Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[O:8][C:9]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].Cl.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30]Cl>CN(C)C=O>[N:1]1([C:7]2[O:8][C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:30][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)=[CH:16][CH:15]=3)=[CH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: ClCc1ccccn1
Reactant: O=c1cc(-c2ccc(O)cc2)oc(N2CCOCC2)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2ccc(OCc3ccccn3)cc2)oc(N2CCOCC2)c1
Temperature: 55 °C
Reaction time: 4 h
Yield: 34 %

Procedure:
2-Morpholinyl-6-(4-hydroxyphenyl)-4-pyrone, as prepared in Example 5, (273 mg, 1.0 mmole) was suspended in 6 ml dimethylformamide in a 25 ml one neck round bottom flask under nitrogen. The suspension was treated with sodium hydride suspension (192 mg, 4.0 mmole) and the reaction mixture was warmed to 55° C. for 40 minutes. The reaction was treated with 2-picolyl chloride hydrochloride (492 mg, 3.0 mmole) and the mixture was stirred 4 hours at 55° C. The reaction was poured into 50 ml 2N sodium hydroxide/ice and the precipitated solid was collected, washed with water and diethyl ether and was dried (188 mg). The crude material was recrystallized from ethyl acetate to give 123 mg (34%) of Compound 6 as an off-white solid.
Reaction SMILES: BrC1C=CC(O)=C([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[CH3:37][C:38]1[C:42](C(=O)C)=[C:41]([CH3:46])[N:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[N:39]=1.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:42]2[C:38]([CH3:37])=[N:39][N:40]([C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=4)[C:41]=2[CH3:46])[CH:17]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CC(=O)c1c(C)nn(-c2ccccc2)c1C
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(-c2ccccc2)c(C)c1-c1ccc2cc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)ccc2n1
Yield: 37 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (47 mg, 37% yield).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[C:6]([O:10][C:11]([O:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl>[C:17]([O:16][C:15]([N:14]([O:13][C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])[C:1](=[O:4])[CH:2]=[CH2:3])=[O:21])([CH3:20])([CH3:19])[CH3:18]
Reactant: C=CC(=O)Cl
Reactant: CC(C)(C)OC(=O)NOC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N(OC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
A solution of acryloyl chloride (700 μL; 779.8 mg; 8.6 mmole) dissolved in dry dichloromethane (20 mL) was cooled at 0° C. with an ice bath. A mixture of tert-butyl N-(tert-butoxycarbonyloxy)carbamate (31) (2.0038 g; 8.6 mmole) and triethylamine (1.32 mL; 958.3 mg; 9.5 mmole) in dry dichloromethane (20 mL) was slowly added over a period of 1 hour to the cooled solution. The ice bath was removed after 4 hours and the reaction mixture was left stirring overnight while its temperature warmed up gradually to room temperature. Water (100 mL) was added to the reaction and the layers were separated. The organic solution was washed with a 10% ammonium chloride solution (3×80 mL), water (2×100 mL), and finally brine (1×100 mL). The organic layer was then dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure. The residue was purified by flash chromatography using a mixture of hexane and ethyl acetate (90:10) to elute the product. The purification gave 690 mg (28%) of N-(tert-butoxycarbonyl),N-(tert-butoxycarbonyloxy)acrylamide (32) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[Cl-:12].[NH2:13][N+:14]1[CH:18]=[CH:17][N:16]([NH2:19])[C:15]=1[CH2:20][CH2:21][CH3:22]>C(O)(=O)C>[Cl-:12].[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:13][N+:14]2[CH:18]=[CH:17][N:16]([N:19]=[CH:7][C:6]3[CH:9]=[CH:10][C:3]([N:2]([CH3:11])[CH3:1])=[CH:4][CH:5]=3)[C:15]=2[CH2:20][CH2:21][CH3:22])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CCCc1n(N)cc[n+]1N
Agent: [Cl-]
Solvent: CC(=O)O
Product: CCCc1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Reaction time: 48 h

