Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:20]([O-:22])=O)[C:8]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[CH2:16][CH2:15][CH2:14]3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][CH:24]1[C:37](=[O:38])[N:26]2[CH:27]([C:32]3[NH:36][N:35]=[N:34][N:33]=3)[C:28]([CH3:31])([CH3:30])[S:29][C@H:25]12>>[CH2:15]1[C:14]2[C:13](=[CH:12][C:11]([O:10][C:8]([CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:20]([NH:23][CH:24]3[C:37](=[O:38])[N:26]4[CH:27]([C:32]5[NH:33][N:34]=[N:35][N:36]=5)[C:28]([CH3:30])([CH3:31])[S:29][C@H:25]34)=[O:22])=[O:9])=[CH:19][CH:18]=2)[CH2:17][CH2:16]1
Reactant: O=C([O-])C(C(=O)Oc1ccc2c(c1)CCC2)c1ccccc1
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnn[nH]1
Product: CC1(C)S[C@@H]2C(NC(=O)C(C(=O)Oc3ccc4c(c3)CCC4)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Yield: 63 %

Procedure:
(2.0 mmole) of 5-indanyl 2-phenylmalonate with 480 mg. (2.0 mmole) of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, according to the procedure of Example CXLVII affords 680 mg. (63% yield) of 6-(2-[5-indanyloxycarbonyl]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam as its sodium salt. The infrared spectrum (KBr disc) of the product shows absorption bands at 1780 cm-1 (β-lactam), 1705 cm-1 (ester), 1680 cm-1 (amide I) and 1565 cm-1 (amide II). The NMR spectrum (D2O) shows absorption bands at 7.80-6.80 ppm (multiplet, aromatic hydrogens), 5.70 ppm (multiplet, C-5 and C-6 hydrogens), 5.25 ppm (doublet, C-3 hydrogen), 2.60-2.00 ppm (multiplet, C-1 and C-3 indanyl hydrogens), 2.00-1.80 ppm (multiplet, C-2 indanyl hydrogens), 1.35 ppm (doublet, C-2 methyl hydrogens) and 0.90 ppm (doublet C-2 methyl hydrogens).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:5][CH:4]=1.C(O)(=O)C>I>[CH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)[N:10]=1
Reactant: COc1ccc(-c2cc3ccccc3cn2)cc1
Agent: I
Solvent: CC(=O)O
Product: Oc1ccc(-c2cc3ccccc3cn2)cc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
2-(4-Methoxy phenylethynyl)benzaldehyde (2.06 g, 8.73 mmol) and t-butylamine (3.83 g, 52.4 mmol) were stirred under nitrogen for 24 h at room temperature. The resulting mixture was extracted with ether and the organic layer was dried over anhydrous Na2SO4, concentrated to give the imine (2.4 g, 94%) which was used in the next step without further purification. To a solution of this imine (2.39 g, 8.2 mmol) in 100 mL anhydrous DMF was added (0.156 g, 0.82 mmol) copper(I) iodide and flushed with nitrogen. The reaction mixture was heated at 100° C. for 4 hours. The mixture was cooled to room temperature, and diluted with ether (200 mL). The organic layer was washed with saturated aqueous ammonium chloride (3×100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to give the crude compound as a dark colored solid. Purification by column chromatography (SilicaGel 230-400 mesh; 10% ethylacetate in hexanes as eluent) afforded 3-(4-methoxyphenyl)isoquinoline (1.064 g, 55%) as a white solid. The 3-(4-methoxyphenyl)isoquinoline (1.05 g, 4.47 mmol) was suspended in 30 mL hydroiodic acid and 12 mL of acetic acid was added. The reaction mixture was stirred at 110° C. for 2 h, then cooled to room temperature. The precipitate formed was filtered off, washed with acetic acid (2×5 mL) and dried under vacuum to give a yellow solid. The crude compound was purified by triturating with 5% methanol in ether to give 4-isoquinolin-3-yl-phenol (0.83 g, 84%) as a white powder. MS (ES) m/z: 222.89 (M+1), 221.86 (M); MP 218-219° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][CH3:18])[CH2:13][CH2:12]1.C([Li])CCC.B(OC)(OC)[O:25]C.OO>C1COCC1.C1(C)C=CC=CC=1.O>[F:8][C:7]1[C:2]([F:1])=[C:3]([O:9][CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([CH2:17][CH3:18])[CH2:13][CH2:12]2)[CH:4]=[CH:5][C:6]=1[OH:25]
Reactant: CC[C@H]1CC[C@H](COc2cccc(F)c2F)CC1
Reactant: COB(OC)OC
Agent: OO
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CC[C@H]1CC[C@H](COc2ccc(O)c(F)c2F)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
37 g of 2,3-difluoro-1-(trans-4-ethylcyclohexyl)methoxybenzene was dissolved in 222 mL of THF, and 59.9 mL of butyllithium (2.67 M hexane solution) was added dropwise thereto at an internal temperature of −40° C. or lower. Then, further stirring was continued for 30 min. To this solution, 18.1 g of trimethyl borate was added dropwise at an internal temperature of −40° C. or lower, and then the temperature was increased to 0° C. Then, 24.7 mL of 30% hydrogen peroxide solution was added dropwise for 5 min, and the stirring was continued for 3 hours. Water and toluene were added thereto, and the organic layer was fractioned while the aqueous layer was extracted with toluene. The organic layers were combined and washed with water, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography, to thereby obtain 20 g of 2,3-difluoro-4-(trans-4-ethylcyclohexyl)methoxyphenol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH2:17]C(=O)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(C)=C(C=1)N.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CC(C)=O)c(NC(=O)OC(C)(C)C)c1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: COc1ccc(C)c(N)c1
Product: COc1ccc(C)c(NC(=O)OC(C)(C)C)c1
Yield: 80 %

