Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:10]([C:13]1[CH:17]=[C:16]([Cl:18])[S:15][C:14]=1Cl)(=[O:12])[CH3:11].O>CN(C=O)C.[Cu]I>[C:10]([C:13]1[CH:17]=[C:16]([Cl:18])[S:15][C:14]=1[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)c1cc(Cl)sc1Cl
Reactant: Oc1ccccc1
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cc(Cl)sc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 66.9 %

Procedure:
A mixture of phenol (1.22 g, 13 mM) and NaH (60% oil dispersion, 0.52 g, 13 mM) in DMF (25 mL) was stirred for 40 minutes at room temperature. 3-Acetyl-2,5-dichlorothiophene (1.95 g, 10 mM) and copper (I) iodide (50 mg) was added to the above mixture, and the resulting mixture was heated at 130° C. for 1.5 hours. After cooling, the mixture was poured into water. The whole was extracted with ethyl acetate-hexane (1:1, 200 mL×1, 100 mL×1), and the combined organic layers washed with water, brine, dried over MgSO4, and concentrated in vacuo. Chromatographic purification eluting with ethyl acetate-hexane (1:20) provided the subtitle compound (1.69 g. 67% yield) as a brown oil.
Reaction SMILES: [C:1]1([P:7](=O)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si](Cl)(Cl)(Cl)Cl.[H][H]>[S]>[C:14]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: [H][H]
Reactant: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Si](Cl)(Cl)Cl
Agent: [S]
Product: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Temperature: 250 °C
Yield: 86.8 %

Procedure:
To an oven-dried 50-ml autoclave liner were added 16.68 g of triphenylphosphine oxide (.06 mole) and 0.057 g of sulfur (.0018 mole). The solids were treated with 11.12 g of silicon tetrachloride (.066 mole) and the mixture was placed in an autoclave which was then charged to a pressure of 715 p.s.i.g. (48 atm.) with hydrogen. The mixture was heated to 250°C for 15 hours at a maximum pressure of 77 atm. After cooling and venting, the reaction mixture was worked up by first partitioning between warm 30% by weight aqueous sodium hydroxide solution and toluene. The aqueous layer was extracted once with toluene and the combined organic layers were washed with water and with brine and dried over anhydrous sodium sulfate. Filtration and solvent removal gave 13.66 g (86.9%) of crude triphenylphosphine, mp 68°-77° which contained 2% triphenylphosphine oxide and 3% triphenylphosphine sulfide by gas-liquid chromatographic (glc) analysis. Recrystallization from methanol gave 11.25 g (71%) of purified triphenylphosphine, mp 75°-9°, still containing 1-2% triphenylphosphine sulfide by glc analysis.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][C:9]([NH:11][C@H:12]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=3[O:14][B:13]2[OH:25])=[O:10])[CH2:4][CH2:3]1.Br[CH2:27][C:28]([O:30]CC)=[O:29].[OH-].[Na+]>CO>[C:28]([CH2:27][NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][C:9]([NH:11][C@H:12]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=3[O:14][B:13]2[OH:25])=[O:10])[CH2:4][CH2:3]1)([OH:30])=[O:29]
Reactant: N[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Reactant: CCOC(=O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (R)-3-(2-(trans-4-aminocyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid (Example 6) in MeOH was added TEA (2.5 eq), followed by ethyl bromoacetate (1.2 eq). The reaction mixture was stirred at RT overnight. To this reaction mixture was then added 1N NaOH and stirred for 6 hr. After concentration in vacuo, 1N HCl was added to adjust pH to 1. The reaction mixture was purified using reverse phase HPLC to afford the title compound. ESI-MS m/z 405 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([C:12]([O:14]C)=[O:13])=[CH:9][CH:8]=2)[N:3]=1.Cl>[OH-].[Na+].CO.O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][CH:8]=2)[N:3]=1
Reactant: COC(=O)c1ccc(-c2noc(C)n2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc(-c2ccc(C(=O)O)s2)no1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
A mixture of methyl 5-(5-methyl-1,2,4-oxadiazol-3-yl)-2-thiophenecarboxylate, prepared according to Example 22, (86 mg, 0.38 mmoles) in 3 ml of 2N sodium hydroxide was diluted with 1 ml of methanol and warmed to 60° C. for 10 minutes. The solution was cooled to room temperature, diluted with 2 ml of water and acidified to pH 2 with concentrated hydrochloric acid. After standing for 30 minutes the fluffy crystalline solid which slowly separated was collected by filtration and dried in vacuo to furnish the title compound (45 mg, 56%), m.p. 218°-20° C.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[C:15]([F:32])[CH:14]=2)[CH2:8]1)(=O)=O.[N-:33]=[N+:34]=[N-:35].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:33]([CH2:6][C@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:21][CH2:20]3)=[C:15]([F:32])[CH:14]=2)[CH2:8]1)=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3C[C@@H](COS(C)(=O)=O)OC3=O)cc2F)CC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N3C[C@@H](CN=[N+]=[N-])OC3=O)cc2F)CC1
Temperature: 60 °C
Yield: 99.8 %

