Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:13][CH3:14])[C:7]([OH:9])=O)([O-:3])=[O:2].C(Cl)Cl.ClC(N(C)C)=C(C)C.[Br:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:13][CH3:14])[C:7]([NH:31][C:30]1[CH:32]=[CH:33][C:27]([Br:26])=[CH:28][CH:29]=1)=[O:9])([O-:3])=[O:2]
Reactant: CNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: Nc1ccc(Br)cc1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CNc1ccc(C(=O)Nc2ccc(Br)cc2)cc1[N+](=O)[O-]

Procedure:
A mixture of 3-Nitro-4-methylaminobenzoic acid (196 mg, 1.00 mmol), 20 ml DCM, 0.15 ml pyridine and 160 mg 1-Chloro-N,N,2-trimethylprop-1-enylamine was stirred until a clear solution was obtained. 4-Bromoaniline (172 mg, 1.0 mmol) was added and the mixture was stirred for 16 h. The mixture was filtered through a pad of ALOX B and concentrated. 5 ml DMF and 20 ml H2O were added and the precipitate was collected and dried. Yield: 240 mg (68%).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[Br:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([CH3:33])[CH:27]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C(C)=CC=CC=1>[Br:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:2]2[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]3[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=3[N:3]=2)=[C:28]([CH3:33])[CH:27]=1
Reactant: Cc1cc(Br)ccc1N
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: CCOC(=O)CCCn1c(Nc2ccc(Br)cc2C)nc2c(Cl)ccc(C(CC)CC)c21
Temperature: 150 °C
Reaction time: 20 h
Yield: 75.1 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 2.00 g, 5.39 mmol), 4-bromo-2-methylaniline (3.01 g, 16.2 mmol), p-toluenesulfonic acid monohydrate (1.10 g, 5.78 mmol) and xylene (15 mL) was stirred at 150° C. for 20 hr. The mixture was neutralized with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-15% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless crystal (2.11 g, 4.05 mmol, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][CH:7]1[C:14]2[CH:13]=[C:12]([C:15]([O:17]C)=[O:16])[NH:11][C:10]=2[CH2:9][CH2:8]1.[OH-].[Li+].CO>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][CH:7]1[C:14]2[CH:13]=[C:12]([C:15]([OH:17])=[O:16])[NH:11][C:10]=2[CH2:9][CH2:8]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc(CC2CCc3[nH]c(C(=O)O)cc32)c1

Procedure:
The title compound was synthesized from methyl 4-(3-methoxybenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (116 mg, 0.40 mmol) and lithium hydroxide (167 mg, 4.00 mmol in 1 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (2 mL) was used. The resulting product was purified by chromatography, eluting with heptane-EtOAc, gradient 0 to 50% EtOAc to afford the title compound. 74, mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.09-2.18 (m, 1H), 2.53-2.65 (m, 1H), 2.65-2.73 (m, 2H), 2.74-2.85 (m, 2H), 3.28-3.37 (m, 1H), 3.81 (s, 3H), 6.56 (d, J=1.46 Hz, 1H), 6.73-6.83 (m, 3H), 7.22 (t, J=7.81 Hz, 1H), 8.85 (br. s, 1H). LCMS m/e 272 (M+H). Purity 99% (HPLC).
Reaction SMILES: C(OC([NH:8][C:9](=[NH:34])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH:17]([C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=2[O:29][CH2:30][C:31]([OH:33])=[O:32])[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:9]([C:10]1[CH:11]=[CH:12][C:13]([NH:16][CH:17]([C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=2[O:29][CH2:30][C:31]([OH:33])=[O:32])[C:18]([OH:20])=[O:19])=[CH:14][CH:15]=1)(=[NH:8])[NH2:34]
Reactant: COc1ccc(OCC(=O)O)c(C(Nc2ccc(C(=N)NC(=O)OC(C)(C)C)cc2)C(=O)O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(OCC(=O)O)c(C(Nc2ccc(C(=N)N)cc2)C(=O)O)c1

