Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([OH:31])[C:28]=1[O:29][CH3:30])/[CH:6]=[C:7]1/[C:8]([O:10][CH2:11][C@H:12]/1[CH2:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1)=[O:9].[N+:32]([C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Br)=[CH:37][CH:36]=1)([O-:34])=[O:33].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH2:39][C:38]2[CH:41]=[CH:42][C:35]([N+:32]([O-:34])=[O:33])=[CH:36][CH:37]=2)[C:28]=1[O:29][CH3:30])/[CH:6]=[C:7]1/[C:8]([O:10][CH2:11][C@H:12]/1[CH2:13][C:14]1[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=1)=[O:9]
Reactant: COc1cc(/C=C2/C(=O)OC[C@H]2Cc2cc(OC)c(OC)c(OC)c2)cc(O)c1OC
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C[C@@H]2COC(=O)/C2=C/c2cc(OC)c(OC)c(OCc3ccc([N+](=O)[O-])cc3)c2)cc(OC)c1OC
Yield: 91.5 %

Procedure:
A solution of (S)-(E)-2-(3,4-dimethoxy-5-hydroxybenzylidene)-3-(3,4,5-trimethoxybenzyl)butanolide (7.5 g, 17.4 mmol), p-nitrobenzyl bromide (4.6 g, 21.3 mmol) and potassium carbonate (3.0 g, 21.7 mmol) in 100 ml of acetone was heated under reflux for 3.5 hours. After the solvent was distilled off under reduced pressure, the residue was added with water and then ethyl acetate. The organic layer was washed successively with 2N-HCl, water, saturated NaHCO3 and saturated NaCl and then, dried over anhydrous magnesium sulfate. The solvent was thereafter distilled off. The residue thus obtained was purified by column chromatography, whereby 9 g of the title compound were obtained as colorless foam (yield: 91%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:15]/[OH:16])/[C:8]([O:10][CH2:11][CH2:12][S:13][CH3:14])=[O:9])[N:6]=1.Br[CH:18]([CH2:26][CH2:27][CH3:28])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:15]/[O:16][CH:18]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:26][CH2:27][CH3:28])/[C:8]([O:10][CH2:11][CH2:12][S:13][CH3:14])=[O:9])[N:6]=1
Reactant: CCCC(Br)C(=O)OC(C)(C)C
Reactant: CSCCOC(=O)/C(=N\O)c1csc(N)n1
Product: CCCC(O/N=C(\C(=O)OCCSC)c1csc(N)n1)C(=O)OC(C)(C)C

Procedure:
Starting from 2-methylthioethyl 2-(2-aminothiazol-4-yl)-2(Z)-hydroxyiminoacetate and tert-butyl 2-bromovalerate, the above-identified compound is obtained by the procedure of Reference Example 16.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14](=[NH:17])OC)=[N:6]1.C(O)(=O)C.[Cl-].[NH4+:27]>CO>[F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]([NH2:27])=[NH:17])=[N:6]1
Reactant: [NH4+]
Reactant: COC(=N)c1nn(Cc2ccccc2F)c2ncccc12
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: CO
Product: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12

Procedure:
The above solution of methyl (2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidate from Example 24A in methanol is admixed with 33.76 g (32.19 ml, 562 mmol) of glacial acetic acid and 9.28 g (173 mmol) of ammonium chloride, and the mixture is stirred under reflux overnight. The solvent is evaporated off under reduced pressure, the residue is triturated well with acetone and the precipitated solid is filtered off with suction. The product is added to 2 l of water, the mixture is admixed with stirring with 31.8 g of sodium carbonate and extracted three times with a total of 1 l of ethyl acetate, and the organic phase is dried with magnesium sulphate and concentrated under reduced pressure.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:40])[C:16]2[CH:21]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][CH:24]=3)[CH:19]=[C:18]([O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Mn]([O-])(=O)(=O)=[O:43].[K+]>C1COCC1.O>[C:1]([O:5][C:6]([NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:16]2[CH:21]=[C:20]([CH:19]=[C:18]([O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=3)[CH:17]=2)[O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([OH:43])=[O:30])=[CH:25][CH:24]=2)=[O:40])[CH2:10][CH2:9]1)=[O:41])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C=O)cc3)c2)CC1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C(=O)O)cc3)c2)CC1
Temperature: 25 °C
Yield: 48.6 %

