Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C:7]([O:10][C:11]1[CH:19]=[CH:18]C(C(O)=O)=[CH:13][CH:12]=1)(=[O:9])[CH3:8]>C(Cl)Cl.CN(C=O)C>[C:7]([O:10][C:11]1[CH:19]=[CH:18][C:1]([C:2]([Cl:4])=[O:3])=[CH:13][CH:12]=1)(=[O:9])[CH3:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(C(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Oxalyl chloride (0.35 ml) was added to a stirred suspension of 4-acetoxybenzoic acid (0.57 g) in methylene chloride (15 ml) which had been cooled to 0° C. DMF (2 drops) was added and the mixture was stirred at ambient temperature for 4 hours. The mixture was evaporated to give 4-acetoxybenzoyl chloride which was used without further purification. A mixture of the acid chloride so obtained, N-(3-amino-4-chlorophenyl)-4-cyanobenzamide (0.813 g) and pyridine (15 ml) was stirred and heated at 100° C. for 16 hours. The mixture was cooled to ambient temperature and poured into 2N aqueous hydrochloric acid solution (175 ml). The precipitate was isolated, washed with water and dried. The material so obtained was purified by column chromatography on silica using a 7:3 mixture of isohexane and ethyl acetate as eluent. There was thus obtained the title compound (0.74 g); m.p. 195-196° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[CH2:23]1[O:31][C:30]2[CH:29]=[CH:28][C:27]([N:32]=[C:33]=[O:34])=[CH:26][C:25]=2[O:24]1.C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[CH2:23]1[O:31][C:30]2[CH:29]=[CH:28][C:27]([NH:32][C:33]([NH:2][CH2:3][C:4]3[CH:12]=[CH:11][CH:10]=[C:9]4[C:5]=3[C:6](=[O:22])[N:7]([CH:14]3[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]3=[O:21])[C:8]4=[O:13])=[O:34])=[CH:26][C:25]=2[O:24]1
Reactant: O=C=Nc1ccc2c(c1)OCO2
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)Nc4ccc5c(c4)OCO5)c3C2=O)C(=O)N1
Temperature: 40 °C
Yield: 77.7 %

Procedure:
A mixture of 4-aminomethyl-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (0.50 g, 1.6 mmol), 3,4-methylenedioxyphenyl isocyanate (0.25 g, 1.6 mmol), and diisopropylethylamine (0.40 g, 3.1 mmol) in 10 mL pyridine was warmed to 40° C. with stirring under N2, and the resulting solution was stirred at the same temperature for 2 hours. The mixture was cooled, and the solvent was evaporated under vacuum. The residue was chromatographed, eluting with 95:5 methylene chloride-methanol, to provide 0.56 g of the product in 81% yield: mp 216-218° C.; 1H NMR (DMSO-d6) δ 2.05-2.09 (m, 1H), 2.50-2.58 (m, 2H), 2.84-2.91 (m, 1H), 4.69 (d, J=5.8 Hz, 2H), 5.16 (dd, J=12.4 Hz, d=5.1 Hz, 1H), 5.93 (s, 2H), 6.67-6.70 (m, 2H), 6.77 (d, J=8.4 Hz, 1H), 7.16 (d, J=1.6 Hz, 1H), 7.75-7.88 (m, 3H), 8.67 (s, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 38.7, 48.9, 100.5, 100.6, 108.0, 110.4, 121.8, 127.2, 131.6, 133.6, 134.7, 134.8, 140.3, 141.5, 147.1, 155.3, 167.0, 167.6, 169.8, 172.8; Anal. calcd. for C22H18N4O5: C, 58.67; H, 4.03; N, 12.44. Found: C, 58.35; H, 3.95; N, 12.25.
