Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[CH:5][C:4]=1[CH2:13][CH2:14][CH3:15].C(C1C(=O)C(Cl)=C(Cl)C(=[O:21])C=1C#N)#N.C1(C=CC(O)=CC=1)O>O1CCOCC1.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[CH:5][C:4]=1[CH:13]=[CH:14][CH:15]=[O:21]
Reactant: CCCc1cc(OC)c(OC)cc1OC
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: Oc1ccc(O)cc1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COc1cc(OC)c(OC)cc1C=CC=O
Temperature: 95 °C
Yield: 82 %

Procedure:
A solution of 2,4,5-Trimethoxyphenylpropane (5 g) in 70 mL of dry dioxane was placed in 100 ml round bottom flask. To this was added a catalytic amount of acetic acid (2-4 drops) and 16 g of DDQ and finally started refluxing the mixture at 50 to 140° C. for 5 to 9 hrs. The solution, which was initially deep green, turned into pale yellow with the formation of hydroquinone (DDQH2). The mixture was cooled and the solid DDQH2 was filtered and further washed with chloroform. The filtrate and washings were combined and evaporated under reduced pressure. The product was taken in ether (80 ml) and the ether layer was washed with aqueous NaOH (15%, 2×15 ml). The combined aqueous layers are further extracted with ether (3×15 ml). The ether layers were combined and washed with saturated sodium chloride (3×15 ml), dried over anhydrous sodium sulphate and filtered. The solvent was removed to afford a crude yellow liquid which was loaded on silica gel column and the column was eluted with hexane (70-80 ml) and then with an increasing amount of hexane/ethyl acetate (9:1 to 1:9). The fractions were monitored on TLC plate and the desired fractions were combined and solvent was removed under vacuum to afford 2,4,5-trimethoxycinnamaldehyde in 82% yield as a yellow solid; mp 140° C.; UV (MeOH) λmax 244, 298, 366 nm; IR (film) νmax 1648 (conjugated carbonyl), 1602, 1504, 1466, 1448, 1350, 1254, 1120, 1024, 856 cm−1; 1H NMR δ 9.65 (1H, d, J=7.8 Hz, H-3′), 7.81 (1H, d, J=15.8 Hz, H-1′), 7.03 (1H, s, H-6), 6.64 (1H, dd, J=15.8 Hz, J=7.8 Hz, H-2′), 6.51 (1H, s, H-3), 3.95 (s, 3H, 2-OCH3), 3.91 (s, 3H, 4-OCH3), 3.87 (s, 3H, 5-OCH3); 13C NMR δ 194.1 (C-3′), 154.1 (C-1′), 153.2 (C-2), 147.6 (C-4), 143.3 (C-5), 126.4 (C-2′), 114.5 (C-1), 110.5 (C-6), 96.5 (C-3), 56.4 (5-OCH3), 56.2 (2-OCH3), 56.0 (4-OCH3); EIMS m/z 222 [M]+ (44), 207 (18), 191 (100), 179 (14), 171 (27), 151 (14), 147 (7), 69 (58), 58 (80).
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1[C:14]([O:16]CC)=O)#[N:2].[CH3:19][NH2:20]>CN(C=O)C>[C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1[C:14]([NH:20][CH3:19])=[O:16])#[N:2]
Reactant: CCOC(=O)c1cnn(-c2ccccn2)c1C#N
Reactant: CN
Solvent: CN(C)C=O
Product: CNC(=O)c1cnn(-c2ccccn2)c1C#N

Procedure:
To a solution of 2.5 g of 5-cyano-1-(2-pyridinyl)-1H-pyrazole-4-carboxylic acid, ethyl ester in 20 ml of DMF was added an excess of 40% aqueous monomethylamine so as not to precipitate out the pyrazole starting material. Approximately 24 hours later additional monomethylamine was added to the reaction mixture as well as additional DMF so as to keep these reactants in solution. The reaction mixture was heated and subsequently added to 150 ml of ice water. The precipitated solid was collected by filtration and recrystallized from methanol to afford 1.2 g of 5-cyano-1-(2-pyridinyl)-N-methyl-1H-pyrazole-4-carboxamide. MP=200°-202° C.
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([NH:20]C(=O)OC(C)(C)C)[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].OP(O)(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.O>[S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([NH2:20])[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:2])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NC(=O)OC(C)(C)C)cnc32)cc1
Agent: O=P(O)(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(N)cnc32)cc1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 93.6 %

