC1C=CC=C(C(OO)=[O:68])C=1.O>C(Cl)Cl>[I:1][CH2:2][C:3]1[CH2:4][S:5](=[O:68])[C@@H:6]2[CH:26]([NH:27][C:28](=[O:58])/[C:29](=[N:55]\[O:56][CH3:57])/[C:30]3[N:31]=[C:32]([NH:35][C:36]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[S:33][CH:34]=3)[C:25](=[O:59])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O
Solvent: ClCCl
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.3 %

Procedure:
A mixture of benzhydryl 3-iodomethyl-7-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (VIIa) (1.10 g, 1.19 mmoles) and m-chloroperbenzoic acid (m-CPBA) (322 mg, 1.30 mmoles) in CH2Cl2 (22 ml) was stirred at 0° C. for 15 minutes, poured into H2O (50 ml), and then extracted with CHCl3 (50 ml×3). The combined extracts were washed with saturated aqueous NaHCO3 (50 ml) and NaCl successively, dried and evaporated to afford the title compound (VIIa 1-oxide) (1.12 g, quantitative) as an amorphous powder.
Reaction SMILES: [CH2:1]([C:5]1[C:14]([C:15]#[N:16])=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:23][CH3:24])[CH:11]=2)[N:6]=1)[CH:2]([CH3:4])[CH3:3].N.O1CCCC1>[Ni].CO>[CH2:1]([C:5]1[C:14]([CH2:15][NH2:16])=[C:13]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:23][CH3:24])[CH:11]=2)[N:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COc1ccc2nc(CC(C)C)c(C#N)c(-c3ccccc3)c2c1
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2nc(CC(C)C)c(CN)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 43.5 %

Procedure:
To a mixture of 2-isobutyl-6-methoxy-4-phenylquinoline-3-carbonitrile (1.00 g, 3.16 mmol), 25% aqueous ammonia (4 ml), tetrahydrofuran (30 ml) and methanol (50 ml) was added Raney-nickel (1 ml) and the mixture was stirred under a hydrogen atmosphere at 0.5 MPa, room temperature for 6 hrs. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and recrystallized from n-hexane-ethyl acetate to give the title compound (0.44 g, yield 44%) as colorless crystals.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([C:15]2[O:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[N:17][C:16]=2[CH3:30])[CH3:14])=[CH:8][C:7]=1[CH3:31].CO.[OH-].[Li+].Cl>C1COCC1.O>[CH3:31][C:7]1[CH:8]=[C:9]([O:12][CH:13]([C:15]2[O:19][C:18]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=3)=[N:17][C:16]=2[CH3:30])[CH3:14])[CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][C:3]([OH:32])=[O:2]
Reactant: COC(=O)CCc1ccc(OC(C)c2oc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(OC(C)c2oc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1CCC(=O)O
Temperature: 60 °C

Procedure:
3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-phenyl)-propionic acid methyl ester (0.176 g, 0.393 mmol) is dissolved in 20 mL of a 3:2:1 mixture of THF:MeOH:H2O. Lithium hydroxide (0.050 g, 2.08 mmol) is added and the resulting mixture is heated to 60° C. for 1 hr. The mixture is cooled to room temperature, diluted with 50 mL water and the pH is adjusted to 2–3 with 1M HCl. The product is extracted with two 50 mL portions of ethyl acetate. The combined organic extracts are washed with 50 mL water, dried over anhydrous magnesium sulfate, filtered, and concentrated to yield the title compound, 3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-phenyl)-propionic acid as a white solid, 0.12 g (71%). MS (M++1) 434.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][S:7]([CH:10]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)[C:11]([OH:14])([CH3:13])[CH3:12])(=[O:9])=[O:8].FC(F)(F)C(O)=O.O.C(=O)([O-])O.[Na+]>ClCCl>[CH2:22]([O:21][C:18]1[CH:19]=[CH:20][C:15]([CH:10]([S:7]([NH2:6])(=[O:9])=[O:8])[C:11]([OH:14])([CH3:13])[CH3:12])=[CH:16][CH:17]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COc1ccc(CNS(=O)(=O)C(c2ccc(OCc3ccccc3)cc2)C(C)(C)O)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)C(c1ccc(OCc2ccccc2)cc1)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 77.3 %

