Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([F:13])[C:6]([CH3:12])=[N:7]2.C([Sn](CCCC)(CCCC)[C:19]([O:21]CC)=[CH2:20])CCC.Cl>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[F:13][C:5]1[C:6]([CH3:12])=[N:7][C:8]2[C:3]([N:4]=1)=[C:2]([C:19](=[O:21])[CH3:20])[CH:11]=[CH:10][CH:9]=2
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1nc2cccc(Br)c2nc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)c1cccc2nc(C)c(F)nc12
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 63.2 %

Procedure:
A 1-L, three-necked round-bottomed flask equipped with a mechanical stirrer, reflux condenser, nitrogen gas inlet, and a temperature probe was charged with 5-bromo-3-fluoro-2-methylquinoxaline (30 g, 124 mmol), Pd(PPh3)4 (4.31 g, 3.73 mmol), toluene (300 mL), and tributyl(1-ethoxyvinyl)tin (Synthonix, Wake Forest, N.C.; 46.2 mL, 137 mmol), and the resulting mixture was heated under N2 atmosphere at 90° C. for 18 hours. The mixture was cooled to RT, HCl (6.0 N, aq.; 12.45 mL, 74.7 mmol) was added, and the resulting mixture was stirred at RT for 10 min. The mixture was extracted with EtOAc (500 mL). The organic layer was separated and sequentially washed with brine (2×200 mL) and saturated aq. NaHCO3 (100 mL) and then concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-100% DCM/heptane followed by repurification with silica gel, 0-75% EtOAc/heptane) furnished 1-(3-fluoro-2-methylquinoxalin-5-yl)ethanone (126 g; 16.0 g, 78.4 mmol, 63% yield) as an orange solid: 1H NMR (400 MHz, CDCl3) δ ppm 8.20 (1H, dd, J=8.3, 1.3 Hz), 8.10 (1H, dd, J=7.3, 1.1 Hz), 7.77 (1H, t, J=7.8 Hz), 2.92 (3H, s), 2.79 (3H, d, J=1.6 Hz). 19F NMR (377 MHz, CDCl3) δ ppm −69.81 (1F, s). m/z (ESI, +ve) 205.1 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][C@@H:12]([N:14]2[CH2:21][C:20]3[C:16](=[N:17][N:18]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:19]=3)[CH2:15]2)[CH2:11][O:10][C@@H:9]1[C:26]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:27]=1[F:34])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:34][C:27]1[CH:28]=[C:29]([F:33])[C:30]([F:32])=[CH:31][C:26]=1[C@@H:9]1[C@@H:8]([NH2:7])[CH2:13][C@@H:12]([N:14]2[CH2:21][C:20]3[C:16](=[N:17][N:18]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:19]=3)[CH2:15]2)[CH2:11][O:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2Cc3cn(S(C)(=O)=O)nc3C2)CO[C@@H]1c1cc(F)c(F)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)n1cc2c(n1)CN([C@H]1CO[C@H](c3cc(F)c(F)cc3F)[C@@H](N)C1)C2
Reaction time: 2 h

Procedure:
Intermediate obtained in Step A above (379 mg, 0.734 mmol) in dichloromethane (20 mL) was treated with trifluoroacetic acid (10 mL) at room temperature. After 2 h, the reaction was concentrated and the crude material was purified on a silica gel column (40S Biotage™) eluting with in 0-2% methanol, containing 10% NH4OH, in dichloromethane to give the title compound as a white solid. 1H NMR (500 MHz, CD3OD): δ 1.50 (q, 1H, J=12 Hz); 2.43-2.49 (m, 1H); 2.88 (td, 1H, J=12, 6 Hz); 3.11-3.18 (m, 1H); 3.34 (s, 3H); 3.40 (t, 1H, J=12 Hz); 3.48-3.92 (m, 4H); 4.23-4.28 (m, 2H); 7.14-7.20 (m, 1H); 7.36-7.42 (m, 1H); 7.86 (s, 1H). LC-MS: 417.12 (M+1).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:10](Cl)=[O:11].[CH3:18][C:19]1[NH:20][CH:21]=[C:22]([CH3:24])[CH:23]=1>ClCCl.C(OCC)(=O)C>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:10]([C:21]2[NH:20][C:19]([CH3:18])=[CH:23][C:22]=2[CH3:24])=[O:11])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: Cc1c[nH]c(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)c2[nH]c(C)cc2C)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.6 %