Procedure:
356 mg of (RS)-[4-(tert-butoxy carbonylamino-imino-methyl)-phenylamino]-(2-carboxymethoxy-5-methoxy-phenyl)-acetic acid were stirred in 3.7 ml of methylene chloride and 3.7 ml of TFA for one hour. The reaction mixture was evaporated in a vacuum and the residue was chromatographed on silica gel with ethyl acetate-acetone-water-acetic acid (6:2:1:1). From ethyl acetate-acetone-water-acetic acid (12:2:1:1) there was obtained crystalline (RS)-(4-carbamimidoyl-phenylamino)-(2-carboxymethoxy-5-methoxy-phenyl)-acetic acid, m.p. 213° C. MS: 374 (M+H)+.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]2[N:20]=[C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]3[CH2:31][C:30]([CH3:33])([CH3:32])[N:29]([OH:34])[C:28]([CH3:36])([CH3:35])[CH2:27]3)[N:18]=[C:17]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH:42]3[CH2:47][C:46]([CH3:49])([CH3:48])[N:45]([OH:50])[C:44]([CH3:52])([CH3:51])[CH2:43]3)[N:16]=2)[CH2:4][C:3]1([CH3:54])[CH3:53].[CH2:55]1[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1>>[CH:55]1([O:50][N:45]2[C:44]([CH3:52])([CH3:51])[CH2:43][CH:42]([CH2:41][CH2:40][CH2:39][CH2:38][NH:37][C:17]3[N:16]=[C:15]([NH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:5]4[CH2:4][C:3]([CH3:54])([CH3:53])[N:2]([O:1][CH:55]5[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]5)[C:7]([CH3:9])([CH3:8])[CH2:6]4)[N:20]=[C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]4[CH2:31][C:30]([CH3:32])([CH3:33])[N:29]([O:34][CH:55]5[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]5)[C:28]([CH3:36])([CH3:35])[CH2:27]4)[N:18]=3)[CH2:47][C:46]2([CH3:49])[CH3:48])[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1
Reactant: C1CCCCC1
Reactant: CC1(C)CC(CCCCNc2nc(NCCCCC3CC(C)(C)N(O)C(C)(C)C3)nc(NCCCCC3CC(C)(C)N(O)C(C)(C)C3)n2)CC(C)(C)N1O
Product: CC1(C)CC(CCCCNc2nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1

Procedure:
The title compound is prepared from the reaction of 2,4,6-tris[N-(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-s-triazine and cyclohexane following a procedure similar to that of Example 10.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][N:32]=[C:31]2[CH:37]=O.N1CCCCC1>CO>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:37]/[C:31]3[C:30]4[C:34](=[CH:35][CH:36]=[C:28]([O:27][CH3:26])[CH:29]=4)[NH:33][N:32]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: COc1ccc2[nH]nc(C=O)c2c1
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2[nH]nc(/C=C3\Oc4c(ccc(O)c4CN4CCN(C(=O)OC(C)(C)C)CC4)C3=O)c2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
A solution of tert-butyl 4-[1-(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.313 g, 0.898 mmol) in methanol (4 mL) was added with 5-methoxy-1H-indazole-3-carbaldehyde (0.158 g, 0.898 mmol), and piperidine (0.00764 g, 0.0898 mmol) at room temperature, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was suspended in acetonitrile and thereby washed to obtain tert-butyl (Z)-4-({6-hydroxy-3-oxo-2-[(5-methoxy-1H-indazol-3-yl)methylene]-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.318 g, 69%).
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH:16]=O)=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].[N+:23]([CH3:26])([O-:25])=[O:24]>CCOCC>[N+:23]([CH:26]=[CH:16][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=1)([O-:25])=[O:24]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cn(-c2ccccc2)c2ccccc12
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOCC
Product: O=[N+]([O-])C=Cc1cn(-c2ccccc2)c2ccccc12

Procedure:
120 g 1-phenylindole-3-carboxaldehyde and 16.2 g ammonium acetate are heated under reflux in 406 ml nitromethane for 5 hours. The mixture is cooled, diluted with ether to give 3-(2-nitroethenyl)-1-phenylindole, m.p. 154°-155°.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[CH:5][N:4]=1.O=[C:11]1[CH2:15][S:14][CH2:13][CH:12]1[C:16](OC)=[O:17]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:11]2[CH2:15][S:14][CH2:13][C:12]=2[C:16](=[O:17])[NH:9][C:8]2[CH:7]=[CH:6][CH:5]=[N:4][C:3]1=2
Reactant: CNc1ncccc1N
Reactant: COC(=O)C1CSCC1=O
Solvent: Cc1ccccc1
Product: CN1C2=C(CSC2)C(=O)Nc2cccnc21