Procedure:
1.49 g (10 mmol) of 4-dimethylamino-benzaldehyde are added to a solution of 0.88 g (5 mmol) of 1,3-diamino-2-propyl-imidazolium chloride in 15 ml of glacial acetic acid. After leaving to stand at room temperature for 2 days the product is crystallized out by the addition of ether and then recrystallized from ethanol. There is obtained 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-propyl-imidazolium chloride of melting point 252°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26]([OH:28])=O)=[CH:21][CH:20]=[CH:19]2.[F:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[C:32]([NH2:37])[CH:31]=1>>[NH2:37][C:32]1[CH:31]=[C:30]([F:29])[CH:35]=[CH:34][C:33]=1[NH:36][C:26]([C:22]1[C:23]2[C:18](=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:25][CH:24]=2)[CH:19]=[CH:20][CH:21]=1)=[O:28]
Reactant: COc1cc2nccc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Reactant: Nc1ccc(F)cc1N
Product: COc1cc2nccc(Oc3ccc4c(C(=O)Nc5ccc(F)cc5N)cccc4c3)c2cc1OC
Yield: 80.9 %

Procedure:
The title compound (39.1 mg, 81% yield) was prepared as a brown solid from 6-(6,7-dimethoxyquinolin-4-yloxy)-1-naphthoic acid (37.5 mg, 0.1 mmol) and 4-fluoro-o-phenylenediamine (15.1 mg, 0.12 mmol) by an analogous procedure to that described in example 16. 1H NMR (DMSO-d6) δ 3.93 (s, 3H, —OCH3), 3.95 (s, 3H, —OCH3), 5.31 (s, 2H, benzene-NH2), 6.40 (s, 1H, Ar—H), 6.55-6.59 (m, 2H, Ar—H), 7.30 (d, J=7.6 Hz, 1H, Ar—H), 7.42 (s, 1H, Ar—H), 7.54-7.57 (m, 2H, Ar—H), 7.64 (t, J=8.0 Hz, 1H, Ar—H), 7.89-7.91 (m, 2H, Ar—H), 8.07 (d, J=8.0 Hz, 1H, Ar—H), 8.42 (d, J=9.2 Hz, 1H, Ar—H), 8.49 (d, J=5.2 Hz, 1H, Ar—H), 9.79 (s, 1H, benzene-NH). LC-MS (m/z) 484 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.[CH2:8](O)[CH2:9][OH:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[O:7]1[CH2:8][CH2:9][O:10][CH:6]1[C:3]1[CH:4]=[CH:5][S:1][CH:2]=1
Reactant: OCCO
Reactant: O=Cc1ccsc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: c1cc(C2OCCO2)cs1
Temperature: 25 °C

Procedure:
A solution of 28.04 g (250 mmol) of 3-thiophenecarboxaldehyde, 20.2 g (330 mmole) of ethyleneglycol, 10 mg (0.05 mmole) of p-toluenesulfonic acid monohydrate and 25 ml of benzene was heated to reflux untill the calculated amount of water was removed via a Dean-Stark trap (5 hours). The reaction mixture was allowed to cool to room temperature and was washed with 30 ml of saturated NaHCO3 solution. The organic layer was dried over MgSO4 and the solvent was removed by evaporation to give the title compound as a clear colorles oil.
Reaction SMILES: [CH:1](=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[CH2:14](I)[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:11][O:10][C:9]1[CH:12]=[C:2]([CH:3]=[C:4]([O:5][CH3:6])[C:7]=1[O:8][CH2:14][CH3:15])[CH:1]=[O:13]
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1c(OC)cc(C=O)cc1OC
Yield: 102.1 %

Procedure:
A mixture of syringaldehyde (50 g, 0.275 mol), ethyl iodide (85.8 g, 0.55 mol) and potassium carbonate (151.7 g, 1.09 mol) in DMF (60 ml) was stirred and heated at 60°-70° for 6 h. The mixture was cooled and evaporated in vacuo then treated with water and extracted with diethyl ether. The extracts were dried (Na2SO4) and evaporated to give the title compound (59 g) as a white solid, pure by tlc, and used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH:23]2[CH2:24][CH2:25][CH:19]1[CH2:20][NH:21][CH2:22]2)=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([O:15][C:16]([N:18]1[CH:19]2[CH2:25][CH2:24][CH:23]1[CH2:22][N:21]([C:8]([C:5]1[N:6]=[N:7][C:2]([NH2:1])=[CH:3][CH:4]=1)=[O:10])[CH2:20]2)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Reactant: Nc1ccc(C(=O)O)nn1
Product: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)c1ccc(N)nn1)C2
Yield: 51 %