Procedure:
To a solution of tert-butyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (12.35 g, 31.8 mmol, Example #3 Step E) in THF (35 mL) was added H3PO4 (20.16 mL, 350 mmol). The reaction mixture was heated to about 65° C. After about 90 min, the reaction mixture was cooled to about 0° C. and a solution of K3PO4 (29.0 mL, 350 mmol) in water (100 mL) was added. A white precipitate was removed by filtration. The organic layer was separated, dried over anhydrous MgSO4, and concd in vacuo to provide crude 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-amine (8.58 g, 94%) as a tan solid: LC/MS (Table 1, Method a) Rt=1.85 min; MS m/z: 289 (M+H)+.
Reaction SMILES: [CH:1]([N:3]1[CH:8]([C:9]([O:11]CC)=[O:10])[CH2:7][C:6](=[CH2:14])[CH2:5][CH:4]1[C:15]([O:17]CC)=[O:16])=[O:2]>C1CCCCC1.C(OCC)(=O)C>[CH:1]([N:3]1[CH:8]([C:9]([OH:11])=[O:10])[CH2:7][C:6](=[CH2:14])[CH2:5][CH:4]1[C:15]([OH:17])=[O:16])=[O:2]
Reactant: C=C1CC(C(=O)OCC)N(C=O)C(C(=O)OCC)C1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: C=C1CC(C(=O)O)N(C=O)C(C(=O)O)C1
Yield: 51.2 %

Procedure:
Using the procedure of Step D of Example 1, 997 mg of the product of Step C were reacted to obtain 404 mg of the desired product with a Rf=0.2, eluant ethanol-ammonium hydroxide (8-2).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[C:9]([O:12][C:13]3[CH:14]=[C:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:16]=[CH:17][CH:18]=3)[CH:10]=[CH:11][C:4]=2[N:3]=1.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH:27]1([C:30]([NH:1][C:2]2[N:6]([CH3:7])[C:5]3[CH:8]=[C:9]([O:12][C:13]4[CH:14]=[C:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH:16]=[CH:17][CH:18]=4)[CH:10]=[CH:11][C:4]=3[N:3]=2)=[O:31])[CH2:29][CH2:28]1
Reactant: O=C(Cl)C1CC1
Reactant: Cn1c(N)nc2ccc(Oc3cccc(NC(=O)OC(C)(C)C)c3)cc21
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cn1c(NC(=O)C2CC2)nc2ccc(Oc3cccc(NC(=O)OC(C)(C)C)c3)cc21
Yield: 64.7 %

Procedure:
Using tert-butyl {3-[(2-amino-1-methyl-1H-benzimidazol-6-yl)oxy]phenyl}carbamate (2.45 g, 6.91 mmol), pyridine (100 mL), cyclopropanecarbonyl chloride (3.0 mL, 33.1 mmol) and N,N-dimethylpyridine-4-amine (258 mg, 2.11 mmol) as starting materials, and in the same manner as in Example C1(v), the title compound (1.89 g, 65%) was obtained as a pale-brown amorphous substance.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[CH:6]([C:9]1[S:13][CH2:12][N:11]([CH3:14])[CH:10]=1)[O:7][CH3:8].CN(C)C=O.[CH3:24][CH:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[H-].[Na+]>CCOCC>[CH3:8][O:7][CH:6]([C:9]1[S:13][CH2:12][N:11]([CH3:14])[CH:10]=1)[C:5]1[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=1[CH:3]=[N:2][O:1][CH:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:24]
Reactant: CC(Br)c1ccccc1
Reactant: COC(C1=CN(C)CS1)c1ccccc1C=NO
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(C1=CN(C)CS1)c1ccccc1C=NOC(C)c1ccccc1
Reaction time: 3 h
Yield: 86.8 %

