Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:16])[N:4]([C:11](=[O:15])[N:12]([CH3:14])[CH3:13])[O:5][C:6]=1[CH2:7][S:8]([CH3:10])=[O:9].ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)Cl>[Cl:1][C:2]1[C:3](=[O:16])[N:4]([C:11](=[O:15])[N:12]([CH3:13])[CH3:14])[O:5][C:6]=1[CH2:7][S:8]([CH3:10])(=[O:25])=[O:9]
Reactant: CN(C)C(=O)n1oc(CS(C)=O)c(Cl)c1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CN(C)C(=O)n1oc(CS(C)(=O)=O)c(Cl)c1=O
Reaction time: 8 h
Yield: 87.5 %

Procedure:
363 mg of 4-chloro-2-dimethylcarbamoyl-5-methylsulphinylmethyl-4-isoxazolin-3-one were dissolved in 20 ml of methylene chloride, and then 300 mg of crystals of m-chloroperbenzoic acid were added little by little, whilst ice-cooling and stirring. The mixture was allowed to stand overnight at room temperature, and was then washed, in turn, with 20 ml of a 5% w/v aqueous solution of sodium hydrogen carbonate and then twice, each time with 20 ml of water. The washings were combined and then extracted twice, each time with 10 ml of chloroform. The organic phases were combined and dried over anhydrous sodium sulphate, after which the solvent was distilled off. The residue was recrystallized from a mixture of methylene chloride and diisopropyl ether, to give 337 mg (yield 87.5% of theory) of the title compound in the form of crystals melting at 129°-129.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH2:18])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[Cl:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=1[N:30]=[C:31]=[O:32]>C(Cl)Cl>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH:18][C:31]([NH:30][C:21]2[CH:22]=[CH:23][C:24]([C:26]([F:27])([F:29])[F:28])=[CH:25][C:20]=2[Cl:19])=[O:32])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C(C)C
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1Cl
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(C(F)(F)F)cc2Cl)cc1-c1c(Cl)cnn1C(C)C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
To a solution of 3-(4-chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.1 g, 0.433 mmol) in CH2Cl2, was added 2-chloro-4-trifluoromethyl-phenyl isocyanate (0.107 g, 0.476 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 57 as a colorless solid (0.085 g, 40%). LCMS m/z (%)=489 M+H+ (37Cl, 25), 488 M+H+ (35Cl 37Cl, 25), 487 M+H+ (35Cl, 100), 1NMR (400 MHz, acetone-d6) δ: 8.88 (bs, 1H), 8.544 (bs, 1H), 8.063 (s, 1H), 7.669 (d, J=1.54 Hz, 1H), 7.606 (d, J=2.69 Hz, 1H), 7.58 (t, 1H), 7.549 (d, J=1.51 Hz, 1H), 7.385 (d, J=2.68 Hz, 1H), 7.68-7.64 (m, 1H), 7.080 (d, J=8.98 Hz, 1H), 4.145 (m, 1H), 3.742 (s, 3H), 1.345 (d, J=6.61 Hz, 3H), 1.188 (d, J=6.61 Hz, 3H).
Reaction SMILES: [O:1]([CH:8]([C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].O1CCCC1.Cl>O.CO>[O:1]([CH:8]([C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:18][CH:19]=1)[CH3:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C(C)Oc2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(Oc1ccccc1)c1ccc(C(=O)O)cc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 76.4 %

Procedure:
A mixture of methyl 4-(1-phenoxyethyl)benzoate (0.7 g, 2.7 mmol), lithium hydroxide monohydrate (571 mg, 13.6 mmol), tetrahydrofuran (15 mL), methanol (5 mL) and water (5 mL) was stirred at 20° C. for 4 hours. The mixture was adjusted to pH=1 with concentrated hydrochloric acid and then extracted with ethyl acetate (15 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to give 4-(1-phenoxyethyl)benzoic acid (0.5 g, 76%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=O)[O:9]C(=O)[NH:7][C:6]=2[CH:13]=1.[Br:14][C:15]1[C:16]([CH3:22])=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>C1(C)C(C)=CC=CC=1>[NH2:7][C:6]1[CH:13]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[C:10]([NH:18][C:17]1[CH:19]=[CH:20][CH:21]=[C:15]([Br:14])[C:16]=1[CH3:22])=[O:9]
Reactant: O=c1[nH]c2cc(F)ccc2c(=O)o1
Reactant: Cc1c(N)cccc1Br
Solvent: Cc1ccccc1C
Product: Cc1c(Br)cccc1NC(=O)c1ccc(F)cc1N
Yield: 40.9 %