Procedure:
Aluminum chloride (1.7 g, 12.75 mmol) in dichloromethane (100 mL) was added to the 3,4-dimethoxybenzoyl chloride (2.0 g, 10 mmol) at room temperature, followed by a solution of 2,4-dimethylpyrrole (1.5 g, 15.8 mmol) in dichloromethane (5 mL). The mixture was then stirred at room temperature for overnight. The reaction was diluted with ethyl acetate, washed with brine, dried and concentrated. The residue was chromatographed eluting with ethyl acetate and hexane to give 1 g (39%) of (3,4-dimethoxy-phenyl)-(3,5-dimethyl-1H-pyrrol-2-yl)-methanone as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:22])=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:8].C[Li].C([Li])(C)(C)C.[CH2:30]1[O:32][CH2:31]1>O1CCCC1>[Cl:22][C:5]1[CH:4]=[CH:3][C:2]([CH2:30][CH2:31][OH:32])=[CH:21][C:6]=1[C:7]([NH:9][CH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:8]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Br)ccc1Cl
Reactant: C1CO1
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCO)ccc1Cl
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-bromo-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (3.0 g, Example 23a) in anhydrous tetrahydrofuran (100 ml) was cooled to −78° C. under a nitrogen atmosphere. A solution of methyllithium (1.4M in diethyl ether, 4.9 ml) was added over 2 min. The mixture was stirred at −78° C. for 10 min., then a solution tert-butyllithium (1.7M in pentane, 9.3 ml) was added dropwise. The mixture was stirred at −78° C. for a further 10 min., then ethylene oxide (1.0 ml) was added. The resulting solution was stirred at −78° C. for 30 min. then was warmed to 0° C. and stirred for another 6 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (70 ml) and extracted with ethyl acetate (3×100 ml). The combined extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by chromatography over silica gel eluting with dichloromethane:ethanol (98:2) to give the subtitle compound as a pale yellow solid (0.89 g).
Reaction SMILES: N[C:2]1[C:7]([Br:8])=[N:6][C:5]([Br:9])=[CH:4][N:3]=1.S(=O)(=O)(O)[OH:11].N([O-])=O.[Na+]>>[Br:8][C:7]1[C:2](=[O:11])[NH:3][CH:4]=[C:5]([Br:9])[N:6]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1ncc(Br)nc1Br
Agent: O=N[O-]
Agent: [Na+]
Product: O=c1[nH]cc(Br)nc1Br
Temperature: 20 °C
Reaction time: 15 h

Procedure:
A solution of 12.65 g of 2-amino-3,5-dibromo-pyrazine and 18.5 ml of 96% sulfuric acid is added dropwise to a solution of 3.45 g of sodium nitrite and 27.5 ml of 96% sulfuric acid at 0° to 5° C. The mixture is then allowed to warm to 20° C. in the course of 2 hours and is stirred at 20°-25° C. for a further 15 hours. The reaction mixture is poured into ice and the product is filtered off, washed with ice-water and dried to give 5.8 g of 3,5-dibromo-pyrazin-2-one.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([O:9][C:10]([NH:12][OH:13])=[O:11])([CH3:8])([CH3:7])[CH3:6]>>[C:1]([O:13][NH:12][C:10]([O:9][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:11])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NO
Reactant: CC(=O)Cl
Product: CC(=O)ONC(=O)OC(C)(C)C

