Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[NH:14][NH2:15].[NH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]2[N:33]=[C:34]([NH:37][C:38](=[O:40])[CH3:39])[S:35][CH:36]=2)=[CH:26][CH:25]=1>O1CCCC1>[C:38]([NH:37][C:34]1[S:35][CH:36]=[C:32]([CH2:31][CH2:30][C:27]2[CH:28]=[CH:29][C:24]([CH2:23][NH:22][C:1]([NH:15][NH:14][C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:2])=[CH:25][CH:26]=2)[N:33]=1)(=[O:40])[CH3:39]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(=O)Nc1nc(CCc2ccc(CN)cc2)cs1
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CCc2ccc(CNC(=O)NNC(=O)OC(C)(C)C)cc2)cs1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.4 %

Procedure:
To a suspension of 1,1′-carbonyldiimidazole (332.1 mg, 2.048 mmol) in anhydrous tetrahydrofuran (1.3 ml) was added tert-butyl carbazate (270.7 mg, 2.048 mmol). After stirring at room temperature for 15 min, N-(4-{2-[4-(aminomethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (282.6 mg, 1.024 mmol) was added, and the mixture was stirred at room temperature for 6 hr and concentrated under reduced pressure. Ethyl acetate and water were added to the residue, and the mixture was stirred, stood still and then partitioned. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. BW-300SP 24 g, dichloromethane:methanol=30:1→20:1). The residue was further purified by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. DM-2035 16 g, dichloromethane:methanol=30:1) to give tert-butyl 2-[(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}benzyl)carbamoyl]hydrazinecarboxylate (348.3 mg, 0.803 mmol, yield 78.5%) as a white solid.
Reaction SMILES: BrC1C2C(S([Cl:15])(=O)=O)=CC=CC=2C=NC=1.C(OC(NC1CCNC1)=O)(C)(C)C.C(OC([NH:36][CH2:37][CH:38]1[CH2:41][N:40]([S:42]([C:45]2[C:46]3[C:47]([Cl:55])=[CH:48][N:49]=[CH:50][C:51]=3[CH:52]=[CH:53][CH:54]=2)(=[O:44])=[O:43])[CH2:39]1)=O)(C)(C)C>>[NH2:36][CH2:37][CH:38]1[CH2:39][N:40]([S:42]([C:45]2[C:46]3[C:47]([Cl:55])=[CH:48][N:49]=[CH:50][C:51]=3[CH:52]=[CH:53][CH:54]=2)(=[O:43])=[O:44])[CH2:41]1.[ClH:15]
Reactant: O=S(=O)(Cl)c1cccc2cncc(Br)c12
Reactant: CC(C)(C)OC(=O)NCC1CN(S(=O)(=O)c2cccc3cncc(Cl)c23)C1
Agent: CC(C)(C)OC(=O)NC1CCNC1
Product: Cl
Product: NCC1CN(S(=O)(=O)c2cccc3cncc(Cl)c23)C1

Procedure:
4-Chloro-5-isoquinolinesulfonyl chloride obtained in Reference Example 7 and 3-(tert-butoxycarbonylaminomethyl)azetidine were used in the method of Example 1, Step A instead of 4-bromo-5-isoquinolinesulfonyl chloride and 3-(tert-butoxycarbonylamino)pyrrolidine, respectively, to prepare 3-[(tert-butoxycarbonylamino)methyl]-1-(4-chloro-5-isoquinolinesulfonyl)azetidine, and then the resultant was used in the method of Example 1, Step B to obtain the title compound as hydrochloride.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C.[C:42]([O:46][C:47]([NH:49][C@@H:50]([CH2:54][S:55][S:56][C:57]([CH3:60])([CH3:59])[CH3:58])[C:51](O)=[O:52])=[O:48])([CH3:45])([CH3:44])[CH3:43]>O1CCCC1>[C:42]([O:46][C:47](=[O:48])[NH:49][C@@H:50]([CH2:54][S:55][S:56][C:57]([CH3:60])([CH3:59])[CH3:58])[C:51]([NH:32][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:52])([CH3:44])([CH3:45])[CH3:43]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CSSC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CSSC(C)(C)C)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (2.52 g, 6.62 mmol), benzylamine (0.723 ml, 6.62 mmol) and N,N-diisopropylethylamine (1.153 ml, 6.62 mmol) were added to a solution of (R)-2-((tert-butoxycarbonyl)amino)-3-(tert-butyldisulfanyl)propanoic acid (Compound tk91) (1.95 g, 6.30 mmol) in tetrahydrofuran (20 ml), and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (R)-tert-butyl(1-(benzylamino)-3-(tert-butyldisulfanyl)-1-oxopropan-2-yl)carbamate (Compound tk92) (2.357 g, 5.91 mmol, 94%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7](Cl)[N:6]=[CH:5]2.[NH2:15][C:16]1[CH:27]=[CH:26][C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][CH:17]=1>C(O)(C)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([NH:15][C:16]1[CH:27]=[CH:26][C:19]([C:20]([NH:22][CH:23]([CH3:24])[CH3:25])=[O:21])=[CH:18][CH:17]=1)[N:6]=[CH:5]2
Reactant: CC(C)NC(=O)c1ccc(N)cc1
Reactant: COc1cc2nc(Cl)ncc2cc1Br
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: COc1cc2nc(Nc3ccc(C(=O)NC(C)C)cc3)ncc2cc1Br
Temperature: 100 °C

