Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([Cl:10])[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]1=[O:24].C(N(CC)CC)C.[F:32][C:33]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>O1CCCC1>[Cl:10][C:6]1[CH:5]=[C:4]([F:11])[C:3]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[C:2]([NH:1][C:35](=[O:36])[C:34]2[CH:38]=[CH:39][C:40]([F:42])=[CH:41][C:33]=2[F:32])[C:7]=1[O:8][CH3:9]
Reactant: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1N
Reactant: O=C(Cl)c1ccc(F)cc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1NC(=O)c1ccc(F)cc1F
Yield: 80.2 %

Procedure:
3-(2-Amino-4-chloro-6-fluoro-3-methoxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (2.0 g, 5.4 mmol) and triethylamine (0.66 g, 6.5 mmol) were dissolved in anhydrous tetrahydrofuran (30 ml) and stirred under ice cooling. To this solution was slowly added 2,4-difluorobenzoyl chloride (0.96 g, 5.4 mmol) and solution refluxed for 2 hr. Another batch of 2,4-difluorobenzoyl chloride (0.19 g, 1.1 mmol) was added and solution refluxed for 2 hr. Solvent was removed in vacuo and the product purified by column chromatography on silica gel using hexane-ethyl acetate (3:1) as the eluent to afford the title compound (2.2 g).
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:4]([O:6]N1C(=O)CCC1=O)=O)[CH3:3].[NH2:24][C@H:25]([C:31]([OH:33])=[O:32])[CH2:26][CH2:27][C:28](=[O:30])[NH2:29]>O1CCCC1.O.C(N(CC)CC)C>[NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])[C@H:2]([C:4]([NH:24][C@H:25]([C:31]([OH:33])=[O:32])[CH2:26][CH2:27][C:28](=[O:30])[NH2:29])=[O:6])[CH3:3]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: NC(=O)CC[C@H](N)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 73.5 %

Procedure:
To a solution of 4.80 g of Z-Ala-OSu in 60 ml of tetrahydrofuran was added a solution of 2.19 g of H-Gln-OH in 40 ml of water and 2.10 ml of triethylamine and the mixture was stirred at a room temperature for 20 hours. Tetrahydrofuran and water were removed by distillation and the residue thus obtained was extracted with n-butanol. The n-butanol extract was washed with a 2%-acetic acid and butanol was removed by distillation. The precipitated substance thus obtained was collected by filtration and reprecipitated with methanol-ethyl acetate to obtain 3.87 g of Z-Ala-Gln-OH.
Reaction SMILES: [CH2:1]([C@H:8]([NH:33][C:34](=[O:46])[C@@H:35]([N:39]1[CH2:44][CH2:43][CH2:42][NH:41][C:40]1=[O:45])[CH:36]([CH3:38])[CH3:37])[CH2:9][C@H:10]([OH:32])[C@@H:11]([NH:19][C:20](=[O:31])[CH2:21][O:22][C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:30])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)[P:50]([O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)C.N1C=NN=N1.ClC1C=CC=C(C(OO)=[O:82])C=1>C1COCC1.C(OCC)(=O)C.ClCCl>[P:50]([O:32][C@H:10]([C@@H:11]([NH:19][C:20](=[O:31])[CH2:21][O:22][C:23]1[C:24]([CH3:30])=[CH:25][CH:26]=[CH:27][C:28]=1[CH3:29])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:9][C@@H:8]([NH:33][C:34](=[O:46])[C@@H:35]([N:39]1[CH2:44][CH2:43][CH2:42][NH:41][C:40]1=[O:45])[CH:36]([CH3:38])[CH3:37])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([O:51][CH2:52][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)([O:59][CH2:60][C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)=[O:82]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cccc(C)c1OCC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)[C@H](C(C)C)N1CCCNC1=O
Reactant: CCN(CC)P(OCc1ccccc1)OCc1ccccc1
Agent: c1nnn[nH]1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cccc(C)c1OCC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@H](Cc1ccccc1)NC(=O)[C@H](C(C)C)N1CCCNC1=O)OP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: -45 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
A solution of the compound of Example 3 (0.250 g, 0.40 mmol), dibenzyl diethylphosphoramidite (0.28 mL), and 1H-tetrazole (0.14 g) in THF (4.0 mL) was stirred at room temperature for 68 hours. Dichloromethane (4.0 mL) was added and the mixture was cooled to −45° C., followed by addition of m-chloroperbenzoic acid (0.089 g). After stirring for 30 minutes at −45° C., the reaction was diluted with ethyl acetate and washed twice with 10% Na2CO3 and then with brine. The organic phase was dried over MgSO4, filtered and evaporated. The residue was chromatography on silica gel, eluting with a gradient starting with 33% ethyl acetate in chloroform and ending with 5% methanol in ethyl acetate, to give the title compound (0.324 g, 90% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[OH-].[Na+].ClC(OC(CC)C)=O.[CH3:21][C:22]([O:25][OH:26])([CH3:24])[CH3:23]>C(OCC)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][O:26][O:25][C:22]([CH3:24])([CH3:23])[CH3:21])=[O:6]
Reactant: CC(C)(C)OO
Reactant: O=C(O)c1cccc(Cl)c1
Agent: CCC(C)OC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OOOC(=O)c1cccc(Cl)c1
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 76.8 %

