Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH2:9][CH2:10][CH:11]([CH:13]1[CH2:18][CH2:17][C:16]([CH3:19])=[CH:15][CH2:14]1)[CH3:12])=[O:7].ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH2:9][CH2:10][CH:11]([CH:13]1[CH2:18][CH2:17][C:16]2([O:28][CH:15]2[CH2:14]1)[CH3:19])[CH3:12])=[O:7]
Reactant: CC1=CCC(C(C)CCOC(=O)c2ccco2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(CCOC(=O)c1ccco1)C1CCC2(C)OC2C1

Procedure:
The procedure of Example 1 was followed for the epoxidation of 5.2g (0.02 mole) of furoic acid, 3-(4-methyl-3-cyclohexenyl)butyl ester using 4.2g (0.02 mole) of 85% m-chloroperbenzoic acid in 150 ml of methylene chloride. Obtained following distillation was 3.7g of pure furoic acid, 3-(3,4-epoxy-4-methylcyclohexyl)butyl ester as a clear, colorless liquid with a boiling point of 156°-161°C. (0.10mm). (See Table I).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=O)[CH:3]=1.[CH3:12][O:13][C:14]([C:16]1[N:20]([CH:21]2C3C(=CC=CC=3)C[CH2:23][C:22]2([CH3:32])[CH3:31])[CH:19]=[N:18][CH:17]=1)=[O:15].C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[CH3:12][O:13][C:14]([C:16]1[N:20]([CH:21]2[C:3]3[C:4](=[CH:5][CH:6]=[CH:7][CH:2]=3)[C:8](=[O:10])[CH2:23][C:22]2([CH3:32])[CH3:31])[CH:19]=[N:18][CH:17]=1)=[O:15]
Reactant: COC(=O)c1cncn1C1c2ccccc2CCC1(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cncn1C1c2ccccc2C(=O)CC1(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 4 %

Procedure:
10.6 g of 3-chloroperbenzoic acid are added to a solution, cooled to 0° C., of 7.1 g of 1-(2,2-dimethyltetralin-1-yl)-5-imidazolecarboxylic acid methyl ester in 200 ml of methylene chloride. The mixture is stirred at room temperature for a further 72 hours. A solution of 7.5 g of sodium hydrogen carbonate in 100 ml of water is then added. The organic phase is separated off, washed with water, dried and concentrated by evaporation. The residue is purified by column chromatography on silica gel using chloroform as eluant. The product-containing fraction is again chromatographed on silica gel using a chloroform/methanol mixture (99.5:0.5). 0.3 g of 1-(2,2-dimethyl-4-oxotetralin-1-yl)-5-imidazolecarboxylic acid methyl ester is obtained in the form of a solid.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:30]=[CH:29][C:9]([CH2:10][N:11]3[C:27](=[O:28])[N:14]4[N:15]=[CH:16][C:17]([C:20]5[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=5)=[C:18](Cl)[C:13]4=[N:12]3)=[CH:8][CH:7]=2)=[CH:4][CH:3]=[N:2]1.[NH:31]1[CH:35]=[CH:34][N:33]=[CH:32]1>CN1CCCC1=O>[O:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][N:11]3[C:27](=[O:28])[N:14]4[N:15]=[CH:16][C:17]([C:20]5[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=5)=[C:18]([N:31]5[CH:35]=[CH:34][N:33]=[CH:32]5)[C:13]4=[N:12]3)=[CH:29][CH:30]=2)=[CH:4][CH:3]=[N:2]1
Reactant: c1c[nH]cn1
Reactant: O=c1n(Cc2ccc(-c3ccno3)cc2)nc2c(Cl)c(-c3ccc(Cl)cc3)cnn12
Solvent: CN1CCCC1=O
Product: O=c1n(Cc2ccc(-c3ccno3)cc2)nc2c(-n3ccnc3)c(-c3ccc(Cl)cc3)cnn12
Yield: 54.5 %