Procedure:
1-[2-(tert-Butoxycarbonylamino)-4-methoxyphenyl]-2-propanone. 12 g (87 mmol) of 5-methoxy-2-methylaniline was treated by the method in Example 1, Part A, with 19 g (87 mmol)of di-tert-butyl dicarbonate to give on concentrating a reaction mixture containing 16.4 g (80% yield) of N-tert-butoxycarbonyl-5-methoxy-2-methylaniline. This material (69 mmol) was reacted with 106 mL of 1.3M sec-butyl lithium in cyclohexane and then 7.1 g (69 mmol) of N-methoxy-N-methylacetamide (as described in Example 9, Part B) to give after chromatography on silica, eluting with 33% EtOAc/hexane, 13.8 g (72% yield) of 1-[2-(tert-butoxycarbonylamino-4-methoxyphenyl]-2-propanone.
Reaction SMILES: [F:1][C:2]1[C:3]([N:17]=[CH:18][N:19](C)C)=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.Cl.N[OH:24]>CCO>[F:1][C:2]1[C:3]([NH:17][CH:18]=[N:19][OH:24])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1
Reactant: CN(C)C=Nc1nc(OCc2ccc(F)cc2)ncc1F
Reactant: NO
Agent: Cl
Solvent: CCO
Product: ON=CNc1nc(OCc2ccc(F)cc2)ncc1F
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 94.5 %

