Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[NH:28][CH2:27][CH2:26][CH2:25]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([NH:19][C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:29]=3[NH:28][CH2:27][CH2:26][CH2:25]4)=[O:17])[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1cccc2c1NCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc2c1NCCC2
Yield: 50.5 %

Procedure:
The product is prepared according to the procedure described in example 5, using 340 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 212 mg of 8-amino-1,2,3,4-tetrahydroquinoline and 330 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 210 μl of pyridine and 5.0 ml of N,N-dimethylformamide. 243 mg of 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-(1,2,3,4-tetrahydroquinolin-8-yl)acetamide are obtained in the form of a beige powder, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:25]=[CH:24][C:15]3[CH:16]=[C:17]([C:19]([O:21]CC)=[O:20])[S:18][C:14]=3[CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+]>CO.C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:25]=[CH:24][C:15]3[CH:16]=[C:17]([C:19]([OH:21])=[O:20])[S:18][C:14]=3[CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cc2ccc(NC(=O)c3nc(Cl)c(CC)[nH]3)cc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1[nH]c(C(=O)Nc2ccc3cc(C(=O)O)sc3c2)nc1Cl
Temperature: 50 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
Ethyl 6-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-1-benzothiophene-2-carboxylate obtained in Example (184a) (74.4 mg) was dissolved in methanol (3 ml) and THF (6 ml). A 2 N aqueous lithium hydroxide solution (4 ml) was added, and the mixture was stirred at 50° C. for two hours. The organic solvent was evaporated under reduced pressure, followed by neutralization with 1 N hydrochloric acid. The resulting solid was collected by filtration, washed with distilled water, and dried under reduced pressure at 45° C. to obtain 64 mg of the title compound as a solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([N:16]3[CH2:23][CH2:22][CH2:21][C@H:17]3[C:18]([OH:20])=[O:19])(=[O:15])=[O:14])=[CH:10][CH:11]=2)[C:6]([NH:24][C:25]([NH2:27])=[NH:26])=[N:5][CH:4]=1.Cl.NC(N)=N.[C:33](OC(=O)[C@@H]1CCCN1NS(C1C=C2C(C(Cl)=CN=C2Cl)=CC=1)(=O)=O)([CH3:36])([CH3:35])[CH3:34]>COCCOC>[C:33]([O:19][C:18](=[O:20])[C@@H:17]1[CH2:21][CH2:22][CH2:23][N:16]1[S:13]([C:9]1[CH:8]=[C:7]2[C:12]([C:3]([Cl:2])=[CH:4][N:5]=[C:6]2[NH:24][C:25]([NH2:27])=[NH:26])=[CH:11][CH:10]=1)(=[O:15])=[O:14])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1NS(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N3CCC[C@H]3C(=O)O)cc12
Agent: Cl
Agent: N=C(N)N
Solvent: COCCOC
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 60 °C
Yield: 69.6 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-L-proline hydrochloride ##STR40## NaH (35 mg, 80% dispersion by wt in mineral oil, 1.16 mmol) was added in one portion to a stirred solution of guanidine hydrochloride (177 mg, 1.85 mmol) in DME (5 mL) and the mixture was heated at 60° C. under N2 for 45 min. A solution of 1-{[(1,4-dichloro-7-isoquinolinyl)sulphonyl]amino}-L-proline t-butyl ester (200 mg, 0.46 mmol) in DME (2 mL) was added and the mixture heated at 95° C. for 4 h. The solvents were evaporated in vacuo and the residue was purified by column chromatography upon silica gel using pentane-EtOAc (80:20 to 0:100) as eluant, followed by azeotroping with CH2Cl2, to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-L-proline t-butyl ester (153 mg, 0.32 mmol) as a pale yellow foam.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][CH:17]=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:22][CH3:23].C(=O)([O-])[O-].C1(C)C=CC(S([CH2:37][C@@H:38]2[NH:42][C:41](=[O:43])[CH2:40][CH2:39]2)(=O)=O)=CC=1>CN(C=O)C>[NH:18]1[C:19]2[C:15](=[CH:14][C:13]([O:12][C:6]3[C:5]4[C:10](=[CH:11][C:2]([O:1][CH2:37][C@@H:38]5[NH:42][C:41](=[O:43])[CH2:40][CH2:39]5)=[C:3]([O:22][CH3:23])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:21][CH:20]=2)[CH:16]=[CH:17]1