Procedure:
A solution of 2-(4-(isoxazol-5-yl)benzyl)-8-chloro-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (149 mg, 0.34 mmol) and imidazole (69.5 mg, 1.02 mmol) in dry 1-methyl-2-pyrrolidinone (3 mL) was heated at 100° C. for 18 h. HPLC/MS analysis indicated 90% complete reaction. The reaction mixture was concentrated under vacuum with co-evaporation of toluene (5 mL×2) to obtain a dark yellow solid. The crude product was purified by silica gel column chromatography (ISCO) eluting with CH2Cl2/EtOAc to obtain pure title compound (87 mg, 55%) as a yellow solid. MS [M+H]+ 470; HPLC retention time=2.59 min; 1HNMR (400 MHz, CDCl3) δ 8.29 (d, 1H, J=0.5 Hz), 8.18 (s, 1H), 7.80-7.85 (m, 2H), 7.78 (s, 1H), 7.49 (d, 2H, J=7.0 Hz), 7.43 (d, 2H, J=7.0 Hz), 7.13-7.15 (m, 3H), 6.94 (m, 1H), 6.53 (d, 1H, J=0.5 Hz), 5.27 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][C@@H:9]2[C:20]([O-:22])=O)[CH:5]=[CH:6][CH:7]=1.ClCCCl.CCN(C(C)C)C(C)C.[NH2:36][C:37]1[CH:46]=[CH:45][C:44]([C:47]([NH2:49])=[O:48])=[C:43]2[C:38]=1[CH:39]=[CH:40][CH:41]=[N:42]2>>[C:47]([C:44]1[CH:45]=[CH:46][C:37]([NH:36][C:20]([CH:9]2[C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:10]2)=[O:22])=[C:38]2[C:43]=1[N:42]=[CH:41][CH:40]=[CH:39]2)(=[O:48])[NH2:49]
Reactant: CC(C)(C)OC(=O)N1C[C@H](C(=O)[O-])[C@@H](c2cccc(F)c2)C1
Reactant: NC(=O)c1ccc(N)c2cccnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(C(=O)Nc2ccc(C(N)=O)c3ncccc23)[C@@H](c2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl(3R,4S)-4-(3-fluoro-phenyl)-pyrrolidine-1,3-dicarboxylate (125.00 mg; 0.40 mmol; 1.00 eq.) in DCE (4.0 ml) bis(2-oxo-1,3-oxazolidin-3-yl)phosphinic chloride (102.87 mg; 0.40 mmol; 1.00 eq.) was added. After stirring for 15 mins at RT, DIEA (0.15 ml; 0.81 mmol; 2.00 eq.) and 5-aminoquinoline-8-carboxamide (75.65 mg; 0.40 mmol; 1.00 eq) were added. The reaction mixture was stirred overnight at 60° C. The crude was purified by prep HPLC to yield (4S)-tert-butyl 3-((8-carbamoylquinolin-5-yl)carbamoyl)-4-(3-fluorophenyl)pyrrolidine-1-carboxylate, which was added 1 ml 4.0M HCl and 1 ml methanol, stirred at RT for 3 h. The reaction mixture was concentrated, neutralized to Ph 7 and purified by prep HPLC to afford Example 27. (M+H=479, obsd=479).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:3]1.[CH3:32][S:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Cl)=[CH:36][CH:35]=1>>[CH3:32][S:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][O:1][CH:2]2[CH:7]([C:8]3[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]4[S:21][CH:22]=[CH:23][CH:24]=4)=[CH:12][CH:13]=3)[CH2:6][CH2:5][N:4]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:3]2)=[CH:36][CH:35]=1
Reactant: CSc1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3cccs3)cc2)C(O)C1
Product: CSc1ccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3cccs3)cc2)cc1

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-[3-(thiophen-2-ylmethoxy)-propoxy]-phenyl]-piperidine-1-carboxylate with 4-methylthio-benzyl chloride [J.Org.Chem. (1988), 53(3), 561-569] there was obtained tert-butyl (3RS,4RS)-3-(4-methylsulphanyl-benzyloxy)-4-[4-[3-(thiophen-2-ylmethoxy)-propoxy]-phenyl]-piperidine-1-carboxylate as a yellowish oil; MS: 584 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[CH2:3][OH:4].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>ClCCl>[CH3:1][CH:2]([CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[CH:3]=[O:4]
Reactant: CC(CO)COC1CCCCO1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C=O)COC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.8 %

