Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C([O:15][B:16](OC(C)C)[O:17]C(C)C)(C)C.C([Li])CCC.CCCCCC>O1CCCC1>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:5]=[N:4][CH:3]=[C:2]([B:16]([OH:17])[OH:15])[CH:7]=1
Reactant: FC(F)(F)c1cncc(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1cncc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
To a solution of 3-bromo-5-(trifluoromethyl)pyridine (2.5 g, 11.06 mmol) and triisopropylborate (3.06 mL, 13.27 mmol) in anhydrous tetrahydrofuran (20 mL) at −78° C. under nitrogen was added dropwise a solution of n-butyl lithium in hexane (2.5 M, 4.9 mL, 12.17 mmol) The reaction was stirred at −78° C. for 3 hours then allowed to warm slowly to −10° C. The reaction mixture was then quenched by the addition of water (20 mL) and the tetrahydrofuran removed under reduced pressure. The resulting aqueous phase was diluted with water (40 mL) and washed with ether (2×40 mL). The aqueous phase was then acidified to pH 5 by the addition of acetic acid and the resulting suspension extracted with ethyl acetate (80 mL). The organic phase was separated, dried (MgSO4), filtered and concentrated under reduced pressure to give 3-(trifluoromethyl)pyridine-5-boronic acid (2.022 g, 96% yield) as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4](N)=[O:5].S(=O)(=O)(O)[OH:15]>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([OH:15])=[O:5]
Reactant: O=S(=O)(O)O
Reactant: NC(=O)c1cc(F)c(F)c(Cl)c1Cl
Product: O=C(O)c1cc(F)c(F)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 9 h

Procedure:
A mixture of 2,3-dichloro-4,5-difluorobenzamide (0.5 g) and 18N-sulfuric acid (2.5 ml) was stirred at 125° to 135° C. for 9 hours, and then poured into ice water. After standing overnight, the resulting precipitate was collected by filtration and recrystallized from hexane-benzene to give the title compound (0.3 g) as colorless prisms.
Reaction SMILES: COC(C1C(C)=CC(C2C=CC=C(C(F)(F)F)C=2)=CN=1)=O.ClC1C=C([C:30]2[CH:31]=[C:32]([CH3:49])[C:33]([C:36]([N:38]3[CH2:43][CH2:42][CH:41]([N:44]4[CH2:48][CH2:47][CH2:46][CH2:45]4)[CH2:40][CH2:39]3)=[O:37])=[N:34][CH:35]=2)C=CC=1Cl.[F:50][C:51]1[C:56]([C:57]([F:60])([F:59])[F:58])=[CH:55][CH:54]=[CH:53][C:52]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.[Pd](Cl)Cl>[F:50][C:51]1[C:56]([C:57]([F:60])([F:59])[F:58])=[CH:55][CH:54]=[CH:53][C:52]=1[C:30]1[CH:31]=[C:32]([CH3:49])[C:33]([C:36]([N:38]2[CH2:39][CH2:40][CH:41]([N:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)[CH2:42][CH2:43]2)=[O:37])=[N:34][CH:35]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1F
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)cnc1C(=O)N1CCC(N2CCCC2)CC1
Agent: Cl[Pd]Cl
Agent: COC(=O)c1ncc(-c2cccc(C(F)(F)F)c2)cc1C
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2cccc(C(F)(F)F)c2F)cnc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of intermediate 1A, (5-bromo-3-methyl-pyridin-2-yl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (see example 28) was reacted with 2-fluoro-3-trifluoromethyl-phenyl-boronic acid, (1,1′-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride (1:1 complex with CH2Cl2) and sodium carbonate in dioxane/water to give the title compound as brown amorphous solid. MS: 436.4 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:32]=[CH:33][C:34]=2[F:35])[CH2:25][CH2:24]1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:36][C:37](=[O:41])[CH:38]([CH3:39])[CH3:40])[CH:32]=[CH:33][C:34]=3[F:35])[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Product: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCNC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Example 35 was prepared from bis(4-fluorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.58 (dd, 1H, J=2.8, 6.4 Hz), 7.53 (s, 1H), 7.49 (br s, 1H), 7.31–6.92 (m, 10H), 4.81 (s, 1H), 3.40 (dd, 2H, J=5.6, 11.2 Hz), 2.93 (d, 2H, J=11.6 Hz), 2.76 (m, 1H), 2.49 (m, 1H), 2.42 (t, 2H, J=6.0 Hz), 2.02–1.96 (m, 2H), 1.77 (d, 2H, J=11.6 Hz), 1.69–1.62 (m, 4H), 1.22 (d, 6H, J=6.8 Hz); ESMS m/e: 552.3 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH2:13][CH:14]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]1.C(N(CC)CC)C>ClCCl>[O:11]=[CH:12][CH2:13][CH:14]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC(CCO)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(CC=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of oxalyl chloride (488 μl, 5.58 mmol) in 40 ml dichloromethane at −78° C. was added dimethyl sulfoxide (792 μl, 11.16 mmol) dropwise by syringe. The mixture was stirred for 15 minutes at −78° C. when a solution of tert-butyl 3-(2-hydroxyethyl)azetidine-1-carboxylate (936 mg, 4.65 mmol) in 10 ml dichloromethane was added dropwise by syringe. After 1 hour at −78° C., triethylamine (3241 μl, 23.25 mmol) was added and the suspension was warmed to room temperature and stirred for an additional hour. The mixture was quenched with water (25 ml) and saturated aqueous potassium carbonate (10 ml), stirred vigorously and separated. The aqueous layer was extracted with dichloromethane (2×20 ml) and the combined organic layers were dried with magnesium sulfate, filtered and concentrated. The crude material was flash chromatographed to give the title compound.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(N(CC)CC)C.Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>ClCCl.C(Cl)(Cl)Cl>[O:7]=[C:6]1[C:5]2[C:4](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3](=[O:12])[N:2]1[O:1][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To a solution of N-hydroxyphthalimide (16.31 g, 100 mmol) in dichloromethane (300 ml) was added triethylamine (20.91 ml, 150 mmol) and the mixture was stirred at 0° C. tert-Butyl bromoacetate (14.77 ml, 100 mmol) was added and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with chloroform (100 ml) and washed with water (300 ml). The organic layer was washed with brine (300 ml) and dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo. n-Hexane:ethyl acetate (80:20, 100 ml) was added to the residue and the obtained precipitate was collected by filtration to obtain the title compound (26.72 g, 96%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=3)[CH:11]=[N:10]2)[CH:6]=[CH:5][N:4]=1.C1C[O:22][CH2:21][CH2:20]1>C(Cl)(=O)C.C(N(CC)CC)C.C(Cl)Cl.CO>[CH3:1][S:2][C:3]1[N:8]=[C:7]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:21](=[O:22])[CH3:20])[CH:16]=3)[CH:11]=[N:10]2)[CH:6]=[CH:5][N:4]=1
Reactant: CSc1nccc(-n2ncc3ccc(N)cc32)n1
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CSc1nccc(-n2ncc3ccc(NC(C)=O)cc32)n1
Reaction time: 0.5 h