Procedure:
To a 0.25M suspension of 6-bromo-2-chloro-7-methoxyquinazoline in isopropanol was added 4-amino-N-isopropylbenzamide (1.0 eq). The reaction mixture was heated to 100° C. in an oil bath for 14 h. Reaction mixture was diluted with ethyl acetate and filtered to collect desired product. ES/MS m/z 415/417 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:9][O:8][B:7]([OH:10])[C:6]=2[CH:11]=1.CN1CCOCC1.[CH3:19][O:20][CH2:21][CH2:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[S:32](Cl)(=[O:34])=[O:33]>CC#N>[OH:10][B:7]1[C:6]2[CH:11]=[C:2]([NH:1][S:32]([C:24]3[CH:25]=[CH:26][C:27]([N+:29]([O-:31])=[O:30])=[CH:28][C:23]=3[CH2:22][CH2:21][O:20][CH3:19])(=[O:33])=[O:34])[CH:3]=[CH:4][C:5]=2[CH2:9][O:8]1
Reactant: Nc1ccc2c(c1)B(O)OC2
Reactant: COCCc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Solvent: CN1CCOCC1
Solvent: CC#N
Product: COCCc1cc([N+](=O)[O-])ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
To a solution of 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (0.59 g, 3.9 mmol) and N-methylmorpholine (2.53 g, 25 mmol) in MeCN (70 mL) was added 2-(2-methoxyethyl)-4-nitrobenzene-1-sulfonyl chloride (1.4 g, 5 mmol) in MeCN (20 mL) at 0° C., then the solution was stirred at room temperature overnight. The mixture was concentrated in vacuo, and ethyl acetate and water was added to the residue. The organic layer was dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:1 to 0:1) to give N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(2-methoxyethyl)-4-nitrobenzene sulfonamide (1 g, yield 50%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]2[C:9]3[C:14]([NH:15][C:16]4[CH:25]=[CH:24][C:19]5[NH:20][C:21](=[O:23])[S:22][C:18]=5[CH:17]=4)=[N:13][CH:12]=[N:11][C:10]=3[S:26][C:5]=2[CH2:4]1.[OH:27][C:28]([CH3:33])([CH3:32])[C:29](O)=[O:30]>>[OH:27][C:28]([CH3:33])([CH3:32])[C:29]([NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]2[C:9]3[C:14]([NH:15][C:16]4[CH:25]=[CH:24][C:19]5[NH:20][C:21](=[O:23])[S:22][C:18]=5[CH:17]=4)=[N:13][CH:12]=[N:11][C:10]=3[S:26][C:5]=2[CH2:4]1)=[O:30]
Reactant: CC(C)(O)C(=O)O
Reactant: NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1
Product: CC(C)(O)C(=O)NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1