Procedure:
To a solution of N′-[5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]-N,N-dimethyl-formamidine (0.10 g, 0.34 mmol) in EtOH (2 mL) was added hydroxylamine hydrochloride (0.047 g, 0.68 mmol) and the mixture was agitated on an orbital shaker for 1.5 h at 50° C. The reaction mixture was cooled and evaporated to dryness. Water was added to produce a slurry which was filtered to isolate the title compound (0.090 g, 94% yield) as a white solid: mp 169-171° C.; 1H NMR (300 MHz, CDCl3) δ 8.15 (d, J=2.2 Hz, 1H), 8.02 (bs, 2H), 7.49-7.43 (m, 2H), 7.11-7.02 (m, 3H), 5.35 (s, 2H); HPLC-MS (ESI) m/z 281 (M+H)+, 279 (M−H)−.
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.[Cl:16][C:17]1[N:22]=[C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][C@H:24]2[CH3:29])[CH:20]=[C:19]([CH2:30][S:31]([CH3:33])=[O:32])[N:18]=1.[F:34][C:35]([F:40])([F:39])[C:36]([NH2:38])=[O:37].[O-2].[Mg+2]>C(Cl)Cl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[Cl:16][C:17]1[N:18]=[C:19]([CH2:30][S:31]([CH3:33])(=[O:32])=[N:38][C:36](=[O:37])[C:35]([F:40])([F:39])[F:34])[CH:20]=[C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][C@H:24]2[CH3:29])[N:22]=1
Reactant: C[C@@H]1COCCN1c1cc(CS(C)=O)nc(Cl)n1
Reactant: NC(=O)C(F)(F)F
Agent: [Rh+2]
Agent: CC(=O)[O-]
Agent: [Mg+2]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: Ic1ccccc1
Product: C[C@@H]1COCCN1c1cc(CS(C)(=O)=NC(=O)C(F)(F)F)nc(Cl)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 81.6 %

Procedure:
Iodobenzene diacetate (6.54 g, 20.29 mmol) was added to (3R)-4-(2-chloro-6-(methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine (5.88 g, 20.29 mmol), 2,2,2-trifluoroacetamide (4.59 g, 40.58 mmol), magnesium oxide (3.27 g, 81.16 mmol) and rhodium(II) acetate dimer (0.224 g, 0.51 mmol) in DCM (169 ml) under air. The resulting suspension was stirred at RT for 3 days. Further 2,2,2-trifluoroacetamide (1.15 g, 10.15 mmol), magnesium oxide (0.818 g, 20.29 mmol), rhodium(II) acetate dimer (0.056 g, 0.13 mmol) and iodobenzene diacetate (1.64 g, 5.07 mmol) were added and the suspension was stirred at RT for a further 24 hours. The reaction mixture was filtered and silica gel (3 g) was added to the filtrate and then the mixture was evaporated. The resulting powder was purified by flash chromatography on silica, eluting with a gradient of 20 to 50% EtOAc in isohexane. Fractions containing product were evaporated and the residue was triturated with isohexane/methyl tert-butylether to give a solid which was collected by filtration and dried under vacuum to afford N—[({2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}methyl)(methyl)oxido-λ6-sulfanylidene]-2,2,2-trifluoroacetamide (6.64 g, 82%); 1H NMR (400 MHz, CDCl3) 1.33 (3H, d), 3.28 (1H, dd), 3.43 (3H, d), 3.46-3.59 (1H, m), 3.62-3.71 (1H, m), 3.79 (1H, d), 3.90-4.50 (2H, br s), 4.21 (1H, s), 4.66 (1H, dd), 4.86 (1H, dd), 6.50 (1H, d); m/z: (ES+) MH+, 401.01, 402.93. b) Sodium hydroxide (Sigma-Aldrich 415413, d=1.515 g/ml, 50 ml of a 50% solution, 937.57 mmol) was added to N—[({2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}methyl)(methyl)oxido-λ6-sulfanylidene]-2,2,2-trifluoroacetamide (5.2 g, 12.97 mmol), 1,2-dibromoethane (4.47 ml, 51.90 mmol) and tetrabutylammonium hydrogensulfate (0.441 g, 1.30 mmol) in toluene (500 ml). The resulting mixture was stirred at RT for 24 hours. Further 1,2-dibromoethane (1.00 ml, 11.60 mmol) was added and the mixture was stirred at RT for a further 2 hours. The reaction mixture was diluted with EtOAc (500 ml), and washed sequentially with water (750 ml) and saturated brine (100 ml). The organic layer was dried over MgSO4, filtered and evaporated. The residue was dissolved in DCM (100 ml) and then purified by flash chromatography on silica, eluting with a gradient of 0 to 5% MeOH in DCM.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[NH2:19])[O:5][C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:15])[CH3:14])[CH:9]=[CH:10][CH:11]=1.[Cl:20][C:21]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=S)=[CH:31][C:22]=1[CH2:23][N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1.C(Cl)CCl>CC#N>[Cl:20][C:21]1[CH:34]=[CH:33][C:32]([NH:35][C:36]2[NH:19][C:18]3[CH:17]=[CH:16][C:4]([O:5][C:6]4[CH:7]=[C:8]([NH:12][C:13](=[O:15])[CH3:14])[CH:9]=[CH:10][CH:11]=4)=[CH:3][C:2]=3[N:1]=2)=[CH:31][C:22]=1[CH2:23][N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1
Reactant: CC(=O)Nc1cccc(Oc2ccc(N)c(N)c2)c1
Reactant: CN1CCN(Cc2cc(N=C=S)ccc2Cl)CC1
Solvent: CC#N
Solvent: ClCCCl
Product: CC(=O)Nc1cccc(Oc2ccc3[nH]c(Nc4ccc(Cl)c(CN5CCN(C)CC5)c4)nc3c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of N-[3-(3,4-diamino-phenoxy)-phenyl]-acetamide (Step B, 320 mg, 1.2 mmol, 1.0 eq.) in 20 mL of anhydrous CH3CN was added drop-wise to a solution of 1-(2-chloro-5-isothiocyanato-benzyl)-4-methyl-piperazine (300 mg, 1.2 mmol, 1.0 eq.) in 10 mL of CH3CN. The reaction was stirred for 2 h at RT. EDC (360 mg, 1.9 mmol, 1.5 eq.) was added and the reaction was heated to 80° C. and stirred for 1 h. The mixture was cooled and concentrated. The residue was dissolved into EtOAc and washed with H2O and sat. NaHCO3 (aq.). The organic layer was dried (MgSO4), filtered and concentrated. The crude was further purified by column chromatography (0-10% MeOH/CH2Cl2 with 1% NH4OH) followed by recrystallization from CH2Cl2 to give pure N-(3-{2-[4-chloro-3-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-1H-benzimidazol-5-yloxy}-phenyl)-acetamide. MS m/z=506.2 (M+H)+; Calc'd for C27H29N6O2: 504.20.
Reaction SMILES: Cl.[F:2][C:3]([F:18])([F:17])[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Cl:19][C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[O:28])[CH:23]=[CH:24][CH:25]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:19][C:20]1[CH:21]=[C:22]([NH:26][C:27]([N:10]2[CH2:11][CH2:12][CH:7]([O:6][C:5]3[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=3[C:3]([F:2])([F:17])[F:18])[CH2:8][CH2:9]2)=[O:28])[CH:23]=[CH:24][CH:25]=1
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Reactant: O=C=Nc1cccc(Cl)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cccc(Cl)c1)N1CCC(Oc2ccccc2C(F)(F)F)CC1