Procedure:
A solution of the 16.8 g (35.5 mmol) of the mesylate 3 in 400 mL of dimethylformamide was treated with 11.5 g (177.5 mmol) of sodium azide followed by warming at 60° C. for 16 h. The solution was diluted with ethyl acetate and extracted with water. The organic layer was dried (Na2SO4) and concentrated in vacuo to afford 14.9 g (100%) of the azide 4 as a light yellow solid, mp 101°-104° C., sufficiently pure for further use.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].CN(C)C=O.[H-].[Na+].[Br:21][C:22]1[CH:23]=[CH:24][C:25]2[C:31]3[S:32][C:33]([C:35](Cl)=[O:36])=[CH:34][C:30]=3[CH2:29][CH2:28][O:27][C:26]=2[CH:38]=1>>[Br:21][C:22]1[CH:23]=[CH:24][C:25]2[C:31]3[S:32][C:33]([C:35]([N:12]([C:11]4[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=4[Cl:1])[CH3:13])=[O:36])=[CH:34][C:30]=3[CH2:29][CH2:28][O:27][C:26]=2[CH:38]=1
Reactant: CNc1ccc(C(=O)OC)cc1Cl
Reactant: O=C(Cl)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(Br)cc2OCC3)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a solution containing methyl 3-chloro-4-(methylamino)benzoate (0.184 g, 0.922 mmol) in N,N-dimethylformamide (11.0 mL, 142 mmol) was added sodium hydride (0.0369 g, 0.922 mmol). The mixture was stirred at room temperature 30 min then 8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbonyl chloride (0.288 g, 0.838 mmol) was added. The reaction mixture was stirred for 16 hr. The reaction mixture was quenched with sat. NH4Cl, extracted with DCM (2×). The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography EtOAc/Hex (0-100%) to give methyl 4-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-3-chlorobenzoate (yield 65%). MS: (ESI+) 508.2
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=3)[CH3:20])=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:41]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:42]>ClCCl.C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH:29][C:41]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:42])=[CH:23][CH:22]=3)[CH3:20])=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCCCCCOC(=O)Cl
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCCCCCOC(=O)NC(=N)c1ccc(N(C)Cc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Yield: 58 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-hexyl chloroformate. Yield: 58% of theory, C35H43N7O5 (641.2) Rf value: 0.42 (silica gel; dichloromethane/ethanol=19:1) ##EQU88##
Reaction SMILES: [CH:1]1([NH:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)=[O:16]>>[CH:8]1([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[OH:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CC(C)=O
Reactant: C1CCC(NC2CCCCC2)CC1
Product: ON(C1CCCCC1)C1CCCCC1
Yield: 82.6 %

Procedure:
A solution of 0.057 M DMD in acetone (49.2 ml, 3.317 mmol) was added to a cold stirred solution of N,N-dicyclohexylamine (Kodak; 0.508 g, 3.317 mmol) in acetone (5 ml). The reaction mixture was stirred for ten minutes in an ice bath. The solution was dried over Na2SO4, filtered, and the solvent removed in vacuo to give a colorless crystalline solid. This solid was purified by flash chromatography on silica gel with ethyl acetate:petroleum ether (20:80) elution to give a white crystalline solid (0.457 g, 82.6% yield), mp 70-72.
Reaction SMILES: [C:1]([OH:6])(=O)[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[N:36]1([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>ClCCl>[C:1]([N:39]1[CH2:38][CH2:37][N:36]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:41][CH2:40]1)(=[O:6])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 78 %