Procedure:
0.5 g (0.9 mmol) of {4-[3-(4-cyano-phenoxy)-5-(4-formyl-phenoxy)-benzoyl-amino]-cyclohexyl}-carbamic acid tert-butyl ester was dissolved in 15 ml of THF and 0.43 g (2.7 mmol) of potassium permanganate, dissolved in 8 ml of water, was added to THF solution at 10° C. during 10 min. The reaction mixture stirred over night at RT. Reaction progress was monitored by TLC. Reaction mixture was filtered through celite and washed with THF and thus obtained mother liquor was concentrated under vacuo. Product was crystallized with ethyl acetate to afford 0.25 g of the required product. 1H NMR (DMSO-d6): δ 1.25 (4H, m), 1.36 (9H, s), 1.78 (4H, m), 3.18 (1H, m), 3.66 (1H, m), 6.75 (1H, d), 6.94 (3H, m), 7.18 (2H, d), 7.36 (2H, s), 7.86 (4H, d), 8.38 (1H, d).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C-:17]#[N:18].[K+]>O1CCCC1.O.O1CCOCCOCCOCCOCCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:17]#[N:18])=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Fc1ccc(CCl)cc1Oc1ccccc1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: N#CCc1ccc(F)c(Oc2ccccc2)c1
Yield: 113.2 %

Procedure:
A stirred mixture of 5.0 grams (0.021 mole) of 4-fluoro-3-phenoxyphenylmethyl chloride, 4.1 grams (0.063 mole) of potassium cyanide and 0.6 gram (0.002 mole) of 1,4,7,10,13,16-hexaoxacyclooctadecane in 180 ml of tetrahydrofuran was heated at reflux for about four hours. After this time the reaction mixture was diluted with 180 ml of water, and then extracted with two 100 ml portions of diethyl ether. The combined ether extracts were washed with five 200 ml portions of water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 5.4 grams of 4-fluoro-3-phenoxyphenylacetonitrile. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: O=[C:2]1[NH:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:4]=[C:3]1[C:18]([O:20][CH2:21][CH3:22])=[O:19].P(Cl)(Cl)([Cl:25])=O>CN(C)C=O>[Cl:25][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc(C(=O)OCC)c(=O)[nH]c1C(=O)OCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C(=O)OCC)c(C(=O)OCC)nc1Cl
Yield: 47 %

Procedure:
A solution of triethyl 1,6-dihydro-6-oxo-2,3,5-pyridine-tricarboxylate (39.7 g) in 300 mL of phosphorous oxychloride and 0.5 mL dimethylformamide is stirred at 100° C. for four hours and 15 minutes. After cooling, the excess phosphorous oxychloride is removed under vacuum. The residue is taken up in 200 mL methylene chloride and the solution poured into 500 mL of ice water and the layers are separated. The aqueous layer, made basic with concentrated ammonium hydroxide and ice, is extracted with 150 mL methylene chloride. The combined methylene chloride extracts are dried over magnesium sulfate, filtered and concentrated under vacuum, and the resulting crude product is chromatographed on silica using 5:1 hexanes:ethyl acetate and then 4:1 hexanes:ethyl acetate as eluants affording 26.5 g (47%) of the title product as an oil.
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([O:28]C)=[O:27])=[N:24][CH:25]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.[OH-].[Na+]>O1CCCC1>[CH:1]1([CH:7]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([OH:28])=[O:27])=[N:24][CH:25]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(c2oc3ccc(F)cc3c2C)C2CCCCC2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)O)nc2)C2CCCCC2)oc2ccc(F)cc12
Yield: 85.6 %