Reaction SMILES: O[C@@H:2]1[C:11]2[C:6](=[C:7]([O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.P([N:46]=[N+:47]=[N-:48])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:46]([C@H:2]1[C:11]2[C:6](=[C:7]([O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1)=[N+:47]=[N-:48]
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCC[C@@H]2O)(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](Oc1cccc2c1CCC[C@H]2N=[N+]=[N-])(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of (1S)-1-hydroxy-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (1.0 g) and diphenyl phosphorazidate (0.65 ml) was dissolved in toluene (10 ml). The mixture was cooled to 0° C. under N2, and neat 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) (0.45 ml) was added. The reaction mixture was stirred for 2 hours at 0° C. then at 20° C. for 16 hours. The resulting mixture was washed with water and 1N-HCl. The organic layer was concentrated in vacuo and purified by silica gel chromatography to give (1R)-1-azido-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (950 mg). MS (m/z): (400 (M+ +() IR (Neat): 2100 cm-1NMR (CDCl3, δ): 1.10 (9H, s), 1.8-2.2 (4H, m), 2.6-3.1 (2H, m), 4.5-4.7 (1H, m), 6.3-6.4 (1H, m), 6.7-7.0 (2H, m), 7.1-7.8 (10H, m)
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:9]=[C:10]([CH:14]3[N:18]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[N:17]=[C:16]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])[CH2:15]3)[CH:11]=[CH:12][CH:13]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[N:18]1[CH:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([N:2]3[CH2:3][CH2:4][N:5]([S:42]([CH3:41])(=[O:44])=[O:43])[CH2:6][CH2:7]3)[CH:9]=2)[CH2:15][C:16]([C:27]([F:33])([F:32])[C:28]([F:29])([F:30])[F:31])=[N:17]1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cccc(N3CCNCC3)c2)c(F)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.1 %

Procedure:
5-[3-(piperazin-1-yl)-phenyl]-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (100.0 mg, 0.2 mmol) prepared in Step 1, triethylamine (143.0 uL, 1.02 mmol) and methanesulfonyl chloride (35.0 mg, 0.30 mmol) were added to dichloromethane (2.0 mL). The reaction mixture was stirred at room temperature for 18 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 55.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH2:1]([NH:7][C:8](=O)[CH3:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:11][N:12](C)[C:13](Cl)=O>C1(C)C=CC=CC=1>[CH3:11][N:12]([CH3:13])[C:8](=[N:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH3:9]
Reactant: CN(C)C(=O)Cl
Reactant: CCCCCCNC(C)=O
Solvent: Cc1ccccc1
Product: CCCCCCN=C(C)N(C)C
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
To a solution of N-hexyl acetamide (15.0 g, 105 mmol) in 15 mL of dry toluene was slowly added 11.2 g (104.9 mmol) of dimethylcarbamyl chloride. The solution was refluxed under a nitrogen atmosphere for 24 h. The volatile materials were removed on a rotary evaporator and then in vacuo at room temperature. The residue was dissolved 30 mL of chloroform and stirred vigorously with a solution of 4.2 g sodium hydroxide in 40 mL of water for 30 min. Calcium carbonate (4.2 g) was added and stirring was continued for another 30 min. The organic phase was separated and the aqueous phase was extracted with dichloromethane (25 mL×3). The combined organic phases were dried (calcium carbonate) and the solvent was removed on a rotary evaporator. The residue was distilled at 52-54° C./0.25 Torr (lit. bp 125° C./30 Torr (see Oszczapowicz, J.; Raczynska, E. J. Chem. Soc., Perkin Trans. 2 1984, 1643-1666)) product to yield 8.7 g (49%) of liquid (purity 99% by GC). IR (neat) 2955, 2926, 2856 (C—H), 1626 (N═C) cm−1. 1H NMR 3.18 (t, 2H, JHH 7.5 Hz, —CH2—N═), 2.87 (s, 6H, —N—(CH3)2); 1.87 (s, 3H, —N═C(CH3)—N); 1.49 (m, 2H, —CH2—CH2—N═); 1.25-1.4 (m, 6H, CH3—(CH2)3—); 0.88 (t, 3H, JHH 7.2 Hz, CH3). 13C NMR 158.79; 50.32; 38.07; 32.49; 32.00; 27.38; 22.80; 14.17; 12.45.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]1)=[O:39].[C:47](Cl)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:47]([N:42]1[CH2:43][CH2:44][CH2:45][CH:40]([C:38]([NH:37][C:29]2[CH:30]=[CH:31][C:32]3[NH:33][C:34]4[N:35]=[C:19]([NH:20][C:21]5[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=5)[CH2:26][CH2:27][C:28]=2[CH:36]=3)[N:18]=[CH:17][C:16]=4[Cl:15])=[O:39])[CH2:41]1)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCCNC1
