Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:19])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2].[CH2:24](N(CC)CC)[CH3:25]>CN(C=O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:19])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:24][CH3:25])[CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Solvent: CN(C)C=O
Product: CCN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3CC)CC1
Yield: 72 %

Procedure:
A mixture of 1-ethyl-6-fluoro-7-(1-piperazinyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (0.96 g) (3 millimole), iodoethyl (0.94 g) (6 millimole), triethylamine (0.6 g) (6 millimole) and 10 ml DMF was heated to 70° to 80° C. for 2.5 hours under stirring. After cooling, the reaction mixture was evaporated under vacuum and the residue was dissolved in dichloromethane, washed with water, dried over anhydrous Na2SO4 and the solvent was removed. The residue was recrystallized from a mixture of CHCl3 and benzene to obtain 0.75 g (72%) of 1-ethyl-6-fluoro-7-(4-ethyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([OH:9])=[CH:7][C:6]([OH:10])=[C:5]([C:11](=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:4]=1[CH2:21][C:22]([OH:24])=O)[CH3:2].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:48][O:49][CH2:50][CH2:51][NH:52][CH3:53]>ClCCl.O>[CH2:1]([C:3]1[C:8]([OH:9])=[CH:7][C:6]([OH:10])=[C:5]([C:11](=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:4]=1[CH2:21][C:22]([N:52]([CH2:51][CH2:50][O:49][CH3:48])[CH3:53])=[O:24])[CH3:2]
Reactant: CCc1c(O)cc(O)c(C(=O)c2ccc(OC)cc2)c1CC(=O)O
Reactant: CNCCOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCc1c(O)cc(O)c(C(=O)c2ccc(OC)cc2)c1CC(=O)N(C)CCOC
Temperature: 25 °C
Reaction time: 14 h
Yield: 13.2 %

Procedure:
2-Ethyl-3,5-dihydroxy-6-(4-methoxybenzoyl)phenyl-acetic acid (0.18 g, 0.53 mmol) obtained in Example 10, Step 1 was dissolved in dichloromethane (2.0 mL). To the solution were added 1-hydroxybenzotriazole hydrate (0.11 g, 0.72 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.14 g, 0.72 mmol) and 2-methoxy-N-methylethylamine (0.12 mL, 1.1 mmol), followed by stirring at room temperature for 14 hours. To the reaction mixture was added water (10 mL), and the mixture was extracted with chloroform (50 mL×2). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by preparative thin layer chromatography (methanol/chloroform=1/9) to obtain Compound 10 (28 mg, 13%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:12]=2[C:13]([NH2:15])=[O:14])=O)=[CH:4][CH:3]=1.[OH-].[Na+].CCOC(C)=O>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:15][C:13](=[O:14])[C:12]3[C:11](=[CH:19][C:18]([O:20][CH3:21])=[C:17]([O:22][CH3:23])[CH:16]=3)[N:10]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(NC(=O)c2ccc(Cl)cc2)c(C(N)=O)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc2nc(-c3ccc(Cl)cc3)[nH]c(=O)c2cc1OC
Reaction time: 0.08 h

Procedure:
To a solution of 2-((4-chlorophenyl)carbonylamino)-4,5-dimethoxybenzamide (1.0 g, 2.99 mmol) in ethanol (10 mL) was added aqueous NaOH solution (15 mL) at rt for 10 min. The reaction mixture was refluxed for 10 min and allowed to rt. The mixture was poured into ice cold water and stirred for 10 min EtOAc (20 mL) was added to the solution and stirred for 5 min. The separated solid was filtered, washed with ice cold water and dried to the product as a white color solid (900 mg, 95%), mp>360° C. 1H NMR (400 MHz, DMSO-d6): δ 12.47 (1H, s), 8.19 (2H, d, J=8.6 Hz), 7.62 (2H, d, J=8.6 Hz), 7.50 (1H, s), 7.23 (1H, s), 3.94 (3H, s), 3.90 (3H, s); LC-MS (positive ion mode): m/z 317, 319 (M+H)±.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:40]=[CH:41][N:42]=3)[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:26][C:27]4[CH:39]=[CH:38][C:30]([C:31]([O:33]C(C)(C)C)=[O:32])=[CH:29][CH:28]=4)=[O:25])[CH2:19]3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:40]=[CH:41][N:42]=3)[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:26][C:27]4[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:38][CH:39]=4)=[O:25])[CH2:19]3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2cc(N3CCCC(C(=O)Nc4ccc(C(=O)OC(C)(C)C)cc4)C3)nn3ccnc23)nc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2cc(N3CCCC(C(=O)Nc4ccc(C(=O)O)cc4)C3)nn3ccnc23)nc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.7 %