Procedure:
To a mixture of methyl 5-{[cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl]amino}pyridine-2-carboxylate (909 mg) synthesized above, ethanol (20 mL) and tetrahydrofuran (20 mL) was added 1N aqueous sodium hydroxide solution (20 mL), and the mixture was stirred with heating under reflux for 5 hr, and concentrated under reduced pressure. 1N Hydrochloric acid (20 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with hexane to give the title object compound (751 mg, 86%) as a pale-brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[N:10]([CH3:19])[C:9]=2[C:20]([N:22]([CH2:24]C2C=CC=CC=2OC)C)=[O:21])=[CH:4][CH:3]=1.[F:33][C:34]([F:49])([F:48])[C:35]1[CH:36]=[C:37]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:38]CN>>[F:49][C:34]([F:33])([F:48])[C:35]1[CH:36]=[C:37]([CH:41]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:43]=1)[CH2:38][N:22]([CH3:24])[C:20]([C:9]1[N:10]([CH3:19])[C:11](=[O:18])[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:17]=2[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:21]
Reactant: NCCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COc1ccccc1CN(C)C(=O)c1c(-c2ccc(F)cc2)c2cccnc2c(=O)n1C
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1c(-c2ccc(F)cc2)c2cnccc2c(=O)n1C

Procedure:
Employing 4-(4-fluorophenyl)-1,2-dihydro-2-methyl-1-oxo-3-pyrido[4,3-c]pyridine carboxylic acid (Reference Example 4) and N-[3,5-bis(trifluoromethyl)benzyl]methylamine, reaction was allowed to proceed and the reaction mixture was processed in substantially the same manner as in Example 1 to give the above-titled compound as colorless crystals, m.p.136°-138° C. (recrystallized from ethyl acetate-isopropyl ether).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[NH2:11][C:12]1[CH:13]=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][C:16]=2[Br:22]>N1C=CC=CC=1>[Br:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[N:14]=[CH:13][C:12]([NH:11][S:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)(=[O:9])=[O:8])=[CH:21]2
Reactant: Nc1cnc2c(Br)cccc2c1
Reactant: O=S(=O)(Cl)c1cccnc1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cnc2c(Br)cccc2c1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In pyridine (5 ml) was dissolved 3-amino-8-bromoquinoline (Preparation Example 5) was dissolved in pyridine (5 ml), and 3-pyridinesulfonyl chloride (254 mg) was added thereto, followed by stirring at room temperature for 30 minutes. After the completion of the reaction, the reaction mixture was poured onto brine, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated. The resulting crude crystals were washed with ethyl acetate and IPA, to give the title compound (270 mg).
Reaction SMILES: [NH2:1][C@H:2]([CH2:9][C:10]([OH:12])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[CH2:14](O)[CH3:15]>>[NH2:1][CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:9][C:10]([O:12][CH2:14][CH3:15])=[O:11]
Reactant: CCO
Reactant: N[C@H](CC(=O)O)c1ccccc1
Agent: Cl
Product: CCOC(=O)CC(N)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
β-Phenylalanine from II.2a (93) was suspended in ethanol (1.5 l) and the solution was saturated with gaseous HCl at room temperature. It was then heated under reflux for 4 h and stirred overnight at room temperature. The solution was cooled to 5° C. and filtered with suction. The filtrate was concentrated in vacuo, and the residue was washed with ether and dried. A white solid was obtained (yield: 52 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([OH:20])=O)[N:9]=2)=[CH:4][CH:3]=1.[F:21][C:22]([F:32])([F:31])[C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH2:27].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH:13]3[CH2:14][CH2:15]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:27][CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[C:23]([C:22]([F:21])([F:31])[F:32])[CH:24]=3)=[O:20])[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Reactant: NCc1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O)NCc1cccc(C(F)(F)F)c1
Reaction time: 0.17 h

