Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][C:16]([NH:18][C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=3[O:26]CC=C)=[O:17])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:30](OC1C=CC(Cl)=CC=1N)[CH:31]=[CH2:32]>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][C:16]([NH:18][C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([CH2:32][CH:31]=[CH2:30])[C:20]=3[OH:26])=[O:17])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C=CCOc1ccc(Cl)cc1NC(=O)Cc1ccc(OC)c(OC2CCCC2)c1
Reactant: C=CCOc1ccc(Cl)cc1N
Solvent: c1ccc(Oc2ccccc2)cc1
Product: C=CCc1cc(Cl)cc(NC(=O)Cc2ccc(OC)c(OC3CCCC3)c2)c1O

Procedure:
A solution of N-(3-cyclopentyloxy4-methoxyphenyl-acetyl)-2-allyloxy-5-chloroaniline (33 grams, 0.079 mol) in 330 millimeters of diphenyl ether was heated at 180° for 6.5 hours. This reaction mixture was combined with a second reaction mixture containing N-3-cyclopentyloxy-4-methoxyphenylacetyl)-2-allyloxy-5-chloroaniline and 250 milliliters of diphenyl ether which had been heated at 180° for 20 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[N:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)C>[CH3:9][O:10][C:11]1[N:16]=[CH:15][C:14]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Nc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc(N)nc2)cn1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
A degassed mixture of 2-amino-5-bromopyridine (3.5 g, 20.23 mmol), 6-methoxypyridin-3-ylboronic acid (3.71 g, 24.28 mmol) and bis[3-(diphenylphosphanyl)-cyclopenta-2,4-dien-1-yl]iron-dichloropalladium-dichloromethane complex (413 mg, 0.51 mmol) in 1,4-dioxane (36 mL) and a 2M aqueous potassium carbonate solution (36.4 mL) was heated at 90° C. under a nitrogen atmosphere for approximately 16 h. The reaction mixture was allowed to cool to room temperature and diluted with diethyl ether (100 mL). The organic phase was separated off, washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude product was triturated with DCM (10 mL) and filtered, to afford the title compound (3.36 g, 83%) as a light brown solid. Method C LCMS: MH+ m/z 202, RT 0.60 minutes.
Reaction SMILES: CO[C:3](=[S:18])[CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CO.[NH3:21]>O>[C:6]1([CH:5]([CH2:4][C:3]([NH2:21])=[S:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=S)CC(c1ccccc1)c1ccccc1
Reactant: N
Solvent: O
Solvent: CO
Product: NC(=S)CC(c1ccccc1)c1ccccc1
Temperature: 35 °C
Reaction time: 16 h

Procedure:
A reactor equipped with an impeller stirrer and a gas introduction tube was charged with methyldiphenylmethylthioacetate (100 g; 1 equivalent) and methanol (300 mL; 3 volumes) at room temperature. The mixture was heated to 35° C. Ammonia (7 equivalents) was introduced within 3 hours, and the mixture contacted at 35° C. for 16 hours before adding 3 equivalents of ammonia. When the reaction was completed, the mixture was cooled to 25° C. and water (90 ml; 0.9 volume) added. The mixture was filtered and dried under vacuum.
Reaction SMILES: C([Li])(C)(C)C.I[C:7](=[CH2:16])[CH2:8][C@H:9]1[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10]1.[S:17]([Cl:20])(Cl)=[O:18].CC[O:23]CC>>[CH3:14][C:11]1([CH3:15])[O:10][C@@H:9]([CH2:8][C:7]([S:17]([Cl:20])(=[O:18])=[O:23])=[CH2:16])[CH2:13][O:12]1
Reactant: O=S(Cl)Cl
Reactant: CCOCC
Reactant: C=C(I)C[C@H]1COC(C)(C)O1
Agent: [Li]C(C)(C)C
Product: C=C(C[C@H]1COC(C)(C)O1)S(=O)(=O)Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl lithium is added to a solution of (S)-4-(2-iodoallyl)-2,2-dimethyl-1,3-dioxolane in ether at −78° C. and the mixture stirred at −78° C. for 30 mins. A solution of thionyl chloride in ether is then added, the mixture warmed to room temperature and concentrated under reduced pressure. The residue is dissolved in chloroform, filtered and dried under reduced pressure.
Reaction SMILES: [F:1][C:2]1[C:3]([N:12]2[N:16]=[CH:15][CH:14]=[N:13]2)=[C:4]([C:8]([F:11])=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][C@@H:19]1[CH2:24][N:25]1C(=O)C2C(=CC=CC=2)C1=O.Cl[C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1>>[F:1][C:2]1[C:3]([N:12]2[N:16]=[CH:15][CH:14]=[N:13]2)=[C:4]([C:5]([N:20]2[CH2:21][CH2:22][CH2:23][C@@H:18]([CH3:17])[C@H:19]2[CH2:24][NH:25][C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=2)=[O:7])[C:8]([F:11])=[CH:9][CH:10]=1
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: O=C(O)c1c(F)ccc(F)c1-n1nccn1
Product: C[C@@H]1CCCN(C(=O)c2c(F)ccc(F)c2-n2nccn2)[C@@H]1CNc1ccc(C(F)(F)F)cn1