Procedure:
A mixture of tert-butyl 4-(1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)piperidine-3-carboxamido)benzoate (150 mg, 0.26 mmol) and TFA (2 mL) in dichloromethane (2 mL) was stirred at room temperature for 2 h. The residue was concentrated in vacuo. The crude product was purified by prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 40% acetonitrile/60% water (0.1% TFA, v/v) in a linear fashion over 9 min) to give 4-(1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)piperidine-3-carboxamido)benzoic acid (5 mg, 4%) as yellow solid. 1H NMR (300 MHz, DMSO): δ 10.36 (s, 1H), 10.25 (s, 1H), 8.14 (brs, 2H), 7.90-7.74 (m, 5H), 7.44 (s, 1H), 6.97 (s, 1H), 4.25-4.15 (m, 4 h), 3.91 (s, 3H), 3.77 (s, 3H), 2.67 (brs, 2H), 2.04-1.57 (m, 3H). LC-MS: [M+H]+, 517.9, tR=1.366 min, HPLC: 95.06% at 214 nm, 95.20% at 254 nm, tR=4.927 min.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[C:26]1([CH2:32][C:33](Cl)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:33](=[O:34])[CH2:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)Cc2ccccc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (100 mg, 0.43 mmol) and triethylamine (88 μL, 0.64 mmol) in methylene chloride (20 mL) was added dropwise phenylacetyl chloride (70 mg, 0.45 mmol) in methylene chloride (5 mL). After the addition, the reaction was allowed to stir at ambient temperature for 10 min and then washed with water. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. Yield: 95 mg (61%) of the title compound as white crystals: mp 151-152° C.; [α]21D -4.3° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 363 (21, M+).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]([CH3:17])[S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[C:4]([C:20]([O:22]C)=[O:21])[CH:3]=1.Cl>CO.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([C:20]([OH:22])=[O:21])[C:5]([N:6]([CH3:17])[S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[CH:18][CH:19]=1
Reactant: COC(=O)c1cc(Cl)ccc1N(C)S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N(C)c2ccc(Cl)cc2C(=O)O)cc1
Temperature: 25 °C
Yield: 81.6 %

Procedure:
To a suspension of 4′-chloro-2′-methoxycarbonyl-N-methyl-p-toluenesulfonanilide (13.3 g (37.5 mmol)) in methanol (30.0 ml), 10% aqueous sodium hydroxide solution (30.0 ml) was added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 48 hours, and then concentrated under reduced pressure. Water was added to the residue to get a homogeneous solution, followed by addition of concentrated hydrochloric acid (10.0 ml) to bring about precipitation of crystals. To this, ethyl acetate was added to extract the product. The extract was then washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Diethyl ether was added to the crystals. The crystals were collected by filtration and washed to give 10.4 g (82%) of the title compound as white crystals.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:11]([O-:13])=O)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[NH2:18].C1(N=C=NC2CCCCC2)CCCCC1>>[Cl:14][C:15]1[CH:16]=[C:17]([NH:18][C:11](=[O:13])[CH:3]([O:2][CH3:1])[C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5])[CH:19]=[C:20]([Cl:22])[CH:21]=1
Reactant: COC(C(=O)[O-])C(=O)OC(C)(C)C
Reactant: Nc1cc(Cl)cc(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: COC(C(=O)Nc1cc(Cl)cc(Cl)c1)C(=O)OC(C)(C)C
Yield: 30 %

