Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:7]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][C:10]([CH:11]=O)=[CH:9][C:8]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[C:23]([NH:27][OH:28])([CH3:26])([CH3:25])[CH3:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:1]([C:7]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][C:10]([CH:11]=[N+:27]([C:23]([CH3:26])([CH3:25])[CH3:24])[O-:28])=[CH:9][C:8]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)c1c(C(C)(C)C)cc(C=O)cc1C(C)(C)C
Reactant: CC(C)(C)NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCCC(=O)c1c(C(C)(C)C)cc(C=[N+]([O-])C(C)(C)C)cc1C(C)(C)C
Yield: 56.5 %

Procedure:
To a solution of 4-pentanoyl-3,5-di-tert-butylbenzaldehyde (17.48 g, 0.050 mol) in benzene (250 mL) was added tert-butylhydroxylamine (4.57 g, 0.0510 mol) and p-toluenesulfonic acid (0.080 g). Using a Dean-Stark trap, the resulting mixture was refluxed until no more aldehyde was detected by TLC (Rf=0.43 for product using 1:1 hexanes/EtOAc). The solvent was removed in vacuo and the residue was thoroughly washed with hexanes. The title compound was isolated (56.50% yield) as a white solid, m.p. 195.5-204.8° C.
Reaction SMILES: O[Li].O.C([O:6][C:7](=[O:29])[CH2:8][C:9](=[O:28])[N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:27])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([F:26])([F:25])[F:24])[CH2:12][CH2:11]1)C>CO.C1COCC1.O>[O:28]=[C:9]([N:10]1[CH2:11][CH2:12][N:13]([C:16](=[O:27])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([F:26])([F:25])[F:24])[CH2:14][CH2:15]1)[CH2:8][C:7]([OH:29])=[O:6]
Reactant: CCOC(=O)CC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)CC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
LiOH.H2O (400 mg, 9.5 mmol) was added to a solution of 3-oxo-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionic acid ethyl ester (1.4 g, 3.8 mmol) in methanol (10 mL), THF (4 mL) and H2O (10 mL) and the resulting mixture was stirred for 2 hours at room temperature. The mixture was and the residue was diluted with water, washed with diethyl ether, acidified with concentrated HCl, extracted with ethyl acetate and evaporated to dryness. The residue was recrystallized from hexane to afford 1.2 g (92%) of 3-oxo-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionic acid. LCMS: 345.1 (M+1)+, 96%
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[CH2:4][CH2:3]1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C.C([O-])([O-])=O.[K+].[K+]>ClCCl>[C:26]1([NH:32][C:33]([N:2]2[CH2:7][CH2:6][C:5](=[CH:8][C:9]3[CH:25]=[CH:24][CH:23]=[C:11]([O:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=4)[CH:10]=3)[CH2:4][CH2:3]2)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: O=C=Nc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccccc1)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.1 %

Procedure:
A solution of 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (0.371 g, 1.00 mmol) (from Example 1, Step 5) and phenylisocyanate (0.143 g, 1.2 mmol) in dichloromethane (20 mL) was treated with diisopropylethylamine (0.155 g, 1.2 mmol) and stirred at RT for 18 h. The reaction mixture was stirred with 10% K2CO3 for 1 h and then partitioned after diluting with additional dichloromethane (200 mL). The combined organic layer was washed with brine and dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (1% of the 1N NH3 in MeOH, in dichloromethane) to