Procedure:
To a solution of isobutyric acid (6.608 g, 75 mmol) in anhydrous dichloromethane (130 mL) was added triethylamine (8.33 g, 82.5 mmol), 1-hydroxybenzotriazole (10.125 g, 75 mmol), followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (14.25 g, 75 mmol). After the addition, the mixture was stirred at room temperature for 40 mins. Then the mixture was cooled to 0° C., and tert-butyl piperazine-1-carboxylate (13.97 g, 75 mmol) was added portion-wise. After the addition, the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (200 mL), washed with saturated sodium bicarbonate (150 mL×2), 10% citric acid (150 mL), brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give tert-butyl 4-isobutyrylpiperazine-1-carboxylate (15 g, yield 78%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.13-1.14 (d, J=6.8 Hz, 6H), 1.47 (s, 9H), 2.75-2.82 (m, 1H), 3.43-3.58 (m, 4H); LC-MS (ESI) m/z: 257(M+1)+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12](C(OC(C)(C)C)=O)[CH:13]=2)O1.Br[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:9]2[CH:13]=[N:12][NH:11][CH:10]=2)=[N:24][CH:25]=1
Reactant: Fc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Fc1ccc(-c2cn[nH]c2)nc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (15.4 g, 52.5 mmol) and 2-bromo-5-fluoropyridine (8.4 g, 47.7 mmol) in 1,4-dioxane (100 mL), Pd(PPh3)4 (5.5 g, 4.77 mmol) and a 2M aqueous solution of Na2CO3 (71.6 mL, 0.14 mol) were added, then the resulting mixture was stirred at 100° C. for 3 hours and then at room temperature for 72 hours. Water was added to the reaction mixture, followed by extraction with EtOAc. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over MgSO4, then the drying agent was filtered off, and then the solvent was distilled off under reduced pressure. A small amount of EtOAc was added to the obtained residue and the resulting mixture was filtered out and dried to obtain the title compound (4.9 g) (colorless solid).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[N:11]1.[CH3:26][C:27]([CH3:30])([O-])[CH3:28].[K+].BrCC1CC1>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:26][CH:27]2[CH2:30][CH2:28]2)=[CH:4][C:3]=1[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=2[F:23])=[N:11]1
Reactant: O=C(Nc1ccn(Cc2cc(O)ccc2Cl)n1)c1c(F)cccc1F
Reactant: CC(C)(C)[O-]
Agent: BrCC1CC1
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(Nc1ccn(Cc2cc(OCC3CC3)ccc2Cl)n1)c1c(F)cccc1F
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 29.6 %

Procedure:
To a solution of N-{1-[(2-chloro-5-hydroxyphenyl)methyl]-1H-pyrazol-3-yl}-2,6-difluorobenzamide (for as preparation see Intermediate 13) (46 mg, 0.126 mmol) in DMSO (0.5 ml) was added potassium t-butoxide (15 mg, 0.134 mmol). The reaction was stirred for 10 min. To the reaction mixture was added (bromomethyl)cyclopropane (0.012 ml, 0.126 mmol, Lancaster). The reaction was heated to 60° C. and stirred overnight under nitrogen. The reaction mixture was filtered through a hydrophobic frit and the filtrate diluted with methanol (0.5 ml) and the sample purified by MDAP on Sunfire C18 column using Acetonitrile-Water with a Formic acid modifier (Method B). The solvent was evaporated in vacuo to give the title compound as a white solid (15.6 mg); LCMS: (System 4) MH+=418, tRET=3.20 min.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:13])[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[N:22]=[C:23]=S>C(#N)C>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[NH:22][C:23]1[NH:1][C:2]2[CH:3]=[C:4]([OH:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]=2[N:12]=1
Reactant: Fc1cccc(Cl)c1N=C=S
Reactant: COC(=O)c1cc(N)c(N)cc1O
Solvent: CC#N
Product: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)[nH]c2cc1O
Yield: 39.6 %