Procedure:
10 mg (130 μmol) (RS)-6-{[7-(aminomethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yl]amino}-1,3-benzothiazol-2(3H)-one (prepared according to example 20) were transformed in analogy to example 23 using 2-hydroxy-2-methylpropanoic acid to give after working up and purification 23.8 mg (38%) of the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:15])[C:11]=2[O:13][CH3:14])[C:6](=[O:16])[C:5]([C:17]([O:19]CC)=[O:18])=[CH:4]1)[CH3:2]>C(O)(=O)C.O.S(=O)(=O)(O)O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:15])[C:11]=2[O:13][CH3:14])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2c(OC)c(F)ccc2c1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2ccc(F)c(OC)c21
Temperature: 25 °C

Procedure:
Ethyl 1-ethyl-1,4-dihydro-7-fluoro-8-methoxy-4-oxo-3-quinolinecarboxylate (1.37 g, 4.7 mmol) is suspended in a mixture of acetic acid:water:sulfuric acid (8:6:1). The mixture is refluxed for 3 hours, and then cooled to room temperature. The crystals are filtered and rinsed with cold water.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>O1CCCC1>[C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:34]([NH:33][C:30]4[CH:29]=[CH:28][C:27]([C:26]([F:25])([F:36])[F:37])=[CH:32][CH:31]=4)=[O:35])[CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 4-trifluoromethylphenyl isocyanate (0.184 ml, 1.22 mmol), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 248 mg (70.5%) of the desired product as a solid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]([CH3:25])[C@@H:19]([CH2:23][OH:24])[C:20]([OH:22])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:26][O:27][C:28]1[CH:49]=[CH:48][C:31]([C:32](Cl)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)=[CH:30][CH:29]=1.[N:50]1[CH:55]=[CH:54]C=[CH:52][CH:51]=1>>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([N:18]([CH3:25])[C@@H:19]([CH2:23][O:24][C:32]([C:31]3[CH:48]=[CH:49][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:20]([O-:22])=[O:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1.[CH2:55]([NH+:50]([CH:49]([CH3:48])[CH3:28])[CH:51]([CH3:52])[CH3:1])[CH3:54]
Reactant: CN(C(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](CO)C(=O)O
Reactant: c1ccncc1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: CC[NH+](C(C)C)C(C)C
Product: COc1ccc(C(OC[C@@H](C(=O)[O-])N(C)C(=O)OCC2c3ccccc3-c3ccccc32)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 13 h
Yield: 92 %

Procedure:
(2S)-2-[9H-Fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-hydroxypropanoic acid (Compound SP823) (920 mg, 2.70 mmol) was dissolved in dehydrated pyridine (2.5 mL), and the reaction solution was concentrated under reduced pressure. This operation was repeated twice, after which the reaction solution was dissolved in dehydrated pyridine (2.5 mL) under a nitrogen atmosphere, and 4,4′-dimethoxytrityl chloride (931 mg, 2.75 mmol) was added at room temperature. The reaction mixture was stirred at the same temperature for 13 hours and then concentrated under reduced pressure. The resulting residue was dissolved in chloroform (15 mL) and washed with saturated sodium bicarbonate (5 mL). The organic layer was dried over sodium sulfate and then concentrated under reduced pressure, and the resulting crude product was purified by normal-phase silica gel column chromatography (1% diisopropylethylamine-containing dichloromethane/methanol) to afford N-ethyl-N-isopropylpropan-2-aminium (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(bis(4-methoxyphenyl)(phenyl)methoxy)propanoate (Compound SP816) (1.92 g, 92%).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:33])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([CH:29]3[CH2:32][CH2:31][CH2:30]3)[C:15]3[C:20]([C:21]=2[C:22]#[N:23])=[CH:19][CH:18]=[C:17]([O:24][CH2:25][CH2:26][CH2:27]Cl)[CH:16]=3)=[CH:9][CH:8]=1)([CH3:3])[CH3:2].[I-].[Na+].[Na].[NH:37]1[CH:41]=[N:40][CH:39]=[N:38]1>CC#N>[CH:1]([O:4][C:5](=[O:33])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([CH:29]3[CH2:32][CH2:31][CH2:30]3)[C:15]3[C:20]([C:21]=2[C:22]#[N:23])=[CH:19][CH:18]=[C:17]([O:24][CH2:25][CH2:26][CH2:27][N:37]2[CH:41]=[N:40][CH:39]=[N:38]2)[CH:16]=3)=[CH:9][CH:8]=1)([CH3:3])[CH3:2]
Reactant: c1nc[nH]n1
Reactant: CC(C)OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCCCCl)cc3n2C2CCC2)cc1
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Solvent: CC#N
Product: CC(C)OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCCCn4cncn4)cc3n2C2CCC2)cc1
Yield: 77.7 %