Procedure:
50.0 mg (0.170 mmol) of [3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetic acid from Example 88A and 32.8 mg (0.187 mmol) of 3-trifluoromethylbenzylamine are placed in 2 ml dimethylformamide and treated with 27.6 mg (0.204 mmol) of HOBt. After 10 mins' stirring, 42.4 mg (0.221 mmol) of EDC hydrochloride are added and the mixture stirred overnight at room temperature. For the workup, the reaction mixture is partitioned between dichloromethane and water, and the organic phase is separated, dried over sodium sulphate and concentrated. The residue is purified by flash chromatography on silica gel (eluent: dichloromethane/methanol first 200:1, then 100:1) and thus yields 76 mg (99% of theory) of the target compound.
Reaction SMILES: N[C:2]1[C:3]([CH3:13])=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[C:5]([CH3:8])=[CH:6][CH:7]=1.N([O-])=[O:15].[Na+].NC(N)=O>OS(O)(=O)=O.O>[OH:15][C:2]1[C:3]([CH3:13])=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: CC(=O)Nc1c(C)ccc(N)c1C
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1c(C)ccc(O)c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.6 %

Procedure:
To a solution of N-(3-amino-2,6-dimethyl-phenyl)acetamide (2 g, 11 mmol, 1.1 eq) in a mixture of H2SO4 (10 mL) and H2O (70 mL) at 0° C. was added a solution of NaNO2 (1 g, 14.6 mmol, 1.3 eq) in H2O (140 mL). The solution was stirred at 0° C. for 30 min then urea (425 mg, 7.1 mmol, 0.63 eq) was added. The reaction was poured into boiling water and the mixture stirred at 100° C. for 2 h. The aqueous phase was extracted with EtOAc, and the combined extracts were dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (MeOH:DCM, 0:1 to 1:20) to give the title compound as a white solid (800 mg, 40%).
Reaction SMILES: [CH2:1]([N:3]([C:12]1[CH:13]=[CH:14][C:15]([CH3:28])=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][C:23]([CH:26]=[O:27])=[CH:24][N:25]=1)=[CH:17]2)[S:4]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)(=[O:6])=[O:5])[CH3:2].CO.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH2:1]([N:3]([C:12]1[CH:13]=[CH:14][C:15]([CH3:28])=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][C:23]([CH2:26][OH:27])=[CH:24][N:25]=1)=[CH:17]2)[S:4]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:6])[CH3:2]
Reactant: CCN(c1ccc(C)c2cc(-c3ncc(C=O)s3)[nH]c12)S(=O)(=O)c1cccs1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(c1ccc(C)c2cc(-c3ncc(CO)s3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 2 h
Yield: 56.7 %

Procedure:
To a solution of N-ethyl-N-[2-(5-formyl-1,3-thiazol-2-yl)-4-methyl-1H-indol-7-yl]thiophene-2-sulfonamide (1.3 g) in a mixed solvent of methanol (15 ml) and tetrahydrofuran (40 ml) was added sodium borohydride (0.14 g) under ice-cooling, and the mixture was stirred at the same temperature for 2 hr. Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (0.74 g) as pale-yellow crystals. The mother liquor was concentrated, and the residue was subjected to silica gel column chromatography (ethyl acetate:hexane=3:7-6:4) to give the title compound (0.20 g) as pale-yellow crystals. total yield 0.94 g (yield 72%). melting point 166-167° C.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11](=[O:18])[N:12]=[C:13]([S:16][CH3:17])[NH:14][CH:15]=2)=[CH:5][N:4]=1.B(Br)(Br)Br>O>[CH3:17][S:16][C:13]1[NH:14][CH:15]=[C:10]([CH2:9][C:6]2[CH:5]=[N:4][C:3](=[O:2])[NH:8][CH:7]=2)[C:11](=[O:18])[N:12]=1
Reactant: COc1ncc(Cc2c[nH]c(SC)nc2=O)cn1
Agent: BrB(Br)Br
Solvent: O
Product: CSc1nc(=O)c(Cc2cnc(=O)[nH]c2)c[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26.4 %