Procedure:
[(tert-Butoxy)carbonyl]amino acetate is prepared from acetyl chloride and N-tert-butoxycarbonyl hydroxylamine according to Scheme 1 and the method described by Carpino et al. J. Am. Chem. Soc. 1959, 955-957. (10 g, 100%), 1H NMR (500 MHz, DMSO-d6) δ ppm 10.57 (1H, br. s.), 2.10 (3H, s), 1.41 (9H, s).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[CH2:17][CH2:16][C@@H:15]([CH2:18][C:19](=[O:38])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][NH2:28])=[CH:23][C:22]=3[CH2:29][CH2:30][CH:31](C(O)=O)[C:32]([OH:34])=[O:33])[N:7]3[C:8](=[O:14])[C:9](=[O:13])[NH:10][C:11]([CH:12]=1)=[C:6]23.Cl>C(O)(=O)C>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]2[CH2:17][CH2:16][C@@H:15]([CH2:18][C:19](=[O:38])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][NH2:28])=[CH:23][C:22]=3[CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[N:7]3[C:8](=[O:14])[C:9](=[O:13])[NH:10][C:11]([CH:12]=1)=[C:6]23
Reactant: NCc1ccc(NC(=O)C[C@@H]2CCc3cc(Cl)cc4[nH]c(=O)c(=O)n2c34)c(CCC(C(=O)O)C(=O)O)c1
Agent: Cl
Solvent: CC(=O)O
Product: NCc1ccc(NC(=O)C[C@@H]2CCc3cc(Cl)cc4[nH]c(=O)c(=O)n2c34)c(CCCC(=O)O)c1
Yield: 176.1 %

Procedure:
A suspension of (S)-9-chloro-5-[p-aminomethyl-o-(3,3-dicarboxypropyl)phenylcarbamoylmethyl]-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione hydrochloride (550 mg, 0.98 mmol) in acetic acid (300 mL) was refluxed for 5 h. To the mixture was added 0.5N hydrochloric acid and the solvent was removed in vacuo. The residual solid was recrystallized from water to give 450 mg of the title compound (89%).
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].C[O-].[Na+].[O:8]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[O:21][CH:20]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:19]/[C:18]/2=[N:31]/[C:32]#[N:33])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CO>[CH3:2][N:3]1[C:32]([NH2:33])=[N:31][C:18]2([C:17]3[C:22](=[CH:23][CH:24]=[C:15]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:16]=3)[O:21][CH:20]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:19]2)[O:4]1
Reactant: N#C/N=C1/CC(c2ccccc2)Oc2ccc(Oc3ccccc3)cc21
Reactant: CNO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1OC2(CC(c3ccccc3)Oc3ccc(Oc4ccccc4)cc32)N=C1N
Reaction time: 0.17 h
Yield: 51.6 %

Procedure:
To a solution of methylhydroxylamine HCl salt (83.6 mg, 1 mmol) in anhydrous MeOH (11 mL) was added NaOMe (25% in MeOH (Wt. %), 0.2 mL, 0.9 mmol), followed by (Z)—N-(6-phenoxy-2-phenylchroman-4-ylidene)cyanamide (340 mg, 1 mmol). After stirring for 10 min, the solvent was removed in vacuo. The residue was redissolved in DCM (30 mL). The mixture was filter, and the solvent was removed to give the residue, which was purified by column chromatography to give 2′-methyl-6-phenoxy-2-phenyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (200 mg, 52%). 1H-NMR (CDCl3): 2.41-2.66 (m, 1H), 2.65 (m, 1H), 2.75 (m, 1H), 3.32 (m, 3H), 5.35 (m, 1H), 6.95 (m, 2H), 7.06 (m, 1H), 7.20 (m, 2H), 7.42 (m, 3H), 7.48 (m, 3H), 7.51 (m, 2H).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.OS(O)(=O)=O.[N:16]([O-])=[O:17].[Na+]>C(Cl)Cl>[N:16]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:17]
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=NN1CCCc2ccccc21
Reaction time: 1.5 h