Procedure:
To a mixture of 0.25 g (1 mmol) of 5-(2-hydroxyiminomethyl-α-methoxybenzyl)-3-methylthiazole, 3 ml of N,N-dimethylformamide and 0.24 g (1.3 mmol) of α-methylbenzyl bromide was added 0.05 g (1.3 mmol) of 60% sodium hydride under ice-cooling and stirred at the same temperature for 3 hours. After completion of the reaction, 100 ml of ether was added and washed twice with 80 ml of brine. The ether layer was dried over anhydrous magnesium and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 5-[α-methoxy-2-(4-phenyl-2-aza-3-oxa-1-pentenyl)benzyl]-3-methylthiazole (0.32 g, 91.3%) as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[F:21][C:22]1[CH:35]=[CH:34][C:25]([C:26](Cl)=[N:27]OS(C)(=O)=O)=[CH:24][CH:23]=1.CN(C)CCN(C)C.O>O1CCCC1>[F:21][C:22]1[CH:35]=[CH:34][C:25]([C:26]2[NH:1][C:2]3[CH:3]=[CH:4][C:5]([C@@H:8]4[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]4)=[CH:6][C:7]=3[N:27]=2)=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)cc2)C1
Reactant: CS(=O)(=O)ON=C(Cl)c1ccc(F)cc1
Agent: CN(C)CCN(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc3[nH]c(-c4ccc(F)cc4)nc3c2)C1
Yield: 38.6 %

Procedure:
A solution of (S)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate (140 mg, 0.5 mol), 4-fluoro-N-(methylsulfonyloxy)benzimidoyl chloride (152 mg, 0.6 mmol) and N,N,N′,N′-tetramethylethylenediamine (123 mg, 1.06 mmol) in tetrahydrofurane (0.8 ml) was shaken in a closed vial at 60° C. overnight. Water was added, and the mixture was extracted twice with ethyl acetate. The cobined organic layers were dried (MgSO4) and evaporated. Flash chromatography (10 g silica gel, 10 to 30% ethyl acetate in heptane) yielded a white solid (92 mg, 46%), MS (ISP): 398.2 ([M+H]+).
Reaction SMILES: [C:1]1([C:7]2[C:8]3[C:13]([CH:14]=[C:15]4[C:20]=2[CH:19]=[CH:18][CH:17]=[CH:16]4)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)(Cl)Cl.[Br:26]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>CO>[Br:26][C:14]1[C:15]2[C:20]([C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:8]3[C:13]=1[CH:12]=[CH:11][CH:10]=[CH:9]3)=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: BrBr
Reactant: c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CO
Product: Brc1c2ccccc2c(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
In a 300 mL three-neck flask, 5.8 g (23 mmol) of 9-phenylanthracene and 100 mL of carbon tetrachloride were placed. Then, 30 mL of a carbon tetrachloride solution containing 4.0 g (25 mmol) of bromine was dripped into the mixture under nitrogen stream. After dripping, the solution was stirred for 12 hours at room temperature. After a certain period, 100 mL of a 1.0 M sodium thiosulfate solution was added and stirred for 1 hour, and an aqueous layer of the mixture was extracted with chloroform. The obtained extracted solution and the organic layer were combined and washed with a 0.10 M sodium thiosulfate solution, a saturated aqueous solution of sodium hydrogen carbonate, and saturated saline in this order, and then, the organic layer was dried with magnesium sulfate. The mixture was gravity filtered, and the obtained filtrate was condensed to give a solid. A toluene solution of the solid was subjected to suction filtration through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135), and alumina, and the filtrate was condensed to give a solid. Methanol was added to the solid, and this suspension was irradiated with ultrasonic waves. Then, 6.4 g of a solid substance, which was target pale yellow powder, was obtained by suction filtration in a yield of 84%.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[CH3:8])=[O:5].Cl[C:21](OC(Cl)(Cl)Cl)=[O:22].[OH-].[Na+]>C1COCC1>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:1][C:21]2=[O:22])[CH3:8])=[CH:10][CH:11]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC(NC(=O)c1ccccc1N)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(c1ccc(Cl)cc1)n1c(=O)[nH]c2ccccc2c1=O
Temperature: 90 °C
Reaction time: 4 h
Yield: 166.3 %