Procedure:
The title compound was prepared following the procedure described for step-2 of intermediate-55 using methyl 4,5-diamino-2-hydroxybenzoate (step-1 of Intermediate-55, 0.700 g, 3.840 mmol), acetonitrile (5.0 mL), 1-chloro-3-fluoro-2-isothiocyanatobenzene (Intermediate-14, 0.700 g, 3.760 mmol) and N,N-di-isopropyl carbodimide (1.0 mL) to afford 0.5 g of the desired product. 1HNMR (DMSO-d6): δ 3.87 (s, 3H), 6.61 (s, 1H), 7.29-7.46 (m, 4H), 10.62 (s, 1H); MS [M+H]+: 336.17.
Reaction SMILES: [C:1]([O:4][CH2:5]Br)(=[O:3])[CH3:2].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]([CH2:32][C@@H:33]([OH:37])[C:34]([OH:36])=[O:35])[NH:23][C:24]([C:26]2[N:27]=[N:28][N:29]([OH:31])[CH:30]=2)=[O:25])=[CH:17][CH:16]=1.CC(C)=O.CCN(CC)CC>>[C:1]([O:4][CH2:5][O:31][N:29]1[CH:30]=[C:26]([C:24]([NH:23][N:22]([CH2:32][C@@H:33]([OH:37])[C:34]([OH:36])=[O:35])[CH2:21][C:18]2[CH:19]=[CH:20][C:15]([C:9]3[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=3[Cl:7])=[CH:16][CH:17]=2)=[O:25])[N:27]=[N:28]1)(=[O:3])[CH3:2]
Reactant: O=C(NN(Cc1ccc(-c2cc(Cl)ccc2Cl)cc1)C[C@@H](O)C(=O)O)c1cn(O)nn1
Reactant: CC(=O)OCBr
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)OCOn1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3Cl)cc2)C[C@@H](O)C(=O)O)nn1
Temperature: 55 °C
Reaction time: 1 h
Yield: 14.5 %

Procedure:
Bromomethyl acetate (15.3 mg, 100 μmol) was added to a solution of (R)-3-[N-(2′,5′-dichlorobiphenyl-4-ylmethyl)-N′-(1-hydroxy-1H-1,2,3-triazole-4-carbonyl)hydrazino]-2-hydroxypropionic acid (31.2 mg, 66.8 μmol) in acetone (0.5 mL, 6.8 mmol) followed by Et3N (18.6 μL, 134 μmol). The resulting mixture was stirred at 55° C. for 1 hour. The mixture was then concentrated in vacuo to yield a yellow liquid. The crude liquid was purified (preparative scale C18 column chromatography, small column, using 30-90% MeCN in water with 0.05% TFA) to yield the title compound (5.2 mg, purity 96%) as a white solid. MS m/z [M+H]+ calc'd for C22H21Cl2N5O2, 538.08. found 538.1.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25](O)=[O:26])[CH:23]=3)[NH:18][CH:17]=2)=[N:6][C:5]=1[CH3:28])(=[O:3])[CH3:2].FC1C(O)=C(F)C(F)=C(F)C=1F.C[CH2:42][N:43](C(C)C)[CH:44](C)C.C(Cl)CCl.CNC>CN(C=O)C>[C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([N:43]([CH3:44])[CH3:42])=[O:26])[CH:23]=3)[NH:18][CH:17]=2)=[N:6][C:5]=1[CH3:28])(=[O:3])[CH3:2]
Reactant: CC(=O)c1sc(N2CCOC[C@@H]2Cc2c[nH]c3ccc(C(=O)O)cc23)nc1C
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(=O)c1sc(N2CCOC[C@@H]2Cc2c[nH]c3ccc(C(=O)N(C)C)cc23)nc1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 32.3 %