Procedure:
To a solution of {4-[6-(3-chloro-propoxy)-3-cyano-1-cyclobutyl-1H-indol-2-yl]-phenyl}-carbamic acid isopropyl ester (37 mg, 0.08 mmol) in CH3CN (1 mL) is added sodium iodide (71 mg, 0.48 mmol). The resulting mixture is stirred at reflux temperature overnight. The solvent is then evaporated and the residue is diluted with anhydrous DMF (1 mL) and then treated with the sodium salt of 1,2,4-triazole (0.16 mmol) at room temperature overnight. The solvent is removed under reduced pressure and the residue is diluted with ethyl acetate and then washed with water. The organic layer is concentrated and triturated with hexane and the precipitate is collected by filtration and washed well with 50% ethyl acetate in hexane and dried in vacuo to afford {4-[3-cyano-1-cyclobutyl-6-(3-[1,2,4]triazol-1-yl-propoxy)-1H-indol-2-yl]-phenyl}-carbamic acid isopropyl ester, compound 1255 (31 mg, 78%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH3:19])[C:6]([O:17][CH3:18])=[C:7]([CH:9]([O:12][Si](C)(C)C)[C:10]#[N:11])[CH:8]=1.[CH2:20]([OH:22])[CH3:21]>>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH3:19])[C:6]([O:17][CH3:18])=[C:7]([CH:9]([OH:12])[C:10](=[NH:11])[O:22][CH2:20][CH3:21])[CH:8]=1
Reactant: COc1c(C)cc(Cl)cc1C(C#N)O[Si](C)(C)C
Reactant: CCO
Agent: Cl
Product: CCOC(=N)C(O)c1cc(Cl)cc(C)c1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
Ethanol (100 ml.) was saturated with hydrogen chloride at 0° C. 2-(5-Chloro-2-methoxy-3-methylphenyl)-2-trimethylsiloxyethanenitrile (2.9 g.) in 5 ml. of ethanol was added dropwise, keeping the temperature less than 10° C. The reaction mixture was stirred at 0° C. for about 1 hour, evaporated to dryness and the residue triturated with ether to yield ethyl 1-(5-chloro-2-methoxy-3-methylphenyl)-1-hydroxymethanecarboximidate hydrochloride [2.67 g., 89%; m.p. 131°-133° C. (dec); ir (KBr) 1653, 1538, 1488, 1227, 1093 cm-1 ].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[C:12](Cl)(=[O:14])[CH3:13].C(OCC)(=O)C>O1CCCC1>[O:11]=[C:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:12](=[O:14])[CH3:13])[CH:3]=2)[NH:7]1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2c(c1)CC(=O)N2
Temperature: -30 °C
Reaction time: 0.33 h
Yield: 88.9 %

Procedure:
A stirred solution of 5-amino-1,3-dihydro-indol-2-one (3.5 g, 23.6 mmol, prepared according to U.S. Pat. No. 6,114,371) in 20 ml of tetrahydrofuran was added with tirethylamine (1.3 ml, 9 mmol). The solution was cooled down to −30° C. in an acetone-dry ice bath and added with acetyl chloride (1.3 ml, 9 mmol) dropwise. Upon the completion of the addition, the resulting mixture was stirred for 20 minutes at room temperature and added with ethyl acetate (20 ml) until precipitate was formed. The solid was filtered, washed with water (50 ml×3) and dried in vacuo to give N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (4 g, 88.9%) as a white solid.
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([I:16]=O)=[CH:12][CH:11]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>C(OC(=O)C)(=O)C>[F:23][C:24]([F:29])([F:28])[C:25]([O-:27])=[O:26].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([I+:16][C:19]2[S:18][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:11]=1
Reactant: c1ccsc1
Reactant: O=Ic1ccc(Cl)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Clc1ccc([I+]c2cccs2)cc1
Product: O=C([O-])C(F)(F)F
Temperature: -20 °C
Reaction time: 0.92 h