Procedure:
A solution of 4-(2-trifluoromethylphenoxy)piperidine hydrochloride (42 mg, 0.15 mmol), 3-chlorophenyl isocyanate (36 mg, 0.30 mmol), and N,N-diisopropylethylamine (78 μL, 0.45 mmol) was stirred in dichloromethane (2 mL) at room temperature for overnight. The reaction mixture was diluted with dichloromethane and the solution was washed successively with 1N HCl, and NaHCO3 (sat.)/brine. The organic fraction was dried over MgSO4, filtered, and concentrated. The compound was purified by radial silica gel chromatography (1:20 to 1:2 ethyl acetate:hexanes) to afford the product which was 98% pure by LCMS analysis (15.7 mg, 26%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[Cl:26])[C:18](=[O:27])[NH:17][N:16]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:28]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][NH:40][CH:41]=2)O1>>[NH:39]1[CH:38]=[C:37]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[S:12][C:13]([C:15]5[N:19]([C:20]6[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=6[Cl:26])[C:18](=[O:27])[NH:17][N:16]=5)=[CH:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:28]=2)[CH:41]=[N:40]1
Reactant: O=c1[nH]nc(-c2cc3c(s2)-c2ccc(Br)cc2OCC3)n1-c1ccccc1Cl
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: O=c1[nH]nc(-c2cc3c(s2)-c2ccc(-c4cn[nH]c4)cc2OCC3)n1-c1ccccc1Cl