afford the title compound (100 mg, 22%) as a white solid after trituration with diethyl ether. MS (APCI 10V) AP+ 454.28; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.34 (t, J=5.46 Hz, 2H) 2.46 (t, J=5.46 Hz, 2H) 3.29 (s, 3H) 3.46 (t, J=5.46 Hz, 2H) 3.54 (t, J=5.46 Hz, 2H) 6.37 (s, 1H) 6.89 (t, J=8.60 Hz, 1H) 7.03 (m, 2H) 7.12 (d, J=7.60 Hz, 1H) 7.19-7.22 (m, 3H) 7.38 (d, J=7.8 Hz, 1H) 7.41 (d, J=8.77 Hz, 2H) 8.20 (dd, J=8.8 Hz, 2.8 Hz, 1H) 8.50 (s, 1H) 8.55 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([CH2:16][S:17]([NH2:20])(=[O:19])=[O:18])=[CH:15][C:9]=3[CH:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C[Si]([CH:31]([Si](C)(C)C)[C:32](N)=O)(C)C.CC(C)([O-])C.[K+].C(I)C.Cl.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:31]([O:1][C:2]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([CH2:16][S:17]([NH2:20])(=[O:19])=[O:18])=[CH:15][C:9]=3[CH:8]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH3:32]
Reactant: NS(=O)(=O)Cc1ccc2c(c1)C(c1ccccc1)Oc1cccc(O)c1-2
Reactant: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCI
Product: CCOc1cccc2c1-c1ccc(CS(N)(=O)=O)cc1C(c1ccccc1)O2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of Example 35F (77 mg, 0.210 mmol) in THF (5 mL) at 0° C. was treated with bistrimethylsilylacetamide (52 μL, 0.210 mmol), stirred for 1 hour, and concentrated. The concentrate was dissolved in THF (5 mL), cooled to 0° C., treated with 1M potassium tert-butoxide (210 μL, 0.210 mmol), stirred for 1 hour, treated with ethyl iodide (17 μL, 0.210 mmol), stirred at room temperature for 72 hours, treated with 1M HCl (5 mL), stirred for 2 hours, poured into saturated NaHCO3, and extracted with ethyl acetate. The extract was washed with brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by reverse-phase HPLC with CH3CN/water to provide the desired product as the fraction which eluted at 25 minutes. MS (ESI(−)Q1MS) m/z 394 (M−H)−; 1H NMR (400 MHz, DMSO-d6) δ 9.84 (br s, 1H), 8.43-8.41 (d, J=8.7 Hz, 1H), 7.37-7.23 (m, 6H), 7.14-7.10 (t, J=8.0 Hz, 1H), 6.89 (d, J=2.4 Hz, 1H), 6.71-6.69 (dd, J=7.6, 0.7 Hz, 1H), 6.63-6.60 (dd, J=7.3, 1.0 Hz, 1H), 6.20 (s, 1H), 4.16-4.09 (m, 2H), 3.00 (s, 3H), 1.46-1.42 (t, J=6.9, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][C:16](=[O:18])[N:15]([CH3:19])[C:14]([CH3:20])=[C:13]1[C:21]([OH:23])=O.[NH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][C:33]=1[F:34])[NH:30][N:29]=[CH:28]2.C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[F:34][C:33]1[CH:32]=[C:31]2[C:27]([CH:28]=[N:29][NH:30]2)=[CH:26][C:25]=1[NH:24][C:21]([C:13]1[CH:12]([C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:7][C:2]=2[F:1])[CH2:17][C:16](=[O:18])[N:15]([CH3:19])[C:14]=1[CH3:20])=[O:23]
Reactant: Nc1cc2cn[nH]c2cc1F
Reactant: CC1=C(C(=O)O)C(c2ccc(C(F)(F)F)cc2F)CC(=O)N1C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC1=C(C(=O)Nc2cc3cn[nH]c3cc2F)C(c2ccc(C(F)(F)F)cc2F)CC(=O)N1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 3 %

Procedure:
The product of Step 2 (165 mg, 0.498 mmol, 1.00 equiv), 5-amino-6-fluoroindazole (75 mg, 0.498 mmol, 1.0 equiv), and EDC (114 mg, 0.598 mmol, 1.20 equiv) were suspended in 1.0 mL DMF. Et3N (0.083 mL, 0.598 mmol, 1.2 equiv) was added and the solution was stirred at room temperature for 18 hrs. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was purified by flash chromatography (0-80% EtOAc in Hexanes) and further purified by reverse-phase HPLC (10-80% CH3CN/H2O, 0.1% TFA over 24 minutes, retention time 15.55 min) to provide 7 mg (3%) of the title compound as a white solid. MS (ES+) m/e 465 [M+H]+