Procedure:
A solution of 2-methyl-3-tetrahydropyranyloxy-1-propanol (250 mg; 1.4 mmol) in dichloromethane (4 ml) was added to a suspension of pyridinium chlorochromate (500 mg; 2.32 mmol) and celite (2.5 g) in dichloromethane (10 ml), and stirred at room temperature for 3 hours. Ether (100 ml) was added thereto. The resultant mixture was filtered, and the filtrate was distilled under reduced pressure to give the solvent. The residue was purified by silica gel chromatography using a mixture of ethyl acetate and benzene (1:4) to give 2-methyl-3-tetrahydropyranyloxypropanal (178 mg; yield, 73%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([OH:15])=[C:10]([Cl:16])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:24](I)[CH3:25]>CC(C)=O>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH2:24][CH3:25])=[C:10]([Cl:16])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(O)c(Cl)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1c(Cl)cc(NC(=O)OC(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of (3,5-dichloro-4-hydroxy-phenyl)-carbamic acid tert-butyl ester (1.0 g) and potassium carbonate (1.0 g) in acetone (18 mL) is added ethyl iodide (0.36 mL) and the mixture is stirred for approximately 15 hours at room temperature. The solution is then filtered, concentrated under reduced pressure, and partitioned between ethyl acetate and water. The separated aqueous layer is further extracted twice with ethyl acetate, and the pooled organic extracts are washed successively with 10% aqueous sodium hydroxide, with water, and then dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave the desired product as a tan solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]([CH:14]([O:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:11]=[CH:12][CH:13]=1.[CH2:24]([C:26]([C:45]1[CH:58]=[CH:57][C:48]([O:49][CH2:50][C@@H:51]2[O:55][C:54](=[O:56])[CH2:53][CH2:52]2)=[C:47]([CH3:59])[CH:46]=1)([C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[C:31]([CH3:44])[CH:30]=1)[CH2:27][CH3:28])[CH3:25].C(OCC)(=O)C>CN(C)C=O>[CH3:16][C:15]([CH3:18])([CH3:17])[CH:14]([C:10]1[CH:9]=[C:8]([C:32]2[CH:33]=[CH:34][C:29]([C:26]([C:45]3[CH:58]=[CH:57][C:48]([O:49][CH2:50][C@@H:51]4[O:55][C:54](=[O:56])[CH2:53][CH2:52]4)=[C:47]([CH3:59])[CH:46]=3)([CH2:24][CH3:25])[CH2:27][CH3:28])=[CH:30][C:31]=2[CH3:44])[CH:13]=[CH:12][CH:11]=1)[O:19][Si:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)C(O[Si](C)(C)C)c1cccc(Br)c1
Reactant: CCC(CC)(c1ccc(OC[C@H]2CCC(=O)O2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(OC[C@H]2CCC(=O)O2)c(C)c1)c1ccc(-c2cccc(C(O[Si](C)(C)C)C(C)(C)C)c2)c(C)c1
Temperature: 85 °C
Reaction time: 13.5 h
Yield: 28.6 %

Procedure:
A [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (1.68 mg, 0.002 mmol), a 2 M sodium carbonate aqueous solution (0.1 mL, 0.2 mmol) and [1-(3-bromo-phenyl)-2,2-dimethyl-propoxy]-trimethyl-silane (Example 18-(1); 43.16 mg, 0.137 mmol) were added to a solution of (R)-5-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one (Example 15-(3); 33.7 mg, 0.068 mmol) in N,N-dimethylformamide (0.1 mL) at room temperature, and the mixture was stirred at 85° C. for 13.5 hours. Ethyl acetate was added to the reaction solution. The organic layer was washed with distilled water and brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=3/1) to give the title compound (11.7 mg, 28.5%).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].[Cl:15][C:16]1[CH:21]=[C:20](I)[CH:19]=[CH:18][N:17]=1.C(N(CC)CC)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[C:20]([C:2]#[C:1][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:5][O:6][C:7]=2[CH3:8])[CH:19]=[CH:18][N:17]=1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Reactant: Clc1cc(I)ccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1C#Cc1ccnc(Cl)c1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 90.5 %

