Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].OCC(O[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]C)=O>>[S:1]([O:8][CH2:9][C:10]([O:12][CH2:13][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:11])([C:4]([F:6])([F:7])[F:5])(=[O:3])=[O:2]
Reactant: CCCCCCOC(=O)CO
Reactant: COC(=O)COS(=O)(=O)C(F)(F)F
Product: CCCCCCOC(=O)COS(=O)(=O)C(F)(F)F

Procedure:
Prepared in the same way as described for TfO-CH2COOMe starting with HO—CH2COOnHex.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][N:40]([NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:41][C@H:42]([OH:52])[C@@H:43]([NH2:51])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:35][CH:34]=2)=[CH:31][N:30]=[CH:29]1>CN(C=O)C>[S:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][N:40]([NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:41][C@H:42]([OH:52])[C@@H:43]([NH:51][C:11](=[O:13])[C@H:6]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:35][CH:34]=2)=[CH:31][N:30]=[CH:29]1
Reactant: CC(C)(C)OC(=O)NN(Cc1ccc(-c2cncs2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2cncs2)cc1)NC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, 1.36 g (7.2 mmol) of N-methoxycarbonyl-(L)-iso-leucine, 2.59 g (13.5 mmol) of EDC and 1.22 g (9 mmol) of HOBT are dissolved in 20 ml of DMF. After 30 min, 3.79 ml (27 mmol) of TEA are added and a solution of 2.11 g (4.5 mmol) of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-amino-6-phenyl-2-azahexane (Example 2b) in 40 ml of DMF are added dropwise. After 3 hours, the reaction mixture is worked up analogously to Example 2c to form the title compound: m.p: 163-166° C.; Anal. (C33H45N5O6S (0.14 H2O)) calc. C, 61.71, H, 7.11, N, 10.90, S, 4.99, H2O 0.39: found C, 61.61, H, 7.10, N, 10.79, S, 4.76, H2O 0.4; HPLC20-100: tRet=16.0; FAB MS (M+H)+=640.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C(O)CCC>[F:9][C:8]([F:11])([F:10])[C:7]1[C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: C1CNCCN1
Solvent: CCCCO
Product: FC(F)(F)c1cccnc1N1CCNCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 40 %

Procedure:
A solution of 2-chloro-3-trifluoromethylpyridine (6.57 g, 36.2 mmol) and piperazine (31.48 g, 365.5 mmol) in n-butanol was heated to 115° C. After 48 hours, the mixture was cooled to room temperature, the solvent removed under reduced pressure and the residue partitioned between water and ethyl acetate. The organic phase was dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (elution with 15% methanol:dichloromethane) to provide 3.35 g (40% yield) of the title compound as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ 2.80 (m, 4H), 3.10 (m, 4H), 7.15 (ddd, 1H, J=7.8, 4.7, 1.0 Hz), 8.03 (dd, 1H, J=7.8, 1.7 Hz), 8.50 (ddd, 1H, J=4.8, 2.0, 0.7 Hz); MS (DCI/NH3) m/e 232 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][S:11](Cl)(=[O:13])=[O:12]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([N:9]([S:11]([CH3:10])(=[O:13])=[O:12])[S:11]([CH3:10])(=[O:13])=[O:12])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)N(c1cc(Br)cnc1Cl)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a stirred solution of 5-bromo-2-chloropyridin-3-amine (3.04 g, 14.7 mmol) of pyridine (20 mL) in 150-mL round-bottom flask, methanesulfonyl chloride (2.83 ml, 36.6 mmol) was added dropwise at 0° C. The ice bath was removed and the light brown solution was stirred at RT for overnight. Water (100 mL) was added and the precipitate was formed. The mixture was stirred at RT to break up lumps. The cream color solid was collcted via filtration and washed with water several times then air dried to afford N-(5-bromo-2-chloropyridin-3-yl)-N-(methylsulfonyl)methanesulfonamide (5.16 g, 96.9% yield) as a cream colored powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.65 (s, 6H), 8.69 (d, J=2.3 Hz, 1H), 8.75 (d, J=2.3 Hz, 1H). m/z (ESI, positive ion): 362.8 [M+H]+.