Procedure:
Mono-t-butyl methoxymalonate (5.42 grams, 0.03 mole), prepared in Part B, 3,5-dichloroaniline (4.62 grams, 0.03 mole) and 1,3-dicyclohexylcarbodiimide (5.88 grams, 0.03 mole) were reacted in a manner similar to that described in Example LVII to give 2.92 grams (0.009 mole) of t-butyl 3-[(3,5-dichlorophenyl)amino]-2-methoxy-3-oxopropanoate having a melting point of 129.5° C.-131.5° C. Elemental analysis of the product indicated the following:
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH2:10][CH2:11][CH3:12])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:14][C@@H:15]([C:19]([OH:21])=[O:20])[C@H:16]([CH3:18])[OH:17].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[C:9]([CH2:10][CH2:11][CH3:12])=[C:8]([NH:14][C@H:15]([C@@H:16]([OH:17])[CH3:18])[C:19]([OH:21])=[O:20])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCCc1c(F)ccc(C#N)c1Cl
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Temperature: 80 °C
Reaction time: 40 h
Yield: 13.4 %

Procedure:
2-Chloro-4-fluoro-3-propylbenzonitrile (CAS 924626-89-1, 3.22 g, 16.3 mmol) was mixed together with H-D-Thr-OH (2.33 g, 19.6 mmol) in DMSO (30 mL) at room temperature. K2CO3 (4.73 g, 34.2 mmol) was added and the reaction mixture was stirred at 80° C. for 40 h. The reaction mixture was then cooled to room temperature and partitioned between water and EtOAc. The layers were separated and the aqueous extract was washed once with EtOAc. The aqueous extract was then acidified by slow addition of citric acid and stirred for 10 min at room temperature. The solution was extracted with EtOAc several times and the organic extracts were combined, washed with water, dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product (0.650 g, 13% yield), which was carried on to the next step without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[S:10][C:9]([CH:11]2[O:15][CH2:14][CH2:13][O:12]2)=[C:8]([CH3:16])[CH:7]=1.[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[K].O>CN(C)C=O>[O:12]1[CH2:13][CH2:14][O:15][CH:11]1[C:9]1[S:10][C:6]([CH:5]([N:21]2[C:17](=[O:27])[C:18]3[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:20]2=[O:22])[CH2:4][CH2:3][CH3:2])=[CH:7][C:8]=1[CH3:16]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1cc(CCCCBr)sc1C1OCCO1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(c1cc(C)c(C2OCCO2)s1)N1C(=O)c2ccccc2C1=O
Reaction time: 18 h
Yield: 99.5 %

Procedure:
2-[5-(4-Bromobutyl)-3-methyl-2-thienyl]-1,3-dioxolane (13.3 g) and potassium phthalimide (8.9 g) were stirred at 50° in dry dimethylformamide (130 ml) for 4 h and then at room temperature for 18 h. The mixture was poured into water (1500 ml) and extracted with ether. The organic extract was evaporated to give the title compound as a light yellow oil (16.1 g)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:25]2[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31]C(=O)OC(C)(C)C)[CH2:26]2)=[N:5][C:6]([N:9]2[C:17]3[CH:16]=[C:15]([C:18]4[CH:23]=[N:22][CH:21]=[C:20]([CH3:24])[N:19]=4)[N:14]=[CH:13][C:12]=3[CH:11]=[N:10]2)=[CH:7][N:8]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[C:4]([N:25]2[CH2:30][CH2:29][CH2:28][C@H:27]([NH2:31])[CH2:26]2)=[N:5][C:6]([N:9]2[C:17]3[CH:16]=[C:15]([C:18]4[CH:23]=[N:22][CH:21]=[C:20]([CH3:24])[N:19]=4)[N:14]=[CH:13][C:12]=3[CH:11]=[N:10]2)=[CH:7][N:8]=1
Reactant: COc1ncc(-n2ncc3cnc(-c4cncc(C)n4)cc32)nc1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ncc(-n2ncc3cnc(-c4cncc(C)n4)cc32)nc1N1CCC[C@H](N)C1
Yield: 39.9 %