Procedure:
A mixture of 4-ethynyl-5-methyl-3-phenyl-isoxazole (110 mg, 0.60 mmol), 2-chloro-4-iodopyridine (172 mg, 0.72 mmol), triethylamine (209 μl, 1.50 mmol) and bis(triphenylphosphine)palladium(II) chloride (13 mg, 0.02 mmol) in N,N-dimethylformamide (1.2 mL) was evaporated and flushed with argon. Cuprous iodide (2 mg, 0.01 mmol) was added and the reaction mixture was stirred for 1.5 h at 90° C. before it was cooled to ambient temperature and separated between aqueous sodium hydroxide (1 M, 20 mL) and ethyl acetate (30 mL). The aqueous layer was extracted with ethyl acetate (30 mL) and the combined organic layers were washed with aqueous sodium hydroxide (1 M, 20 mL), dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 80:20) afforded the title compound (160 mg, 91%) as a colorless oil. MS: m/e=295.0/297.2 [M+H]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[C:31]([NH:39][C:40]1[C:41]2[N:42]=[CH:43][N:44]([C:53]=2[N:54]=[CH:55][N:56]=1)[C@@H:45]1[O:52][C@H:49]([CH2:50][OH:51])[C@@H:47]([OH:48])[CH2:46]1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:20]1(=[O:30])[N:24]([CH:50]([OH:51])[C@H:49]2[O:52][C@@H:45]([N:44]3[C:53]4[N:54]=[CH:55][N:56]=[C:40]([NH:39][C:31](=[O:38])[C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)[C:41]=4[N:42]=[CH:43]3)[CH2:46][C@@H:47]2[OH:48])[C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12
Reactant: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1)c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](C(O)N2C(=O)c3ccccc3C2=O)O1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 29.9 %

Procedure:
13.11 g (50 mmol) triphenylphosphine, 6.99 g (47.5 mmol) phthalimide and 17.77 g (50 mmol) N6-benzoyl-2′-deoxyadenosine were stirred in 400 mL dry THF, and added 9.84 mL (50 mmol) of diisopropyl azodicarboxylate under a nitrogen atmosphere. After stirring in an ice-water bath for 2 h and at the ambient temperature for 4 h, the reaction mixture was concentrated and the residue was added 100 mL dichloromethane. The precipitates thus formed were removed by filtration and the filtrate was concentrated and flashed through a silica gel column with 2:1 dichloromethane-THF and 19:1 dichloromethane-methanol to give 7.1 g of 5′-phthalimido-N6-benzoyl-2′-deoxyadenosine.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][C:15]3=[O:30])[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].I[CH2:34][CH2:35][CH2:36][CH3:37].O>CN(C=O)C>[CH2:34]([N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:9][CH2:10]2)[C:15]1=[O:30])[CH2:35][CH2:36][CH3:37]
Reactant: O=C1Nc2ccccc2C(c2ccccc2)N1C1CCN(CC2CCCCC2)CC1
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCN1C(=O)N(C2CCN(CC3CCCCC3)CC2)C(c2ccccc2)c2ccccc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of 100 mg (0.25 mmol) of 3-[1-(cyclohexylmethyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone in 2 ml of DMF, 22 mg (0.55 mmol) of sodium hydride (60%) were added at room temperature and stirred at about 60° C. for one hour. After allowing the reaction mixture to stand cool, a solution of 69 mg (0.38 mmol) of 1-iodobutane in 1 ml of DMF was added thereto at room temperature and stirred at about 60° C. for 2 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform—10% methanol/chloroform) to give 88 mg (0.19 mmol) of the title compound as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([CH:8]2[CH2:13][C:12]([NH:14][NH:15]S(C3C=CC(C)=CC=3)(=O)=O)=[CH:11][C:10](=[O:26])[CH2:9]2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CO.Br[CH2:37][C:38](=O)[CH3:39]>COCCOC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([CH:8]2[CH2:13][C:12]3[N:14]=[N:15][CH:37]=[C:38]([CH3:39])[C:11]=3[C:10](=[O:26])[CH2:9]2)[CH:7]=1
Reactant: CC(=O)CBr
Reactant: Cc1ccc(S(=O)(=O)NNC2=CC(=O)CC(c3cc(Cl)ccc3F)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Product: Cc1cnnc2c1C(=O)CC(c1cc(Cl)ccc1F)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.8 %