Reaction SMILES: COC[O:4][C:5]1[CH:12]=[C:11]([O:13]COC)[CH:10]=[C:9]([CH2:17][O:18][CH3:19])[C:6]=1[CH:7]=[O:8].Cl>C1COCC1.CCOC(C)=O>[OH:4][C:5]1[CH:12]=[C:11]([OH:13])[CH:10]=[C:9]([CH2:17][O:18][CH3:19])[C:6]=1[CH:7]=[O:8]
Reactant: COCOc1cc(COC)c(C=O)c(OCOC)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCc1cc(O)cc(O)c1C=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.5 %

Procedure:
To a solution of 2,4-bis-methoxymethoxy-6-methoxymethyl-benzaldehyde (3.93 g, 14.45 mmol) in THF (30 mL) was added 6 N HCl (10 mL). The mixture was stirred at room temperature for 20 hours then diluted with EtOAc (200 mL). The mixture was washed with brine, dried and concentrated to give 2,4-dihydroxy-6-methoxymethyl-benzaldehyde (2.62 g, 100%). 1H NMR (400 MHz, CDCl3δ 12.40 (s, 1H), 10.10 (s, 1H), 6.41 (s, 1H), 6.30 (s, 1H), 5.60 (s, 1H), 4.61 (s, 2H), 3.40 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].C(N(CC)CC)C.[Br:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][NH2:28])=[CH:24][CH:23]=1>ClCCl>[Br:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][NH:28][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[C:2]([F:13])([F:12])[F:1])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: NCCc1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCc1ccc(Br)cc1)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
To a mixture of 2-(trifluoromethyl)benzoyl chloride (1.0 g, 5.3 mmol) in dichloromethane (5 mL) was added dropwise a solution of triethylamine (0.41 g, 4.0 mmol) and 4-bromophenethylamine (0.80 g, 4.0 mmol) in dichloromethane (5 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was then diluted with dichloromethane and extracted with 1 N aqueous hydrochloric acid. The aqueous phase was separated and extracted with additional dichloromethane. The organic extracts were then combined, dried (MgSO4), filtered, and concentrated under reduced pressure. The crude residue was purified by chromatography on a silica gel column eluted with 0 to 100% ethyl acetate:hexane to provide the title compound (1.10 g) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=[CH:5]2.[CH3:16][O:17][C:18]1[N:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:16][O:17][C:18]1[N:23]=[CH:22][C:21]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=[CH:5]3)=[CH:20][CH:19]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: COC(=O)c1cccc2cc(O)ccc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc2cc(Oc3ccc(OC)nc3)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution/suspension of methyl 6-hydroxy-1-naphthoate (2.49 g, 12.3 mmol), 6-methoxypyridin-3-ylboronic acid (2.26 g, 14.8 mmol), copper acetate (2.46 g, 13.6 mmol), triethylamine (6.24 g, 61.7 mmol) and 4Å molecular sieves (2.00 g) in acetonitrile (120 mL) was stirred at RT for 16 h. The solids were filtered off. The filtrate was concentrated in vacuo. Water was added and extracted with EtOAc. The organic layer was washed with 1M aqueous NaOH solution, water, brine and dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography afforded the title compound.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:25])[CH2:15][CH2:16][CH2:17][S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.C(N(CC)CC)C.[C:50]1([CH2:56][CH2:57][CH2:58][CH2:59][CH:60]=[O:61])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>C(Cl)Cl>[CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:25])[CH:15]([CH2:16][CH2:17][S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:60]([OH:61])[CH2:59][CH2:58][CH2:57][CH2:56][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCCCCc1ccccc1