Procedure:
Entire reaction was performed under argon atmosphere using syringe septa technique. 5-(2-methoxy-pyrimidin-5-ylmethyl)-2-methylsulfanyl-1H-pyrimidin-4-one (0.984 mmol, 1 eq) was added in dry vessel. Boron tribromide (2.066 mmol, 2.1 eq) was added and reaction mixture was stirred at 0° C. After 30 min, reaction mixture was allowed to reach to room temperature and it was stirred overnight. Reaction mixture was diluted with water (2 ml). The resulting precipitate, 2-methylsulfanyl-5-(2-oxo-1,2-dihydro-pyrimidin-5-ylmethyl)-1H-pyrimidin-4-one (0.260 mmol, yield=26%) was obtained. 1H NMR (300 MHz, DMSO-d6) δ/ppm 2.45 (s, 3H), 7.75-7.88 (m, 2H), 7.97-8.33 (m, 3H), 11.29-13.09 (m, 4H)
Reaction SMILES: [NH2:1][C:2]1[C:10]2[S:9][C:8]([Cl:11])=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[Cl:12].[Cl:13]N1C(=O)CCC1=O.[Cl-].[Li+]>CN(C)C=O>[NH2:1][C:2]1[C:10]2[S:9][C:8]([Cl:11])=[N:7][C:6]=2[C:5]([Cl:13])=[CH:4][C:3]=1[Cl:12]
Reactant: Nc1c(Cl)ccc2nc(Cl)sc12
Reactant: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Nc1c(Cl)cc(Cl)c2nc(Cl)sc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64.3 %

Procedure:
Under a nitrogen atmosphere a solution of 6.0 grams (27 mmole) of 7-amino-2,6-dichlorobenzothiazole in 75 mL of N,N-dimethylformamide was stirred and cooled in an ice bath. To this was then added 4.3 grams (32 mmole) of N-chlorosuccinimide. Upon completion of the addition the reaction mixture was stirred for 20 minutes and then warmed to ambient temperature and stirred for an additional 18 hours. After this time the reaction mixture was poured into 250 mL of ice-water, and about 15 grams of lithium chloride was added, after which the reaction mixture was stirred for 30 minutes. The resulting precipitate was collected by filtration and dried under reduced pressure, yielding a dark solid, which was purified by column chromatography on silica gel. Elution was accomplished with 4:1 hexane:ethyl acetate. The product-containing fractions were combined and concentrated under reduced pressure, yielding 4.4 grams of 7-amino-2,4,6-trichlorobenzothiazole. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C([O-])(O)=O.[Na+].[NH2:6][OH:7].Cl.[Cl:9][C:10]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:11]=1[C:12]([NH:14][C@H:15]([C:33](Cl)=[O:34])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[O:31][CH3:32])=[CH:19][CH:18]=1)=[O:13]>C1COCC1.O.C1COCC1>[OH:7][NH:6][C:33](=[O:34])[C@H:15]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[O:31][CH3:32])=[CH:19][CH:18]=1)[NH:14][C:12](=[O:13])[C:11]1[C:10]([Cl:9])=[CH:39][CH:38]=[CH:37][C:36]=1[Cl:40]
Reactant: COc1cccc(OC)c1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)Cl)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(OC)c1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)NO)cc1
Reaction time: 0.5 h
Yield: 27.2 %

Procedure:
NaHCO3 (0.21 g) was added to a solution of NH2OH HCl (0.14 g) in THF/water (5 mL each) at 0° C. and the mixture was stirred for ½ h. A solution of N-(2,6-dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanyl chloride (0.1 g) in THF (5 mL) was added to the mixture at 0° C. and the mixture was stirred overnight at room temperature. The mixture was partitioned between EtOAc and water. The EtOAc layer was washed successively with 1 N HCl and brine, dried and evaporated. The residue was purified by preparative TLC (silica gel; eluent: CH2Cl2/MeOH 8%) to yield 27 mg of the title compound. ESMS: m/z 489 (MH+).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1>O1CCCC1>[CH:1]1([NH:6][C:8]2[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccnc1NC1CCCC1