Reactant: O=C(Cl)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCCN(C(=O)c2ccccc2)C1
Yield: 36 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-3-carboxamide bis(trifluoroacetate) and benzoyl chloride as starting materials in 36% yield. LCMS for C31H30ClN6O2 (M+H)+: m/z=553.2.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15](SSC2SC3C=CC(OC)=CC=3N=2)[N:14]([CH:29]([C:40]([CH3:42])=[CH2:41])[C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[C:13]1=[O:43])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:44]1([S:50](=[S:64])([O:52]C2SC3C=CC(OC)=CC=3N=2)=[O:51])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.O.C1(S([O-])=O)C=CC=CC=1.[Na+]>CC(C)=O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:52][S:50]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)(=[O:64])=[O:51])[N:14]([CH:29]([C:40]([CH3:42])=[CH2:41])[C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[C:13]1=[O:43])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2cc(OC)ccc2s1
Reactant: COc1ccc2sc(OS(=O)(=S)c3ccccc3)nc2c1
Agent: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C=C(C)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Yield: 96 %

Procedure:
A 263 mg quantity of benzyl 2-[3-phenoxyacetamido-4-(5-methoxybenzothiazol-2-yldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 147 mg of 5-methoxybenzothiazol-2-yl benzenethiosulfonate were dissolved in 2.5 ml of acetone. To the solution were added 0.5 ml of water and then 2 mg of sodium benzenesulfinate and the mixture was stirred at room temperature for 3 hour. The precipitated 5-methoxybenzothiazol-2-yl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 41, giving benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 96%. The NMR spectrum data of the compound were identical with those of the desired compound. Table 2 shows the NMR spectrum data of the compound.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[C:11]([C:22]([F:25])([F:24])[F:23])=[N:12][N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:7]=2[C:6]1=[O:26].P(Br)(Br)Br.[Br-].[CH3:32][NH:33][CH3:34]>C(Cl)Cl>[CH3:32][N:33]([CH3:34])[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[C:11]([C:22]([F:23])([F:25])[F:24])=[N:12][N:13]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[C:7]=2[C:6]1=[O:26]
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CCCO)CC3)cc1
Reactant: CNC
Agent: BrP(Br)Br
Agent: [Br-]
Solvent: ClCCl
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CCCN(C)C)CC3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
Part B: 6-(3-Hydroxy-propyl)-1-(4-methoxy-phenyl)-3-trifluoromethyl-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one (0.200 g, 0.542 mmol) and phosphorus tribromide (0.077 mL, 0.812 mmol) were dissolved in methylene chloride (20 mL) and stirred at rt for 2 hr. The reaction was quenched with water (100 mL), extracted with methylene chloride (3×100 mL), washed with saturated NaHCO3 (1×100 mL), washed with brine (1×100 mL), dried over Na2So4, and concentrated to afford 0.096 g (41%). The bromide intermediate (0.048 g, 0.111 mmol) was redissolved in methylene chloride (6 mL), and 2M dimethylamine (0.389 mL, 0.777) was added. The reaction was stirred at rt overnight. The reaction was evaporated, redissolved in toluene (15 mL), and re-concentrated. Purification was performed by reverse phase HPLC and freeze-dried to afford the title compound (0.014 g, 32%): 1H NMR (CDCl3) δ 7.43 (d, j=8.8 Hz, 2H), 6.96 (d, j=9.1 Hz, 2H), 3.85 (s, 3H), 3.71 (t, j=7.0 Hz, 2H), 3.56 (t, j=6.6 Hz, 2H), 3.08–2.98 (m, 4H), 2.80(s, 6H), 2.15–2.02 (m, 2H) ppm; Mass Spec 397.4(M+H)+.
Reaction SMILES: [C:1]([CH2:11][C:12]([O:14]CC)=[O:13])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:17]([C:20]1[CH:30]=[CH:29][C:23]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1)=[N+:18]=[N-:19].[O-]CC.[Na+].O>C(O)C>[CH2:27]([NH:26][C:24]([C:23]1[CH:29]=[CH:30][C:20]([N:17]2[C:1](/[CH:2]=[CH:3]/[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)=[C:11]([C:12]([OH:14])=[O:13])[N:19]=[N:18]2)=[CH:21][CH:22]=1)=[O:25])[CH3:28]
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Reactant: CCOC(=O)CC(=O)C=Cc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2/C=C/c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