Procedure:
The title compound was prepared from 3,6-difluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid, 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione, and 2-chloro-5-(trifluoromethyl)pyridine using the methods described herein. ESI-MS (m/z): 481 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[C:5]([S:10]([NH:13][C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[O:15])(=[O:12])=[O:11])=[CH:4][N:3]=1.[Na].C(C1C=CC=CC=1)(=[O:28])C1C=CC=CC=1.ClC1C=CC=C(C(OO)=O)C=1>C1COCC1>[CH3:18][CH:17]([NH:16][C:14]([NH:13][S:10]([C:5]1[C:6]([S:8]([CH3:9])=[O:28])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=1)(=[O:12])=[O:11])=[O:15])[CH3:19]
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: CSc1nc(N)ncc1S(=O)(=O)NC(=O)NC(C)C
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na]
Solvent: C1CCOC1
Product: CC(C)NC(=O)NS(=O)(=O)c1cnc(N)nc1S(C)=O
Yield: 84 %

Procedure:
2-Amino-N-[[(1-methylethyl)amino]carbonyl]-4-(methylthio)-5-pyrimidinesulfonamide (3.0 g, 9.84 mmol) was dissolved in dry (freshly distilled from sodium/benzophenone) THF (60 mL) and m-chloroperbenzoic acid (MCPBA) (2.55 g, 11.81 mmol, 80% 1.2 eq) was added as a solid. The reaction turned yellow and a white solid precipitated out of solution. After 30 minutes the reaction was diluted with ethyl ether (60 mL) and the white solid was filtered, washed with THF, then with ether three times and air dried for 2 hours, to yield 2.64 g (8.22 mmol, 84%) of product, m.p. 140° C.(dec.). The product was unstable to heat but could be stored under nitrogen in the freezer for weeks.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]#N)=[CH:5]2)[CH2:3][CH2:2]1.O.[PH2](=O)[O-:21].[Na+]>C(O)(=O)C.O.N1C=CC=CC=1.[Ni]>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:16])[C:6]([CH:17]=[O:21])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=[PH2][O-]
Reactant: N#Cc1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Agent: [Ni]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: O=Cc1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
The 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarbonitrile (150 mg, 0.609 mmol) obtained in (B) was dissolved in a mixed solution of acetic acid, water and pyridine (1:1:2, 4 ml), added with Raney Nickel (catalytic amount) and sodium phosphinate monohydrate (258 mg, 2.44 mmol), and then the mixture was stirred overnight at 60° C. The reaction mixture was left stand for cooling and the catalyst was removed by filtration through a Celite layer and washed with hot ethanol. The reaction mixture was concentrated, then diluted with chloroform, and washed with aqueous copper sulfate. The organic layer was dried over anhydrous magnesium sulfate to obtain the title compound (97.0 mg, 64%) as pale yellow solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[C:28]([CH:45]=[C:46]([O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[CH:47]=1)[O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][OH:44])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:71]([O:75][C:76](=[O:79])[CH2:77]Br)([CH3:74])([CH3:73])[CH3:72]>C1COCC1.CN(C=O)C.C1COCC1>[C:71]([O:75][C:76](=[O:79])[CH2:77][O:44][CH2:43][CH2:42][O:41][CH2:40][CH2:39][O:38][CH2:37][CH2:36][O:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][O:29][C:28]1[CH:27]=[C:26]([O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:47]=[C:46]([O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[CH:45]=1)([CH3:74])([CH3:73])[CH3:72]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OCCOCCOCCOCCOCCOc1cc(OCCOCCOCCOCCOCCOCc2ccccc2)cc(OCCOCCOCCOCCOCCOCc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOc1cc(OCCOCCOCCOCCOCCOCc2ccccc2)cc(OCCOCCOCCOCCOCCOCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
To an ice-cooled suspension of sodium hydride (175 mg, 4.4 mmol; 60% in mineral oil) in THF/DMF (4/1 mixed fluid 5 ml), a solution of Compound 47 (1.05 g, 1.09 mmol) in THF (5 ml) was gradually added, and this was followed by stirring for 30 minutes. A solution of bromoacetic acid tert-butyl ester (847 mg, 4.3 mmol) in THF (6 ml) was added thereto. After the ice bath was removed, stirring was further conducted at room temperature for 2 hours. Water was carefully added to stop the reaction, and this was followed by extraction from ethyl acetate, and the combined organic phases were washed with saturated brine and dried with anhydrous sodium sulfate. Filtration and concentration under reduced pressure were conducted, after which the residue obtained was purified by silica gel column chromatography (Yamazen YFLC Gel, eluent (ethyl acetate-ethyl acetate solution containing 5% methanol)) to yield Compound 48 (light-yellow oil 530 mg, 45%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23](O)=[O:24].N.O1CCOCC1.F[P-](F)(F)(F)(F)F.[N:40]1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C.C(N(CC)CC)C>[O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]([NH2:40])=[O:24]
Reactant: O=C(O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1COCCO1
Product: NC(=O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.1 %