Procedure:
To a mixture of 5-(5-chloro-2-fluorophenyl)-1-[2-(4-methylphenylsulfonyl)hydrazino]cyclohexen-3-one (2.0 g), anhydrous potassium carbonate (1.68 g), methanol (20 ml) and 1,2-dimethoxyethane (10 ml) was added under ice-cooling 1-bromopropan-2-one (0.87 g), and the mixture was stirred for 2 hours at room temperature, and then for 6 hours at 80° C. Under reduced pressure, the solvent was evaporated, and to the residue was added ethyl acetate (70 ml) and water (30 ml). The mixture was shaken, and the separated upper layer was washed with water and concentrated under reduced pressure. The residue was purified with silica gel column chromatography to give 7-(5-chloro-2-fluorophenyl)-4-methyl-5,6,7,8-tetrahydrocinnolin-5-one (0.338 g) as yellowish brown crystals.
Reaction SMILES: [N:1]([O-])=O.[Na+].[Cl:5][C:6]1[CH:22]=[CH:21][C:9]([O:10][C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=2[N+:18]([O-:20])=[O:19])=[CH:8][CH:7]=1.C(O)C.O.O.[Sn](Cl)Cl>O.Cl>[Cl:5][C:6]1[CH:22]=[CH:21][C:9]([O:10][C:11]2[CH:17]=[CH:16][C:14]([NH:15][NH2:1])=[CH:13][C:12]=2[N+:18]([O-:20])=[O:19])=[CH:8][CH:7]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)c([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NNc1ccc(Oc2ccc(Cl)cc2)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 0.52 g of sodium nitrite in 5 ml of water was added dropwise to a stirred mixture consisting of 1.9 g of 4-(4-chlorophenoxy)-3-nitroaniline, 25 ml of concentrated hydrochloric acid and 25 ml of ethanol cooled to 0° C., and the mixture was then stirred at 0° C. for 60 min and subsequently added dropwise to a suspension of 8.5 g of tin dichloride dihydrate in 8 ml of concentrated HCl. The precipitate was filtered off with suction, washed with water, suspended in 200 ml of water under nitrogen and decomposed with 100 ml of 30% strength sodium hydroxide solution at 10-15° C. The oil formed was extracted by shaking with ethyl acetate and washed with water, and the organic phase was dried with sodium sulfate. The product was then precipitated with isopropanolic HCl, filtered off with suction and dried in vacuo.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:13][O-:14].[Na+].[Na]>CO>[CH3:13][O:14][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: C[O-]
Reactant: COC(=O)c1cccc(CBr)c1
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COCc1cccc(C(=O)OC)c1
Temperature: 65 °C
Yield: 66 %