Procedure:
A solution of 3.65 g of N-[2,4-dimethoxybenzyl]-1-(4-benzyloxyphenyl)-2-hydroxy-2-methylpropane-1-sulfonamide in 20 ml of dichloromethane was admixed with 4.00 ml of trifluoroacetic acid and stirred at room temperature for 20 minutes. The conversion was checked by LCMS. Since it was incomplete, another 2.00 ml of trifluoroacetic acid were added and the mixture was stirred for a further 2 hours. The reaction solution was admixed with 20 ml of water and neutralized with saturated aqueous sodium hydrogencarbonate solution. The precipitate was filtered off with suction through a glass frit, washed with dichloromethane and water and dried in a desiccator over P2O5. This gave the product (1.95 g) with a molecular weight of 335.4 g/mol (C17H21NO4S).
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=O)[C:3]([CH3:6])([CH3:5])[CH3:4].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=1.[CH3:20][N:21]1[CH2:25][CH2:24][N:23]=[C:22]1[C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1.C(Cl)CCl>CN(C=O)C.O>[CH3:20][N:21]1[CH2:25][CH2:24][N:23]=[C:22]1[C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:7](=[O:9])[CH:2]([C:3]([CH3:6])([CH3:5])[CH3:4])[NH:1][C:18]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)=[O:19])=[CH:28][CH:27]=1
Reactant: CN1CCN=C1c1ccc(N)cc1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CC(C)(C)C(N)C(=O)O
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN1CCN=C1c1ccc(NC(=O)C(NC(=O)Nc2ccc(Cl)cc2)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
To a solution of DL-tert-leucine (43 mg, 0.33 mmol) in DMF (2 mL), 4-chlorophenyl isocyanate (50 mg, 0.33 mmol) was added. The mixture was then stirred at room temperature overnight. To the reaction mixture, 4-(1-Methyl-4,5-dihydro-1H-imidazol-2-yl)-phenylamine (150 mg, 0.86 mmol) and H2O (0.5 mL, to solubilize the amine) were added. To the solution, EDC (127 mg, 0.66 mmol) was added. After being stirred at room temperature overnight, the solution was concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a powder (35 mg). MS 442.1 and 444.1 (M+H, Cl pattern).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.C([Li])CCC.[C:19](=[O:21])=[O:20].CO>O1CCCC1>[F:1][C:2]1[C:3]([C:19]([OH:21])=[O:20])=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: O=C=O
Reactant: Fc1ccc(-c2ccccc2)nc1
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2ccccc2)ncc1F
Temperature: -45 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a solution of 5-fluoro-2-phenylpyridine (760.0 mg, 4.39 mmol) in tetrahydrofuran (15.0 ml) was added n-butyllithium (2.11 ml, 2.50 M in THF, 5.27 mmol) at −45° C. The mixture was stirred for 1 h at −45° C., then poured into THF containing dry ice Stirred for 1 h, then MeOH (2 ml) was added. The solution was concentrated, and purified on Flashmaster II to get 560 mg (58%) of 5-fluoro-2-phenylisonicotinic acid.
Reaction SMILES: [Cl:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]2[N:6]([C@@H:9]3[CH2:13][C@H:12]([CH2:14][OH:15])[CH:11]=[CH:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1.C(OC(=O)C)(=O)C.[Br:26]N1C(=O)CCC1=O>N1C=CC=CC=1>[Br:26][C:7]1[N:6]([C@@H:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[CH:11]=[CH:10]2)[C:5]2[CH:16]=[C:17]([Cl:18])[C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OC[C@@H]1C=C[C@H](n2cnc3cc(Cl)c(Cl)cc32)C1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: OC[C@@H]1C=C[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)C1
Yield: 14.8 %

Procedure:
(±)-cis-[4-(5,6-Dichloro-1H-benzimidazol-1-yl)-2-cyclopenten-1-yl]methanol (1.55 g, 5.47 mmol) was acetylated in pyridine (17 mL) with acetic anhydride (0.6 mL) at ambient temperature for 2 days. Volatiles were removed in vacuo and the residual oil partitioned between chloroform and aqueous sodium bicarbonate. The chloroform solution was dried (sodium sulfate) and concentrated to dryness. The residue was dissolved in dry dioxane (10 mL) and the solution brought to reflux. N-bromosuccinimide (930 mg, 5.23 mmol) was added all at once. The dark solution was cooled after 4 minutes of reflux. Volatiles were evaporated in vacuo and the residue was chromatographed on silica gel. Elution with 2-5% methanol-chloroform gave fractions containing starting material (1.05 g) followed by fractions containing title compound as a dark oil (0.28 g). The recovered starting material was again treated with N-bromosuccinimide and the crude product chromatographed. All product-containing fractions were combined and rechromatographed on silica gel with elution by hexanes-ethyl acetate to give the acetate of title compound as a yellow oil (0.62 g). Deacetylation was carried out as in Example 4. Volatiles were evaporated in vacuo from the neutralized solution and the residue was chromatograped on silica gel. Elution with 2% methanol-chloroform gave (±)-cis-[4-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-2-cyclopenten-1-yl]methanol as off-white powder (293 mg, 15%), after resolidification from hexanes-ethyl acetate, m.p. 126°-128.5° C.; 1H-NMR(DMSO-d6) δ: 8.09 and 7.95 (both s, 1 each, aromatic CH), 6.24-6.20 and 5.98-5.94 (both m, 2, CH=CH), 5.81-5.76 (2 m, 1 each, CH2O), 4.96 (t, J=4.9 Hz, 1, OH), 3.02-2.95 (m, 1, CH), 2.67-2.51 (m overlapping solvent, 1/2CH2), 2.0-1.8 (m, 1, 1/2CH2); mass spectrum (CI) consistent with structure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][N:3]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>>[N:10]1([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[N:3][CH:4]=2)[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: BrCc1ccc(Br)nc1
Reactant: c1c[nH]cn1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Brc1ccc(Cn2ccnc2)cn1