Procedure:
A mixture of 7-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (5.00 g, 27.6 mmol) and 3-bromo-2-methylaniline (5.14 g, 27.6 mmol) in xylene (50 mL) was heated at reflux for 8 h. The cooled mixture was filtered. The collected solid was washed with 3 times with DCM and the combined filtrates were concentrated. The residue was purified by column chromatography on silica gel (330 g), eluting with EtOAc-hexanes (gradient from 0-45%), to give 2-amino-N-(3-bromo-2-methylphenyl)-4-fluorobenzamide (3.65 g, 41% yield). Mass spectrum m/z 323, 325 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 7.65 (1 H, d, J=8.14 Hz), 7.45-7.57 (3 H, m), 7.14 (1 H, t, J=8.03 Hz), 6.39-6.50 (2 H, m), 5.80 (2 H, br. s.), 2.43 (3 H, s).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)CC(O)=O.[NH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][NH:54][S:55]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)(=[O:57])=[O:56]>>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@H:13]([C:14](=[O:15])[NH:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][NH:54][S:55]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)(=[O:57])=[O:56])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: NCCCCCNS(=O)(=O)c1ccccc1
Agent: O=C(O)CC(=O)O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NCCCCCNS(=O)(=O)c1ccccc1
Yield: 162.5 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (45 mg) and N-(5-aminopentyl)-benzenesulphonamide malonate (45 mg, 0.08 mmol) according to Method C with HPLC purification to give the title compound (4.2 mg, 0.13 mmol). 1H-NMR (400 MHz, CD3OD) δ 0.97 (m, 1H) 1.16-1.49 (m, 16H) 2.73-3.16 (m, 6H) 4.26 (m, 1H) 4.50 (m, 1H) 4.68 (s, 2H) 7.09-7.9 (m, 13H); HRMS 754.2859 (calc of monoisotopic mass for C37H46N4O11S gives 754.2884).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:16][N+:17]([CH3:19])=[CH2:18].[I-]>CN(C=O)C>[CH3:16][N:17]([CH2:19][C:14]1[N:10]([C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:9][C:6]=2[C:7]#[N:8])[CH:11]=[N:12][C:13]=1[CH3:15])[CH3:18]
Reactant: Cc1cn(-c2ccc(I)cc2C#N)cn1
Reactant: C=[N+](C)C
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1ncn(-c2ccc(I)cc2C#N)c1CN(C)C
Yield: 38 %

Procedure:
In analogy to example 5b, 5-iodo-2-(4-methyl-imidazol-1-yl)-benzonitrile (+regioisomer) was reacted with Eschenmoser's salt in DMF for 72 h at 90° C. Evaporation of the solvent, aqueous workup and chromatography (SiO2, dichloromethane:methanol=100:0 to 97:3) afforded the title compound as a white solid (yield: 38%). MS: m/e=367.0 [M+H]+.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH:14]([C:23]([F:26])([F:25])[F:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH3:22])=[O:12])=[C:7]([F:27])[CH:6]=1)(=O)C.C(O)C.C(N)C1C=CC=CC=1>O>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH:14]([C:23]([F:24])([F:25])[F:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH3:22])=[O:12])=[C:7]([F:27])[CH:6]=1
Reactant: CCOCCCCCC(OC(=O)c1ccc(OC(C)=O)cc1F)C(F)(F)F
Solvent: CCO
Solvent: O
Solvent: NCc1ccccc1
Product: CCOCCCCCC(OC(=O)c1ccc(O)cc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A reactor was charged with 1 g of 4-acetoxy-2-fluoro-1-(6-ethoxy-1-trifluoromethylhexyloxycarbonyl)-benzene, 15 ml of ethanol and 0.6 g of benzylamine, and the mixture was stirred at room temperature for 5 hours. After the reaction, the reaction mixture solution was poured into water and subjected to extraction with dichloromethane. An organic layer was consecutively washed with a hydrochloric acid aqueous solution and with water, and dried over anhydrous sodium sulfate. The solvent was removed to give a crude 4-hydroxy-2-fluoro-1-(6-ethoxy-1-trifluoromethylhexyloxycarbonyl)benzene. This product was analyzed by thin film chromatography to show that benzylacetamide was co-present in addition to the end product.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N+:15]([O-])=[CH:14][C:13]=2[N:12]=[CH:11]1)[CH:7]([CH3:9])[CH3:8].[OH-].[NH4+]>CN(C)C=O>[Cl:3][C:14]1[C:13]2[N:12]=[CH:11][N:10]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: CC(C)Cn1cnc2c[n+]([O-])c3ccccc3c21
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)Cn1cnc2c(Cl)nc3ccccc3c21
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
To 40 ml of cold N,N-dimethylformamide (10°-20° C.) was added slowly 5.9 g (0.0385 mole) of phosphorus oxychloride with swirling, the temperature of the mixture being maintained at 10°-20° C. 1-Isobutyl-1H-imidazo[4,5-c]quinolin-5-oxide (6.2 g; 0.0257 mole) from Step (C) above was added gradually with swirling and cooling. After addition was complete, the solution was allowed to stand at room temperature for about 30 minutes with occasional swirling. The solution was then heated on a steam bath for thirty minutes. After allowing it to cool, the solution was poured onto ice with stirring, and the resulting mixture was brought to pH 8-9 with concentrated ammonium hydroxide. The resulting off-white solid was filtered, washed with water, rinsed with ether, and dried to provide 6.0 g of crude 4-chloro-1-isobutyl-1H-imidazo[4,5-c]quinoline having a m.p. of 135°-138° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([C@@H:18]1[C@@H:20]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C@@H:19]1[C:31]([OH:33])=[O:32])=[O:17].[C:34]([O-])([O-])=O.[K+].[K+].IC.[OH-].[Na+]>CN(C=O)C>[CH3:34][O:32][C:31]([C@H:19]1[C@H:20]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C@H:18]1[C:16](=[O:17])[NH:15][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[CH:7][C:2]=1[F:1])=[O:33]
Reactant: COc1ccc(OC[C@@H]2[C@@H](C(=O)Nc3ccc(-n4ccccc4=O)cc3F)[C@H]2C(=O)O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1[C@H](COc2ccc(OC)cc2)[C@H]1C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Reaction time: 3 h
Yield: 101.5 %