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1O
Reactant: Cc1ccc(S(=O)(=O)C[C@H]2CCC(=O)N2)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@H]1CCC(=O)N1
Temperature: 90 °C
Yield: 6.7 %

Procedure:
To a solution of 7-hydroxy-4-(1H-indol-5-yloxy)-6-methoxyquinazoline (800 mg, 2.6 mmol), (prepared as described for the starting material in Example 107), in DMF (20 ml) was added powdered potassuim carbonate (1.08 g, 7.8 mmol) and (5R)-5-(p-toluenesulphonylmethyl)-2-pyrrolidinone (1.13 g, 4.2 mmol). The reaction was then heated at 90° C. for 4 hours. The inorganic material was filtered off and the DMF removed by evaporation. The residue was then purified by chromatography eluting from methylene chloride to 12% methanol/88% methylene chloride (+1% ammonium hydroxide). A small portion was recolumned using the same gradient. The product was evaporated, triturated with ether and filtered to give (5R)-4-(1H-indol-5-yloxy)-6-methoxy-7-(2-oxopyrrolidin-5-ylmethoxy)quinazoline (70 mg, 6.5%) as a white solid.
Reaction SMILES: Cl.[CH:2]1[C:7](/[CH:8]=[C:9]2\[C@@H:10](C3C=C(O)C=C(O)C=3)[C@H:11](C3C=CC(O)=CC=3)[C:12]3[C:17]\2=[CH:16][C:15]([OH:18])=[CH:14][C:13]=3[OH:19])=[CH:6][CH:5]=[C:4]([OH:35])[CH:3]=1>CO>[CH:6]1[C:7]([CH2:8][C:9]2[C:17]3[C:12](=[C:13]([OH:19])[CH:14]=[C:15]([OH:18])[CH:16]=3)[C@H:11]([C:17]3[CH:16]=[C:15]([OH:18])[CH:14]=[C:13]([OH:19])[CH:12]=3)[C:10]=2[C:7]2[CH:2]=[CH:3][C:4]([OH:35])=[CH:5][CH:6]=2)=[CH:2][CH:3]=[C:4]([OH:35])[CH:5]=1
Reactant: Oc1ccc(/C=C2/c3cc(O)cc(O)c3[C@@H](c3ccc(O)cc3)[C@@H]2c2cc(O)cc(O)c2)cc1
Agent: Cl
Solvent: CO
Product: Oc1ccc(CC2=C(c3ccc(O)cc3)[C@@H](c3cc(O)cc(O)c3)c3c(O)cc(O)cc32)cc1
Yield: 19.2 %

Procedure:
Concentrated HCl (50 mL, 0.600 mmol, 5.5 equiv.) was added to a solution of ampelopsin D (2, 5.0 mg, 0.110 mmol, 1.0 equiv) in MeOH (0.5 mL) at 25° C., and the resultant mixture was stirred at 80° C. for 12 h. Upon completion, the reaction mixture was quenched with water (3 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were then washed with water (5 mL) and brine (5 mL), dried (MgSO4), and concentrated. The resulted light yellow product was purified by flash column chromatography (silica gel, CH2Cl2/MeOH, 9:1) to give isoampelopsin D 17 (4.8 mg, 96%) as a colorless oil. 17: Rf=0.13 (silica gel, CH2Cl2/MeOH, 9:1); IR (film) νmax 3411, 2810, 1680, 1628, 1511, 1443, 1371, 1333, 1206, 1149, 1055, 1006, 833; 1H NMR (300 MHz, methanol-d4) δ 7.11 (d, J=8.4 Hz, 2H), 7.07 (d, J=8.7 Hz, 2H), 6.73 (d, J=8.7 Hz, 2H), 6.66 (d, J=8.7 Hz, 2H), 6.17 (d, J=2.1 Hz, 1H), 6.06 (d, J=1.5 Hz, 1H), 6.06 (d, J=2.1 Hz, 2H), 5.99 (t, J=2.1 Hz, 1H), 4.80 (s, 1H), 3.84 (s, 2H); 13C NMR (75 MHz, methanol-d4) δ 158.9, 158.7, 157.5, 156.5, 154.0, 150.4, 149.9, 144.0, 136.6, 132.1, 131.1, 130.2, 128.9, 125.4, 116.3, 115.8, 108.1, 101.4, 100.7, 56.7, 32.2; HRMS (MALDI-FTMS) calcd for C28H22O6+[M+]454.1416. found 454.1428. All spectroscopic data for this synthetic material match those reported by Niwa and co-workers for natural isoampelopsin (15) [22].