Procedure:
To a stirred solution of 1,2,3,4-tetrahydroquinoline (10.0 g, 75.08 mmol) in 150 mL CH2Cl2 was added 150 mL 1M H2SO4, followed by NaNO2 (5.70 g, 82.59 mmol). The reaction was stirred for 1.5 hours. The reaction mixture was partitioned, the organic layer retained, washed with a saturated solution of NaCl (aqueous), dried over Na2SO4 and concentrated to give the product (13.4 g 100%) as a dark oil. 1H-NMR (300 MHz, CDCl3): δ 8.08 (d, 1H), 7.28 (m, 3H), 3.92 (m, 2H), 2.82 (m, 2H), 2.03 (m, 2H) ppm; MS m/z calculated for C9H10N2O (M+H): 163.09. Found: 163.1 (M+, ESI+).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[C:7]([OH:8])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]>[Ag]=O.CCOCC>[C:1]([C:5]1[C:6](=[O:16])[C:7](=[O:8])[CH:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(O)c(O)c(C(C)(C)C)c1
Agent: O=[Ag]
Solvent: CCOCC
Product: CC(C)(C)C1=CC(=O)C(=O)C(C(C)(C)C)=C1
Reaction time: 0.5 h

Procedure:
To a solution of 5 g.(22.5 mmol.) of 3,5-di-t-butylcathechol in 75 ml. of ether at 0° was added 25 g. of silver oxide. The reaction mixture was stirred at 0° for 30 minutes then at ambient temperature for an additional 30 minutes. The mixture was filtered and the filtrate was evaporated to dryness. Benzene was added to the residue and the resulting precipitate was collected by filtration and air dried to give 3,5-di-t-butyl-1,2-dioxobenzene, m.p. 110°-112°.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[CH2:13]([O:15][C:16]1[C:17](=O)[C:18](=[O:23])[C:19]=1[O:20]CC)[CH3:14]>C(O)C>[CH2:13]([O:15][C:16]1[C:19](=[O:20])[C:18](=[O:23])[C:17]=1[NH:8][C:7]1[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=1)[CH3:14]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(Nc2ccc(OC(F)(F)F)cc2)c(=O)c1=O
Yield: 53 %

Procedure:
4-Trifluoromethoxyaniline (5.00 g, 28.2 mmol) was added to a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (5.00 g, 29.4 mmol) in absolute ethanol (50 mL). The mixture was heated at reflux overnight, then vacuum filtered hot. The filtrate was reduced in volume and the resulting precipitate was filtered to afford 4.50 g (53%) of white solid: mp 145°-146° C.; 1H NMR (DMSO-d6): δ 10.87 (s, 1H), 7.45 (d, 2H), 7.36 (d, 2H), 4.75 (q, 2H), 1.41 (t, 3H).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:31]=[CH:30][C:10]2[C@@H:11]3[C@H:16]([CH2:17][CH2:18][C:9]=2[CH:8]=1)[N:15]([C:19]([C:21]1[CH:29]=[CH:28][C:24]2[NH:25][CH:26]=[N:27][C:23]=2[CH:22]=1)=[O:20])[CH2:14][CH2:13][CH2:12]3)=[O:6]>O1CCCC1>[NH:25]1[C:24]2[CH:28]=[CH:29][C:21]([C:19]([N:15]3[C@@H:16]4[C@@H:11]([C:10]5[CH:30]=[CH:31][C:7]([C:5]([OH:6])=[O:4])=[CH:8][C:9]=5[CH2:18][CH2:17]4)[CH2:12][CH2:13][CH2:14]3)=[O:20])=[CH:22][C:23]=2[N:27]=[CH:26]1
Reactant: COC(=O)c1ccc2c(c1)CC[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)CC[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1 M aqueous NaOH solution (15 mL) is added to a solution of cis-4-(1H-benzoimidazole-5-carbonyl)-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline-8-carboxylic acid methyl ester (1.60 g) in tetrahydrofuran (15 mL) at room temperature. The resulting solution is stirred at room temperature for 5 h. The solution is concentrated under reduced pressure and water (100 mL) is added to the residue. 1 M Aqueous hydrochloric acid (15 mL) is then added and the precipitate formed is separated by filtration. The precipitate is washed with water and diethyl ether and dried to afford the title compound as a solid. Yield: 1.24 g (80% of theory); LC (method 1): tR=2.09 min; Mass spectrum (ESI+): m/z=376 [M+H]+.
Reaction SMILES: O[CH:2]([C:4]1[C:12]2[O:11][CH2:10][CH:9]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[C:8]=2[C:7]([CH3:22])=[C:6]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:5]=1[CH3:31])[CH3:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:19]([C:16]1[CH:17]=[CH:18][C:13]([CH:9]2[C:8]3[C:7]([CH3:22])=[C:6]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:5]([CH3:31])=[C:4]([CH:2]=[CH2:3])[C:12]=3[O:11][CH2:10]2)=[CH:14][CH:15]=1)([CH3:20])[CH3:21]
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1C(C)O)OCC2c1ccc(C(C)C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=Cc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Temperature: 80 °C
Yield: 89 %