Procedure:
A solution of 3.4 g. of 2-methylamino-3-aminopyridine and 2.9 g. of methyl tetrahydro-4-oxo-3-thiophene carboxylate in 200 ml. of toluene is heated under reflux for 3 hours, during which 100 ml. of distillate is collected in a Dean-Stark trap. The solution is concentrated under reduced pressure and the solid residue is recrystallized from ethyl acetate to give pale yellow crystals, m.p. 240°-241°C.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@H:6]([OH:13])[CH2:7][C:8](OCC)=[O:9])(=[O:3])[CH3:2].O.[NH2:15][NH2:16]>CO>[C:1]([NH:4][CH2:5][C@H:6]([OH:13])[CH2:7][C:8]([NH:15][NH2:16])=[O:9])(=[O:3])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C[C@@H](O)CNC(C)=O
Solvent: O
Solvent: CO
Product: CC(=O)NC[C@H](O)CC(=O)NN
Temperature: 65 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
A 5.00 g (26.4 mmol) of ethyl (R)-4-acetylamino-3-hydroxybutyrate (optical purity: 95%e.e.) was dissolved in 20 ml of methanol, and 2.00 g (39.6 mmol) of hydrazine monohydrate was added thereto dropwise at room temperature. After the addition, the mixture was heated to 65° C. and then stirred overnight. After the mixture was cooled to room temperature, 20 ml of methanol was added thereto and crystallization was carried out at 10° C. to give 3.90 g (84%) of the title compound. Melting point: 177.5° C. Optical purity: >99.9%e.e.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C[Al](C)C.C([O:15][C:16]([C:18]1[C:27]2[C:26]3=[N:28][N:29]([CH3:31])[CH:30]=[C:25]3[CH2:24][CH2:23][CH2:22][C:21]=2[NH:20][CH:19]=1)=O)C.O>C(Cl)Cl.[NH4+].[Cl-].CCOCC>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:16]([C:18]1[C:27]2[C:26]3=[N:28][N:29]([CH3:31])[CH:30]=[C:25]3[CH2:24][CH2:23][CH2:22][C:21]=2[NH:20][CH:19]=1)=[O:15]
Reactant: CCOC(=O)c1c[nH]c2c1-c1nn(C)cc1CCC2
Reactant: Nc1ccccc1F
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: Cn1cc2c(n1)-c1c(C(=O)Nc3ccccc3F)c[nH]c1CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.1 %

Procedure:
To a solution of 2-fluoroaniline (103 mg, 0.926 mmol) in CH2Cl2 (2.0 mL) at 0° C. under N2 is slowly added AlMe3 (0.46 mL, 2.0 M in toluene). The resulting solution is stirred at room temperature for 1 h. Next, 2-methyl-4,5,6,7-tetrahydro-2H-1,2,7-triaza-cyclopenta[e]azulene-9-carboxylic acid ethyl ester (60 mg, 0.231 mmol) is added in one portion. The resulting mixture is then stirred at reflux for 2 h. After cooling, the reaction mixture is carefully diluted with saturated aq NH4Cl (˜5 mL) and some H2O. The mixture is stirred vigorously for 30 min. and then extracted three times with CH2Cl2 (containing some (˜5%) MeOH). The combined extracts are dried over K2CO3 and concentrated. The crude material is purified by flash chromatography on silica gel. Elution with 40:1 CHCl3—MeOH followed by 30:1 CHCl3—MeOH and finally 20:1 CHCl3—MeOH afforded, after concentration of the fractions containing pure product, a residue, which is then granulated with Et2O. The suspension is filtered, and the solid washed with Et2O and dried, affording 45 mg (60%) of 2-methyl-4,5,6,7-tetrahydro-2H-1,2,7-triaza-cyclopenta[e]azulene-9-carboxylic acid (2-fluoro-phenyl)-amide as an off-white solid. Electrospray mass spectrum: m/z 325 [M+1].
Reaction SMILES: [CH3:1][C:2]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])=[CH2:3].[OH-].[Na+].Br[CH2:17][CH:18]([CH3:21])[CH2:19][Cl:20]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[Cl:20][CH2:19][CH:18]([CH3:21])[CH2:17][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:4]([C:2]([CH3:1])=[CH2:3])[C:5]1=[O:13]
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Reactant: CC(CCl)CBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: C=C(C)n1c(=O)n(CC(C)CCl)c2ccccc21
Temperature: 55 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
To a stirred mixture of 17.4 parts of 1,3-dihydro-1-(1-methylethenyl)-2H-benzimidazol-2-one, 5-parts of N,N,N-triethyl benzenemethanaminium chloride and 180 parts of sodium hydroxide solution 60% are added dropwise 21 parts of 1-bromo-3-chloro-2-methylpropane while heating at 55° C. Upon completion, stirring at 55° C. is continued for 3 hours. The reaction mixture is cooled, poured onto water and the product is extracted with methylbenzene. The extract is dried, filtered and evaporated, yielding 24 parts (90.6%) of 1-(3-chloro-2-methylpropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one as a residue.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].C1N2CN3CN(C2)CN1C3.S(=O)(=O)(O)O.[C:25](O)(=[O:27])C>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9])[CH:25]=[O:27]
Reactant: CC(=O)O
Reactant: Oc1c(Cl)cccc1Cl
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=S(=O)(O)O
Product: O=Cc1cc(Cl)c(O)c(Cl)c1
Temperature: 100 °C
Reaction time: 0.42 h
Yield: 84 %