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([OH:17])[CH:11]=[CH:10]2)(C)C.C([O-])([O-])=O.[K+].[K+]>CO.C1COCC1.C(OCC)(=O)C>[C:6]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([OH:17])[CH:11]=[CH:10]2)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc2cc(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1ccc2cc(O)ccc2c1

Procedure:
Compound 110A (770 mg, 3.20 mmol) in MeOH (5 ml) and THF (10 ml) was treated with K2CO3 (885 mg, 6.41 mmol) at room temperature for 3 h. The reaction was diluted with ethyl acetate and washed with water. The organic layer was concentrated and the residue was purified by flash chromatography, eluted with DCM to provide the compound 110B.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20].N1C=CN=C1>CN(C=O)C>[Si:22]([O:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH2:1])=[N:7][CH:6]=3)[S:9][C:10]=2[CH:16]=1)([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23]
Reactant: Nc1ccc(-c2nc3ccc(O)cc3s2)cn1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2nc(-c3ccc(N)nc3)sc2c1
Yield: 76.6 %

Procedure:
A solution of 2-(6-aminopyridin-3-yl)-1,3-benzothiazol-6-ol (177 mg, 0.73 mmol), TBDMSCl (121 mg, 1.1 equiv) and imidazole (124 mg, 2.5 equiv) in DMF (2.0 ml) was stirred at ambient temperature for 2 h. The reaction mixture was then partitioned between water and ethyl acetate. The aqueous phase was extracted twice with ethyl acetate and the combined organics dried (MgSO4) and concentrated in vacuo. The crude product thus obtained was purified by silica gel chromatography, using a mixture of DCM and methanol (95:5) as eluent, to yield 200 mg of the title compound as a white solid. 1H NMR δ 8.56 (d, 1H) 7.96 (dd, 1H) 7.80 (d, 1H) 7.54 (d, 1H) 6.98 (dd, 1H) 6.67 (s, 2H) 6.56 (d, 1H) 0.97 (s, 9H) 0.22 (s, 6H); MS m/z (M+H) 358.
Reaction SMILES: [C:1]([C@@:3]1([CH3:21])[CH2:7][CH2:6][C@@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4]1([CH3:20])[CH3:19])#[N:2]>C1COCC1>[NH2:2][CH2:1][C@@:3]1([CH3:21])[CH2:7][CH2:6][C@@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:4]1([CH3:20])[CH3:19]
Reactant: CC1(C)[C@H](NC(=O)OCc2ccccc2)CC[C@]1(C)C#N
Solvent: C1CCOC1
Product: CC1(C)[C@H](NC(=O)OCc2ccccc2)CC[C@]1(C)CN
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.7 %

Procedure:
To a solution of benzyl ((1R,3S)-3-cyano-2,2,3-trimethylcyclopentyl)carbamate (1.53 g, 5.34 mmol) in THF (10.69 ml) at 0° C. was added a 2 M THF solution of borane-methyl sulfide complex (9.35 ml, 18.70 mmol). The reaction was allowed to warm to room temperature and stirring was continued for 14 hrs. The reaction was cooled to 0° C. and quenched with methanol (8 ml). The reaction solution was partitioned between ethyl acetate and 1.0 N NaOH. The organic extract was washed with brine, dried with sodium sulfate, filtered, and concentrated under reduced pressure, yielding benzyl ((1R,3S)-3-(aminomethyl)-2,2,3-trimethyl cyclopentyl)carbamate (1.39 g, 4.79 mmol, 90% yield) as a colorless oil. ESI-MS m/z 291.3 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[N:25]1([CH2:31][CH2:32][O:33][C:34]2[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:38]([C:37]3[CH:40]=[CH:41][C:34]([O:33][CH2:32][CH2:31][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:35][CH:36]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc(OCCN2CCOCC2)cc1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3ccncc3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Brc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1N1CCN(Cc2ccncc2)CC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a mixture of 5-bromo-3-nitro-4-(4-pyridin-4-ylmethyl-piperazin-1-yl)-pyridin-2-ylamine (0.040 g, 0.10 mmol) and EtOH (3.0 ml) was added 4-(2-morpholin-4-yl-ethoxy)-benzaldehyde (0.031 g, 0.13 mmol) with the aid of ethanol (1 ml) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.40 ml, 0.40 mmol). The reaction mixture was stirred at 80° C. for 20 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with a gradient of methanol (0 to 10%) in ethyl acetate/dichloromethane (v:v; 1:1). afforded a pale yellow solid. This material was triturated with diethyl ether, and the resulting white precipitate was collected by filtration, and successively washed with diethyl ether, water, and diethyl ether, then dried in vacuo (0.014 g, 24%); 1H-NMR (500 MHz, DMSO-d6) 2.63 (br s, 4H, piperazine N(CH2)2), 2.72 (t, J=5.7 Hz, 2H, OCH2CH2N), 3.59 (t, J=4.7 Hz, 4H, morpholine O(CH2)2), 3.62, (s, 2H, NCH2-pyridyl), 3.68 (br t, 4H, piperazine N(CH2)2), 4.18 (t, J=5.8 Hz, 2H, OCH2CH2N), 7.11 (d, J=8.9 Hz, 2H) and 8.12 (d, J=8.9 Hz, 2H) (3,5-C6H4— and 2,6-C6H4—), 7.39 (d, J=5.9 Hz, 2H, pyridine 3-H, 5-H), 8.20 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.54 (d, J=5.9 Hz, 2H, pyridine 2-H, 6-H), 13.34 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=O)[CH2:7]Cl)=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][CH2:15][CH2:16][N:17]=1.C(O)C>O>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[N:12]=[C:13]3[N:17]([CH:7]=2)[CH2:16][CH2:15][S:14]3)=[CH:4][CH:3]=1
Reactant: NC1=NCCS1
Reactant: O=C(CCl)c1ccc(F)cc1
Solvent: O
Solvent: CCO
Product: Fc1ccc(-c2cn3c(n2)SCC3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A mixture of 51.6 g (0.3 mol) of 4-fluorophenacylchloride, 33.66 g (0.33 mol) of 2-aminothiazoline and 200 ml of ethanol was heated at reflux for 2 hours. The mixture was cooled to room temperature at which point 300 ml of water was added. After a reflux period of 2 hours, the mixture was concentrated to remove about 190 ml of aqueous alcohol. The pH of the residue was adjusted to about 2 with 10% hydrochloric acid (10 ml). The solid product was separated and dried to give 65.4 g (85%) of 6-(4-fluorophenyl)-2,3-dihydroimidazo[2,1-b]thiazole, m.p. 116-118°.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21]1[N:26]=[CH:25][N:24]=[C:23]([O:27][CH:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37](C)([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]3)[CH:22]=1)[CH2:16][CH2:15]2)(=[O:11])=[O:10].ClC(OC(C)C)=O.C(N(CC)CC)C>O.ClCCl>[CH3:8][S:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21]1[N:26]=[CH:25][N:24]=[C:23]([O:27][CH:28]3[CH2:29][CH2:30][N:31]([C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:33]3)[CH:22]=1)[CH2:16][CH2:15]2)(=[O:11])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(S(C)(=O)=O)ccc43)ncn2)CC1
Agent: CC(C)OC(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(S(C)(=O)=O)ccc43)ncn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.4 %

Procedure:
Trifluoroacetic acid (1 mL) was added to a dichloromethane (1 mL) solution of the tert-butyl 4-({6-[5-(methylsulfonyl)indolin-1-yl]pyrimidin-4-yl}oxy)piperidine-1-carboxylate (188 mg, 0.396 mmol) produced in Example 1, and the mixture was stirred at room temperature for 2 hours. From the reaction solution, the solvent was distilled off under reduced pressure. To a dichloromethane (2.5 mL) solution of the obtained residue, isopropyl chloroformate (68 μL, 0.60 mmol) and triethylamine (276 μL, 1.98 mmol) were added at 0° C., and the mixture was stirred at room temperature. After 1.5 hours, isopropyl chloroformate (100 μL, 0.878 mmol) and triethylamine (410 μL, 2.94 mmol) were added to the reaction solution, and the mixture was further stirred for 1 hour. To the reaction solution, water was added, followed by extraction with ethyl acetate three times. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [(i) hexane:ethyl acetate=70:30-50:50, V/V; (ii) ethyl acetate] to obtain the title compound as white powder (82.8 mg, yield: 45%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH2:32][CH2:33]O)[CH:29]=2)[CH:24]=[CH:23][N:22]=1>CN(C)C=O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:33][CH2:32][O:31][C:28]2[CH:29]=[C:30]3[C:25]([CH:24]=[CH:23][N:22]=[CH:21]3)=[CH:26][CH:27]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: OCCOc1ccc2ccncc2c1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccc3ccncc3c2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 39.4 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (1.267 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.305 g), stirred for 15 minutes and treated with the mesylate prepared from 1.135 g of 2-(7-isoquinolyloxy)ethanol. The mixture was heated under argon at 60° C. for 5 hours. The cooled mixture was treated with glacial acetic acid (2 drops) and the volatiles were removed under vacuum. The residue was partitioned between dichloromethane and dilute cold sodium bicarbonate solution. The dichloromethane layer was washed with water, dried (Na2SO4), filtered, and evaporated to give crude product. The material was purified by HPLC (ethyl acetate) and crystallized from dichloromethane-hexane to provide 0.83 g of 4-[[2-(7-isoquinolyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester as a colorless solid, mp 144°-145° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([NH:15]C(=O)O)[N:11]=[CH:12][CH:13]=3)[C:8](=[O:19])[N:7]([CH3:20])[C:6]=2[CH:21]=1.Cl.C(=O)(O)[O-].[Na+].[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>CO>[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29].[NH2:15][C:10]1[N:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[C:8](=[O:19])[N:7]([CH3:20])[C:6]1[CH:21]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]2=1
Reactant: Cn1c(=O)c2c(NC(=O)O)nccc2c2ccc(Cl)cc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cn1c(=O)c2c(N)nccc2c2ccc(Cl)cc21
Yield: 27 %

Procedure:
A solution of (8-chloro-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-4-yl)carbamic acid (300 mg, 0.415 mmol) in conc. HCl (15 mL, 494 mmol) was heated at 90° C. for 2 h. The pH of the reaction mixture was adjusted to 8 with saturated sodium bicarbonate solution and extracted with DCM (2×30 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep. HPLC (0.1% TFA in MeOH) to yield 4-amino-8-chloro-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (30 mg, 0.110 mmol, 27% yield) as a mono TFA salt. LC/MS (ESI) m/e 260.0 [(M+H)+, calcd for C13H11ClN3O 260.05]; LC/MS retention time (method B): tR=1.18 min; HPLC retention time (method A): tR=5.24 min; HPLC retention time (method B): tR=6.31 min; 400 MHz, 1H NMR (DMSO-d6) δ 9.95 (s, 1H), 8.75 (s, 1H), 8.56 (d, J=8.80 Hz, 1H), 8.23 (d, J=6.80 Hz, 1H), 7.82 (dd, J=6.80, 7.20 Hz, 2H), 7.54 (dd, J=2.00, 8.80 Hz, 1H), 3.72 (s, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C([OH:15])C.[ClH:16]>CCOCC>[ClH:16].[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11](=[NH:12])[OH:15])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CCO
Reactant: CC(C)c1ccc(CC#N)cc1
Agent: Cl
Solvent: CCOCC