Procedure:
A solution of N-(7-(1-hydroxyethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (1.23 g, 3.02 mmol) obtained in Example 22 and p-toluenesulfonic acid monohydrate (20 mg) in toluene (20 mL) was refluxed with heating at 80° C. for 1 hour under an argon atmosphere. The reaction solution was washed with an aqueous saturated sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9) to obtain 1.09 g (yield: 89%) of the title compound. Melting point: 171-172° C. (hexane-ethyl acetate).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([OH:27])=O)[CH:4]=[N:3]1.Cl.[F:29][CH:30]1[CH2:33][NH:32][CH2:31]1.C(N(C(C)C)CC)(C)C.CCCP(=O)=O>O1CCCC1>[F:29][CH:30]1[CH2:33][N:32]([C:25]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[C:7]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[O:24])=[O:27])[CH2:31]1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Reactant: FC1CNC1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)N2CC(F)C2)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 95.9 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 μmol), 3-fluoroazetidine hydrochloride (30.8 mg, 276 mmol), diisopropylethylamine (241 μl, 1.38 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 407 μl, 690 μmol) in tetrahydrofurane (7 ml) is stirred for 3 hours at 70° C. under nitrogen atmosphere in a closed vessel and then over the weekend at room temperature. The solvent is evaporated and to the residue is added sat. aqueous sodium hydrogencarbonate solution. The mixture is stirred for 20 minutes while a white solid precipitates. The solid is collected by filtration, washed with diethylether and dried affording 4-(3-fluoroazetidine-1-carbonyl)-1-methyl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide (111 mg, 93.3%) as an insoluble white solid. mp.: 259-262° C. MS: m/z=420.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([N:13]([C:15]3[CH:28]=[CH:27][C:18]([O:19][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=3)[CH3:14])[N:8]=[C:9]2O)=[CH:4][CH:3]=1.P(Br)(Br)([Br:31])=O>>[Br:31][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2)[CH:6]=[C:7]([N:13]([C:15]2[CH:28]=[CH:27][C:18]([O:19][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=2)[CH3:14])[N:8]=1
Reactant: CCOC(=O)C(C)Oc1ccc(N(C)c2cc3ccc(Cl)cc3c(O)n2)cc1
Reactant: O=P(Br)(Br)Br
Product: CCOC(=O)C(C)Oc1ccc(N(C)c2cc3ccc(Cl)cc3c(Br)n2)cc1
Temperature: 120 °C