Reaction SMILES: [N:1]([C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]([OH:11])=[O:10])=[N+:2]=[N-:3].Br[CH2:13][CH:14]([CH3:16])[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:13]([O:10][C:9]([C:5]1[S:6][CH:7]=[CH:8][C:4]=1[N:1]=[N+:2]=[N-:3])=[O:11])[CH:14]([CH3:16])[CH3:15]
Reactant: [N-]=[N+]=Nc1ccsc1C(=O)O
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)COC(=O)c1sccc1N=[N+]=[N-]
Temperature: 80 °C
Yield: 77 %

Procedure:
Compound 13a (5.8 g, 34.3 mmol) was treated with 1-bromo-2-methylpropane (4.47 mL, 1.2 equiv.) and cesium carbonate (7.82 g, 0.7 equiv.) in anhydrous DMF (0.1 M) and heated to 80° C. for 6 h under argon. The mixture was cooled, dissolved in H2O (150 mL), and extracted with 1:1 diethyl ether:ethyl acetate (3×200 mL). The organic layer was washed with distilled H2O (5×100 mL), dried over Na2SO4, and concentrated in vacuo to give 14a as an oil (6.77 g, 77% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:28]1([C:34]2[S:35][C:36]([CH:39]=O)=[CH:37][N:38]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][CH2:39][C:36]4[S:35][C:34]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)=[N:38][CH:37]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=Cc1cnc(-c2ccccc2)s1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NCc4cnc(-c5ccccc5)s4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 12, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-phenyl-thiazole-5-carbaldehyde.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][C:10]1([C:41]1[CH:46]=[C:45]([CH:47](O)[C:48]2[CH:53]=[CH:52][C:51]([CH2:54][CH2:55][NH:56][C:57]([C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[CH:50][CH:49]=2)[C:44]([CH3:77])=[CH:43][C:42]=1[O:78][CH2:79][C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SiH](CC)(CC)CC.B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>C(#N)C>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][C@H:10]1[C:41]1[CH:46]=[C:45]([CH2:47][C:48]2[CH:49]=[CH:50][C:51]([CH2:54][CH2:55][NH:56][C:57]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)([C:70]3[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=3)[C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=3)=[CH:52][CH:53]=2)[C:44]([CH3:77])=[CH:43][C:42]=1[O:78][CH2:79][C:80]1[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(OCc2ccccc2)c(C2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1C(O)c1ccc(CCNC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])O
Solvent: CC#N
Solvent: CCOCC
Product: Cc1cc(OCc2ccccc2)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(CCNC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 64.9 %

Procedure:
To an acetonitrile solution (6 mL) of 2,3,4,6-tetra-O-benzyl-1-C-[2-(benzyloxy)-5-[hydroxy[4-[2-(tritylamino)ethyl]phenyl]methyl]-4-methylphenyl]-D-glucopyranose (0.638 g, 0.565 mmol) were added under nitrogen atmosphere at 0° C. Et3SiH (0.27 mL, 1.695 mmol) and BF3.Et2O (1.58 mL, 1.24 mmol), and the mixture was stirred for 30 minutes at the same temperature. To the reaction solution cooled in ice was added a saturated sodium bicarbonate aqueous solution and the resulting mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the title compound (0.402 g, 59%) as a pale yellow oily compound.