Procedure:
Following general amide formation method 1, 6-amino-pyridazine-3-carboxylic acid (212 mg, 1.0 mmol) was combined with 3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (139 mg, 1.0 mmol), which gave 3-(6-Amino-pyridazine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester as a white solid (169 mg, 0.51 mmol) in 51% yield. MS m/z 334.4 (M+H)+.
Reaction SMILES: O[CH:2]([C:4]1[CH:17]=[CH:16][C:7]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:10][C:6]=2[CH:5]=1)[CH3:3].C1(P([N:32]=[N+:33]=[N-:34])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1.[N-]=[N+]=[N-]>C1(C)C=CC=CC=1>[N:32]([CH:2]([C:4]1[CH:17]=[CH:16][C:7]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:10][C:6]=2[CH:5]=1)[CH3:3])=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1cc2ccc(C(C)O)cc2s1
Agent: [N-]=[N+]=[N-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2ccc(C(C)N=[N+]=[N-])cc2s1
Reaction time: 24 h

Procedure:
To a solution of ethyl 6-(1-hydroxyethyl)-1-benzothiophene-2-carboxylate (2.0 g, 8.06 mmol) in toluene (30 mL) was added diphenylphosphorylazide (2.64 g, 9.58 mmol), then DBU (1.31 mL, 8.79 mmol) dropwise. After 24 h, added more azide (0.5 mL) and DBU (0.3 mL) to the thick solution. After an additional 24 h, the reaction mixture was concentrated and purified via column chromatography yielding the desired product. 1H NMR (CDCl3, 600 MHz) δ 8.03 (d, J=0.9 Hz, 1H), 7.87 (d, J=8.2 Hz, 1H), 7.81 (m, 1H), 7.36 (dd, J=8.2, 0.9 Hz, 1H), 4.75 (q, J=6.8 Hz, 1H), 4.40 (q, J=7.3 Hz, 2H), 1.58 (d, J=6.8 Hz, 3H), 1.41 (t, J=7.3 Hz, 3H). MS: cal'd 276 (MH+), exp 276 (MH+).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12]C(Cl)=O.[C:16](=[N:19][OH:20])([NH2:18])[CH3:17]>N1C=CC=CC=1>[CH3:17][C:16]1[N:18]=[C:12]([N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])[O:20][N:19]=1
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Reactant: CC(N)=NO
Solvent: c1ccncc1
Product: Cc1noc(N2C(=O)c3ccccc3C2=O)n1
Yield: 26.6 %

Procedure:
To 4.4 g of (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride in 20 ml of pyridine are added 1.48 g of acetamidoxime, and the mixture is refluxed for 1 hour. The reaction medium is concentrated and taken up in ethyl acetate and water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a 7/3 (v/v) toluene/ethyl acetate mixture to give 1.2 g of expected product.
Reaction SMILES: [CH:1]1([N:4]([CH3:27])[C:5]2[C:6](OS(C(F)(F)F)(=O)=O)=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=3)[CH2:3][CH2:2]1.[O:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[CH:30]=[C:29]1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[O:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[CH:30]=[C:29]1[C:6]1[C:5]([N:4]([CH:1]2[CH2:3][CH2:2]2)[CH3:27])=[N:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=2)[N:7]=1
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N(C)C3CC3)nc2c1
Reactant: OB(O)c1cc2ccccc2o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3cc4ccccc4o3)c(N(C)C3CC3)nc2c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-(cyclopropyl(methyl)amino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (180.0 mg, crude) in dioxane (6 mL) was added benzofuran-2-ylboronic acid (149.0 mg, 0.92 mmol), K3PO4 (195.0 mg, 0.92 mmol), Pd(PPh3)4 (30.0 mg, 0.03 mmol) and water (3 drops). The resulting solution was stirred for 1 h at 90° C. and then concentrated under vacuum to give a residue, which was purified by a silica gel column (5%-20% ethyl acetate in petroleum ether) to afford methyl 2-(benzofuran-2-yl)-3-(cyclopropyl(methyl)amino)quinoxaline-6-carboxylate as a yellow solid (95.0 mg, 39% 2 steps).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11](O)[C:10]=1[N+:17]([O-:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O>[Cl-].C[N+](C)(C)C>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([Cl:22])[C:10]=1[N+:17]([O-:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(NCc2ccccc2)c([N+](=O)[O-])c(O)n1
Agent: C[N+](C)(C)C
Agent: [Cl-]
Product: Cc1cc(NCc2ccccc2)c([N+](=O)[O-])c(Cl)n1