Procedure:
A solution of tert-butyl N-[(3S)-1-[3-methoxy-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyrazin-2-yl]-3-piperidyl]carbamate (75 mg, 0.15 mmol) in dichloromethane 4.0 ml and trifluoroacetic acid (0.80 mL, 10 mmol) was stirred at RT 4 h. The reaction was concentrated and submitted for reverse phase HPLC to give 222 (25 mg) in 41% yield. MS (ESI) m/z: 418.2. 1H NMR (400 MHz, DMSO) δ 9.45 (s, 2H), 9.32 (s, 1H), 8.67 (s, 1H), 8.63 (s, 1H), 8.15 (s, 1H), 4.24 (d, J=10.2 Hz, 1H), 4.06 (d, J=13.3 Hz, 1H), 4.00 (s, 3H), 3.09 (dd, J=24.2, 12.0 Hz, 3H), 2.63 (s, 3H), 1.94 (d, J=15.0 Hz, 2H), 1.76 (d, J=10.0 Hz, 1H), 1.49 (d, J=10.0 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[CH:12])[CH:4]=[CH:5][N:6]=1.[Br:13][C:14]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:15]=1[O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23](OS(C(F)(F)F)(=O)=O)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1>>[Br:13][C:14]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:15]=1[O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([C:12]#[C:11][CH2:10][CH2:9][CH2:8][CH2:7][N:3]3[CH:4]=[CH:5][N:6]=[C:2]3[CH3:1])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1
Reactant: COc1cc2c(Oc3ccc(F)cc3Br)ncnc2cc1OS(=O)(=O)C(F)(F)F
Reactant: C#CCCCCn1ccnc1C
Product: COc1cc2c(Oc3ccc(F)cc3Br)ncnc2cc1C#CCCCCn1ccnc1C

Procedure:
Using an analogous procedure to that described in the second last paragraph of Note [115] above, 6-(2-methylimidazol-1-yl)-1-hexyne was reacted with 4-(2-bromo-4-fluorophenoxy)-6-methoxy-7-trifluoromethanesulphonyloxyquinazoline to give 4-(2-bromo-4-fluorophenoxy)-6-methoxy-7-[6-(2-methylimidazol-1-yl)-1-hexynyl]quinazoline; NMR Spectrum: (DMSOd6) 1.56 (m, 2H), 1.85 (m, 2H), 2.28 (s, 3H), 2.56 (m, 2H), 3.9 (m, 2H), 3.98 (s, 3H), 6.75 (br m, 1H), 7.1 (br m, 1H), 7.36-7.82 (m, 3H), 7.63 (s, 1H), 8.61 (s, 1H); Mass Spectrum: M+H+ 509 and 511.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:10][C:11](=O)[C:12]2[N:13]([CH:15]=[CH:16][N:17]=2)[CH:14]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C.P(Cl)(Cl)([Cl:32])=O>>[Cl:32][C:11]1[C:12]2[N:13]([CH:15]=[CH:16][N:17]=2)[CH:14]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:10]=1
Reactant: O=c1[nH]c(-c2ccc(Cl)cc2Cl)cn2ccnc12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Clc1ccc(-c2cn3ccnc3c(Cl)n2)c(Cl)c1

Procedure:
650 mg (2.3 mmol) of 6-(2,4-dichlorophenyl)imidazo[1,2-a]pyrazin-8(7H)-one (Example 4A) were dissolved in 7 ml of phosphoryl chloride and stirred under reflux for 12 h. The reaction mixture was poured into 100 ml of saturated sodium bicarbonate solution, and solid sodium bicarbonate was added until a pH of 7 had been reached. Ethyl acetate was added, and the mixture was extracted. The organic phase was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated on a rotary evaporator. Methanol was added to the residue, and the precipitated solid was filtered off and washed with methanol and diethyl ether and dried under high vacuum. This gave 400 mg (58% of theory) of the product as a solid.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C:12]2[NH:13][C:14]3[C:15]([N:38]=2)=[N:16][CH:17]=[C:18]([C:20]2[CH:21]=[CH:22][C:23]4[O:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][C:24]=4[CH:37]=2)[CH:19]=3)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[O:29]1[C:23]2[CH:22]=[CH:21][C:20]([C:18]3[CH:19]=[C:14]4[NH:13][C:12]([NH:11][C:9](=[O:10])[O:8][CH2:7][C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[N:38][C:15]4=[N:16][CH:17]=3)=[CH:37][C:24]=2[CH2:25][NH:26][CH2:27][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3cnc4nc(NC(=O)OCc5ccccc5)[nH]c4c3)cc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1nc2ncc(-c3ccc4c(c3)CNCCO4)cc2[nH]1)OCc1ccccc1
Temperature: 50 °C