Reactant: O=C(CCCSc1ccccc1)N1C(=O)OCC1Cc1ccccc1
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1OCC(Cc2ccccc2)N1C(=O)C(CCSc1ccccc1)C(O)CCCCc1ccccc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 68.6 %

Procedure:
To a solution containing (+)-4-benzyl-3-(4-phenylsulfanylbutanoyl)oxazolidin-2-one (2 g, 5.63 mmol) in anhydrous CH2Cl2 (30 mL) under nitrogen atmosphere at 0° C. is added di-n-butyl boron triflate (1 M in CH2Cl2, 6.6 mL, 6.59 mmol). To the resulting brown solution is added triethylamine (1 mL, 7.38 mmol). The pale yellow solution is cooled to -78° C. and a solution of 5-phenyl-1-pentanal (1 g, 6.25 mmol) in CH2Cl2 (5 mL) is added via syringe. The mixture is stirred at -78° C. for 1 hour and at 0° C. for 45 minutes then is quenched by the dropwise addition of 3:1 methanol/pH 7 phosphate buffer (40 mL) followed by 2:1 methanol/30% H2O2 (30 mL). The biphasic mixture is stirred at 0° C. for 1 hour then is combined with an identical reaction performed on 1.3 g-scale and evaporated to 50% volume in vacuo. The residue is partitioned between 5% NaHCO3 (200 mL) and diethyl ether (200 mL) and the layers are separated. The aqueous phase is extracted with diethyl ether (200 mL). The combined organic extracts are washed successively with 5% NaHCO3 (3×100 mL), 5% Na2S2O3 (3×100 mL), water (100 mL), brine (100 mL), dried over anhydrous MgSO4, filtered and concentrated to afford a yellow oil which is chromatographed on silica gel (pet-ether/EtOAc 9:1→4:1) to provide (+)-4-benzyl-3-[3-hydroxy-7-phenyl-2-(2-phenylsulfanylethyl)heptanoyl]-oxazolidin-2-one (2 g, 43%) as a colorless oil. TLC analysis [pet-ether/EtOAc, 4:1, Rf (oxazolidinone)=0.50, Rf (aldol product)=0.20]. [α]23D +7.2° (c 1.3, CHCl3). 1H NMR (300 MHz, CDCl3) δ 1.50-1.60 (m, 7H), 1.90 (m, 1H), 2.20 (m, 1H), 2.31 (d, J=3.6 Hz, 1H), 2.58 (t, J=7.5 Hz), 2.67 (dd, J=13.3, 9.9 Hz), 2.85 (m, 1H), 3.00 (m, 1H), 3.32 (dd, J=13.3, 3.4 Hz), 3.88 (m, 1H), 4.20 (m, 2H), 4.65 (m, 1H), 7.1-7.35 (m, 15H) ppm. Mass spectrum (FAB) m/z 517 (M)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=O)O[C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[NH2:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18].O>C(Cl)Cl>[CH3:19][C:16]([N:15]1[CH2:11][C:6]2[C:7](=[CH:13][CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:8]1)([CH3:20])[CH2:17][OH:18]
Reactant: CC(C)(N)CO
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)(CO)N1Cc2ccc([N+](=O)[O-])cc2C1

Procedure:
20 g of 4-Nitro-phthalic anhydride and 8.94 g of 2-amino-2-methylpropanol were heated to 170° C. for 30 min. After cooling, water and CH2Cl2 were added, and the organic phase separated, concentrated and purified by chromatography on silica (eluent CH2Cl2/MeOH 97/3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[H-].[Na+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)[C:6](=[O:11])[C:5]2=[O:12]
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)C(=O)c3cc(F)ccc32)cc1
Reaction time: 0.25 h
Yield: 82.4 %

Procedure:
A solution of 5-fluoroisatin (5 g, 30.2 mmol) in DMF (60 mL) was cooled in an ice/water bath and treated with sodium hydride (1.44 g, 60.6 mmol) portionwise. The reaction was stirred for 15 minutes after the addition of the last portion and then treated with p-methoxybenzyl chloride (5.32 g, 45.3 mmol) and allowed to stir for 1 hour. The reaction was then quenched by slow addition of excess methanol. After bubbling had stopped, the reaction was poured into water (100 mL) and extracted twice with ethyl acetate. The organics were combined, dried over MgSO4 and the solvent was removed. The residue was purified by silica