Procedure:
To a well-stirred reaction vessel equipped with a thermometer and a pH-electrode were added 39 g of water and 0.20 g of Arquad CB50 at 5° C. After the addition of 0.05 mole of 3-chlorobenzoic acid the pH was adjusted to 6 using a 10 wt % aqueous NaOH solution. Then, 0.05 mole of sec-butyl chloroformate was dosed within 5 min at 5° C. During this time and a post-reaction time of 165 min at 5° C. the pH was kept at a value between 6 and 9. After the post-reaction, 8.1 g of TBHP were added (0.063 mole), and using a 33 wt % aqueous NaOH solution the pH was adjusted to 13 within 5 min while keeping the temperature at 5° C. During a post-reaction time of 75 min at 5° C. the pH was maintained at 13. Then, 25 g of diethyl ether were added, and the reaction mixture was allowed to separate. After separation of the water layer, the organic layer was washed, twice with 40 g of a 15 wt % aqueous NaCl solution. The ether layer was dried over MgSO4, and the diethyl ether was removed under vacuum. As a result, 9.4 g of tert-butylperoxy 3-chlorobenzoate having a content of 95.4% were obtained in a yield of 80% based on 3-chlorobenzoic acid. The molar ratio of tert-butylperoxy 3-chlorobenzoate to tert-butylperoxy 1-methyl-1-propylcarbonate was calculated to be 97.6:2.4.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([OH:13])=O)=[CH:7][CH:8]=2)[NH:3]1.[NH:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:14]1([C:11]([C:6]2[CH:5]=[C:4]3[C:9]([CH2:10][C:2](=[O:1])[NH:3]3)=[CH:8][CH:7]=2)=[O:13])[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: O=C1Cc2ccc(C(=O)O)cc2N1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C1Cc2ccc(C(=O)N3CCC[C@@H]4c5ccccc5C[C@@H]43)cc2N1
Yield: 34 %

Procedure:
The title compound is prepared from 2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 34% of theory; LC (method 4): tR=1.88 min; Mass spectrum (ESI+): m/z=333 [m+H]+.
Reaction SMILES: C(O[CH:4](OCC)[N:5]1[CH2:9][CH2:8][NH:7][C:6]1=[N:10][N+:11]([O-:13])=[O:12])C.[NH2:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21].CN1CCN(C)C1=O>Cl[Sn](Cl)(Cl)Cl.CCOCC>[C:20]([C:19]1[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=1[N:17]=[CH:4][N:5]1[CH2:9][CH2:8][NH:7][C:6]1=[N:10][N+:11]([O-:13])=[O:12])#[N:21]
Reactant: N#Cc1ccccc1N
Reactant: CCOC(OCC)N1CCNC1=N[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CN1CCN(C)C1=O
Product: N#Cc1ccccc1N=CN1CCNC1=N[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 130.4 %

Procedure:
0.05 g of SnCl4 was added to a mixture of 2.0 g of 1-diethoxymethyl-2-nitroiminoimidazolidine, 1.02 g of o-aminobenzonitrile and 5 ml of 1,3-dimethyl-2-imidazolidinone, followed by agitation at room temperature for 10 minutes. Ether was added to the reaction mixture, and the resultant crystals were collected by filtration and dried to give 2.9 g of 1-(2-cyanophenyliminomethyl)-2-nitroimino-imidazolidine.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([NH2:10])[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.CO.[CH:13](I)([CH3:15])[CH3:14]>C(N(CC)CC)C>[CH:13]([NH:10][C:7]1[CH:8]=[CH:9][C:4]2[CH2:3][CH2:2][O:1][C:5]=2[CH:6]=1)([CH3:15])[CH3:14]
Reactant: Nc1ccc2c(c1)OCC2
Reactant: CC(C)I
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)Nc1ccc2c(c1)OCC2