Procedure:
A 250 ml three neck round bottom flask fitted with reflux condenser, pot thermometer and mechanical stirrer, was charged with 10 g (0.061 mol) of 2,6-dichlorophenol, 40 ml glacial acetic acid and 3.44 g (0.024 mol) of hexamethylenetetramine. The reaction mass was heated at reflux for 3 hrs (a clear solution was obtained at 70° C.). The progress of reaction was checked by TLC. The mixture was allowed to cool at 100° C.; 30 ml of 10% sulphuric acid were slowly added and stirred at 100° C. for 20-30 min. The reaction mass was poured into 200 g crushed ice. The solid was filtered and washed well with 100 ml water and drying at 70° C. afforded 9.2 g (84%) of 3,5-dichloro-4-hydroxy-benzaldehyde. Melting point: 153-155° C. 1H NMR (400 MHz, CD3OD) δ 9.72 (s, 1H), δ 7.80 (s, 1H).
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[CH2:6]([NH2:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>>[CH2:6]([NH:14][C:1](=[O:5])[CH2:2][OH:3])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCN
Reactant: O=C(O)CO
Product: CCCCCCCCNC(=O)CO

Procedure:
0.75 mol of glycolic acid were melted at 80° C., then 1.11 mol of octylamine were added dropwise with stirring. After the exothermic reaction had subsided, the mixture was heated for one hour to 165° C. and then the excess amine was distilled off under reduced pressure. The product was obtained after cooling in the form of a white, crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[NH:12]1[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:9])=[C:6]([NH:7][C:8]([N:12]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13]2)=[O:10])[CH:11]=1
Reactant: O[C@H]1CCNC1
Reactant: O=c1[nH]c2cc(Cl)ccc2o1
Product: O=C(Nc1cc(Cl)ccc1O)N1CC[C@H](O)C1
Yield: 880 %

Procedure:
5-chloro-1,3-benzoxazole-2(3H)-one (577 mg, 0.34 mmol) and (3S)-pyrrolidin-3-ol (0.6 mL, 0.74 mmol) was heated to 90° C. for 2 hrs. The resulting red solidified oil was purified on silica (dichloromethane/methanol) to give the titled compound (768 mg, 88%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:21](O)=[O:22])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[CH:10][C:9]2=[O:20])(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.[CH3:53][N:54]([CH3:58])[CH2:55][CH2:56][NH2:57]>C(Cl)Cl>[C:1]([C:4]1[CH:5]=[C:6]([C:21]([NH:57][CH2:56][CH2:55][N:54]([CH3:58])[CH3:53])=[O:22])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)=[CH:10][C:9]2=[O:20])(=[O:3])[CH3:2]
Reactant: CN(C)CCN
Reactant: CC(=O)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cc(C(=O)NCCN(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reaction time: 0.25 h
Yield: 61.4 %

Procedure:
To a suspension of 8-acetyl-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (470 mg, 1.48 mmol) in DCM (10 mL) at room temperature, were added to DIPEA (0.284 mL, 1.63 mmol) and TSTU (491 mg, 1.63 mmol). The mixture was stirred for 15 minutes, N1,N1-dimethylethane-1,2-diamine (0.171 mL, 1.56 mmol) was added stirring was maintained for an additional hour. The mixture was adsorbed on silica gel and purified by flash chromatography on silica gel eluting with 5 to 10% methanol in DCM then with 10% methanolic ammonia (7 N) in DCM. The solvent was evaporated to dryness to afford 8-acetyl-N-(2-(dimethylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamide (352 mg, 61.3%) as a beige solid. Mass Spectrum: M+H+ 388.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15]O)[CH:10]=1.[H-].[Na+].[Cl-].[NH4+]>CN(C)C=O>[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C:2]2[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=2)[CH:10]=1
Reactant: OCc1cccnc1
Reactant: CSc1nsc(Cl)n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CSc1nsc(Cc2cccnc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
Into 2 ml of N,N-dimethylformamide were dissolved 100 mg of 5-chloro-3-methylthio-1,2,4-thiadiazole and 78 mg of 3-pyridinemethanol, 78 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 0.5 hour under ice-cooling and for 1 hours at room temperature. The reaction mixture was added to saturated ammonium chloride aqueous solution, and extracted with t-butyl methyl ether. The organic layer was concentrated, and the residue obtained was subjected to silica gel column chromatography to give 88 mg of 5-(3-pyridylmethyl)-3-methylthio-1,2,4-thiadiazole (hereinafter, referred to as the present compound (20)).
Reaction SMILES: O[CH2:2][N:3]([CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11]1)[C:4](=[O:8])[O:5][CH2:6][CH3:7].B(F)(F)F.CCOCC>ClCCl>[CH:10]12[CH2:15][CH:14]([CH:13]=[CH:12][CH2:11]1)[CH2:2][N:3]([C:4]([O:5][CH2:6][CH3:7])=[O:8])[CH2:9]2
Reactant: CCOC(=O)N(CO)CC1CC=CCC1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)N1CC2C=CCC(C2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.3 %