Procedure:
To a solution of 1,1-dimethylethyl 7-[2-({[(phenylmethyl)oxy]carbonyl}amino)-1H-imidazo[4,5-b]pyridin-6-yl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (0.49 g, 1.9 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL) and the resulting solution was heated at 50° C. After 1 h the reaction mixture was concentrated and the residue was concentrated three times from ethyl acetate (30 mL) to afford phenylmethyl [6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridin-2-yl]carbamate as the bis-trifluoroacetate salt (0.48 g, 95% yield). MS (EI) for C23H21N5O3: 416 (MH+).
Reaction SMILES: [CH:1]1([N:4]([CH2:24][CH3:25])[C:5]2[N:9]=[C:8](/[CH:10]=[CH:11]/[C:12]3[N:22]=[C:15]4[C:16]([CH3:21])=[N:17][CH:18]=[C:19]([CH3:20])[N:14]4[N:13]=3)[N:7]([CH3:23])[N:6]=2)[CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([N:4]([C:5]2[N:9]=[C:8]([CH2:10][CH2:11][C:12]3[N:22]=[C:15]4[C:16]([CH3:21])=[N:17][CH:18]=[C:19]([CH3:20])[N:14]4[N:13]=3)[N:7]([CH3:23])[N:6]=2)[CH2:24][CH3:25])[CH2:2][CH2:3]1
Reactant: CCN(c1nc(/C=C/c2nc3c(C)ncc(C)n3n2)n(C)n1)C1CC1
Agent: [Pd]
Solvent: CO
Product: CCN(c1nc(CCc2nc3c(C)ncc(C)n3n2)n(C)n1)C1CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 86 %

Procedure:
A mixture of (E)-N-cyclopropyl-5-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)vinyl)-N-ethyl-1-methyl-1H-1,2,4-triazol-3-amine (75 mg, 222 μmol, Eq: 1.00) and palladium on carbon 10% (11.8 mg, 11.1 μmol, Eq: 0.05) in methanol (15 ml) was stirred for 5 hours at 25° C. under hydrogen atmosphere. The catalyst was filtered off, the filtrate was evaporated affording cyclopropyl-{5-[2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-1-methyl-1H-[1,2,4]triazol-3-yl}-ethyl-amine (65 mg, 86.2%) as a light yellow viscous oil. MS: m/z=341.5 (M+H+)
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([OH:14])=O)[O:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]1[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]>>[CH3:15][O:16][C:17]1[CH:26]=[C:25]([NH:27][C:12]([C:6]2[O:7][C:8]([CH:9]([CH3:10])[CH3:11])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=2)=[O:14])[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1ccc(N)cc1OC
Reactant: CC(C)c1cc(C(=O)O)oc1C(C)C
Product: COC(=O)c1ccc(NC(=O)c2cc(C(C)C)c(C(C)C)o2)cc1OC
Yield: 44.3 %

Procedure:
In the same manner as that of Example 24, 4,5-diisopropylfuran-2-carboxylic acid (80 mg, 0.408 mmol) and methyl 2-methoxy-4-aminobenzoate (133 mg, 0.734 mmol) were condensed, the reaction mixture was treated in a conventional manner, and then the residue was purified by silica gel chromatography [hexane-ethyl acetate (5:1)] to obtain methyl 2-methoxy-4-[(4,5-diisopropylfuran-2-carbonyl)amino]benzoate (65 mg, 45%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14]C(=O)C)[CH2:6][CH2:7][C:8](Cl)=[O:9].[NH2:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([OH:24])=[O:23]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[OH:14])[CH2:6][CH2:7][C:8]([NH:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([OH:24])=[O:23])=[O:9]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: COc1cc(CCC(=O)Cl)ccc1OC(C)=O
Product: COc1cc(CCC(=O)Nc2cccc(C(=O)O)c2)ccc1O

