Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7](C=O)=[CH:6]1)(=[O:4])=[O:3].ClC1C=CC=C(C(OO)=[O:24])C=1>ClCCl>[CH3:1][S:2]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7](=[O:24])[CH2:6]1)(=[O:4])=[O:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS(=O)(=O)n1cc(C=O)c2cccnc21
Solvent: ClCCl
Product: CS(=O)(=O)N1CC(=O)c2cccnc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
1-Methanesulfonyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (2.84 g, 12.7 mmol) from step 2 was dissolved in dichloromethane (150 ml) and cooled to 0° C. Meta-chloroperbenzoic acid (3.4 g, 15 mmol) was added in several portions. The reaction mixture was stirred under a nitrogen atmosphere overnight, while slowly warming to room temperature. The reaction mixture was filtered through a plug of basic alumina and concentrated under reduced pressure to a yellow solid. The crude product was chromatographed over silica gel eluting with 50% ethyl acetate in hexane to yield 1-methanesulfonyl-1,2-dihydro-pyrrolo[2,3-b]pyridin-3-one (700 mg, 26%). 1H NMR (DMSO-d6) δ: 3.59 (3H, s), 4.60 (2H, s), 7.45 (1H, dd, J=4.9 Hz, 7.7 Hz), 8.31 (1H, dd, J=1.8 Hz, 7.7 Hz), 8.84 (1H, dd, J=1.8 Hz, 4.9 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[CH3:12][C:13]1[S:14][C:15]([C:18]([NH:20][NH2:21])=[O:19])=[CH:16][N:17]=1>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:11])[NH:21][NH:20][C:18]([C:15]1[S:14][C:13]([CH3:12])=[N:17][CH:16]=1)=[O:19]
Reactant: Cc1ncc(C(=O)NN)s1
Reactant: Cc1ccc(N=C=O)c(C)c1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)NNC(=O)c2cnc(C)s2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound was prepared from a mixture 2,4-dimethylphenylisocyanate (50 mg, 0.34 mmol) and 2-methylthiazole-5-carboxylic acid hydrazide (59 mg, 0.37 mmol) in methylenedichloride (10 mL). The mixture was stirred at room temperature for 2 h, and the resultant precipitate was collected by filtration and isolated as pale white solid (66 mg, 64%). 1H NMR (DMSO-d6): 10.00 (s, 1H), 8.39 (s, 1H), 8.25 (s, 1H), 7.88 (s, 1H), 7.46 (d, J=8.1 Hz, 1H), 6.99 (s, 1H), 6.87 (d, J=8.1 Hz, 1H), 2.72 (s, 3H), 2.22 (s, 3H), 2.16 (s, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])=[CH:30][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12])C1C=CC=CC=1>CO.C(OCC)(=O)C.[C].[Pd]>[CH2:40]([N:37]([CH2:38][CH3:39])[CH2:36][CH2:35][O:34][C:31]1[CH:32]=[CH:33][C:9]([OH:8])=[C:10]([CH:30]=1)[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12])[CH3:41]
Reactant: CCN(CC)CCOc1ccc(OCc2ccccc2)c(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCN(CC)CCOc1ccc(O)c(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.3 %

Procedure:
To a solution mixture of the obtained methyl 2-(2-(benzyloxy)-5-(2-(diethylamino)ethoxy)benzamido)-4-phenylbenzoate (0.15 g) in methanol (3.0 mL) and ethyl acetate (3.0 mL), 10% palladium-carbon (0.030 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 3 hours. The insoluble substance was removed by filtration, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-96% chloroform/methanol] to obtain 0.087 g of methyl 2-(5-(2-(diethylamino)ethoxy)-2-hydroxybenzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH:57]1[C:65]2[C:60](=[CH:61][C:62]([CH:66]([CH3:73])[CH2:67][C:68]([O:70][CH2:71][CH3:72])=[O:69])=[CH:63][CH:64]=2)[CH2:59][CH2:58]1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:57]2[C:65]3[C:60](=[CH:61][C:62]([CH:66]([CH3:73])[CH2:67][C:68]([O:70][CH2:71][CH3:72])=[O:69])=[CH:63][CH:64]=3)[CH2:59][CH2:58]2)=[O:23])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: CCOC(=O)CC(C)c1ccc2c(c1)CCN2
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC(C)c1ccc2c(c1)CCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Reaction time: 1 h
Yield: 57.3 %