Procedure:
Synthesized using 1b (1.32 g, 5.26 mmol), imidazole (0.75 g, 11.00 mmol), K2CO3 (1.13 g, 8.16 mmol) and 18-crown-6 according to Method B. Yellow solid. Yield: 0.75 g, 60%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=5.12 (s, 2H), 6.88 (t, J=1.2 Hz, 1H), 7.13 (s, 1H), 7.28 (d, J=2.5 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.56 (s, 1H), 8.28 (d, J=2.5 Hz, 1H); MS (ESI): m/z=239.08 [M+H]+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:19]([C:21]4([N:47](C=O)[CH3:48])[CH2:25][CH2:24][N:23]([CH2:26][C:27](=[O:46])[N:28]5[CH2:33][CH:32]=[C:31]([C:34]6[CH:39]=[CH:38][C:37]([C:40]7[N:45]=[CH:44][CH:43]=[CH:42][N:41]=7)=[CH:36][CH:35]=6)[CH2:30][CH2:29]5)[CH2:22]4)=[O:20])[CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.O.[OH-].[Na+]>CO>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:19]([C:21]4([NH:47][CH3:48])[CH2:25][CH2:24][N:23]([CH2:26][C:27](=[O:46])[N:28]5[CH2:29][CH:30]=[C:31]([C:34]6[CH:39]=[CH:38][C:37]([C:40]7[N:41]=[CH:42][CH:43]=[CH:44][N:45]=7)=[CH:36][CH:35]=6)[CH2:32][CH2:33]5)[CH2:22]4)=[O:20])[CH:16]=3)[NH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: CN(C=O)C1(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)CCN(CC(=O)N2CC=C(c3ccc(-c4ncccn4)cc3)CC2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CNC1(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)CCN(CC(=O)N2CC=C(c3ccc(-c4ncccn4)cc3)CC2)C1