gel chromatography using a gradient of 0-100% ethyl acetate in hexane to afford 7.1 g (82%) of 5-Fluoro-1-(4-methoxy-benzyl)-1H-indole-2,3-dione; 1H NMR (CDCl3, 400 MHz) δ 3.79 (s, 3H), 4.86 (s, 2H), 6.75 (dd, 1H, J1=3.6, J2=8.6), 6.84-6.90 (m, 2H), 7.19 (ddd, 1H, J1=J2=8.6, J3=3.6), 7.22-7.27 (m, 1H), 7.26-7.31 (m, 2H); HPLC-MS calcd. for C16H12FNO3 (M+H+) 286.1, found 286.3. Step B: A solution of 5-fluoro-1-(4-methoxy-benzyl)-1H-indole-2,3-dione (7.1 g, 24.9 mmol) in hydrazine hydrate (35 mL) and ethanol (15 mL) was refluxed overnight, diluted with water and extracted twice with ethyl acetate. The combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient of 0-100% ethyl acetate in hexane to afford 6.1 g (90%) of 5-fluoro-1-(4-methoxy-benzyl)-1,3-dihydro-indol-2-one; 1H NMR (CDCl3, 400 MHz) δ 3.59 (s, 2H), 3.77 (s, 3H), 4.83 (s, 2H), 6.63 (dd, 1H, J1=4.2, J2=8.6), 6.82-6.91 (m, 3H), 6.96-7.01 (m, 1H), 7.19-7.23 (m, 1H), 7.27-7.31 (m, 1H); HPLC-MS calcd. for C16H14FNO2 (M+H+) 272.1, found 272.3.
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4].[CH3:16][C:17]1[C:18]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:19][C:20]([CH:23]=O)=[N:21][CH:22]=1>CO>[CH3:16][C:17]1[C:18]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:19][C:20]([CH:23]=[CH:4][C:3]([C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][CH:7]=2)=[O:5])=[N:21][CH:22]=1
Reactant: Cc1cnc(C=O)cc1N1CCCCC1
Reactant: CC(=O)c1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cnc(C=CC(=O)c2cccc3ccccc23)cc1N1CCCCC1
Reaction time: 8 h

Procedure:
A 10% aqueous solution of sodium hydroxide (1.6 ml) and then 174 mg of 1-acetylnaphthalene at about 4° C. were added to a solution of 204 mg (1.0 mmole) of 5-methyl-4-piperidino-2-pyridinecarbaldehyde in 3 ml of methanol, and the mixture was allowd to stand overnight at the above temperature. The reaction mixture was concentrated under reduced pressure. The residue was mixed with water, and then extracted with dichloromethane. The dichloromethane layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with dichloromethane) to give 5-methyl-2-[3-(1-naphthyl)-3-oxo-1-propenyl]-4-piperidinopyridine. The product was treated with an ethanol solution of hydrogen chloride to form its hydrochloride. Recrystallization from methanol/ether gave 350 mg (yield 75%) of the captioned compound as crystals.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:30]=[CH:29][C:18]([CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH:33]1([CH2:36]Br)[CH2:35][CH2:34]1>>[C:24]([O:23][C:22](=[O:28])[N:21]([CH2:36][CH:33]1[CH2:35][CH2:34]1)[CH2:20][CH2:19][C:18]1[CH:29]=[CH:30][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:31])[F:32])=[CH:9][CH:8]=3)[N:11]=2)=[CH:16][CH:17]=1)([CH3:25])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: BrCC1CC1
Product: CC(C)(C)OC(=O)N(CCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)CC1CC1

Procedure:
The title compound was prepared as described in Example 102 using tert-butyl 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethylcarbamate (C50) and cyclopropylmethyl bromide and isolated as a clear oil (0.155 g, 96%): 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.16-8.07 (m, 2H), 7.84-7.77 (m, 2H), 7.39 (dq, J=8.0, 0.9 Hz, 2H), 7.31 (s, 2H), 3.50 (t, J=7.6 Hz, 2H), 3.17-2.86 (m, 4H), 1.48 (s, 9H), 0.87 (ddd, J=11.2, 9.0, 6.7 Hz, 1H), 0.49 (d, J=8.0 Hz, 2H), 0.21 (s, 2H); 19F NMR (376 MHz, CDCl3) δ −58.03; ESIMS m/z 503 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.[N+:11]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=[O:18])([O-:13])=[O:12]>C1(C)C(C)=CC=CC=1>[N+:11]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([NH:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1)=[O:18])([O-:13])=[O:12]