Procedure:
To a solution of 2.8 g. of 2,3-dihydro-6-benzofuranamine in 150 ml. of methanol is added 18 ml. of isopropyl iodide and 26.5 ml. of triethylamine. The solution is refluxed for 60 hours and then concentrated in vacuo. The resultant oil is extracted repeatedly with diethyl ether. The extracts are combined, filtered through Celite, and the ether removed in vacuo to give an oil of N-isopropyl-2,3-dihydro-6-benzofuranamine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH:4]([CH3:7])[CH2:5][OH:6].[CH3:9][C:10](=[CH2:12])[CH3:11]>>[C:10]([O:6][CH2:5][CH:4]([CH3:7])[C:3]([O:2][CH3:1])=[O:8])([CH3:12])([CH3:11])[CH3:9]
Reactant: COC(=O)C(C)CO
Reactant: C=C(C)C
Product: COC(=O)C(C)COC(C)(C)C
Yield: 43.5 %

Procedure:
Treatment of rac. methyl-3-hydroxy-2-methylpropionate with isobutylene using the procedure described in Example 1 gave rac.-methyl 3-tert. butoxy-2-methylpropionate in 43.5% yield as a colorless liquid, b.p. 75°-85° C. (bath temperature) (11 mm Hg.).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[O:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[F:51][C:52]([F:67])([F:66])[C:53]1[CH:54]=[C:55]([CH:63]=[CH:64][CH:65]=1)[O:56][CH:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1>CN(C=O)C.O>[O:27]=[C:25]([N:60]1[CH2:59][CH2:58][CH:57]([O:56][C:55]2[CH:63]=[CH:64][CH:65]=[C:53]([C:52]([F:51])([F:66])[F:67])[CH:54]=2)[CH2:62][CH2:61]1)[CH2:24][NH:23][C:21]([C:18]1[CH:17]=[C:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:20][N:19]=1)=[O:22]
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)on1
Reactant: FC(F)(F)c1cccc(OC2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1cc(-c2ccccc2)on1
Reaction time: 8 h
Yield: 51.1 %

Procedure:
DIPEA (96 mg, 0.745 mmol) was added to a stirred solution of [(5-phenyl-isoxazole-3-carbonyl)-amino]-acetic acid (67 mg, 0.27 mmol) in DMF (3 mL) followed by HOBt (36 mg, 0.273 mmol) and EDCI.HCl (62 mg, 0.32 mmol). After 2 minutes 4-(3-trifluoromethyl-phenoxy)-piperidine hydrochloride (70 mg, 0.248 mmol) (prepared by method used for the synthesis of Intermediate 15) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure The residue was purified by column chromatography (using 60-120 silica gel and 50% EtOAc in hexane as eluent) to afford 60 mg (34% Yield) of 5-phenyl-isoxazole-3-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 474, 70.17%. 1H NMR (300 MHz, DMSO-d6): δ8.7-8.6 (t, 1H), 8.0-7.9 (m, 2H), 7.6-7.5 (m, 4H), 7.4 (s, 1H), 7.3-7.26 (t, 3H), 4.8 (m, 1H), 4.2 (d, 2H), 3.9 (m, 1H), 3.7 (m, 1H), 3.5 (m, 1H), 3.3 (m, 1H), 2.0 (m, 2H), 1.8-1.4 (m, 2H).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]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.CN(C1C=CC=CN=1)C.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.O>N1C=CC=CC=1>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][S:34]([C:31]2[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C
Yield: 73.2 %

Procedure:
To 2.39 g (10 mmol) of 1-benzhydryl-3-hydroxyazetidine dissolved in 20 ml of pyridine were added 1.46 g (12 mmol) of dimethylaminopyridine. Thereto was added 12.10 g (11 mmol) of p-toluenesulfonyl chloride at -40° C., followed by gradual increase in the temperature and subsequent 1 day of stirring at room temperature. This was mixed with 150 ml of water, extracted with chloroform (100 ml×3) and then dried over anhydrous sodium sulfate. After evaporation of the solvent, the resulting residue was purified by a silica gel column chromatography (250 ml, ethyl acetate:hexane 1:2) to yield 2.88 g (73%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH2:13][C:14]2[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([O:22]CC)=[O:21])=[C:16]([NH:27][C:28](=[O:48])[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]=[CH:36][C:37]4[S:38][CH:39]=[C:40]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[N:41]=4)[CH:30]=3)[CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CO.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH2:13][C:14]2[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[C:16]([NH:27][C:28](=[O:48])[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]=[CH:36][C:37]4[S:38][CH:39]=[C:40]([C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)[N:41]=4)[CH:30]=3)[CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)COc1ccc(CCCS(=O)(=O)c2ccc(Cl)cc2)cc1NC(=O)c1cccc(C=Cc2nc(-c3ccccc3)cs2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)COc1ccc(CCCS(=O)(=O)c2ccc(Cl)cc2)cc1NC(=O)c1cccc(C=Cc2nc(-c3ccccc3)cs2)c1
Yield: 83.7 %