Procedure:
Following the procedure of Example 44, 3-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-4-(2-chlorophenyl)-1H-1,2,4-triazol-5(4H)-one and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were reacted to give 277. MS: (ESI+) 462.1
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:17]=[C:18]([CH2:22][CH2:23][C:24]([O:26]C)=[O:25])[CH:19]=[CH:20][CH:21]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:17]=[C:18]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:19]=[CH:20][CH:21]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCc1cccc(Oc2ccnc(NC(=O)OC(C)(C)C)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(Oc2cccc(CCC(=O)O)c2)ccn1
Reaction time: 18 h
Yield: 80.8 %

Procedure:
To a solution of methyl 3-[3-({2-[(tert-butoxycarbonyl)amino]pyridin-4-yl}oxy)phenyl]propanoate (427 mg, 1.15 mmol) in MeOH (10 mL) and THF (5 mL), was added 1M NaOH solution (4.59 mL, 4.49 mmol). The reaction was stirred for 18 h. The solvents were evaporated and the residue was dissolved in water. The solution was acidified to pH=3 by addition of 1N HCl. The precipitate was filtered off and washed with water and then hexane, then dried under vacuum to yield the title compound as a white solid (333 mg, 81%). LCMS: (FA) ES+ 359.1 (M+1), ES− 357.0 (M−1).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][C:52]1[CH:53]=[C:54]2[C:59](=[CH:60][CH:61]=1)[CH:58]=[C:57]([C:62]1[CH:63]=[C:64]([NH2:68])[CH:65]=[CH:66][CH:67]=1)[CH:56]=[CH:55]2>CN(C=O)C>[CH3:50][O:51][C:52]1[CH:53]=[C:54]2[C:59](=[CH:60][CH:61]=1)[CH:58]=[C:57]([C:62]1[CH:63]=[C:64]([NH:68][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:65]=[CH:66][CH:67]=1)[CH:56]=[CH:55]2
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: COc1ccc2cc(-c3cccc(N)c3)ccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2cc(-c3cccc(NC(=O)c4cc5cccc(OC)c5oc4=O)c3)ccc2c1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
DIEA (0.0115 mL, 0.067 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.013 g, 0.06 mmol) and HATU (0.025 g, 0.067 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(6-methoxy-naphthalen-2-yl)-phenylamine (0.015 g, 0.06 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.023 g of product in 83% yield: LCMS (ESI) m/z 452 (MH+).
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15](I)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:33][O:34][C:35]1[CH:40]=[C:39](B(O)O)[CH:38]=[CH:37][N:36]=1>>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15]([C:39]3[CH:38]=[CH:37][N:36]=[C:35]([O:34][CH3:33])[CH:40]=3)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Reactant: COc1cc(B(O)O)ccn1
Product: CCCCCCc1cccc(-c2nc(-c3ccnc(OC)c3)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1