Reactant: Nc1nc(C(Cl)(Cl)Cl)ns1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: Cc1ccccc1C
Product: O=C(Nc1nc(C(Cl)(Cl)Cl)ns1)c1cccc([N+](=O)[O-])c1
Yield: 69.1 %

Procedure:
A solution of 21.8 g (0.1 mole) 5-amino-3-trichloromethyl-1,2,4-thiadiazole and 18.6 g (0.1 mole) 3-nitrobenzoyl chloride in 250 ml xylene was heated at reflux for 20 hours. Unreacted starting amino compound was recovered by cooling the reaction mixture and filtering the resulting precipitate. The filtrate was concentrated in vacuo and the residue recrystallized from xylene. After washing with petroleum ether, 25.4 g (69% yield) of pure product was obtained; m.p. 198° C.
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.[CH3:13][C:14]1(C)OC(=O)CC(=O)[O:15]1.ClC(OC(C)C)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[OH:5][C:3]1[CH2:2][N:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[C:14](=[O:15])[CH:13]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CC(C)OC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(O)=CC1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To Boc-Gly-OH (1 g, 5.71 mmol) in DCM (12 mL) under N2 atmosphere at 0° C. was added DMAP (1.743 g, 14.27 mmol) and Meldrum's acid (0.987 g, 6.85 mmol). A solution of isopropyl chloroformate (8.56 mL, 8.56 mmol) in toluene was added dropwise. The reaction mixture was stirred at 0° C. for 3 h. The reaction mixture was washed with 15% KHSO4 twice, dried over sodium sulfate, filtered and evaporated. The crude product was taken in 50 mL of EtOAc and refluxed for 1 h. After volatile materials were evaporated, the crude product was triturated with EtOAC and the resulting solid was filtered and dried to provide a yellow solid (75%). LCMS (m/z): 200.1 (MH+), 0.504 min.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].CO[C:7]1[C:8]([N+:41]([O-:43])=[O:42])=[C:9]([C:19]2[O:20][C:21]([C:24]3[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][C:27]([N+:33]([O-:35])=[O:34])=[C:26](OC)[C:25]=3[N+:38]([O-:40])=[O:39])=[N:22][N:23]=2)[C:10]([N+:16]([O-:18])=[O:17])=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14]>CO>[OH:2][CH2:1][CH2:3][NH:4][C:28]1[C:29]([N+:30]([O-:32])=[O:31])=[C:24]([C:21]2[O:20][C:19]([C:9]3[C:10]([N+:16]([O-:18])=[O:17])=[CH:11][C:12]([N+:13]([O-:15])=[O:14])=[C:7]([NH:4][CH2:3][CH2:1][OH:2])[C:8]=3[N+:41]([O-:43])=[O:42])=[N:23][N:22]=2)[C:25]([N+:38]([O-:40])=[O:39])=[CH:26][C:27]=1[N+:33]([O-:35])=[O:34]
Reactant: NCCO
Reactant: COc1c([N+](=O)[O-])cc([N+](=O)[O-])c(-c2nnc(-c3c([N+](=O)[O-])cc([N+](=O)[O-])c(OC)c3[N+](=O)[O-])o2)c1[N+](=O)[O-]
Solvent: CO
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(-c2nnc(-c3c([N+](=O)[O-])cc([N+](=O)[O-])c(NCCO)c3[N+](=O)[O-])o2)c([N+](=O)[O-])c1NCCO
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 0.3 g (0.0049 mole) of ethanolamine in 20 ml of methanol was stirred in an ice bath during the addition of 1.0 g (0.0018 mole) of 2,5-bis(3-methoxy-2,4,6-trinitrophenyl)-1,3,4-oxadiazole. After 10 min. at 0° C., the mixture was stirred at room temperature for 5 hr. before the crude product [1.1 9 (94%), mp 250° dec] was removed by filtration. Digestion with boiling acetone gave the purified product, as an insoluble yellow solid, mp 264° C. dec.; 1H NMR (DMSO-d6 +D2O): 3.22 (t, 4H), 3.70 (t, 4H), 9.32 (s, 2H); IR(KBr): 3700-3200 (OH and NH), 1610, 1625 (C=N), 1545, 1340 (NO2). Anal. Calcd. for C18H14N10O15 : C, 35.42; H, 2.31; N, 22.95. Found: C, 35.62; H, 2.30; N, 22.93.