Ethyl cinnamoylacetate (1.17 g, 4.82 mmol, 1.2 eq.) obtained in Example 106a) and 4-azido-N-ethylbenzamide (0.750 g, 3.94 mmol) were dissolved in ethanol (25 ml), sodium ethoxide (373 mg, 4.93 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 30 min, and then at 60° C. for 10.5 hr. Water (20 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was diluted with 2% aqueous sodium carbonate solution (20 ml) and washed with ethyl acetate-hexane (2:1, 50 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, washed with ethyl acetate-hexane (2:1, 40 ml), acidified (pH<3) with 6N hydrochloric acid, and extracted with ethyl acetate (25 ml×3). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, and ethyl acetate was added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a pale-brown powder (627 mg, 1.73 mmol, 43.9%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[C:16]1[C:17](CCCC2C=CC=CC=2)=[C:18](S([O-])(=O)=O)C=CC=1C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:36]([NH:39][CH2:40][CH2:41][CH:42]([C:49]1[CH:54]=[C:53]([CH3:55])[CH:52]=[CH:51][C:50]=1[O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([CH3:38])[CH3:37].O>CS(C)=O>[CH2:57]([O:56][C:50]1[CH:51]=[CH:52][C:53]([CH3:55])=[CH:54][C:49]=1[CH:42]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:41][CH2:40][N:39]([CH2:18][CH2:17][CH:16]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:36]([CH3:38])[CH3:37])[C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1
Reactant: Cc1ccc(OCc2ccccc2)c(-c2c(C)ccc(S(=O)(=O)[O-])c2CCCc2ccccc2)c1
Reactant: Cc1ccc(OCc2ccccc2)c(C(CCNC(C)C)c2ccccc2)c1
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(OCc2ccccc2)c(C(CCN(CCC(c2ccccc2)c2cc(C)ccc2OCc2ccccc2)C(C)C)c2ccccc2)c1
Temperature: 65 °C

Procedure:
A mixture of 3-(2-(benzyloxy)-5-methylphenyl)-3-phenylpropyl-4-methylbenzenesulfonate of Formula IVa (120 g) and N-isopropyl-3-(2-benzyloxy-5-methylphenyl)-3-phenylpropylamine (92 g) in dimethylsulfoxide (600 ml) was heated at 60-70° C. for 18-20 hours. The reaction mass was cooled to 25-35° C., decomposed with water (600 ml), and extracted with toluene (600 ml). The toluene layer was washed with a mixture of concentrated hydrochloric acid (60 ml) and water (606 ml). The organic layer was then washed with 10% sodium hydroxide solution (240 ml), followed by water (600 ml). The organic layer was distilled completely to obtain the title compound as a syrup. Yield: 128 g (75.4%).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:20]([NH:22][C@H:23]([C:30]([NH:32][C@H:33]([C:40]([NH:42][C@H:43]([C:50]([NH:52][C@H:53]([C:61]([NH:63][CH2:64][C:65]([NH:67][C@H:68]([C:79]([NH:81][C@H:82]([C:87]([O:89]C(C)(C)C)=[O:88])[CH2:83][C:84](=[O:86])[NH2:85])=[O:80])[CH2:69][C:70]1[C:78]2[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=2)[NH:72][CH:71]=1)=[O:66])=[O:62])[C@@H:54]([CH3:60])[O:55]C(C)(C)C)=[O:51])[CH2:44][O:45]C(C)(C)C)=[O:41])[CH2:34][O:35]C(C)(C)C)=[O:31])[CH2:24][O:25]C(C)(C)C)=[O:21])[CH2:12][C:13](=[O:19])[O:14]C(C)(C)C)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[OH:6]>FC(F)(F)C(O)=O.O.SCCS>[NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:20]([NH:22][C@H:23]([C:30]([NH:32][C@H:33]([C:40]([NH:42][C@H:43]([C:50]([NH:52][C@H:53]([C:61]([NH:63][CH2:64][C:65]([NH:67][C@H:68]([C:79]([NH:81][C@H:82]([C:87]([OH:89])=[O:88])[CH2:83][C:84](=[O:86])[NH2:85])=[O:80])[CH2:69][C:70]1[C:78]2[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=2)[NH:72][CH:71]=1)=[O:66])=[O:62])[C@@H:54]([CH3:60])[OH:55])=[O:51])[CH2:44][OH:45])=[O:41])[CH2:34][OH:35])=[O:31])[CH2:24][OH:25])=[O:21])[CH2:12][C:13](=[O:14])[OH:19])=[O:9])[CH2:3][CH2:4][C:5](=[O:6])[OH:7]
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)[C@H](COC(C)(C)C)NC(=O)[C@H](COC(C)(C)C)NC(=O)[C@H](COC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@@H](N)CCC(=O)O)C(=O)NCC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CC(N)=O)C(=O)OC(C)(C)C
Agent: SCCS
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](O)[C@H](NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](N)CCC(=O)O)C(=O)NCC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CC(N)=O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