Procedure:
Added 2M HCl (2 ml) to a solution of 3-(Formyl-methyl-amino)-1-{2-oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-ethyl}-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1H-indazol-5-yl]-amide (8T) (11 mg, 0.017 mmol) in MeOH (5 ml) at room temperature for 4 days. Evaporated solvent Added H2O (20 ml), basified with 1N NaOH (2 ml), and extracted with MeCl2 (50 ml). Separated organic layer, dried over MgSO4, filtered and evaporated solvent, yielding residue which chromatographed on silica gel eluting with 10% MeCl2/MeOH yielding 9T (5 mg) ESMS (MH 631)
Reaction SMILES: CN(C)C=O.[N+:6]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11]Br)([O-:8])=[O:7].C(=O)(O)[O-].[Na+].[CH2:22]([O:24][C:25]([C:27]1[CH:36]=[CH:35][C:30]2[N:31]=[C:32]([CH3:34])[NH:33][C:29]=2[CH:28]=1)=[O:26])[CH3:23]>O.C(OCC)(=O)C>[CH2:22]([O:24][C:25]([C:27]1[CH:36]=[CH:35][C:30]2[N:31]([CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[N+:6]([O-:8])=[O:7])[C:32]([CH3:34])=[N:33][C:29]=2[CH:28]=1)=[O:26])[CH3:23]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: CCOC(=O)c1ccc2nc(C)[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)nc(C)n2Cc1ccccc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
N,N-dimethylformamide (15 ml), 2-nitrobenzyl bromide (1.59 g) and sodium bicarbonate (1.23 g) are added to 5-ethoxycarbonyl-2-methylbenzimidazole (1.00 g) and the solution is heated for one hour at 60° C. After adding ethyl acetate (70 ml) and water (70 ml) and separating the solution, the organic layer is washed with water three times and extraction is performed on the aqueous layer using ethyl acetate three times. By concentrating the obtained organic layer under reduced pressure, a mixture of 6-ethoxycarbonyl-2-methyl-1-(2-nitrobenzyl)benzimidazole and 5-ethoxycarbonyl-2-methyl-1-(2-nitrobenzyl)benzimidazole is obtained. Purification using medium pressure silica gel column chromatography (eluate: hexane/etlhyl acetate=1/4˜0/100) produced 6-ethoxycarbonyl-2-methyl-1-(2-nitrobenzyl)benzimidazole (83) (0.614 g) and 5-ethoxycarbonyl-2-methyl-1-(2-nitrobenzyl)benzimidazole (84) (0.259 g). 1H-NMR CDCl3, δ): 1.38 (3H, t, J=7.2 Hz), 2.56 (3H, s), 4.37 (2H, q, J=7.1 Hz), 5.84 (2H, s), 6.41 (1H, d, J=6.8 Hz), 7.44-7.53 (2H, m), 7.78 (1H, d, J=8.6 Hz), 7.88 (1H, s), 8.02 (1H, dd, J=8.3 and 1.5 Hz), 8.30 (1H, dd, J=7.9 and 1.5 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:14])([CH3:13])[CH:4](OS(C)(=O)=O)[C:5]([OH:7])=[O:6].[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19]([SH:25])[N:18]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:24][O:23][C:21]1[CH:22]=[C:17]([O:16][CH3:15])[N:18]=[C:19]([S:25][CH:4]([C:3]([O:2][CH3:1])([CH3:13])[CH3:14])[C:5]([OH:7])=[O:6])[N:20]=1
Reactant: COC(C)(C)C(OS(C)(=O)=O)C(=O)O
Reactant: COc1cc(OC)nc(S)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(SC(C(=O)O)C(C)(C)OC)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
That is, after 3-methoxy-3-methyl-2-methylsulfonyloxybutanoic acid (22.6 g, 0.1 mol) and 4,6-dimethoxy-2-mercaptopyrimidine (17.3 g, 0.1 mol) were added to N,N-dimethylformamide (200 ml) and further anhydrous potassium carbonate (13.8 g) was added, the mixture was stirred at 50° C. for 2 hours. The resulting reaction mixture was added to a 1N hydrochloric acid aqueous solution (300 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated saline solution and dried over magnesium sulfate, and ethyl acetate was removed under reduced pressure. The crystals obtained were washed with n-hexane to obtain 24.1 g (yield: 80%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:28][O:29][C:30]1[C:31](=[O:58])[C:32]([CH3:57])=[C:33]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([O:49][CH2:50][C:51]3[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=3)=[C:44]([CH:48]=2)[C:45](O)=[O:46])[C:34](=[O:38])[C:35]=1[O:36][CH3:37]>C(Cl)Cl>[CH3:28][O:29][C:30]1[C:31](=[O:58])[C:32]([CH3:57])=[C:33]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([O:49][CH2:50][C:51]3[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=3)=[C:44]([CH:48]=2)[C:45]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=2)=[O:46])[C:34](=[O:38])[C:35]=1[O:36][CH3:37]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)O)c2)=C(C)C1=O
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)Nc3ccc(C(F)(F)F)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 12.4 %

Procedure:
4-Trifluoromethylaniline (0.242 g, 1.500 mmol), triethylamine (0.152 g, 1.500 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.254 g, 1.500 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-pyridylmethyloxy)benzoic acid (0.215 g, 0.500 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.035 g, 0.0618 mmol, 12%).
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([CH3:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:27])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:16]([O:18]CC)=[O:17])C.[OH-].[K+]>C(O)C.O>[CH3:27][C:15]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([CH2:14][CH2:13][CH2:12][CH2:11][C:10](=[O:28])[CH2:9][CH2:8][CH2:7][CH2:6][C:5]([CH3:35])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:4]([OH:36])=[O:3])[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)C(C)(CCCCC(=O)CCCCC(C)(C(=O)OCC)c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(CCCCC(=O)CCCCC(C)(C(=O)O)c1ccccc1)(C(=O)O)c1ccccc1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
According to the procedure given for 210f, 209d (3.93 g, 7.9 mmol) was hydrolyzed with KOH (85%, 4.0 g, 60.6 mmol) in ethanol (60 mL) and water (10 mL) at reflux for 3 h and at room temperature overnight. After the usual workup and drying, 210d (3.0 g, 87%) was obtained as an oil. 1H NMR (CDCl3): δ 7.40-7.10 (m, 10H), 2.32 (t, 4H, J=7.2), 2.10-1.80 (m, 4H), 1.60-1.45 (m, 4H), 1.54 (s, 6H), 1.25-1.10 (m, 4H). 13C NMR (CDCl3): δ 211.1, 182.5, 142.8, 128.4, 126.9, 126.0, 49.9, 42.3, 38.7, 24.2, 24.0, 22.3. HRMS (LSIMS, nba): Calcd for C27H35O5 (MH4): 439.2484, found: 439.2497. HPLC: 93.7% pure.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)C.[ClH:16].O1CCOCC1.[NH3:23]>CO>[ClH:16].[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11](=[NH:23])[NH2:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: N
Reactant: N#CCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCO
Solvent: CO
Solvent: C1COCCO1
Product: N=C(N)Cc1ccc([N+](=O)[O-])cc1
Reaction time: 22 h