Procedure:
In analogy to the procedure described for example 7, [2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 2) was reacted with 2-methoxy-pyridin-4-yl-boronic acid to give the title compound as light yellow gum. MS: 530.3 (MH+).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C[CH2:11][CH:12]([OH:17])[C:13](OC)=O.CCC(O)C(OC)=O.N[C@H](C(O)=O)CC(C)C.C(OC(=O)[C@H](CC(C)C)N)C.N[C@H](C(O)=O)C[CH2:49][S:50]C.CCC(O)C(OC)=O.N[C@H](C(O)=O)CCSC>>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:50][CH3:49].[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]1[CH:6]=[CH:13][C:12]([OH:17])=[CH:11][CH:5]=1
Reactant: CCC(O)C(=O)OC
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: CCOC(=O)[C@@H](N)CC(C)C
Agent: CSCC[C@H](N)C(=O)O
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
The papain-catalyzed synthesis of leucine and MHBA co-oligomers was also explored. Synthesis of leucine oligomers and MHBA-leucine co-oligomers was initiated with leucine ethyl ester and MHBA ethyl ester as the substrates. The overall synthesis and purification approach was similar to the one used in the case of methionine and MHBA-methionine. Reaction rates similar to those obtained with methionine and tyrosine were achieved. Approximate oligomer yield was 58%. The freeze-dried oligomers precipitates were solubilized in DMSO. The solution concentration was brought to approximately 2 μg/μl. The solution was mixed with 1:1 acetonitrile:water mixture containing 0.1% acetic acid. The total fluid volume entering the ESI-MS was maintained at 0.2 mL min.−1 The positive mass spectrum of the leucine oligomers is shown in FIG. 33A.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[CH:15][C:10]=3[N:9]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:8]2=[O:25])=[C:4]([O:28][CH3:29])[CH:3]=1.Cl[CH2:31]/[CH:32]=[CH:33]\[CH2:34]Cl.C(N(CC)CC)C>CN(C=O)C>[CH:19]1([N:9]2[C:10]3[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[CH:13]=[CH:12][C:11]=3[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([N:1]4[CH:34]=[CH:33][CH:32]=[CH:31]4)=[CH:3][C:4]=3[O:28][CH3:29])[C:8]2=[O:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2Cc1ccc(N)cc1OC
Reactant: ClC/C=C\CCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2Cc1ccc(-n2cccc2)cc1OC
Yield: 44.4 %

Procedure:
A mixture of 1 g of the compound obtained in Example 6, 1 g of cis-1,4-dichloro-2-butene and 1 ml of triethylamine in 20 ml of DMF is heated at reflux for 1 hour 30 minutes under nitrogen atmosphere. After cooling, the reaction mixture is poured into a water/ice mixture, extracted with EtOAc, the organic phase is washed with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica, eluting with DCM. 0.5 g of the expected product is obtained.
Reaction SMILES: CN1CCNCC1.[Li]CCCC.[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]=[O:23])=[CH:21][C:16]=2[CH:15]=[CH:14]1.CN(C)CCN(C)C.[CH2:32]([Sn:36](Cl)([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH3:35]>CCCCCC.C1COCC1>[CH2:41]([Sn:36]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:37][CH2:38][CH2:39][CH3:40])[C:14]1[O:13][C:17]2[CH:18]=[CH:19][C:20]([CH:22]=[O:23])=[CH:21][C:16]=2[CH:15]=1)[CH2:42][CH2:43][CH3:44]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: O=Cc1ccc2occc2c1
Agent: CN(C)CCN(C)C
Agent: CN1CCNCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc2cc(C=O)ccc2o1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 33.8 %

Procedure:
To a solution of N-methylpiperazine (0.75 g, 7.5 mmol) in hexane (15 mL) at 0° C. under nitrogen was added dropwise a solution of n-BuLi (3 mL, 7.43 mmol, 2.5M/hexanes), and the reaction mixture was stirred at 0° C. for 40 min. 1-Benzofuran-5-carbaldehyde (1.0 g, 6.8 mmol) was added dropwise to the reaction mixture at 0° C. and the resulting mixture was stirred at 0° C. for 15 min. After addition of tetramethylethylenediamine (TMEDA) (1.7 g, 14.96 mmol), a solution of n-BuLi (6.0 mL, 14.86 mmol, 2.5M/hexanes) was added dropwise to the reaction mixture at 0° C. and the reaction mixture was allowed to warm up to room temperature and stirred for a total of 18 h. After the reaction mixture was cooled to 0° C. and THF (30 mL) was added, the reaction mixture was cooled to −50° C., tributyltin chloride (4.87 g, 14.96 mmol) was added dropwise, and the reaction mixture was stirred at −50° C. for 15 min. and at room temperature for 5-6 h. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted into diethyl ether. The organic layer was dried over sodium sulfate and concentrated and the crude product was purified by column chromatography (ethyl acetate/hexane, 2%) to give 1.0 g (34%) of 2-(tributylstannyl)-1-benzofuran-5-carbaldehyde as a yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([O:14][C:12]1[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:16]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccncc3)c1)=N2

Procedure:
The title compound was prepared from {5-ethoxy-2-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M32) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (184 mg).