Procedure:
To a stirred solution of (2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetic acid (0.25 g, 0.74 mmol), triethylamine (0.5 mL), ammonia in dioxane (0.5M, 4.5 mL, 2.3 mmol) in acetonitrile (10 mL) was added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.33 g, 0.9 mmol). The solution was stirred at ambient temperature for 18 h then concentrated in vacuo to dryness. The residue was dissolved in ethyl acetate (50 mL) and washed with 2 M sodium carbonate (2×25 mL) and 1 M hydrochloric acid (2×25 mL). The ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to dryness. Recrystallization from diethyl ether (25 mL) in a Branson ultrasonic bench top water bath afforded 2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide (0.06 g, 23%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ7.66 (s, 1H), 7.29-7.21 (m, 2H), 7.10 (d, J=6.5 Hz, 1H), 7.03-6.90 (m, 2H), 6.55 (s, 1H), 6.36 (s, 1H), 4.72 (ABq, 2H), 4.53-4.38 (m, 1H), 4.29 (ABq, 2H), 2.92 (t, J=8.6 Hz, 2H); MS (ES+) m/z 337.1 (M+1), 359.1 (M+23).
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:28])[C@H:6]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:7][CH2:8][C@@H:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:10]([CH3:12])[CH3:11]>O.COCCOC>[CH3:11][CH:10]([CH3:12])[C@H:9]([NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:8][NH:7][C@H:6]([C:5]([OH:28])=[O:4])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC[C@@H](NC(=O)OC(C)(C)C)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: CC(C)[C@@H](CN[C@@H](Cc1ccccc1)C(=O)O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
A solution of lithium hydroxide (1.63 g, 0.068 mole) in water (70 ml) was added to a solution of the product of Step A (7.6 g, 0.021 mole) in ethylene glycol dimethyl ether (100 ml) with cooling in an ice bath. The reaction mixture was stirred at room temperature under Ar for 2 hours, concentrated in vacuo, and extracted (2×) with ethyl acetate. The aqueous phase was neutralized with 10% of citric acid, cooled and filtered to give the product as a white solid (6.6 g), mp >193° (dec).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3].S(Cl)(Cl)=O.[Br:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37](O)=[CH:36][CH:35]=1.[Cl-].[NH4+]>O1CCCC1.C(N(CC)CC)C>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][C:37]2[CH:38]=[CH:39][C:34]([O:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][Br:26])=[CH:35][CH:36]=2)=[O:18])=[CH:20][CH:21]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Reactant: Oc1ccc(OCCCCCCBr)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(OCCCCCCBr)cc2)cc1
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