Procedure:
To a solution of 2-amino-N-[1-(4-chloro-phenyl)-ethyl]-benzamide (115 mg, 0.42 mmol) in THF (30 mL) is added trichloromethyl chloroformate (50 mg, 0.25 mmol). The mixture is stirred at 90° C. for 4 hours. The reaction mixture is allowed to cool to room temperature, neutralizes with 1M NaOH aq. The reaction mixture is extracted with EtOAc (50 mL×3). The organic layer is dried over sodium sulfate and is concentrated to give the desired 3-[1-(4-chloro-phenyl)-ethyl]-1H-quinazoline-2,4-dione (125 mg, 99%).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[OH:13][N:14]=[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([CH:31]3[C:44]4[C:43](=[O:45])[CH2:42][C:41]([CH3:47])([CH3:46])[CH2:40][C:39]=4[O:38][C:37]4[CH2:36][C:35]([CH3:49])([CH3:48])[CH2:34][C:33](=[O:50])[C:32]3=4)[CH:24]=2)[N:18]=1)[NH2:16].N12CCCN=C1CCCCC2.[Cl-].[NH4+]>C1COCC1>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:15]3[NH:16][C:1](=[O:2])[O:13][N:14]=3)[N:18]=2)=[CH:24][C:25]=1[CH:31]1[C:32]2[C:33](=[O:50])[CH2:34][C:35]([CH3:49])([CH3:48])[CH2:36][C:37]=2[O:38][C:39]2[CH2:40][C:41]([CH3:46])([CH3:47])[CH2:42][C:43](=[O:45])[C:44]1=2
Reactant: COc1ccc(-c2cccc(C(N)=NO)n2)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(-c2cccc(-c3noc(=O)[nH]3)n2)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reaction time: 2 h
Yield: 69.6 %

Procedure:
1,1′-Carbonyldiimidazole (173 mg, 1.07 mmol) was added to a solution of the N′-hydroxy-6-[4-methoxy-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]pyridine-2-carboximidamide produced in Example 8-1 (424 mg, 0.82 mmol) in THF (8.5 ml) at room temperature, and the mixture thus obtained was then stirred at the same temperature as above for 2 hours. Thereafter, 1,8-diazabicyclo[5.4.0]undec-7-ene (0.160 ml, 1.07 mmol) was added to the resulting solution, and the mixture thus obtained was then stirred for 4.5 hours. Subsequently, an aqueous solution of ammonium chloride was added to the reaction solution, and the mixed solution was then extracted with dichloromethane twice. The organic layer thus obtained was dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the residue thus obtained was then purified by silica gel thin-layer chromatography (methanol:dichloromethane=1:10, v/v). The solid thus obtained was washed with a mixed solution of diethyl ether and hexane, followed by collection by filtration and drying, to obtain the title compound (309 mg, yield: 69%).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19]([OH:20])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[C:12]([CH2:21][CH2:22][N:23]([CH2:28][CH2:29][NH2:30])[C:24](=[O:27])[CH2:25]Cl)[N:11]=2)=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C>ClCCl>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19]([OH:20])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[C:12]([CH2:21][CH2:22][N:23]3[CH2:28][CH2:29][NH:30][CH2:25][C:24]3=[O:27])[N:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: NCCN(CCc1nc(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc12)C(=O)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1ccc(F)cc1)c1nc(CCN2CCNCC2=O)c2cccnc2c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the crude chloroamine from Step 1 (95 mg, 0.21 mmol) and diisopropylethylamine (0.5 mL, 2.87 mmol) in dichloromethane (5 mL) was stirred at room temperature for two hours. The resultant mixture was concentrated under vacuum. The residue was dissolved in DMSO and subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound as yellow solid.
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([OH:30])[CH:24]=1)[CH2:4][NH:5][CH:6]([CH3:20])[CH2:7][C:8]1[CH:19]=[CH:18][C:11]([O:12][CH2:13][C:14]([O:16]C)=[O:15])=[CH:10][CH:9]=1.Cl>O>[ClH:1].[OH:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[OH:29])[O:22][CH2:21][CH:3]([OH:2])[CH2:4][NH:5][CH:6]([CH3:20])[CH2:7][C:8]1[CH:19]=[CH:18][C:11]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1
Reactant: COC(=O)COc1ccc(CC(C)NCC(O)COc2ccc(O)c(O)c2)cc1
Agent: Cl
Solvent: O
Product: CC(Cc1ccc(OCC(=O)O)cc1)NCC(O)COc1ccc(O)c(O)c1
Temperature: 100 °C