Procedure:
A solution of 90 mg (0.19 mmol) of (1S,2R,3R) 2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-3-(4-methoxy-phenoxymethyl)-cyclopropanecarboxylic acid in 3 ml of DMF was treated with 100 mg of K2CO3 and 0.5 ml ml of iodomethane. The mixture was stirred for 3 hrs and poured into a diluted aqueous solution of NaOH. Extraction with AcOEt, drying of the combined organic phases over Na2SO4, filtration and evaprotation of the solvent gave 90 mg (97%) of (1S,2R,3R) 2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-3-(4-methoxy-phenoxymethyl)-cyclopropanecarboxylicacid methyl ester. Yellow oil. MS: 467 (M+H)+.
Reaction SMILES: C(OC(O)O)C.C([O:9][CH:10](OCC)[C:11]#[C:12][C:13]([CH3:17])=[CH:14][CH2:15][OH:16])C.Cl>[Pd]>[CH3:17][C:13](=[CH:14][CH2:15][OH:16])[CH:12]=[CH:11][CH:10]=[O:9]
Reactant: CCOC(C#CC(C)=CCO)OCC
Agent: [Pd]
Agent: CCOC(O)O
Agent: Cl
Product: CC(C=CC=O)=CCO

Procedure:
Trans 3-methyl-3-penten-1-in-5-ol is reacted with orthoformic acid ethyl ester. The resulting 1,1-diethoxy-4-methyl-4-hexen-2-in-6-ol is partially hydrogenated by means of a deactivated palladium catalyst, followed by treatment with hydrochloric acid to form 4-methyl-6-hydroxy-2,4-hexadien-1-al. Reaction with α-carbethoxy-ethylene-triphenyl-phosphoran yields 2,6-dimethyl-8-hydroxy-2,4,6-octatrien-1-oic acid ethyl ester, which can be oxidized by means of manganous oxide to 2,6-dimethyl-8-oxo-2,4,6-octatrien-1-oic acid ethyl ester.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:3]1=[O:18].[H][H]>[Pd].C(O)(=O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]2)[C:3]1=[O:18]
Reactant: Cn1c(=O)n(Cc2cccnc2)c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: Cn1c(=O)n(CC2CCCNC2)c2ccccc21
Yield: 100 %