Procedure:
Heat a solution of 4-benzylamino-6-methyl-3-nitro-pyridin-2-ol (13.70 g, 52.8 mmol) and tetramethylammonium chloride (6.0 g, 52.8 mmol) to reflux in phosphorus oxychloride (15 mL) for 5 h. After cooling, remove the excess phosphorus oxychloride in vacuo. Triturate the residue in ice-water (400 mL) to obtain the title compound as a brown solid.
Reaction SMILES: Cl.[Br:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[CH2:13]([O:20][C:21]([NH:5][CH2:4][CH2:3][Br:2])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCBr
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCBr)OCc1ccccc1
Reaction time: 19 h

Procedure:
To a solution of 2-bromoethylamine hydrochloride (25 g: a product of Tokyo Kasei Kogyo Co., Ltd.) and triethylamine (34 ml) in methylene chloride (450 ml), benzyloxycarbonyl chloride (19 ml) was added dropwise over a period of 20 minutes and the mixture was agitated at room temeprature for 19 hours. The resulting reaction mixture was washed with water, with saturated aqueous sodium bicarbonate solution and with saturated aqueous sodium chloride succeedingly, whereupon the separated organic layer was dried and, then, removed off the solvent by distilling it of under reduced pressure. The residue was cooled with ice and the crystals were collected by filtration and washed with hexane, whereby the above-identified compound was obtained (29.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[N:14][CH:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[C:10](=O)[CH2:9]1.[C:26]([NH:29][NH2:30])([NH2:28])=[NH:27].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[N:14][CH:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[C:10](=[N:30][NH:29][C:26]([NH2:28])=[NH:27])[CH2:9]1
Reactant: N=C(N)NN
Reactant: O=C1CC(c2ccccc2Cl)Cc2nncc(-c3ccc(Cl)cc3)c21
Agent: Cl
Solvent: O
Solvent: CCO
Product: N=C(N)NN=C1CC(c2ccccc2Cl)Cc2nncc(-c3ccc(Cl)cc3)c21
Yield: 115.5 %

Procedure:
To a solution of 7-(2-chlorophenyl)-4-(4-chlorophenyl)-5,6,7,8-tetrahydrocinnolin-5-one (0.18 g) and aminoguanidine hydrochloride (65 mg) in ethanol (10 ml) were added concentrated hydrochloric acid (0.12 ml) and water (0.12 ml), and the mixture was refluxed for 6 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added sodium hydrogen carbonate solution to make the solution alkaline. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate-methanol). The resulting crystals were dissolved in 1N hydrochloric acid (1 ml), and the solution was concentrated. The residue was recrystallized from ethanol-ethyl acetate to give 7-(2-chlorophenyl)-4-(4-chlorophenyl)-5-guanidinoimino-5,6,7,8-tetrahydrocinnoline hydrochloride (Compound 145) (0.13 g) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:10]([O:12]C)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O.OO.Cl>CO.O>[CH2:1]([O:8][C@@H:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](CC(C)C)OCc1ccccc1
Agent: Cl
Agent: OO
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CC(C)C[C@H](OCc1ccccc1)C(=O)O
Reaction time: 24 h