Procedure:
A solution of (SR)-4-{2-[2-hydroxy-3-(3,4-dihydroxyphenoxy)propylamino]propyl}phenoxyacetic acid, methyl ester, hydrochloride (78 mg, 0.17 mMol) in water (2 ml) containing hydrochloric acid (1M, 0.5 ml, 0.51 mMol) was heated at 100° C. under argon for 3 hours. After cooling to room temperature the solution was freeze dried giving the title compound as a colourless solid.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH2:2][C:3]#[CH:4].I[C:19]1[C:27]2[O:26][CH2:25][C:24](=[O:28])[C:23]=2[CH:22]=[CH:21][C:20]=1[O:29][CH3:30]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:30][O:29][C:20]1[CH:21]=[CH:22][C:23]2[C:24](=[O:28])[CH2:25][O:26][C:27]=2[C:19]=1[C:4]#[C:3][CH2:2][CH2:1][N:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]1
Reactant: COc1ccc2c(c1I)OCC2=O
Reactant: C#CCCN1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1C#CCCN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 35.5 %

Procedure:
A solution of tert-butyl 4-(but-3-ynyl)piperazine-1-carboxylate (0.316 g, 1.33 mmol) in triethylamine (5 mL) was added with 7-iodo-6-methoxybenzofuran-3(2H)-one (0.385 g, 1.33 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.0933 g, 0.133 mmol) and copper(I) iodide (0.0127 g, 0.0665 mmol), and the mixture was stirred at 50° C. for 4 hours. The reaction mixture was concentrated, and then added with water, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl 4-[4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)but-3-ynyl]piperazine-1-carboxylate (0.189 g, 35%).
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.Cl.C(N=C=NCCCN(C)C)C.[CH3:23][O:24][C:25]1[C:26](=[O:52])[C:27]([CH3:51])=[C:28]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([O:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[C:39]([CH:43]=2)[C:40](O)=[O:41])[C:29](=[O:33])[C:30]=1[O:31][CH3:32]>C(Cl)Cl>[CH3:23][O:24][C:25]1[C:26](=[O:52])[C:27]([CH3:51])=[C:28]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([O:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[C:39]([CH:43]=2)[C:40]([N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:41])[C:29](=[O:33])[C:30]=1[O:31][CH3:32]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(Oc3ccccc3)c(C(=O)O)c2)=C(C)C1=O
Reactant: c1ccc2c(c1)CCCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(Oc3ccccc3)c(C(=O)N3CCCc4ccccc43)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.2 %

Procedure:
1,2,3,4-Tetrahydroquinoline (0.049 g, 0.367 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.105 g, 0.550 mmol) were added to a methylene chloride solution (10 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-phenoxybenzoic acid (0.075 g, 0.183 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=9:1) to obtain the titled compound (0.050 g, 0.0955 mmol, 52%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[CH2:11](O)[CH3:12].OS(O)(=O)=O>C(OCC)(=O)C>[CH2:11]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][N:10]=[C:2]([Cl:1])[CH:3]=1)[CH3:12]
Reactant: CCO
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccnc(Cl)c1
Temperature: 25 °C

Procedure:
The mixture of 2-chloro-isonicotinic acid (16.8 g, 0.107 mol), 100 mL absolute ethanol and concentrate H2SO4 (3.28 mL, 0.118 mol) was refluxed under nitrogen for 15 h. After all starting material converted, the mixture was cool down to rt, and vacuumed down all ethanol. The resulted mixture was diluted with 250 mL ethyl acetate, washed with sat. NaHCO3, dried over anhydrous Na2SO4. Purified by a short column, the 2-chloro-isonicotinic acid ethyl ester was obtained in as a pale yellow liquid. MS (ES+): 186 (M+H)+.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].F[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][C:12]=1[C:20]([F:23])([F:22])[F:21].CC(C)([O-])C.[K+]>O1CCCC1>[CH2:1]([O:9][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][C:12]=1[C:20]([F:21])([F:22])[F:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCO
Reactant: CC(=O)c1ccc(F)c(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(C(C)=O)cc1C(F)(F)F