Procedure:
A solution of [3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetic acid (2.9 g) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (3.7 g) in dimethylformamide (about 40 ml) was treated with diisopropylethylamine (10 ml), followed after about 30 seconds by a solution of (R/S) ethyl 3-(2,3-dihydro-1H-indol-5-yl)butyrate [about 2.5 g, Reference Example 5(a)] in dimethylformamide (about 10 ml). The resulting clear, dark brown solution was kept at room temperature for about one hour then evaporated to low bulk. The residue was partitioned between water and ethyl acetate and the organic layer was washed with dilute hydrochloric acid, then with aqueous sodium bicarbonate solution, then with brine, then dried and then evaporated. The residual brown gum was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and petrol (3:2 to 3:1, v/v) to give the title compound (2.8 g) as a light yellow, amorphous foam. MS (ES+) 552 (M−Na+).
Reaction SMILES: [CH3:1][C:2]([NH:7][S:8]([C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:14][CH:15]=1)(=[O:10])=[O:9])([CH3:6])[C:3]([OH:5])=O.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[CH3:57][Si:58]([CH3:64])([CH3:63])[CH2:59][CH2:60][O:61][NH2:62]>C(Cl)Cl>[CH3:6][C:2]([NH:7][S:8]([C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:14][CH:15]=1)(=[O:10])=[O:9])([CH3:1])[C:3]([NH:62][O:61][CH2:60][CH2:59][Si:58]([CH3:64])([CH3:63])[CH3:57])=[O:5]
Reactant: CC(C)(NS(=O)(=O)c1ccc(-c2ccccn2)s1)C(=O)O
Reactant: C[Si](C)(C)CCON
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(NS(=O)(=O)c1ccc(-c2ccccn2)s1)C(=O)NOCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.1 %

Procedure:
To a solution of 2-methyl-2-(5-pyridin-2-ylthiophene-2-sulfonylamino)-propionic acid (1.60 grams, 4.91 mmole) in methylene chloride (160 mL) was added triethylamine (2.3 mL, 16.5 mmole), (benzotriazol-1-yloxy)tris(dimethylamino)-phosphonium hexafluorophosphate (2.4 grams, 5.41 mmole) and O-(2-trimethylsilylethyl)hydroxylamine hydrochloride (0.92 grams, 5.41 mmole). The resulting mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was taken up in ethyl acetate. The solution was washed with water, aqueous saturated sodium bicarbonate solution, and brine. After drying over magnesium sulfate, the solvent was evaporated to afford a white foam from which the desired product, 2-methyl-2-(5-pyridin-2-ylthiophene-2-sulfonylamino)-N-(2-trimethylsilanylethoxy)-propionamide (220 mg, 10%), a white solid, was isolated by chromatography on silica gel eluting with 3:2 ethyl acetate/hexanes.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:5])[CH3:2]>[Pd].C(OCC)(=O)C>[NH2:14][C:13]1[C:8]([O:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)COc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ncccc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
A mixture of 48.3 g of 2-(ethoxycarbonyl)methoxy-3-nitropyridine, 7.8 g of 10% palladium/carbon and 540 ml of ethyl acetate was stirred for 3 hours at room temperature under hydrogen atmosphere. The reaction system was purged with nitrogen, then, the reaction solution was filtrated through Celite, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain 37.1 g of 3-amino-2-(ethoxycarbonyl)methoxypyridine. 1H-NMR(CDCl3/300 MHz) δ(ppm): 1.27 (t, 3H, J=7.1 Hz), 3.8-3.9 (b, 2H), 4.24 (q, 2H, J=7.1 Hz), 4.93 (s, 2H), 6.7-6.8 (m, 1H), 6.8-7.0 (m, 1H), 7.4-7.6(m, 1H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=3)[N:10]([C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc2[nH]nc(-c3cccc(F)c3)c2c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)c(-c1cccc(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 75.5 %