Procedure:
To the above methyl(2S)-2-benzoxy-4-methylpentanoate (0.69 g, 2.92 mmol) in MeOH/H2O (5 mL/1 mL) was added LiOH.H2O (0.28 g, 11.7 mmol) and 30% H2O2 (0.3 mL, 11.7 mmol). After stirring the reaction mixture for 24 h, the mixture was treated with 1 N HCl (pH=3) and the methanol was removed in vacuo. The aqueous layer was extracted with EA (4×15 mL). The combined organic layers were washed with 1 N HCl (2×10 mL), sat. NaCl (2×10 mL), dried (MgSO4), filtered and concentrated. (2S)-2-benzoxy-4-methylpentanoic acid was isolated as a colorless oil (0.65 g, 100%): 1H NMR (CDCl3, 300 MHz) δ 0.82-1.60 (m, 6H), 1.53-1.62 (m, 1H), 1.73-1.90 (m, 2H), 3.99-4.50 (m, 1H), 4.46 (d, 1H, J=12.0 Hz), 4.72 (d, 1H, J=12.0 Hz) 7.10-7.26 (m, 5H) ppm.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH2:31][C:30](=[O:32])[NH:29][N:28]=2)=[CH:23][CH:22]=1.[H-].[Na+]>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][O:17][CH3:18])[N:5]=[CH:4][N:3]=[C:2]2[O:32][C:30]1[CH:31]=[C:27]([C:24]2[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[NH:28][N:29]=1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Reactant: COc1ccc(C2=NNC(=O)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1cc2ncnc(Oc3cc(-c4ccc(OC)cc4)[nH]n3)c2cc1OC
Yield: 59.2 %

Procedure:
Using an analogous procedure to that described for Example 9, 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (134 mg, 0.5 mmol), (prepared as described for the starting material in Example 4), was reacted with 3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-5-one (190 mg, 1 mmol) in the presence of sodium hydride (40 mg, 1 mmol, prewashed with THF) in DMF (3 ml) to give 6-methoxy-7-(2-methoxyethoxy)-4-(5-(4-methoxyphenyl)pyrazol-3-yloxy)quinazoline (125 mg, 59%).
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([NH2:5])=[O:4].[BH4-].[Na+].Cl>C(O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([NH2:5])=[O:4]
Reactant: NC(=O)C(=O)c1ccccc1Oc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)C(O)c1ccccc1Oc1ccccc1
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
2-Oxo-2-(2-phenoxyphenyl)acetamide (4.82 g, 20.0 mmol) was dissolved in ethanol (50 ml). Sodium borohydride (0.76 g, 20.0 mmol) was added slowly under ice-cooling. After stirring for 30 minutes, the mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated to give an oil. The oil was purified by column chromatography on silica gel (eluting with n-hexane - ethyl acetate) to give the desired compound 2-hydroxy-2-(2-phenoxyphenyl)acetamide (4.3 g, 89%) as colorless crystals. The compound was recrystallized from a mixed solvent of n-hexane - methylene chloride to give colorless crystals.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)([OH:3])=[O:2].[CH3:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][C:16]=1[CH:24]=O.N1CCCCC1>C(O)C>[CH3:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][C:16]=1[CH:24]=[C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([C:1]([OH:3])=[O:2])[CH:5]=2)[NH:9][C:8]1=[O:13]
Reactant: Cc1c(C=O)[nH]c2ccccc12
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C=C2C(=O)Nc3ccc(C(=O)O)cc32)[nH]c2ccccc12
Temperature: 90 °C
Yield: 67 %

Procedure:
A mixture of 5-carboxy-2-oxindole (113 mg), 3-methylindole-2-carbaldehyde (56 mg) (prepared according to Synthetic Communications, 1986, 16, 1799) and piperidine (30 mg) in ethanol (1 mL) was heated in a sealed tube at 90° C. for overnight. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in oven for overnight to give 75 mg (58% yield) of 3-(3-methyl-1H-indol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid (piperidine salt).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([O:31][CH2:32][CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][N:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:31][CH2:32][CH2:33][O:34][C:35]1[N:36]=[CH:37][C:38]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:39][CH:40]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC1(C)OB(c2ccc(OCCOCc3ccccc3)nc2)OC1(C)C
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(OCCOCc5ccccc5)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 50 mg, 0.132 mmol) and 2-(2-benzyloxy-ethoxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 19.1.1, 65 mg, 0.184 mmol) to give the title compound as a white solid. (HPLC: tR 3.12 min (Method A); M+H=521 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.95 (s, 1H), 8.33-8.24 (m, 1H), 8.16-8.05 (m, 2H), 7.93-7.86 (m, 1H), 7.81-7.75 (m, 1H), 7.51-7.45 (m, 1H), 7.40-7.22 (m, 5H), 7.01-6.93 (m, 1H), 4.55 (s, 2H), 4.47 (t, 2H), 3.92 (s, 3H), 3.78 (t, 2H), 3.57 (s, 3H), 1.97 (s, 3H))