Procedure:
A mixture of 16 parts of 1,3-dihydro-1-methyl-3-(3-pyridinylmethyl)-2H-benzimidazol-2-one and 200 parts of acetic acid is hydrogenated at normal pressure and at 50° C. with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. Water is added to the residue and the whole is alkalized with ammonium hydroxide. The product is extracted with methylbenzene. The extract is dried, filtered and evaporated, yielding 16.5 parts (100%) of 1,3-dihydro-1-methyl-3-(3-piperidinylmethyl)-2H-benzimidazol-2-one as an oily residue.
Reaction SMILES: CCN(CC)CC.[CH2:8]([OH:12])[CH2:9][C:10]#[CH:11].[Cl:13][C:14]1[N:22]=[C:21](I)[N:20]=[C:19]2[C:15]=1[N:16]=[CH:17][N:18]2[CH3:24]>O1CCOCC1.[Cu]I>[Cl:13][C:14]1[N:22]=[C:21]([C:11]#[C:10][CH2:9][CH2:8][OH:12])[N:20]=[C:19]2[C:15]=1[N:16]=[CH:17][N:18]2[CH3:24]
Reactant: Cn1cnc2c(Cl)nc(I)nc21
Reactant: C#CCCO
Agent: [Cu]I
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cn1cnc2c(Cl)nc(C#CCCO)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NEt3 (4.9 ml, 34.5 mmol) and but-3-yn-1-ol (1.1 ml, 25.63 mmol) were added to a solution of 6-chloro-2-iodo-9-methyl-9H-purine (6.8 g, 23.3 mmol), CuI (454 mg, 2.23 mmol) and bis-triphenylphosphine palladium dichloride (811 mg, 1.15 mmol) in dioxane (93 ml). The reaction mixture was stirred at RT for 1 h. The solvents were removed under reduced pressure. Water (50 ml) was added to the dark residue obtained. The aqueous phase was extracted with DCM (3×100 ml). The combined organic phases were dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue was purified by flash chromatography (DCM/MeOH: 94/6) to give an off-white precipitate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[N:5][CH:4]=1.[NH:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH2:14][N:17]2[CH2:18][CH2:19][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:21][CH2:22]2)=[N:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COc1cnc2ccc(=O)n(CC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1cnc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To 58 mL of chloroform, the obtained (7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde was dissolved, 2.67 g of tert-butyl (piperidin-4-yl)carbamate and 0.80 g of acetic acid were added, and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture, 4.23 g of sodium triacetoxyborohydride was added, and the mixture was stirred for 15 hours. Thereto was added a saturated aqueous sodium hydrogen carbonate solution, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using silica gel; Silica Gel 60N made by KANTO CHEMICAL CO., INC. and an eluent of chloroform:methanol=10:1 to obtain 4.36 g of tert-butyl (1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:46]([C:50]1[CH:70]=[CH:69][C:53]([CH2:54][NH:55][CH2:56][CH2:57][C:58]2[CH:63]=[C:62]([C:64]([F:67])([F:66])[F:65])[CH:61]=[C:60]([F:68])[CH:59]=2)=[CH:52][CH:51]=1)([CH3:49])([CH3:48])[CH3:47]>CN(C=O)C.O>[C:46]([C:50]1[CH:51]=[CH:52][C:53]([CH2:54][N:55]([CH2:56][CH2:57][C:58]2[CH:63]=[C:62]([C:64]([F:67])([F:65])[F:66])[CH:61]=[C:60]([F:68])[CH:59]=2)[C:12]([C:9]2[C:10]([F:11])=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:69][CH:70]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)c1ccc(CNCCc2cc(F)cc(C(F)(F)F)c2)cc1
Reactant: O=C(O)c1c(F)c(Cl)cc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCc2cc(F)cc(C(F)(F)F)c2)C(=O)c2c(F)c(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.3 %