Procedure:
To a solution of 2.43 g of methyl 3-(3-fluorophenyl)-1H-5-indazolecarboxylate produced in Production Example I-4-e in 25 ml tetrahydrofuran was added 720 mg of 60% sodium hydride (oily), and the mixture was stirred under ice-cooling for 10 minutes. Then, 3.26 g of chlorotriphenylmethane was added and the mixture was stirred at the same temperature for 30 minutes and at room temperature for 1 hour. The reaction mixture was ice-cooled, saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with 100 ml of ethyl acetate. The organic layer was sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was crystallized from ethyl acetate-diisopropyl ether, to give 3.48 g of the title compound as white crystals. In addition, the mother liquor was concentrated, and then the residue was crystallized from diisopropyl ether, to give 0.37 g of the title compound as white crystals.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:18][C:19]([C:21]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:22]=1[N:23]([CH3:26])[CH:24]=[O:25])=[O:20]>ClCCl>[C:1]([O:9][CH2:18][C:19]([C:21]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:22]=1[N:23]([CH3:26])[CH:24]=[O:25])=[O:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)CCl)c(N(C)C=O)c1
Reactant: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)COC(=O)c2ccccc2)c(N(C)C=O)c1
Temperature: 25 °C

Procedure:
A solution of benzoic acid (30.3 g) and triethylamine (50.1 ml) in dichloromethane (150 ml) was added dropwise at 0° over a period of 15 minutes to the solution of 2'-(2-chloroacetyl)-5'-methyl-N-methylformanilide obtained above. The resultant solution was allowed to warm to ambient temperature and then heated under reflux overnight. After cooling the reaction mixture was washed with water (2×200 ml), dried over magnesium sulphate and evaporated to give crude 2-[4-methyl-2-(N-methylformamido)phenyl]-2-oxoethyl benzoate.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][OH:19])=[CH:16][C:3]1=2.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[CH3:20][S:21]([O:19][CH2:18][CH2:17][C:15]1[CH:14]=[CH:13][C:4]2[O:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:2](=[O:1])[C:3]=2[CH:16]=1)(=[O:23])=[O:22]
Reactant: O=C1c2ccccc2COc2ccc(CCO)cc21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCc1ccc2c(c1)C(=O)c1ccccc1CO2
Reaction time: 0.25 h
Yield: 39.1 %

Procedure:
A stirred chilled (-5° C.) solution of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethanol (5.08 g, 0.02 mol) and anhydrous pyridine (28 ml) was treated over 60 seconds with methanesulfonyl chloride (2.74 g, 0.024 mol). A mild exotherm was noted and a precipitate separated with continued cooling and stirring for 15 minutes after addition of the methanesulfonyl chloride was completed. Additional methanesulfonyl chloride (1.37 g, 0.012 mol) was added over 30 seconds and after stirring for 15 minutes the cooling bath was removed. After stirring 2 hours at ambient temperature, the mixture was decanted into 400 ml of ice cold water. The aqueous phase was decanted and the residual oil was stirred with water (300 ml). The water was decanted and the residual semisolid was triturated with ether. The resultant solid was collected, washed with ether and dried in vacuo to afford 4.92 g of crude material. Recrystallization from acetonitrile (15 ml) afforded 2.60 g (39.1 %) of crystals, m.p. 108°-110° C.
Reaction SMILES: [CH:1]1([NH:4][C:5](=S)[NH:6][NH2:7])[CH2:3][CH2:2]1.[Cl:9][CH:10]([C:16]([CH3:18])=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>Cl>[ClH:9].[CH:1]1([NH:4][C:5]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:16]([CH3:18])[NH:7][N:6]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NNC(=S)NC1CC1
Agent: Cl
Product: CCOC(=O)c1c(NC2CC2)n[nH]c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.9 %