Reaction SMILES: [C:1]([CH2:20][CH2:21][C:22]([OH:24])=[S:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:25][C:26]1[C:31](O)=[C:30]([Cl:33])[C:29]([Cl:34])=[C:28]([Cl:35])[C:27]=1[Cl:36].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[Cl:25][C:26]1[C:31]([O:24][C:22](=[S:23])[CH2:21][CH2:20][C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:30]([Cl:33])[C:29]([Cl:34])=[C:28]([Cl:35])[C:27]=1[Cl:36]
Reactant: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: OC(=S)CCC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: S=C(CCC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a preferred embodiment of the preparation of the above first tetrapeptide hydrazide, the activated ester of 3-tritylthiopropionic acid, preferably the pentachlorophenyl ester, is prepared by combining substantially equimolar amounts of 3-tritylthiopropionic acid, pentachlorophenol and dicyclohexylcarbodiimide in an inert organic solvent, preferably tetrahydrofuran, at about 0° to 10° C. The mixture is stirred at about 0° to 10° C for about 1 hour and then at about 20° to 30° C for about 1 hour. The mixture is cooled to about 0° C, filtered and the filtrate evaporated. The residue is crystallized to obtain 3-tritylthiopropionic acid pentachlorophenyl ester. A solution of said last-named compound and a substantially equimolar amount of the tetrapeptide of formula H-Lys(Boc)-Asn-Phe-Phe-OMe acetate, prepared as described by H. U. Immer et al., cited above, in an inert organic solvent, preferably dimethylformamide or tetrahydrofuran, is treated with a substantially equimolar amount of an organic base, preferably triethylamine, at about 20° to 30° C. The mixture is stirred for 2 to 3 days at about 20° to 30° C and the solvent evaporated under reduced pressure. The residue is triturated with cold dilute aqueous citric acid and water, dried, and crystallized to give the tetrapeptide of formula Trt--SCH2CH2CO--Lys(Boc)--Asn--Phe--Phe--OMe. Said last-named compound is dissolved in an inert organic solvent, for example, methanol, ethanol, or preferably dimethylformamide. The solution is treated with an excess of hydrazine hydrate, for example 15 to 30 molar equivalents. The reaction mixture is kept at about 20° to 30° C for about 20 to 30 hours and evaporated under reduced pressure. The residue is triturated with cold water and dried to give said tetrapeptide hydrazide of formula (2, R = H) Trt--SCH2CH2CO--Lys(Boc)--Asn--Phe--Phe--NHNH2.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1)([O-])=O.[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[O:25]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc3ccccc3o2)cc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: c1ccc(Oc2ccc(-c3nc4ccccc4o3)cc2)cc1
Yield: 90 %

Procedure:
A mixture of 1.20 g (5 mmoles) of 2-(p-nitrophenyl)benzoxazole, 0.80 g (8.5 mmoles) of phenol, 2 g of potassium carbonate and 15 ml of NMP is stirred and refluxed under nitrogen atmosphere for one hour. The title product is recovered from the resulting solution as described in Example 1. The recovery is 1.15 g (80.4 percent yield). The product has a melting point of 70° C.-71° C. The experiment is repeated using 2-4(p-fluorophenyl)benzoxazole as the reagent and the title product is obtained in 90 percent yield.