Procedure:
4-Chloroiodosobenzene diacetate (17.3 grams; 0.05 mole) was dispersed in a mixture of 15 milliliters each of acetic anhydride and trifluoroacetic acid, and a solution of thiophene (8.4 grams; 0.10 mole) in 60 milliliters of acetic anhydride added slowly thereto. The addition was carried out with stirring in 55 minutes at -20°C. Stirring was continued for 65 minutes at -20°C., and the reaction mixture thereafter warmed and maintained at -3°C. with stirring for 15 hours to insure completion of the reaction. The reaction mixture was concentrated by fractional distillation under reduced pressure up to 50°C., and the resulting residue diluted with 100 milliliters of diethyl ether. During the dilution, the 4-chlorophenyl-2-thienyliodonium trifluoroacetate precipitated as a crystalline solid and was separated by filtration. The solid, recrystallized from a mixture of acetone and normal pentane, melted at 156°-157.5°C.
Reaction SMILES: [Al](C)(C)C.CO[C:7]([C:9]1[S:10][C:11]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:12][C:13]=1[C:14]#[C:15][Si](C)(C)C)=[O:8].[C:27]([O:31][C:32]([N:34]1[CH2:37][CH:36]([O:38][C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][C:40]=2[F:46])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1(C)C=CC=CC=1.CCOC(C)=O>[C:27]([O:31][C:32]([N:34]1[CH2:35][CH:36]([O:38][C:39]2[CH:44]=[CH:43][C:42]([N:45]3[CH:15]=[CH:14][C:13]4[CH:12]=[C:11]([C:20]5[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=5)[S:10][C:9]=4[C:7]3=[O:8])=[CH:41][C:40]=2[F:46])[CH2:37]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(N)cc2F)C1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Al](C)C
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(-n3ccc4cc(-c5ccc(Cl)cc5)sc4c3=O)cc2F)C1
Temperature: 0 °C
Yield: 80.1 %

Procedure:
Add 2.0 M Al(CH3)3 (1.28 mL, 2.56 mmol) to a suspension of 5-(4-chloro-phenyl)-3-trimethylsilanylethynyl-thiophene-2-carboxylic acid methyl ester (0.851 g, 2.44 mmol) and 3-(4-amino-2-fluoro-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (0.688 g, 2.44 mmol) in toluene (20 mL). Stir the reaction at 60° C. for 4 h. Cool the mixture to 0° C., quench with 2.0 M NaOH (5 mL) and water (20 mL) and then extract with CHCl3 (3×50 mL). Dry with Na2SO4, filter, and concentrate. Dissolve the crude material in THF (50 mL), treat with 1.0 M TBAF (2.93 mL, 2.93 mmol) and stir at RT overnight. Dilute with EtOAc (100 mL), wash with water (3×40 mL), dry with Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with 5% CH3OH/CHCl3 to give 1.03 g (80%) of the title compound. LC-MS/ES m/z (35Cl) 526.9 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C@H:8]([C:25](=[O:28])[NH:26][CH3:27])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]([OH:24])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:30]([N:32]=[C:33]=[O:34])[CH3:31]>ClCCl.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:29])[NH:7][C@H:8]([C:25](=[O:28])[NH:26][CH3:27])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]([O:24][C:33](=[O:34])[NH:32][CH2:30][CH3:31])[CH:11]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCN=C=O
Reactant: CNC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(O)c1)NC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCNC(=O)Oc1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)NC)ccc1OCc1ccccc1
Temperature: 50 °C

Procedure:
[(S)-2-(4-Benzyloxy-3-hydroxy-phenyl)-1-methylcarbamoyl-ethyl]-carbamic acid tert-butyl ester (348 mg) was dissolved in dry dichloromethane (2 ml) and ethyl isocyanate (0.31 ml) added followed by a catalytic amount of DMAP. The solution was heated at 50° C. for 5 hours and a white solid formed. The mixture was diluted with ethyl acetate and the crude product was filtered off and washed with ethyl acetate. Recrystallisation from methanol afforded [(S)-2-(4-benzyloxy-3-ethylcarbamoyloxy-phenyl)-1-methylcarbamoyl-ethyl]-carbamic acid tert-butyl ester, 253 mg; HPLC/MS Retention time 5.49 min, m/z 472 (MH+).
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:12])[C:9]=1[CH2:10]2.[O:13]1CCCC1.Cl(O)(=O)(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CCOCC.O>[C:8]1([OH:12])[C:9]2[CH2:10][C@@H:11]([OH:1])[C@H:2]([OH:13])[CH2:3][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc2c1CC1OC1C2
Reactant: C1CCOC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Oc1cccc2c1C[C@@H](O)[C@H](O)C2
Reaction time: 4 h