Procedure:
Ethyl 4-[3-(4-chlorophenylsulfonyl)propyl]-2-[3-[2-(4-phenyl-2-thiazolyl)vinyl]benzoylamino]phenoxyacetate (0.30 g, 0.43 mmol) was dissolved in a mixed solution of tetrahydrofuran (10 ml) and methanol (5 ml), 1 N sodium hydroxide aqueous solution (1.0 ml) was added to the solution, and the mixture was subjected to 12 hours of reaction. The reaction solution was acidified by adding ice and 10% citric acid aqueous solution, and the product formed was extracted three times with chloroform. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. By crystallizing the resulting residue from chloroform-acetonitrile, 4-[3-(4-chlorophenylsulfonyl)propyl]-2-[3-[2-(4-phenyl-2-thiazolyl)vinyl]benzoylamino]phenoxyacetic acid (0.24 g, 0.36 mmol, 83%) was obtained as colorless crystals.
Reaction SMILES: NCC(NCC([NH:9][C@H:10]([C:16](NCC(NCC(O)=O)=O)=[O:17])[CH2:11][CH2:12][C:13](=[O:15])[OH:14])=O)=O.CC(CC(NC(C(NC(CNC(CNC(C(N)CC1C=CC(O)=CC=1)=O)=O)=O)CC1C=CC=CC=1)=O)C(O)=[O:33])C.NCC(O)=O>>[NH2:9][C@H:10]([C:16]([OH:17])=[O:33])[CH2:11][CH2:12][C:13]([OH:14])=[O:15]
Reactant: NCC(=O)NCC(=O)N[C@@H](CCC(=O)O)C(=O)NCC(=O)NCC(=O)O
Reactant: CC(C)CC(NC(=O)C(Cc1ccccc1)NC(=O)CNC(=O)CNC(=O)C(N)Cc1ccc(O)cc1)C(=O)O
Agent: NCC(=O)O
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
FIG. 3 shows a product-ion spectrum of the [M+107Ag]+ ion of GGEGG (SEQ. ID. NO. 2), glycylglycylglutamylglycylglycine. Sequencing of the argentinated peptide is straightforward and similar to that discussed in Example 1 for leucine enkephalin. The difference in m/z values between the [M+107Ag]+ ion and the first [bn+OH+Ag]+ ion is 482.1−425.1=57.0, which identifies the C-terminal residue as glycine (theoretical Δm/z 57.0). The difference in m/z values between the first [bn+OH+Ag]+ and the second [bn+OH+Ag]+ is 425.1−368.0=57.1; this identifies the residue preceding the C-terminus as, again, glycine. Repeating the procedure yields the next residue, glutamic acid (experimental Δm/z=128.9 versus theoretical Δm/z=129.0). The triplet peak pattern disappears beyond glutamic acid; however, manual interpretation reveals further sequence information. The [a1−H+Ag]+ in this product-ion spectrum is weak. However, the small m/z value of the [a1−H+Ag]+ ion of the last triplet, 193.1, strongly suggests that it is the [a1−H+Ag]+ ion. This makes G-G as the only possible option for the N-terminal and second residues (theoretical m/z=193.0). Furthermore, FIG. 3 shows a small peak at m/z 136.0, which is assignable as the [a1−H+Ag]+ ion (theoretical m/z=136.0, assuming the first residue is glycine). Thus, the determined sequence is G-G-E-G-G (SEQ. ID. NO. 2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][N:11]1[O:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][N:11]1[O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20]
Reactant: CCOC(=O)CCCON1CCNC1=Nc1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCON1CCNC1=Nc1c(Cl)cccc1Cl
Reaction time: 8 h