Product: CC(C)c1ccc(CC(=N)O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of 4-isopropylphenylacetonitrile (2 g, 12.5 mmol) in anhydrous ether (50 mL) was added absolute ethanol (0.5 g, 12.5 mmol) and an excess of HCl gas was passed into the solution with cooling in an ice bath. The resulting solution was allowed to stir at 0° C. for 1.5 hours and at room temperature overnight. The white solid was collected by filtration, washed with ether (2×20 mL) and dried to give 2.52 g (84%) of 4-isopropylphenylacetimidate hydrochloride as white crystals, mp 118-120° C. A solution of ethylenediamine (1.25 g, 20 mmol) in absolute ethanol (5 mL) was added to a solution of the imidate hydrochloride (2.5 g, 10 mmol) in absolute ethanol (15 mL) cooled at ice-bath temperature. After stirring at 0° C. for 1 hour, the solution was heated at reflux for 20 minutes. The solvent was evaporated and the oily residue was washed with water (2×3 mL) and extracted with methylene chloride (3×15 mL). The solution was dried (MgSO4), filtered and evaporated under reduced pressure to afford 2 g of the free base of the title compound. A solution of the free base in anhydrous ether was treated with dry HCl gas. The crude salt was collected and recrystallized from ethanol/ether to give 1.95 g (79%) of the title compound as a white solid. mp 176-178° C.; Anal. C13H18N2.HCl: C, H, N.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:15].[O:16]=[C:17]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)[CH2:18][CH2:19][C:20](O)=[O:21].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O>[O:16]=[C:17]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)[CH2:18][CH2:19][C:20]([NH:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[NH:7][C:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[CH:14]2)=[O:21]
Reactant: Nc1cccc2cc(-c3nccs3)[nH]c12
Reactant: O=C(O)CCC(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCC(=O)c1cccs1)Nc1cccc2cc(-c3nccs3)[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 220.3 %

Procedure:
To a mixture of 2-(1,3-thiazol-2-yl)-1H-indole-7-amine (0.31 g), 4-oxo-4-(2-thienyl)butanoic acid (0.89 g), 1H-1,2,3-benzotriazol-1-ol (0.75 g) and N,N-dimethylformamide (20 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1.06 g), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography and the title compound (1.21 g, yield. 69%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (3:1, volume ratio). melting point 140-141° C.
Reaction SMILES: [C:1]([C:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[S:11][C:10]=1[N:16]1[C:20]([CH2:21]Cl)=[N:19][C:18]([C:23]([OH:25])=[O:24])=[N:17]1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:27][OH:28].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl>O.C(O)C>[CH3:14][C:13]1[C:9]2[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N+:27]([O-:28])[CH2:21][C:20]3[N:16]([N:17]=[C:18]([C:23]([OH:25])=[O:24])[N:19]=3)[C:10]=2[S:11][C:12]=1[CH3:15]
Reactant: NO
Reactant: Cc1sc(-n2nc(C(=O)O)nc2CCl)c(C(=O)c2ccccc2)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CCO
Product: Cc1sc2c(c1C)C(c1ccccc1)=[N+]([O-])Cc1nc(C(=O)O)nn1-2

Procedure:
A mixture of 0.376 g. of 1-(3-benzoyl-4,5-dimethyl-2-thienyl)-5-chloromethyl-1H-1,2,4-triazole-3-carboxylic acid, 1.4g. of hydroxylamine hydrochloride, 1.46 g. of potassium carbonate, 0.15 g. of sodium iodide, 5 ml. of water and 5 ml. of ethanol is stirred for 1 hour on a water bath at 80° to 90° C. After cooling, the mixture is acidified with 6N-hydrochloric acid, diluted with water and then extracted with dichloromethane. The dichloromethane layer is washed with water, dried over sodium sulfate, and the solvent is evaporated to give 7,8-dimethyl-6-phenyl-4H-thieno[3,2-f]-s-triazolo[1,5-a][1,4]diazepine-2-carboxylic acid 5-oxide as crystals. Recrystallization from acetone gives colorless prisms melting at 224° to 226° C. (decomposition).