850 mg (6.9 mmols) Glu-Asp(OBut)-Ser(But)-Ser(But)-Ser(But)-Thr(But)-Gly-Trp-Asn-OBut are dissolved in a mixture of trifluoroacetic acid, water and 1,2-dimercaptoethane (9:1:1). The batch is abandoned for 1 hour at room temperature, concentrated, and the residue is triturated with ether. Yield 650 mg. For purification, the substance is boiled in 30 ml of methanol, and after cooling to room temperature it is suction-filtered. Yield 430 mg (65%). Amino acid analysis (hydrolysis: 24 hours at 120° C. in 6N HCl):
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][CH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]([CH3:29])[C:21]1=[O:30].N1C2C(=CC=CC=2)CC1=O>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([C:20]2([NH2:19])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH3:29])[C:21]2=[O:30])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CN1C(=O)C(N)c2ccccc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Agent: O=C1Cc2ccccc2N1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)C(=O)N(C)c2ccccc21

Procedure:
Following General Procedure I above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 3-amino-1-methyl-2-indolinone monohydrochloride (Example 5-J), the title compound, as a ˜1:1 diastereomeric mixture at C3 of the indolinone, was prepared as a white solid having a decomposition point of 215-220° C. Purification was by flash chromatography eluting with 3:1 CH2Cl2/EtOAc gradient to straight EtOAc followed by recrystalization from CHCl3. Rf=0.16 and 0.22 (EtOAc).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[CH3:10][C:11]1[O:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:13][C:12]=1[CH2:22][CH2:23]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH2:23][CH2:22][C:12]1[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:15][C:11]=1[CH3:10]
Reactant: Cc1cccc(C)c1O
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(C)c1OCCc1nc(-c2ccccc2)oc1C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
1.1 g of 2,6-Dimethylphenol, 2.01 g of 2-(5-methyl-2-phenyl-oxazole-4yl)-ethanol 2.6 g of triphenylphosphin were dissolved in 30 ml THF and treated at 0° with 1.6 ml DEAD (Diethyl azodicarboxylate). The reaction mixture was kept overnight at RT. Water was added. Twofold extraction with AcOEt, washing with brine, drying over sodium sulfate, and evaporation of the solvents provided a crude product, which was purified by chromatography (SiO2; ether/cyclohexane) to yield 0.89 g of the title compound as a slightly yellow oil.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[CH3:30][N:31]([CH3:39])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][NH2:38]>>[F:25][C:18]1[CH:19]=[C:20]([CH3:24])[C:21]([F:23])=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][N:31]([CH3:39])[CH3:30])=[O:29])[S:14][N:13]=1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)cc1F
Reactant: CN(C)CCCCCCN
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCCCN(C)C)c2C(N)=O)cc1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and N1,N1-Dimethyl-hexane-1,6-diamine by the procedure analogous to Example 6. HPLC ret. time: 3.4 minutes. 1H NMR (400 MHz, CD3OD) δ 7.18 (dd, 1H, J=6.0, 9.2 Hz), 7.03 (dd, 1H, J=6.4, 10 Hz), 5.45 (s, 2H), 3.19 (t, 2H, J=7.2 Hz), 2.28 (m, 2H), 2.24 (s, 3H), 2.22 (s, 6H), 1.55-1.45 (m, 4H), 1.35-1 .33 (m, 4H) ppm; MS (APCl, m/z): 470 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]2[CH:20]=[CH:19]N=C[CH:16]=2)[C:3]=1[O:4][CH2:5][C:6]([NH:8][NH2:9])=[O:7].CC1C=C(C)C=C(C2C=C[N:37]=[CH:36]C=2)C=1OCC([O-])=O.O.NN>CCO>[CH3:1][C:2]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]2[CH:16]=[N:37][CH:36]=[CH:19][CH:20]=2)[C:3]=1[O:4][CH2:5][C:6]([NH:8][NH2:9])=[O:7]
Reactant: Cc1cc(C)c(OCC(=O)[O-])c(-c2ccncc2)c1
Reactant: Cc1cc(C)c(OCC(=O)NN)c(-c2ccncc2)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c(OCC(=O)NN)c(-c2cccnc2)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
Synthesis of 2-(2,4-dimethyl-6-(pyridin-4-yl)phenoxy)acetohydrazide: 2-(2,4-dimethyl-6-(pyridin-4-yl)phenoxy)acetate (0.1 g, 0.37 mmol) was dissolved in EtOH. Hydrazine monohydrate (0.13 g, 2.63 mmol) was added thereto, followed by stirring at 100° C. for 16 hours under reflux. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and purified by column chromatography to obtain 2-(2,4-dimethyl-6-(pyridin-3-yl)phenoxy)acetohydrazide (0.1 g, 100%).