Procedure:
A stirred slurry of 10.4 g (0.079 mole) of 4-cyclopropyl-3-thiosemicarbazide under nitrogen atmosphere was treated with 13 g (0.079 mole) of ethyl 2-chloroacetoacetate, stirred at ambient temperature for 1 hr, treated with 30 mL of 2N ethanolic hydrogen chloride and heated to reflux. The reaction mixture was allowed to cool to ambient temperature while stirring for ~72 hr. The sulfur residue was removed by filtration and the filtrate concentrated in vacuo to an orange oil which solidified. Recrystallization twice from acetone gave 7.4 g of large blade-like crystals, after drying for 2 hr at 98° C. under reduced pressure, mp 147°-148.5° C. The filtrates gave an additional 6 g of crude product. The 2 solids were combined ad recrystallized from methyl ethyl ketone to give 6.3 g of white crystalline power, mp 151°-152° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:28]([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31])=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12]Cl)=[O:9].[CH2:35]([NH:37][CH2:38][CH3:39])[CH3:36]>C(O)CC.[I-].[Na+]>[CH3:1][C:2]1[NH:3][C:4]([CH:28]([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31])=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][N:37]([CH2:38][CH3:39])[CH2:35][CH3:36])=[O:9]
Reactant: CCNCC
Reactant: CCOC(=O)C1=C(C(OCC)OCC)NC(C)=C(C(=O)OCCCl)C1c1cccc([N+](=O)[O-])c1
Agent: [I-]
Agent: [Na+]
Solvent: CCCO
Product: CCOC(=O)C1=C(C(OCC)OCC)NC(C)=C(C(=O)OCCN(CC)CC)C1c1cccc([N+](=O)[O-])c1
Yield: 19.3 %

Procedure:
A mixture of 2-chloroethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate (20 g), diethylamine (1.75 g) and sodium iodide (60.3 mg) in n-propylalcohol (4 ml) was refluxed for 17 hours. After removal of the solvent from the reaction mixture, water and ethyl acetate were added to the residue. The ethyl acetate layer was washed twice with water, dried over magnesium sulfate, and concentrated to give a brown oil (2.46 g) of 2-(N,N-diethylamino)ethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate, which was identified by converting to the corresponding 6-formyl compound (oil) and then to the corresponding 6-cyano compound, m.p. 150° to 152° C.
Reaction SMILES: [F:1][C:2]([F:14])([O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[C:3]([OH:5])=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:22][NH:23][O:24][CH3:25]>C(Cl)Cl.CN(C=O)C>[F:14][C:2]([F:1])([O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[C:3]([N:23]([O:24][CH3:25])[CH3:22])=[O:5]
Reactant: CNOC
Reactant: O=C(O)C(F)(F)Oc1ccc(F)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CON(C)C(=O)C(F)(F)Oc1ccc(F)cc1
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a solution of 2,2-difluoro-2-(4-fluorophenoxy)acetic acid (2.2 g, 10.6 mmol) in DCM (20 ml), were added oxalyl chloride (1.02 ml, 12 mmol) and a couple of drops of DMF and the reaction mixture was stirred for 2 h. The reaction mixture was evaporated to dryness and the yellowish residue was dissolved in DCM. The solvent was evaporated again and the residue was left under light vacuum (30 mm Hg) for 1 h. After dissolving the residue in DCM (20 ml), N,O-dimethyl hydroxylamine hydrochloride (1.24 g, 12.7 mmol) and TEA (25.4 mmol) were added. After stirring the reaction mixture overnight at rt, the heterogeneous mixture was washed with water and brine. After drying over sodium sulfate, the solvent was removed under vacuum to yield 2,2-difluoro-2-(4-fluorophenoxy)-N-methoxy-N-methylacetamide as an oil (2.05 g, 77%).
Reaction SMILES: [OH:1][C:2]([C:31]([F:34])([F:33])[F:32])([CH2:15][C:16]([CH3:30])([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2([CH3:29])OCC[O:25]2)[CH:19]=1)[CH3:17])[CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[CH:6]=[CH:5]1.C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH+]1C=CC=CC=1>O>[C:24]([C:20]1[CH:19]=[C:18]([C:16]([CH3:30])([CH3:17])[CH2:15][C:2]([OH:1])([C:31]([F:32])([F:33])[F:34])[CH2:3][N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:14])[CH:6]=[CH:5]2)[CH:23]=[CH:22][CH:21]=1)(=[O:25])[CH3:29]
Reactant: CC(C)(CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F)c1cccc(C2(C)OCCO2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CCO
Product: CC(=O)c1cccc(C(C)(C)CC(O)(Cn2ccc(=O)c3ccccc32)C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A mixture of 1-{2-hydroxy-4-methyl-4-[3-(2-methyl-[1,3]dioxolan-2-yl)phenyl]-2-trifluoromethylpentyl}-1H-quinolin-4-one (0.35 g, 0.75 mmol), ethanol (24 mL), water (4.8 mL), and pyridinium p-toluenesulfonic acid (95 mg, 0.37 mmol) was heated to reflux for 3 hours, cooled to room temperature, and concentrated in vacuo to remove most of the ethanol. The residue was diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine, and dried over sodium sulfate. Removal of the volatiles in vacuo afforded 1-[4-(3-acetylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1-H-quinolin-4-one. Yield: 0.27 g (84%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:19]4=[N:20][CH:21]=[N:22][CH:23]=[C:18]4[CH:17]=[N:16]3)=[CH:11][CH:10]=2)O1.[OH-:25].[Na+].OO>C1COCC1>[N:15]1([C:12]2[CH:13]=[CH:14][C:9]([OH:25])=[CH:10][CH:11]=2)[C:19]2=[N:20][CH:21]=[N:22][CH:23]=[C:18]2[CH:17]=[N:16]1
Reactant: [OH-]
Reactant: CC1(C)OB(c2ccc(-n3ncc4cncnc43)cc2)OC1(C)C
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1ccc(-n2ncc3cncnc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The title compound 4-(1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenol (22) was prepared by the following procedure: To a solution of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine (22C) (100 mg, 0.31 mmol) in THF (5 mL) was added NaOH (0.248 mL, 0.621 mmol) and hydrogen peroxide (0.048 mL, 0.466 mmol). The mixture was stirred at 0° C. for 30 minutes The reaction mixture was concentrated and the residue was dissolved water (8 mL). The aqueous solution was acidified with diluted HCl. The white precipitate was collected, washed with water and dried to provide the title compound 4-(1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenol (22): 1H NMR (400 MHz, DMSO-D6) δ ppm 9.75 (1H, s), 9.44 (1H, s), 9.09 (1H, s), 8.59 (1H, s), 7.82-7.99 (2H, m), 6.83-7.05 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=O)[CH2:10]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].[ClH:26].Cl.O>C(O)C>[ClH:26].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:10]1
Reactant: Cc1ccc(F)c(C2CC(=O)c3c(C)ccnc3C2)c1
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc(F)c(C2CC(=NNC(=N)N)c3c(C)ccnc3C2)c1
Yield: 94.7 %