Procedure:
A mixture of ethyl 2-{4-[N-(7-chloro-1-hydroxyisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (1.00 g) and phosphorus oxybromide was heated at 120° C. for 10 mins. The mixture was cooled, poured into ice-water and extracted with dichloromethane, which was dried (MgSO4) and evaporated to give an oil. Purification by column chromatography over silica gel (eluant dichloromethane) gave ethyl 2-{4-[N-(1-bromo-7-chloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (0.83 g) as a yellow oil.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:25]([C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>O1CCCC1>[C:25]([C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:37])=[CH:31][CH:30]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 4-tert-butylphenyl isocyanate (0.214 ml, 1.22 mmol), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 235 mg (68.7%) of the desired product as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:12]([C:13](=[O:30])[CH2:14][NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][C:26]([O:28]C)=[O:27])[CH:20]=2)=[O:17])[CH:11]([C:31](=[O:37])[NH:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:10][CH:9]1[C:38]([O:40]C)=[O:39].[OH-].[K+]>O.CO>[C:26]([CH2:25][C:21]1[CH:20]=[C:19]([NH:18][C:16](=[O:17])[NH:15][CH2:14][C:13]([N:12]2[CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH:9]([C:38]([OH:40])=[O:39])[CH2:10][CH:11]2[C:31](=[O:37])[NH:32][CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])[CH:24]=[CH:23][CH:22]=1)([OH:28])=[O:27]
Reactant: COC(=O)Cc1cccc(NC(=O)NCC(=O)N2C(C(=O)NCC(C)C)CC(C(=O)OC)C2c2ccccc2F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)CNC(=O)C1CC(C(=O)O)C(c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(CC(=O)O)c1
Yield: 54 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 3, but from 3.7 g of methyl (2RS,4RS,5SR)-5-(2-fluorophenyl)-2-isobutylcarbamoyl-1-{2-[3-(3-(methoxycarbonylmethyl)phenyl)ureido]acetyl}pyrrolidine-4-carboxylate and 0.56 g of potassium hydroxide in a mixture of 20 cm3 of distilled water and 60 cm3 of methanol. After treatment, there are obtained 1.9 g of (2RS,4SR,5SR)-1-{2-[3-(3-(carboxymethyl)phenyl)ureido]acetyl}-5-(2-fluorophenyl)-2-(isobutylcarbamoyl)pyrrolidine-4-carboxylic acid Rf =0.155 eluant: methylene chloride/methanol (90/10)].
Reaction SMILES: NN.[NH2:3][C:4]1[C:13]2[N:14]=[CH:15][N:16]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][N:22]3C(=O)C4C(=CC=CC=4)C3=O)[C:12]=2[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=1>C(O)C>[NH2:22][O:21][CH2:20][CH2:19][CH2:18][CH2:17][N:16]1[C:12]2[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[N:5]=[C:4]([NH2:3])[C:13]=2[N:14]=[CH:15]1
Reactant: Nc1nc2c(c3c1ncn3CCCCON1C(=O)c3ccccc3C1=O)CCCC2
Agent: NN
Solvent: CCO
Product: NOCCCCn1cnc2c(N)nc3c(c21)CCCC3
Reaction time: 8 h
Yield: 135 %

Procedure:
Anhydrous hydrazine (94 mg, 2.96 mmol) was added to 2-[4-(4-amino-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl)butoxy]-1H-isoindole-1,3(2H)-dione (600 mg, 1.48 mmol) in ethanol (25 mL) at ambient temperature. The reaction was stirred overnight, and additional hydrazine (2 equivalents) was added. After sting for 2 hours at ambient temperature, the reaction was concentrated under reduced pressure. The residue was diluted with dichloromethane and concentrated under reduced pressure three times to remove the hydrazine and then dried under vacuum to provide 550 mg of impure 1-[4-(aminooxy)butyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin4-amine as an orange solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH:29]([O:32][C:33]1[NH:37][C:36]2[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=2[N:34]=1)([CH3:31])[CH3:30]>>[CH:29]([O:32][C:33]1[N:34]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]4)[N:8]3[CH3:11])=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:3]=2)[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1)([CH3:31])[CH3:30]
Reactant: CC(C)Oc1nc2ccccc2[nH]1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: CC(C)Oc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and 2-isopropoxy-1H-benzo[d]imidazole were reacted to give 338. LCMS: M+H+=549.3