Procedure:
To a stirred solution of ethyl N-(hydroxymethyl)cyclohex-3-en-1-ylmethylcarbamate (213 mg, 1.00 mmol) in 15 mL of dichloromethane, cooled in an ice bath, was added drop-wise boron trifluoride etherate (0.19 mL, 1.5 mmol). The initially cloudy reaction mixture slowly cleared. After it had become homogenous, it was warmed to ambient temperature and stirred for 1.5 h. The reaction was quenched by sequential addition of 5 mL of water and 5 mL of 10% KOH solution. The mixture was extracted with dichloromethane (2×20 mL), and the combined extracts were washed with brine (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was column chromatographed on silica gel with 2:1 hexane/ethyl acetate to give the product as a colorless oil (145 mg, 74%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[C:19]([CH3:25])[N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31]>>[CH3:8][C:6]1[N:7]=[C:2]([N:26]2[CH2:30][CH2:29][CH2:28][C:27]2=[O:31])[CH:3]=[CH:4][C:5]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[C:19]([CH3:25])[N:18]=2)[CH2:13][CH2:12]1)=[O:10]
Reactant: O=C1CCCN1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)nc3C)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCC4=O)nc3C)CC2)nc1C

Procedure:
Using (6-bromo-2-methylpyridin-3-yl)[4-(3,5,6-trimethylpyridin-2-yl) piperazin-1-yl]methanone (145 mg) described in Preparation Example 248 and pyrrolidin-2-one (41 μL) and by the reaction and treatment in the same manner as in Example 262, the title compound (148 mg) was obtained.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O.C1(C)C=CC=CC=1>[N:17]1[CH:16]=[CH:15][C:14]([C:13]2[O:20][C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=3[N:12]=2)=[CH:19][CH:18]=1
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1O)c1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc2oc(-c3ccncc3)nc2c1
Reaction time: 1.3 h
Yield: 27.8 %

Procedure:
To a mixture of 1.69 g of N-(2-hydroxy-5-trifluoromethylphenyl) isonicotinamide, 25 ml of tetrahydrofuran and 2.36 g of triphenylphosphine, 3.91 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature. After 1.3 hours, 0.6 g of triphenylphosphine and 1.0 g of 40% toluene solution of diethyl azodicarboxylate were added and stirred for further 40 minutes. Water was poured into the mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was washed with diethyl ether, and 10 ml of methanol and 10 ml of 1 M aqueous solution of sodium hydroxide were added and stirred for two hours at room temperature. After concentrated hydrochloric acid was added to the reaction mixture while ice-cooling so as to make it acidic, the reaction mixture was washed with ethyl acetate. To the aqueous layer, 1 M aqueous solution of sodium hydroxide was added so as to make the solution alkaline, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, and dried over magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.44 g of 2-(pyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 13”).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6](C(C3C=CC(N(C)C)=CC=3)=C[N:10]=2)[N:7]=1.[OH-].[NH4+].[CH2:22](O)C>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:10])=[CH:4][C:3]=1[CH3:22]
Reactant: CCO
Reactant: CN(C)c1ccc(-c2cnc3ccc(Cl)nn23)cc1
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cc(N)nnc1Cl
Temperature: 100 °C
Yield: 72.7 %

Procedure:
3,6-dichloro-4-methylpyridazine 6 (1 g) was dissolved in 5 mL of ethanol and was added ammonium hydroxide (10 mL). The resulting reaction mixture was sealed in a pressure bottle and heated to 100° C. for 48 hours. The reaction mixture is cooled and the solvents were evaporated and purified by CombiFlash Companion using Hexane/DCM 40:60 solvent system (4 g normal phase RediSep Flash column with run time min at flow 18 mL/min) gave 0.640 g (72.7%) of 7 as yellow solid).