Procedure:
To a solution of 7-(2-fluoro-5-methylphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.1 g) and aminoguanidine hydrochloride (0.54 g) in ethanol (30 ml) were added concentrated hydrochloric acid (1.0 ml) and water (1.0 ml), and the mixture was refluxed for 7 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate, and to the aqueous layer 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 saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol, and to the solution was added 1N hydrochloric acid (10 ml). The mixture was concentrated, and precipitated crystals were recrystallized from ethanol to give 7-(2-fluoro-5-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 163) (1.4 g) as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]1[O:21][CH2:22][O:23][C:10]=1[CH:9]=2)=[O:5])[CH3:2].[Se](=O)=[O:25]>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:25])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]1[O:21][CH2:22][O:23][C:10]=1[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2cc3c(cc2C1)OCO3
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(c2ccccc2)c2cc3c(cc2C1=O)OCO3
Reaction time: 24 h
Yield: 69.5 %

Procedure:
5,6-Methylenedioxy-3-phenyl-1H-indene-2-carboxylate ethyl ester (3 g, 9.73 mmol) was dissolved in 1,4-dioxane. Selenium dioxide (10.8 g, 97.3 mmol) was added thereto and the reaction mixture was refluxed while stirring for 1 day, followed by cooling. The solution obtained after filtering residual solid selenium dioxide was combined with 1M sodium bicarbonate, and extracted with ether/water. The extract was dried over anhydrous magnesium sulfate, concentrated, and the resulting residue was purified by column chromatography to obtain 5,6-methylenedioxy-1-oxo-3-phenyl-1H-indene-2-carboxylate ethyl ester (2.18 g, yield 70%).