Procedure:
To a solution of 112 mg (0.53 mmol) of 5-chloro-6-fluoro-1H-indole-7-carboxylic acid and 169 mg of TBTU (0.53 mmol) in 6 ml DMF, were added 0.45 ml (2.63 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 200 mg (0.57 mmol) of (4-tert-butyl-benzyl)-[2-(3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-amine in 2 ml DMF were added. After stirring for 21 h at rt, the reaction mixture was diluted with 80 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; DCM/heptane 9:1) to give 158 mg off-white solid (48%). MS (EI) 548.2 (M)+.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]4[CH2:27][CH2:26][CH2:25]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:30])[CH:3]=1.[C:31]1([CH2:37][C:38]([N:40]=[C:41]=[O:42])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C=O.CCCCCC.C(OCC)C>[F:30][C:4]1[CH:3]=[C:2]([NH:1][C:41]([NH:40][C:38](=[O:39])[CH2:37][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:42])[CH:29]=[CH:28][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]3[CH2:27][CH2:26][CH2:25]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCN(CCN4CCC4)CC3)c2)c(F)c1
Reactant: O=C=NC(=O)Cc1ccccc1
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccnc(NC(=O)N3CCN(CCN4CCC4)CC3)c2)c(F)c1
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of 4-[2-(azetidin-1-yl)ethyl]piperazine-1-carboxylic acid [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide (71 mg) in N,N-dimethylformamide (2 ml) was added a solution of 0.25 M 2-phenylacetyl isocyanate in hexane (2.05 ml) under a nitrogen atmosphere, followed by stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate (100 ml) and a saturated aqueous solution of sodium hydrogencarbonate (50 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 ml), water (50 ml), brine (50 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=9:1). Fractions containing the target compound were concentrated to give a residue, which was then suspended in diethyl ether (1.5 ml) and hexane (3 ml). The solid was filtered off and dried under aeration to provide the titled compound (63.0 mg, 64.0%) as white powder.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:9][O:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>O1CCOCC1>[CH3:9][O:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])[CH2:15][CH2:14]1
Reactant: O=C1CCCC(=O)O1
Reactant: COCCN1CCNCC1
Solvent: C1COCCO1
Product: COCCN1CCN(C(=O)CCCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.9 %

Procedure:
1.52 g of glutaric anhydride and then 1.92 g of 1-(2-methoxyethyl)piperazine in solution in 3 cm3 of dioxane are added to 13 cm3 of dioxane. After stirring for 5 hours at room temperature, an additional 300 mg of glutaric anhydride are added and then the stirring is continued at 20° C. for 18 hours. The solvent is evaporated under reduced pressure and the resulting oil is dried at 20° C. (90 Pa) to give 3.4 g of 5-[4-(2-methoxyethyl)piperazin-1-yl]-5-oxopentanoic acid in the form of an orange-colored lacquer which is used as it is.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=O)[CH3:2].C(N(CC)CC)C>C(Cl)Cl>[CH3:2][C:1]1[O:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5][N:4]=1
Reactant: CCOC(=O)C(=O)NNC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1nnc(C)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a solution of ethyl 2-(2-acetylhydrazinyl)-2-oxoacetate (0.50 g, 2.87 mmol) in CH2Cl2 (10 mL) was added triethylamine (0.53 mL, 3.73 mmol) and p-TsCl (0.65 g, 3.44 mmol) in three portions. The reaction mixture was stirred at rt for 8 h then was diluted with CH2Cl2 and washed with water. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The crude was purified by column chromatography using EtOAc/hexanes to give the title compound as an off-white solid (375 mg, 84%). 1H NMR (300 MHz, CDCl3): δ 4.51 (2H, q, J=7 Hz), 2.65 (3H, s), 1.52 (3H, t, J=5 Hz). MS (M+H): 157.1.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:10]1[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:17][C:18]1[N:23]=[C:22]([N:24]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]2=[O:34])[CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C(#N)C>[CH3:15][N:14]1[C:10]([C:3](=[N:2][O:1][CH2:17][C:18]2[N:23]=[C:22]([N:24]3[C:25](=[O:34])[C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:32]3=[O:33])[CH:21]=[CH:20][CH:19]=2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:11][N:12]=[CH:13]1
Reactant: O=C1c2ccccc2C(=O)N1c1cccc(CBr)n1
Reactant: Cn1cncc1C(=NO)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: Cn1cncc1C(=NOCc1cccc(N2C(=O)c3ccccc3C2=O)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 29 h
Yield: 22.2 %

Procedure:
To a solution of N-hydroxy-1-(1-methyl-1H-imidazol-5-yl)-1-phenylmethanimine (3.90 g, 19.4 mmol) and 2-[6-(bromomethyl)pyridin-2-yl]-1H-isoindole-1,3(2H)-dione (6.79 g, 21.4 mmol) in acetonitrile (50 mL) were added cesium carbonate (13.3 g, 40.7 mmol) and potassium iodide (322 mg, 1.93 mmol). After stirring at room temperature for 29 h, the reaction mixture was filtered, the insolubles washed with acetone and diisopropylether, and the filtrate concentrated in vacuo. Purification on silica gel afforded 2-{6-[({[(1-methyl-1H-imidazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}-1H-isoindole-1,3(2H)-dione [1.88 g, yield 21%; HPLC/MS: m/z=438 (M+H); log P(HCOOH)=1.81].