Procedure:
In a similar manner except that 3-methoxy-4-acetoxyhydrocinnamoyl chloride was used in place of the 4-acetoxycinnamoyl chloride used in Example 1 for reaction with 3-aminobenzoic acid and the reaction product was hydrolyzed, 3-(3'-methoxy-4'-hydroxyhydrocinnamoylamino)benzoic acid was obtained. After recrystallization from an aqueous alcohol, this product had a melting point of 218°-220° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(C(C)C)CC)(C)C.[F:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36](Cl)=[O:37]>C(Cl)Cl>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:36](=[O:37])[C:35]3[CH:39]=[CH:40][CH:41]=[C:33]([F:32])[CH:34]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1cccc(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cccc(F)c4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.16 mmol) in CH2Cl2 (60 ml), was added diisopropylethylamine (0.94 mL, 5.4 mmol) and 3-fluorobenzoyl chloride (0.45 g, 2.8 mmol). The mixture was stirred at room temperature overnight and a suspension was obtained. The reaction mixture was quenched with MeOH (1 mL) and concentrated in vacuo. The resulting oil was purified by ISCO silica gel flash chromatography (eluent: 3% MeOH in CH2Cl2 for 10 min, then 5% MeOH in CH2Cl2 for 10 min) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-fluoro-benzamide as a white solid (0.7 g, 77%): mp, 215-217° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.2 min. (99%); 1H NMR (DMSO-d6): δ 2.07-2.12 (m, 1H), 2.54-2.65 (m, 2H), 2.87-2.93 (m, 1H), 4.96 (d, J=5.8 Hz, 2H), 5.15-5.21 (dd, J=5, 12 Hz, 1H), 7.39-7.84 (m, 7H), 9.26 (t, J=6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.97, 30.92, 38.40, 48.86, 114.29, 118.49, 121.92, 123.50, 127.15, 130.62, 131.52, 133.09, 134.82, 136.31, 138.97, 163.69, 165.31, 166.94, 167.51, 169.83, 172.74. Anal Calcd for C21H16FN3O5: C, 61.61; H, 3.94; N, 10.26; F, 4.64. Found: C, 61.36; H, 3.84; N, 10.00; F, 4.74.
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:27]([OH:28])=[CH:26][C:20]4[N:21]([CH3:25])[C:22](=[O:24])[O:23][C:19]=4[CH:18]=3)[C:9]2=[O:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:36]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:30]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4=[CH:18][C:19]5[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=5[CH:26]=[C:27]4[O:28][CH2:36]3)[C:9]2=[O:29])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Cn1c(=O)oc2cc(C3C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)c(O)cc21
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: Cn1c(=O)oc2cc3c(cc21)OCC31C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 6-[1-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-3-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,3H)-dione was obtained (40%) as a colorless solid: mp 228-229° C. (ethyl acetate); 1H NMR (300 MHz, CDCl3) δ7.42-7.28 (m, 10H), 7.15-6.96 (m, 4H), 6.60 (s, 1H), 6.55 (d, J=7.2 Hz, 1H), 6.44 (s, 1H), 5.04 (d, J=9.0 Hz, 1H), 4.77 (d, J=9.0 Hz, 1H), 3.38 (s, 3H); 13C NMR (75 MHz, CDCl3) δ177.6, 157.7, 155.3, 142.0, 137.7, 137.4, 137.2, 133.2, 132.1, 129.0, 128.9, 128.6, 128.5, 128.3, 128.2, 124.0, 123.5, 122.6, 112.6, 105.4, 92.0, 80.6, 59.1, 58.0, 28.5; MS (ES+) m/z 475.1 (M+1).