Procedure:
To a stirred solution of Example 11 (0.115 g, 0.29 mmol) in DMF (2 mL) was added pentafluorophenol (0.064 g, 0.35 mmol), DIPEA (0.100 mL, 0.57 mmol) and EDC (0.072 g, 0.37 mmol). The reaction mixture was stirred at r.t. for 48 h. Dimethylamine (40% w/v in water, 5 mL) was added and the reaction mixture stirred for 16 h at r.t. The reaction mixture was concentrated in vacuo. DCM (5 mL) and water (5 mL) were added. The aqueous layer was extracted with DCM (2×3 mL). The combined organic fractions were washed with water (3×15 mL), dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue was purified by preparative HPLC (Method 6) to give the title compound (0.040 g, 45%) as a white solid. δH (CD3OD) 8.07 (1H, s), 7.42 (1H, m), 7.25-7.19 (2H, m), 4.39-4.29 (1H, m), 4.14-3.99 (1H, m), 3.88 (1H, d, J 11.9 Hz), 3.72-3.51 (4H, m), 3.42 (1H, dd, J 13.8 Hz and J 10.2 Hz), 3.19-3.03 (7H, m), 2.57 (3H, s), 2.43 (3H, s). Exchangeable proton not observed. LCMS (ES+) 427.0 (M+H)+, RT 2.59 minutes (Method 2).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]4=[O:28])=[CH:18][C:17]=3[S:29][CH3:30])[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:39])C=1>CC(C)=O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]4=[O:28])=[CH:18][C:17]=3[S:29]([CH3:30])=[O:39])[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cc(-n2ccccc2=O)ccc1-n1cnc(CNC(=O)c2ccc(Cl)s2)c1
Solvent: CC(C)=O
Product: CS(=O)c1cc(-n2ccccc2=O)ccc1-n1cnc(CNC(=O)c2ccc(Cl)s2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-chloro-N-((1-(2-(methylthio)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide prepared above (16 mg, 0.035 mmol) in acetone (1 mL), mCPBA (70%, 12 mg, 0.049 mmol) was added. After being stirred at room temperature for 30 min, the mixture was purified by HPLC to give the sulfoxide (5 mg) and sulfone (3 mg). MS 473.0 and 475.0 (M+H, Cl pattern) for sulfoxide and 489.0 and 491.0 (M+H, Cl pattern) for sulfone.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][CH2:10][S:11]([CH2:13][C:14]([OH:16])=O)=[O:12])=[O:7].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[N:42]1([CH2:48][C:49]2[CH:50]=[C:51]([CH:57]=[CH:58][CH:59]=2)[O:52][CH2:53][CH2:54][CH2:55][NH2:56])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>ClCCl>[N:42]1([CH2:48][C:49]2[CH:50]=[C:51]([CH:57]=[CH:58][CH:59]=2)[O:52][CH2:53][CH2:54][CH2:55][NH:56][C:14](=[O:16])[CH2:13][S:11]([CH2:10][CH2:9][NH:8][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])=[O:12])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: O=C(O)CS(=O)CCNC(=O)c1ccco1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(CS(=O)CCNC(=O)c1ccco1)NCCCOc1cccc(CN2CCCCC2)c1
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
There was suspended 3.0 g (0.0122 mol) of 2-[2-(2-furoylamino)ethylsulfinyl)acetic acid inl 100 ml of dichloromethane and added 1.87 g (0.0122 mol) of HOBt and 2.52 g (0.0122 mol) of DCC under cooling with ice, and the mixture was stirred for 30 minutes under cooling with ice. Thereto was added 3.04 g (0.0122 mol) of N-3-[3-(piperidinomethyl)phenoxy]propylamine, and the mixture was stirred for 18 hours at room temperature. The precipitate was filtrated off, and the filtrate was washed with 5 % aqueous solution of sodium hydroxide and with water and dried over Glauber's salt. Then the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=5:1) to give 3.0 g of the titled compound as crystals.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:30])[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.[N+:31]([C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH:36]=[O:37])([O-:33])=[O:32]>O1CCCC1>[C:26]([O:25][C:23]([N:20]1[CH2:19][CH2:18][CH:17]([CH:16]([C:15]([O:14][CH3:13])=[O:30])[CH:36]([OH:37])[C:35]2[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=2[N+:31]([O-:33])=[O:32])[CH2:22][CH2:21]1)=[O:24])([CH3:27])([CH3:29])[CH3:28]
Reactant: COC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(C1CCN(C(=O)OC(C)(C)C)CC1)C(O)c1ccccc1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
N,N-diisopropylamine (4.40 mL, 31.3 mmoles) was dissolved in tetrahydrofuran (50 mL). The mixture was cooled to −78° C. Butyllithium (2.5 M in hexanes, 12.4 mL, 31 mmoles) was added dropwise to the stirred solution. After stirring at −78° C. for 30 min, a solution of tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (6.65 g, 25.8 mmoles) in tetrahydrofuran (15 mL) was added dropwise to the mixture. Stirring was continued at −78° C. for 1 h. A solution of 2-nitrobenzaldehyde (3.90 g, 25.8 mmoles) in tetrahydrofuran (20 mL) was then added to the mixture dropwise, and then stirring was continued at −78° C. for a further 2.5 h. The reaction was quenched with cold aqueous ammonium chloride and then diluted with water. The mixture was extracted twice with ethyl acetate and the aqueous phase was discarded. The material was dried (magnesium sulfate) filtered, and concentrated to dryness. Silica gel chromatography afforded the desired product in 94% yield as light yellow foam. MS m/e (M-C4H8+H)+=353.1.