Procedure:
To a solution of 15 g (65.5 mmol) of methyl 3-(bromomethyl)benzoate in 20 mL of anhydrous MeOH is added dropwise, at room temperature, a solution of sodium methoxide in MeOH, prepared beforehand from 2.25 g (98.2 mmol) of sodium in 65 mL of MeOH. The reaction medium is then heated for 4 hours at 65° C. and then concentrated under reduced pressure, taken up in 500 mL of DCM, washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. 7.8 g of methyl 3-(methoxymethyl)benzoate are obtained in the form of an oil, which is used without further purification in the following step.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[NH2:9][C@H:10]([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][C:13](O)=O.OCCC[NH:23][C@H:24]([C:30](O)=O)[CH2:25][CH2:26]C(=O)N>C([O-])(O)=O.[Na+]>[NH2:23][C:24]1[CH:25]=[CH:26][C:12]([CH2:11][C@@H:10]([C:16]([OH:18])=[O:17])[NH2:9])=[CH:13][CH:30]=1
Reactant: NC(=O)CC[C@H](NCCCO)C(=O)O
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: Nc1ccc(C[C@H](N)C(=O)O)cc1

Procedure:
The polymer of either Examples I and II were reduced by treating a solution of 2 g of the polymer in 0.5 M NaHCO3 (50 ml) with 5% (w/v) sodium dithionite at 50° C for 1 hour. A copolypeptide, as in Example III, containing either glutamic acid or hydroxypropylglutamine and p-aminophenylalanine was obtained, following purification of the low molecular weight material by gel chromatography or dialysis.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][CH3:3].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:28][C:29]1[CH:30]=[N:31][CH:32]=[C:33]([Br:35])[CH:34]=1.CN1CCOCC1>CN(C=O)C>[Br:35][C:33]1[CH:34]=[C:29]([NH:28][C:1](=[O:5])[CH2:2][CH3:3])[CH:30]=[N:31][CH:32]=1
Reactant: CCC(=O)O
Reactant: Nc1cncc(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCC(=O)Nc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of propionic acid (Sigma-Aldrich, St. Louis, USA) (1.5 eq, 8.4 mmol, 0.63 ml) in DMF (15 ml), HOBt (1.2 eq, 6.7 mmol, 0.910 g) and EDC hydrochloride (1.5 eq, 8.4 mmol, 1.65 g) are added. The resulting mixture is stirred for 1 h at r.t. Then 3-amino-5-bromopyridine (Sigma-Aldrich, St. Louis, USA) (1 eq, 5.6 mmol, 1.00 g) and N-methyl-morpholine (3 eq, 16.8 mmol, 1.85 ml) are added and stirring is continued for 18 h at r.t. The solvents are evaporated and the residue is purified by column chromatography (hexane/EtOAc) yielding the title compound; [M+H]+=230.
Reaction SMILES: [F:1][C:2]1[N:3]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:4]=[C:5]([C:7](O)=[O:8])[N:6]=1.[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33][NH2:34]>C1COCC1>[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33][NH:34][C:7]([C:5]1[N:6]=[C:2]([F:1])[N:3]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:4]=1)=[O:8]
Reactant: O=C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: CN(C)CCCN
Solvent: C1CCOC1
Product: CN(C)CCCNC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
2-Fluoro-1-triphenylmethylimidazole-4-carboxylic acid and 3-dimethylaminopropylamine were condensed in THF by the mixed anhydride procedure described for the preparation of starting material for Example 18, to give 4-(3-dimethylaminopropylcarbamoyl)-2-fluoro-1-triphenylmethylimidazole, having the following n.m.r. in CDCl3 : 1.8 (m, 2H); 2.3 (s, 6H); 2.4 (t, 2H); 3.5 (q, 2H); 7.0-7.6 (m, 16H).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.C1C(=O)N([Br:18])C(=O)C1.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1
Reactant: Cc1csc2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1csc2ccccc12
Yield: 42.2 %

Procedure:
3-Methylbenzo[b]thiophene (9.9 g, 67 mmol) is heated in carbon tetrachloride (133 ml ) to near reflux in the presence of n-bromosuccinimide (11.9 g, 67 mmol, 1.0 eq.). 2,2′Azobisisobutyronitrile (2.2 g, 13.3 mmol, 0.2 eq.) is added and the resulting mixture is refluxed for two hours. After cooling, the reaction mixture is filtered through a glass-fritted funnel, and the filtrate is concentrated. The residue is triturated with petroleum ether and toluene to afford 6.42 g of 3-Bromomethylbenzo[b]thiophene (42%).