Procedure:
1-octanol (2 mL), 1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone (2.62 g), potassium tert-butoxide (14 mL, 1.0M) and tetrahydrofuran (30 mL) were heated at 65° C. for 3 hrs to produce the title product as a brownish oil (4.00 g). The product was purified by silica gel column chromatography using the Combi-Flash system (Hex:EtOAc) as white solid in 60% (1.20 g). TLC (1:5 EtOAc:Hex), Rf=0.4; 1H NMR (400 MHz, CDCl3) δ 8.18 (d, 1H, J=2.0 Hz), 8.10 (dd, 1H, J=8.8 Hz, J=2.3 Hz), 7.02 (d, 1H, J=8.8 Hz), 4.12 (t, 2H, J=6.4 Hz), 2.58 (m, 3H), 1.80-1.89 (m, 2H), 1.42-1.54 (m, 2H), 1.22-1.40 (m, 8H), 0.89 (t, 3H, J=6.7 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:15]([O:17]CC)=[O:16])=[C:8]3[S:14][CH2:13][CH2:12][N:9]32)=[CH:4][C:3]=1[F:21].C(O)C.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:15]([OH:17])=[O:16])=[C:8]3[S:14][CH2:13][CH2:12][N:9]32)=[CH:4][C:3]=1[F:21]
Reactant: CCOC(=O)c1c2n(c3cc(Cl)c(F)cc3c1=O)CCS2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1c2n(c3cc(Cl)c(F)cc3c1=O)CCS2
Yield: 91.3 %

Procedure:
Six hundred mg (1.83 mmol) of ethyl 8-chloro-7-fluoro-5-oxo-1,2-dihydro-5H-thiazolo(3,2-a)-quinoline-4-carboxylate obtained in Example 15 was added to a mixed solvent of ethanol and water (1:1), then 2 ml of 2 N aqueous solution of sodium hydroxide was added thereto, and the mixture was heated to reflux for two hours. When the reaction was completed, ethanol was evaporated therefrom, the residual aqueous solution was adjusted to pH nearly 7.0 with 1 N aqueous solution of acetic acid and, after stirring for a while, crystals separated out therefrom were collected by filtration, successively washed with ethanol, acetone and ether and air dried to give 501 mg (91.4 percent) of the title compound, melting point 318° C. (decomposition). Elementary analysis calculated as C12H7FClNO3S: C 48.09, H 2.35, N. 4.67; Found: C 48.28, H 2.14, N 4.37.
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[NH:16][C:15](=[O:18])[CH:14]=[CH:13]3)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[O:19]=[C:20]1[NH:29][C:28]2[N:27]=[C:26]([O:30][CH2:31][CH2:32][CH2:33][CH:34]=O)[CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21]1>>[O:18]=[C:15]1[CH:14]=[CH:13][C:12]2[C:17](=[C:8]([N:2]3[CH2:7][CH2:6][N:5]([CH2:34][CH2:33][CH2:32][CH2:31][O:30][C:26]4[N:27]=[C:28]5[C:23]([CH2:22][CH2:21][C:20](=[O:19])[NH:29]5)=[CH:24][CH:25]=4)[CH2:4][CH2:3]3)[CH:9]=[CH:10][CH:11]=2)[NH:16]1
Reactant: O=c1ccc2cccc(N3CCNCC3)c2[nH]1
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Agent: Cl
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5ccc(=O)[nH]c45)CC3)nc2N1

Procedure:
In a manner similar to that of other examples above, 8-piperazin-1-yl-1H-quinolin-2-one hydrochloride (Chem. Pharm. Bull. 1984, 32, 2100–2110) was coupled by reductive amination to 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound. MS: APCI: M+1: 448.2 (Exact Mass: 447.23).