4-{[6-(acryloyloxy)hexyl]oxy}benzoic acid (4) (2.8 g (grams)) was dissolved in tetrahydrofurane (THF, 100 ml (milliliters)) at a room temperature, and a temperature of the resulting mixture was adjusted to a temperature of 0° C. (Celsius). Then, thionyl chloride (12 ml (milliliters), 1M in THF) was added to the mixture, and stirred for 30 minutes. Then, 4-(6-bromohexyloxy)phenol (2.5 g (grams)) and triethyl amine (13 ml (milliliters)) were added to the resulting reaction mixture, stirred at 0° C. (Celsius) for 1 hour, and then stirred at a room temperature overnight. Next day, a saturated ammonium chloride aqueous solution was poured into the reaction mixture, and the reaction was completed. The resulting reaction mixture was extracted three times with ethyl acetate (50 ml (milliliters)), and waster was removed over magnesium sulfate. Then, the solvents were evaporated, and the resulting reaction mixture was then purified using a column chromatography (developer solution: ethylacetate/hexane=1/2 volume ratio) to obtain 4-(6-bromo hexyloxy)phenyl 4-{[6-(acryloyloxy)hexyl]oxy}benzoate (5) (3 g (grams)).
Reaction SMILES: Br[CH:2]1[CH2:17][CH2:16][C:5]2=[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:7][C:8]([S:9][CH3:10])=[C:4]2[C:3]1=O.[C:19]([NH2:27])(=[S:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)C>C(OCC)(=O)C.O1CCCC1>[CH3:10][S:9][C:8]1[O:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]2[C:4]=1[C:3]1[N:27]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:26][C:2]=1[CH2:17][CH2:16]2
Reactant: NC(=S)c1ccccc1
Reactant: CCOC(=O)c1oc(SC)c2c1CCC(Br)C2=O
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1oc(SC)c2c1CCc1sc(-c3ccccc3)nc1-2
Yield: 57.6 %

Procedure:
A mixture of ethyl 5-bromo-4,5,6,7-tetrahydro-3-methylthio-4-oxobenzo[c]furan-1-carboxylate (2.60 g), thiobenzamide (2.14 g) and ethanol (60 ml) was refluxed under heating for 5 hours, after which it was diluted with ethyl acetate-tetrahydrofuran (3:1, v/v, 400 ml), washed with water and dried (MgSO4), after which the solvent was distilled off to yield ethyl 4,5-dihydro-8-methylthio-2-phenylfuro[3,4-e]benzothiazole-6-carboxylate (1.67 g, 57.6%), which was then recrystallized from ethyl acetate-hexane. Colorless needles. Melting point 170-171° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=[N:19][NH:20][C:21]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[C:25]([N+:33]([O-:35])=[O:34])[CH:24]=3)=[O:22])[CH3:18])[C:12]=2[OH:36])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].Cl>O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=[N:19][NH:20][C:21]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[C:25]([N+:33]([O-:35])=[O:34])[CH:24]=3)=[O:22])[CH3:18])[C:12]=2[OH:36])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(C(C)(C)C)cc3)c2O)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=NNC(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.5 %