Reaction SMILES: C([NH:8][C@H:9]([C:11](O)=O)[CH3:10])(OC(C)(C)C)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CO[C:49](=O)[C@H:50]([NH:53][CH2:54][C:55]1[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=1)[CH2:51][CH3:52]>CN(C=O)C.O>[CH2:51]([C@@H:50]1[CH2:49][NH:8][C@@H:9]([CH3:11])[CH2:10][N:53]1[CH2:54][C:55]1[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=1)[CH3:52]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC[C@@H](NCc1ccc(OC)cc1)C(=O)OC
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
Solvent: O
Product: CC[C@@H]1CN[C@@H](C)CN1Cc1ccc(OC)cc1
Reaction time: 8 h
Yield: 145.2 %

Procedure:
To a solution of 3.99 g of Boc-L-alanine in 50 ml of DMF were added 12.02 g of HATU, 4.3 ml of Hünig's base and 5.00 g (R)-2-(4-Methoxy-benzylamino)-butyric acid methyl ester. The reaction was stirred overnight, and 6.01 g of HATU and 2.1 ml of Hünig's base were added, and the reaction was stirred for 24 h at r.t. and then for 4 h at 50° C. The reaction was poured unto water, the layers were separated and the aqueous phase was extracted with EtOAc twice. The combined organic layers war washed with 10% aqueous citric acid twice, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, heptane/EtOAc) to obtain 7.60 g (88%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[C:5]([Br:12])=[CH:4][N:3]=1.N1C=CC=CC=1.[C:19](Cl)(=[O:24])[CH2:20][CH2:21][CH2:22][CH3:23].C(Cl)Cl>O>[C:19]([NH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[C:5]([Br:12])=[CH:4][N:3]=1)(=[O:24])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: Cc1c(Br)cnc(N)c1[N+](=O)[O-]
Reactant: CCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCCCC(=O)Nc1ncc(Br)c(C)c1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 5 h
Yield: 80.7 %

Procedure:
A mixture comprising 10 g (43.1 mmol) of 2-amino-5-bromo-4-methyl-3-nitropyridine and 6.8 g of pyridine was heated to 110° C. in a nitrogen atmosphere. 5.7 g (47.4 mmol) of valeroyl chloride was dropwise added thereto and the mixture was stirred at 110° C. for 5 hours. The reaction mixture was brought to room temperature, followed by the addition of methylene chloride (50 ml) and water (50 ml). The organic phase was separated. The aqueous phase was further extracted with methylene chloride (50 ml). The organic phases were combined, dried over anhydrous magnesium sulfate and subjected to vacuum concentration to give a crude crystal. It was recrystallized from ethyl acetate to give 11 g of 2-valerylamino-5-bromo-4-methyl-3-nitropyridine (yield 81%). m.p.; 134°-135° C.
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].C(N(CC)CC)C.Cl.[CH3:14][NH:15][C:16]1[CH:58]=[CH:57][C:19]([O:20][CH2:21][C:22]([NH:24][C@H:25]([C:30]([NH:32][C@@H:33]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C@H:34]([OH:49])[C:35]([N:37]2[CH2:48][CH2:47][CH2:46][C@H:38]2[C:39]([NH:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:36])=[O:31])[CH2:26][C:27](=[O:29])[NH2:28])=[O:23])=[CH:18][CH:17]=1.Cl>CN(C)C=O>[Br:1][CH2:2][C:3]([N:15]([C:16]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]([NH:24][C@H:25]([C:30]([NH:32][C@@H:33]([CH2:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[C@H:34]([OH:49])[C:35]([N:37]2[CH2:48][CH2:47][CH2:46][C@H:38]2[C:39]([NH:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:36])=[O:31])[CH2:26][C:27](=[O:29])[NH2:28])=[O:23])=[CH:57][CH:58]=1)[CH3:14])=[O:4]
Reactant: O=C(Cl)CBr
Reactant: CNc1ccc(OCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc2ccccc2)[C@H](O)C(=O)N2CCC[C@H]2C(=O)NC(C)(C)C)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C(=O)CBr)c1ccc(OCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc2ccccc2)[C@H](O)C(=O)N2CCC[C@H]2C(=O)NC(C)(C)C)cc1
Reaction time: 24 h
Yield: 68.5 %

Procedure:
0.59 ml (7.2 mmol) of bromoacetyl chloride and 1.6 ml (11.7 mmol) of triethylamine were added, whilst ice-cooling, to a solution of 3.0 g (4.5 mmol) of 1-[(2S,3S)-3-{N2 -[4-(methylamino)phenoxyacetyl]-L-asparaginyl}amino-2-hydroxy-4-phenylbutyryl]-N-t-butyl-L-prolinamide hydrochloride (prepared as described in Example 20) in 10 ml of dimethylformamide, and the resulting mixture was stirred for 1 day. At the end of this time, the reaction mixture was neutralized by the addition of 1N aqueous hydrochloric acid. It was then concentrated by evaporation under reduced pressure, and the concentrate was diluted with ethyl acetate. The resulting diluted solution was washed with 1N aqueous hydrochloric acid, with a 5% w/v aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. It was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography, using a 1:15 by volume mixture of methanol and methylene chloride as the eluent, to give 2.3 g of the title compound as a colorless powder, melting at 116°-122° C.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10](=[O:73])[NH:11][CH:12]([C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]([CH2:33][C:34]#[C:35][C:36]#[C:37][CH2:38][N:39]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41]([CH2:48][CH:49]3[CH2:53][CH2:52][CH2:51][N:50]3[C:54](=[O:72])[CH:55]([NH:59][C:60](=[O:71])[CH:61]([NH:63]C(OC(C)(C)C)=O)[CH3:62])[CH:56]([CH3:58])[CH3:57])=[CH:40]2)[CH:25]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:63][CH:61]([CH3:62])[C:60]([NH:59][CH:55]([C:54]([N:50]1[CH2:51][CH2:52][CH2:53][CH:49]1[CH2:48][C:41]1[C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:39]([CH2:38][C:37]#[C:36][C:35]#[C:34][CH2:33][N:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:24]([CH2:23][CH:19]3[CH2:20][CH2:21][CH2:22][N:18]3[C:16](=[O:17])[CH:12]([NH:11][C:10](=[O:73])[CH:8]([NH2:7])[CH3:9])[CH:13]([CH3:15])[CH3:14])=[CH:25]2)[CH:40]=1)=[O:72])[CH:56]([CH3:57])[CH3:58])=[O:71]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)NC(C(=O)N1CCCC1Cc1cn(CC#CC#CCn2cc(CC3CCCN3C(=O)C(NC(=O)C(C)NC(=O)OC(C)(C)C)C(C)C)c3ccccc32)c2ccccc12)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(N)C(=O)NC(C(=O)N1CCCC1Cc1cn(CC#CC#CCn2cc(CC3CCCN3C(=O)C(NC(=O)C(C)N)C(C)C)c3ccccc32)c2ccccc12)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 42 (0.030 g, 0.029 mmol) in DCM (5 mL) was added TFA (1 mL) and the reaction mixture was stirred at room temperature for 30 min. Aqueous NaHCO3 (3 mL) was then added to the reaction mixture. The reaction mixture was concentrated, diluted with water, and the product was extracted with DCM (3×30 mL). The organic extracts were washed with water, brine and dried over anhydrous Na2SO4. The solvent was removed on rotary evaporator and the product was purified by reverse phase HPLC. 1H NMR (DMSO, 300 MHz) δ8.0 (s, 2H), 7.9 (d, J=9.9 Hz, 2H), 7.38 (d, J=9.9 Hz, 2H), 7.3-7.1 (m, 6H), 6.8 (m, 2H), 4.8 (s, 4H), 4.62 (m 2H), 4.5-4.4 (m 2H), 4.4-4.0 (m, 4H), 3.7-3.5 (m, 4H), 3.4 (m, 2H), 2.5 (m, 2H), 2.2-1.8 (m, 8H), 1.35 (d, J=9.9 Hz, 6H), 1.05 (d, J=5.5 Hz, 6H), 0.95 (d, J=5.5 Hz, 6H) ppm.
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][CH:9]([C:12]([C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1)=[O:13])[CH2:10][CH3:11])(C)(C)C>O1CCOCC1.C(Cl)Cl>[ClH:1].[NH2:8][CH:9]([CH2:10][CH3:11])[C:12]([C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1)=[O:13]
Reactant: CCC(NC(=O)OC(C)(C)C)C(=O)c1nc2ccccc2o1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCC(N)C(=O)c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Hydrogen chloride in dioxane (1M, 1 ml) was added to a solution of, 1-(Benzooxazole-2-carbonyl)-propyl]-carbamic acid tert-butyl ester (2a) in dry methylene chloride (3 ml) and stirred at room temperature for 4 hrs. Concentration under reduced pressure gave the title compound as white solid (65 mg); 1H NMR (CDCl3) δ 0.99 (t, J=7.5 Hz, 3H), 2.20–2.05 (m, 2H), 4.96 (m, 1H), 7.58 (t, J=7.4 Hz, 1H), 7.69 (t, J=7.4 Hz, 1H), 7.94 (d, J=8.2 Hz, 1H), 8.04 (d, J=8.2 Hz, 1H), 8.75 (m, 3H); MS: 207(MH+).