Procedure:
4.80 g. of ethyl 4-{[2-[(2,6-dichlorophenyl)imino]-1-imidazolidinyl]oxy}butyrate are dissolved in 100 ml. of ethanol, 26.6 ml. of 1 N caustic soda solution are added at room temperature and the mixture is left to stand overnight. The solution is then neutralized with 26.6 ml. of 1 N hydrochloric acid and evaporated in vacuo. The dried residue is digested with a hot 1:1:1 mixture of acetonitrile/ethyl acetate/chloroform. The salt is then filtered off from the solution and the filtrate is evaporated in vacuo. The residue is recrystallized from hot acetonitrile, whereupon 4-{[2-[(2,6-dichlorophenyl)imino]-1-imidazolidinyl]oxy}-butyric acid, m.p. 115°-116° (from acetonitrile) is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([CH3:13])[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([CH2:13][Br:14])[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnn(C(=O)OC(C)(C)C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1cc(CBr)cn1
Temperature: 25 °C
Yield: 29.2 %

Procedure:
To a solution of 4-methylpyrazole-1-carboxylic acid tert-butyl ester (1.0 g, 5.5 mmol) in carbon tetrachloride (20 mL) was added N-bromosuccinimide (1.0 g, 5.6 mmol) and benzoyl peroxide (50 mg), and the reaction mixture was heated at reflux for 16 h. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:4 EtOAc/hexanes) provided 4-bromomethylpyrazole-1-carboxylic acid tert-butyl ester as a light yellow oil (0.42 g, 30%): 1NMR (300 MHz, CDCl3) δ 8.10 (s, 1H), 7.74 (s, 1H), 4.39 (s, 2H), 1.65 (s, 9H).
Reaction SMILES: [ClH:1].O[CH:3]([CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:4][O:5][N:6]=[C:7]([Cl:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>S(Cl)(Cl)=O>[Cl:1][CH:3]([CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:4][O:5][N:6]=[C:7]([Cl:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cl
Reactant: OC(CON=C(Cl)c1ccccc1)CN1CCCCC1
Solvent: O=S(Cl)Cl
Product: ClC(=NOCC(Cl)CN1CCCCC1)c1ccccc1
Reaction time: 2 h

Procedure:
2.0 g of N-[2-hydroxy-3-(1-piperidinyl)propoxy]-benzimidoyl-chloride hydrochloride is dissolved in 10 ml of thionylchloride, then the solution is boiled for 2 hours. The thionylchloride is distilled off; the evaporation residue is taken up in 50 ml of methanol, then evaporated. The light yellow evaporation residue (m=2.48 g) is dissolved in 12.5 ml of ethanol and crystallized with 50 ml of ether. The separated precipitate is filtered off, and washed with a mixture of ethanol/ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].C(O)C.[Cl:27][C:28]1[CH:29]=[C:30]([C:34]([N:36]=[C:37]=[S:38])=[O:35])[CH:31]=[CH:32][CH:33]=1>C1(C)C=CC=CC=1>[Cl:27][C:28]1[CH:29]=[C:30]([CH:31]=[CH:32][CH:33]=1)[C:34]([NH:36][C:37]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[C:17]([F:23])[CH:18]=1)=[S:38])=[O:35]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: O=C(N=C=S)c1cccc(Cl)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(Cl)c4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 3-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (73 mg, yield 90%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10]([CH:12]1[O:14][CH2:13]1)[Cl:11]>N1C=CC=CC=1>[Cl:11][CH2:10][CH:12]([OH:14])[CH2:13][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: ClCC1CO1
Solvent: c1ccncc1
Product: O=Cc1cccc(OCC(O)CCl)c1

Procedure:
A mixture of 3-hydroxybenzaldehyde (24.4 g, 0.2 mol), epichlorohydrin (47 ml) and pyridine (0.4 ml) is heated 5 hours on a steam bath. The crude mixture is partitioned between methylenechloride-water and the CH2Cl2 extract washed with dilute aqueous NaHCO3, dried (Na2SO4), filtered and concentrated in vacuo to give the crude title product. Distillation gives a colorless oil bp 160° (0.2 mm); 21.2 g.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][C:17]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[OH:29])=[O:18].O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:29][C:20]1[CH:21]=[CH:22][C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19]=1[C:17](=[O:18])[CH3:16]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CC(=O)c1c(O)ccc2ccccc12
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc4ccccc4c3C(C)=O)c2cc1OC
Temperature: 160 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), 2-hydroxy-1-acetonaphthone (250 mg), and 4-dimethylaminopyridine (164 mg) were suspended in o-dichlorobenzene (6 ml), and the suspension was stirred at 160° C. for 2 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (100 mg, yield 60%.