Procedure:
To methyl 4-[(2-{1-[5-(4-tert-butylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethylidene}hydrazino)carbonyl]-2-nitrobenzoate (0.945 mmol, 466.2 mg), methanol (33 mL) was added, and 1 M aqueous sodium hydroxide (4.7 mmol, 4.7 mL) was added. After about 26 hours of stirring at room temperature and 3 hours of stirring at 40° C., 1 M hydrochloric acid (4.7 mmol, 4.7 mL) and water were added. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting yellow solid (359.5 mg) was dissolved in THF (50 mL) and stirred at room temperature for 2 days. The insolubles were filtered off, and the filtrate was concentrated and dried by means of a vacuum pump. After addition of chloroform, the precipitated solid was recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (260.7 mg, yield 58%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:19])[C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[N:8]1[CH:20]([CH3:22])[S:21][C:7]1=[C:6]([C:23]([O:25]CC)=[O:24])[C:5]2=[O:28].[OH-].[K+].C(O)(C)(C)C>O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:19])[C:11]=1[N:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]1)[N:8]1[CH:20]([CH3:22])[S:21][C:7]1=[C:6]([C:23]([OH:25])=[O:24])[C:5]2=[O:28]
Reactant: CCOC(=O)c1c2n(c3c(F)c(N4CCN(C)CC4)c(F)cc3c1=O)C(C)S2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: CC1Sc2c(C(=O)O)c(=O)c3cc(F)c(N4CCN(C)CC4)c(F)c3n21
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 38.6 %

Procedure:
To 0.5 g of ethyl 6,8-difluoro-1-methyl-7-(4-methyl-1-piperazinyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate was added 10 ml of 5% solution of potassium hydroxide in 3:1 mixture of tert-butanol and water and stirred at 60° C. for 30 minutes. tert-Butanol was evaporated therefrom in vacuo, the residue was neutralized with acetic acid, extracted with a 3:1 mixture of chloroform and methanol, the extract was washed with saturated sodium chloride solution, dried over magnesium sulfate, the solvent was evaporated therefrom, and the residue was subjected to a silica gel column chromatography (30 g of Wakogel C-300 being used) and eluted with chloroform-methanol (10:1) to give 0.18 g of desired product, m.p. 238° C. (decompn.).
Reaction SMILES: FC1C=CC(C(Cl)=O)=CC=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([N:20]=[C:21]=[S:22])=[O:19])=[CH:14][CH:13]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][CH:29]=[C:28]2[O:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[C:40]([CH3:45])[CH:39]=1.C1(C)C=CC=CC=1>C(O)C>[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([N:20]=[C:21]=[S:22])=[O:19])=[CH:16][CH:17]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][CH:29]=[C:28]2[O:37][C:38]1[CH:44]=[CH:43][C:41]([NH:42][C:21]([NH:20][C:18](=[O:19])[C:15]2[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=2)=[S:22])=[C:40]([CH3:45])[CH:39]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Agent: O=C(Cl)c1ccc(F)cc1
Agent: O=C(N=C=S)c1ccc(F)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(F)cc4)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
4-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-Fluoro-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (35 mg, yield 44%).
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=O.[CH3:18][N:19]([CH3:23])[C:20]([NH2:22])=[S:21].O.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31]([OH:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1>CCO.CC(C)=O>[C:25]1([CH3:35])[CH:26]=[CH:27][C:28]([S:31]([OH:34])(=[O:32])=[O:33])=[CH:29][CH:30]=1.[CH3:18][N:19]([CH3:23])[C:20]1[S:21][CH:3]=[C:4]([C:6]2([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:22]=1
Reactant: O=C(CBr)C1(c2ccccc2)CCNCC1
Reactant: CN(C)C(N)=S
Agent: Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Solvent: CC(C)=O
Product: CN(C)c1nc(C2(c3ccccc3)CCNCC2)cs1
Temperature: 25 °C
Yield: 76.3 %

Procedure:
A mixture of 7.26 g of the compound obtained in step B) and 2.08 g of the compound obtained in step A) in 150 ml of EtOH is refluxed for 1 hour 30 minutes. After cooling to RT, the mixture is concentrated under vacuum, the residue is taken up with water, rendered alkaline to pH 10 by the addition of 10% NaOH solution and extracted with DCM, the organic phase is washed with 10% NaOH solution and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The product obtained is dissolved in acetone, a solution of 3.31 g of p-toluenesulfonic acid monohydrate in 10 ml of acetone is added dropwise and the crystalline product formed is wrung to give 6.1 g of the expected product. M.p.=164° C.