Procedure:
Cyclopentanamine (2.7 g, 32 mmol) was added to a solution of 2-chloro-3-nitropyridine (5.0 g, 32 mmol) in tetrahydrofuran (200 mL), and the reaction mixture was stirred at reflux for 18 hours. After removal of solvent under reduced pressure, the residue was purified via silica gel chromatography to give the product as a yellow solid. Yield: 5.5 g, 26 mmol, 81%. 1H NMR (400 MHz, CD3OD) δ 8.42 (dd, half of ABX pattern, J=8.3, 1.8 Hz, 1H), 8.40 (dd, half of ABX pattern, J=4.5, 1.8 Hz, 1H), 6.69 (dd, J=8.3, 4.5 Hz, 1H), 4.51-4.59 (m, 1H), 2.07-2.17 (m, 2H), 1.62-1.85 (m, 4H), 1.51-1.62 (m, 2H)
Reaction SMILES: [CH:1]([C:3]1[CH:20]=[C:19]([CH:21]=[O:22])[CH:18]=[CH:17][C:4]=1[O:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1)=O.C[O-].[Na+]>CO>[CH:21]([C:19]1[CH:18]=[CH:17][C:4]2[O:5][C:6]([C:7]3[CH:16]=[CH:15][C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[N:8]=3)=[CH:1][C:3]=2[CH:20]=1)=[O:22]
Reactant: O=Cc1ccc(OCc2ccc3ccccc3n2)c(C=O)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=Cc1ccc2oc(-c3ccc4ccccc4n3)cc2c1
Yield: 20.1 %

Procedure:
A mixture of 2-(2,4-diformylphenoxymethyl)quinoline (164.6 mg) and sodium methoxide (140 mg) in methanol (10.5 ml) was stirred under reflux for 30 minutes. The reaction mixture was concentrated under reduced pressure, and to the residue was added water and chloroform. The separated organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give a crude residue. The residue was subjected to column chromatography on silica gel and eluted with a mixture of ethyl acetate and n-hexane (1:10). The fractions containing object compound were combined and concentrated under reduced pressure to give 2-(5-formylbenzofuran-2-yl)quinoline (31 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C@H:9]([C:17]([NH:19][CH2:20][C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].[N:28]1([CH2:34][CH2:35][NH:36][C:37](=[O:49])[C@@H:38]([NH2:48])[CH2:39][CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:28]1([CH2:34][CH2:35][NH:36][C:37](=[O:49])[C@@H:38]([NH:48][C:25](=[O:27])[CH2:24][NH:23][C:21](=[O:22])[CH2:20][NH:19][C:17](=[O:18])[C@H:9]([CH2:10][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)[NH:8][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH2:39][CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: N[C@@H](CCCN1CCCCC1)C(=O)NCCN1CCCCC1
Reactant: O=C(O)CNC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccco1
Product: O=C(CNC(=O)[C@H](CC1CCCCC1)NC(=O)c1ccco1)NCC(=O)N[C@@H](CCCN1CCCCC1)C(=O)NCCN1CCCCC1
Yield: 57.3 %

Procedure:
In the same way as example 1, from 2-furoyl-L-phenylalanyl-glycyl-glycine (23.7 mg, 0.063 mmol) and (S)-2-amino-5-(1-piperidinyl)pentanoic acid N-[2-(1-piperidinyl)ethyl]amide (16.7 mg, 0.054 mmol) synthesized in the same way as reference example 1, (S)-2-[(2-furoyl)-β-cyclohexyl-L-alanyl-glycyl-glycyl-amino]-5-(1-piperidinyl)pentanoic acid [2-(1-piperidinyl)ethyl]amide (20.8 mg) was obtained as a colorless oily material (yield 58%).