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH3:12][O:13][C:14](=[O:32])[C@@H:15]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].F[C:34]1[CH:47]=[CH:46][C:37]([C:38]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:39])=[CH:36][CH:35]=1>O>[CH3:12][O:13][C:14](=[O:32])[C@H:15]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:43]2[CH:44]=[CH:45][C:40]([C:38](=[O:39])[C:37]3[CH:46]=[CH:47][CH:34]=[CH:35][CH:36]=3)=[CH:41][CH:42]=2)=[CH:27][CH:26]=1
Reactant: COC(=O)[C@@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: O=C(c1ccccc1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@@H](Cc1ccc(Oc2ccc(C(=O)c3ccccc3)cc2)cc1)NC(=O)OC(C)(C)C
Yield: 23.6 %

Procedure:
To a solution of N,N-Dimethylformamide (DMF) (3.16 mL) and potassium carbonate (0.222 g, 1.605 mmol) was added Boc-D-Tyrosine-Methyl ester (0.158 g, 0.535 mmol) and 4-Fluorobenzophenone (0.160 g, 0.802 mmol) at 100° C. under an atmosphere of nitrogen for 42 hours. The mixture was poured into 30 mL water solution and extracted with ethyl acetate (EtOAc) (4×10 mL). The combined organic layers were washed with brine (40 mL) and dried over anhydrous Na2SO4. The organic layer was concentrated in vacuo to obtain the crude mixture, which was purified by of silica gel flash chromatography, using EtOAc/hexane (gradient system), to obtain the product (0.060 g, 24%): 1H NMR (400 MHz, CDCL3): δ 1.42 (s, 9H), 2.99-3.17 (m, 2H), 3.71-3.74 (m, 3H), 4.53-4.61 (m, 1H), 4.96-5.16 (m, 1H), 6.75 (d, 1H, J=8.4 Hz), 6.97-7.03 (m, 4H), 7.16 (d, 2H, J=8.4 Hz), 7.46-7.50 (m, 2H), 7.56-7.58 (m, 1H), 7.77-7.83 (m, 3H).
Reaction SMILES: [H][H].[C:3](#[N:12])[C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([C:7]#[N:8])[CH:5]=1.C(C1C=C(C=CC=1)C(N)=O)#N.C(C1C=C(C=CC=1)C(O)=O)#N.N.[OH-].[Na+]>[Pd]>[C:7]([C:6]1[CH:5]=[C:4]([CH:11]=[CH:10][CH:9]=1)[CH2:3][NH2:12])#[N:8]
Reactant: N#Cc1cccc(C#N)c1
Reactant: [H][H]
Agent: [Pd]
Agent: N
Agent: N#Cc1cccc(C(=O)O)c1
Product: N#Cc1cccc(CN)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A commercially available activated carbon-supported palladium catalyst “PDC-3000” available from Toyo C.C.I. Co., Ltd. (supported palladium: 3% by weight) was activated by reduction with hydrogen. A 100-ml autoclave was successively charged with 3.0 g of the activated catalyst, 12.8 g of isophthalonitrile containing as impurities 0.12% by weight of 3-cyanobenzamide and 0.12% by weight of 3-cyanobenzoic acid, 37 g of liquid ammonia, and 0.1 g of sodium hydroxide. Then, hydrogen was introduced into the autoclave to increase the inner pressure to 20 MPa (gauge). The concentration in the reaction solution was 0.043% by weight for the benzamide compound and 0.043% by weight for the benzoic acid compound. The autoclave was shaken at 50° C. for 30 min. The gas chromatographic analysis on the reaction product solution showed that the conversion of isophthalonitrile was 99.0 mol %, the yields of 3-cyanobenzylamine was 76.0 mol %, and the yield of m-xylylenediamine was 8.4 mol %. The by-products were substantially high-boiling substances.