Procedure:
A solution of 8.0 g. (0.048 mole) of 5,6,7,8-tetrahydro-6,7-epoxy-1-naphthol in 100 ml. of tetrahydrofuran is cooled to 0° and 20 ml. of water and 0.5 ml. of 70% perchloric acid are added. After 4 hr., a further 1.5 ml. of acid is added and the solution stirred for 16 hr. at ambient temperature and diluted with 100 ml. each of ether, 10% sodium bicarbonate and saturated salt solution. The aqueous layer is separated and washed with 150 ml. of 1:1 ether-tetrahydrofuran. The organic phase is washed with saturated salt solution, dried and evaporated to give an oil which solidifies on trituration with chloroform. Recrystallization gives in two crops, 4.85 g. of solid which is recrystallized from ethyl acetate to give 3.84 g. m.p. 179.5°-181.5°. Two further recrystallizations of a small sample give the analytical specimen, m.p. 183°-184°.
Reaction SMILES: [C:1]([C:4]1([CH3:10])[N+:8]([O-:9])=[CH:7][CH2:6][CH2:5]1)(=[O:3])[NH2:2].C([C@H](N)C(O)=O)CC([NH:15][C@H](C(NCC(O)=O)=O)CSSC[C@H](NC(CC[C@H](N)C(O)=O)=O)C(NCC(O)=O)=O)=O.C(OOC(C)(C)C)(C)(C)C>P([O-])([O-])([O-])=O>[NH2:15][C:7]1[CH2:6][CH2:5][C:4]([C:1](=[O:3])[NH2:2])([CH3:10])[N+:8]=1[O-:9]
Reactant: N[C@@H](CCC(=O)N[C@@H](CSSC[C@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)NCC(=O)O)C(=O)NCC(=O)O)C(=O)O
Reactant: CC1(C(N)=O)CCC=[N+]1[O-]
Agent: CC(C)(C)OOC(C)(C)C
Agent: O=P([O-])([O-])[O-]
Product: CC1(C(N)=O)CCC(N)=[N+]1[O-]
Reaction time: 0.08 h

Procedure:
Trapping of GS. and t-BuO. radicals. 50 μL 0.1 M phosphate buffer solution containing 30 mM AMPO and 100 mM GSSG or (CH3)3CO—OC(CH3)3. The mixture was then transferred to 50 μL capillary tube and the radicals were generated by UV photolysis. EPR spectrum of the adduct was recorded over a 5 min time period.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:24]=[CH:23][C:15]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=O)=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[Cl:25][C:26]1[CH:33]=[CH:32][C:29](/[CH:30]=[C:19]2\[N:18]=[C:16]([C:15]3[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[CH:24][CH:23]=3)[O:22][C:20]\2=[O:21])=[CH:28][CH:27]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COc1ccc(CCOc2ccc(C(=O)NCC(=O)O)cc2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(CCOc2ccc(C3=N/C(=C\c4ccc(Cl)cc4)C(=O)O3)cc2)cc1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 86.7 %

Procedure:
A mixture of N-{4-[2-(4-methoxyphenyl)ethoxy]benzoyl}glycine (329 mg, 1.00 mmol) prepared in Example 1 (1b), 4-chlorobenzaldehyde (148 mg, 1.05 mmol), sodium acetate (111 mg, 1.35 mmol), and acetic anhydride (467 μL, 5.00 mmol) was stirred at 120° C. for 20 minutes, and then water was added thereto to terminate the reaction. Then, continuously, the mixture was vigorously stirred until the mixture was cooled to room temperature. The deposited precipitate was collected by filtration, washed with water and hexane, and dried by heating under reduced pressure to give 376 mg of the title compound (yellow powder, yield: 87%).