Procedure:
A suspension of (4-nitrophenyl)acetonitrile (4.86 g, 30.0 mmol) in ethanol (6 mL, 99 mmol) in a 250 mL round bottom flask was slowly treated at room temperature with 4N hydrochloric acid in dioxane (38 mL, 152 mmol) and stirred for 22 hours. After carefully removing the solvent under water aspirator vacuum at 40° C. the obtained wet pale yellow product was suspended in 21 mL ethanol. Then, a 7N ammonia solution in methanol (12 mL, 84 mmol) was slowly added giving a pale gray suspension. After stirring for two hours additional 2 mL (14 mmol) 7N ammonia solution in methanol were added. After further stirring for one hour at room temperature all volatiles were removed under water aspirator vacuum at 40° C. To remove residues of ethanol and dioxane methyl t-butyl ether (30 mL) was added and once more all volatiles were removed under water aspirator vacuum at 40° C. giving an off-white solid. The crude product was used without purification in the next step.
Reaction SMILES: [NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4].S(=O)(=O)(O)O.[CH2:24]=[C:25]([CH3:27])[CH3:26].N#N>ClCCl.C(Cl)(Cl)Cl.CCCCCC>[NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:6]([O:8][C:13]([CH3:18])([CH3:14])[CH3:12])=[O:7])[C@@H:3]([CH3:5])[O:4][C:25]([CH3:27])([CH3:26])[CH3:24]
Reactant: C[C@@H](O)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: C=C(C)C
Agent: N#N
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCCCCC
Product: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 48 h

Procedure:
Z-Thr-OH (25.3 g, 0. 1 mol, Peptide Research Laboratories, Japan) was suspended in dichloromethane (250 ml), to which was added conc. sulfuric acid (1 ml). The mixture was cooled on a dry ice-acetone bath, to which was blown isobutene (the volume increased by 200 ml). The vessel was closed tightly, and the mixture was stirred for 2 days at 20° C. The vessel was opened, into which was blown N2 at 20° C. to purge isobutene, followed by addition of water. The mixture was neutralized with a 10% (W/V) aqueous solution of sodium hydrogencarbonate, which was subjected to extraction twice with dichloromethane. The dichloromethane layer was dried over anhydrous sodium sulfate, then the solvent was distilled off. The residue was purified by means of a silica gel column chromatography (n-hexane:chloroform =1:2) to give an oily product. The yield was 26.6 g (72.7%). Rf: 0.21 (n-hexane:chloroform =1:2) FAB-MS (M+H+)=366 (Theoretical value =366)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.[N:9]1([C:14](N2C=CN=C2)=[O:15])[CH:13]=[CH:12][N:11]=[CH:10]1>C(Cl)Cl>[N:9]1([C:14]([O:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:15])[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCc1cccnc1
Solvent: ClCCl
Product: O=C(OCc1cccnc1)n1ccnc1
Yield: 80.6 %

Procedure:
A solution of (pyridin-3-yl)methanol (2 g, 18.32 mmol) and di(1H-imidazol-1-yl)methanone (5.94 g, 36.65 mmol) in 20 mL CH2Cl2 was heated overnight at 50° C. The reaction was washed with water, dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 10-70% EtOAc in CH2Cl2 gave (pyridin-3-yl)methyl 1H-imidazole-1-carboxylate (3 g, 81%). LC/MS: m/z 204.1 (M+H)+ at 0.39 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, CDCl3) δ 8.74 (d, J=1.9 Hz, 1H), 8.68 (dd, J=4.8, 1.4 Hz, 1H), 8.16 (s, 1H), 7.81 (m, 1H), 7.44 (s, 1H), 7.38 (m, 1H), 7.09 (s, 1H), 5.46 (s, 2H).