Procedure:
Acetyl chloride (10 drops) was added dropwise at RT to 1-(2-methylsulfanylpyrimidin-4-yl)-1H-indazol-6-ylamine (0.13 g, 0.5 mmol) and triethylamine (15 drops) in THF (5 mL), and the resulting mixture stirred for 30 min. The reaction mixture was diluted with DCM and MeOH, washed twice with aqueous NaHCO3 and once with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was treated with Et2O and hexane, and the precipitate was collected by filtration to give N-[1-(2-methylsulfanylpyrimidin-4-yl)-1H-indazol-6-yl]-acetamide (146 mg) as an off-white solid.
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13](=[O:39])[N:14]([CH3:38])[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=4)[C:19]=3[CH3:37])[CH:17]=2)=[CH:7][CH:6]=1)C.[OH-].[Na+]>C(O)C>[C:32]([C:29]1[CH:28]=[CH:27][C:26]([C:25]([NH:24][C:20]2[C:19]([CH3:37])=[C:18]([C:16]3[CH:17]=[C:12]([NH:11][C:8]4[CH:9]=[CH:10][C:5]([C:4]([OH:40])=[O:3])=[CH:6][CH:7]=4)[C:13](=[O:39])[N:14]([CH3:38])[CH:15]=3)[CH:23]=[CH:22][CH:21]=2)=[O:36])=[CH:31][CH:30]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CCOC(=O)c1ccc(Nc2cc(-c3cccc(NC(=O)c4ccc(C(C)(C)C)cc4)c3C)cn(C)c2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cc(Nc2ccc(C(=O)O)cc2)c(=O)n(C)c1
Temperature: 25 °C
Yield: 56.6 %

Procedure:
A mixture of 4-{5-[3-(4-tert-butyl-benzoylamino)-2-methylphenyl]-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino}-benzoic acid ethyl ester (6) (460 mg; 0.86 mmol), 1N NaOH (10 mL), and ethanol (10 mL) was heated at reflux for 1.5 h. The mixture was cooled to room temperature, the resulting slurry was washed with ethyl acetate (2×40 mL), and the ethyl acetate was decanted off. The aqueous slurry was taken to pH 5 with 1N HCl, filtered, washed with water and then diethyl ether to yield 4-{5-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino}-benzoic acid (7) as a light brown solid (248 mg), MS 510.34 (M+H).
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[CH2:3][NH:4][C:5](=[O:19])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:7].[CH3:21][Si]([N-][Si](C)(C)C)(C)C.[Na+].IC>CN(C)C=O.O1CCCC1.O>[CH3:21][N:4]([CH2:3][CH:2]([CH3:20])[CH3:1])[C:5](=[O:19])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:7]
Reactant: CC(C)CNC(=O)C(C)c1ccc(-c2ccsc2)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CN(C)C(=O)C(C)c1ccc(-c2ccsc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.3 %

Procedure:
To a room temperature solution of 0.3 g (1.0 mmol) of N-2-methylpropyl-2-(4-(3-thienyl)phenyl)propionamide (prepared in example 12) in 5 mL of dimethylformamide was added 1.1 mL (1.1 mmol) of 1.0 M sodium bis(trimethylsilyl)amide in tetrahydrofuran. The mixture was stirred for 10 minutes whereupon 0.2 g (1.1 mmol) of iodomethane was added and the mixture stirred at room temperature for 16 hours. The mixture was diluted with 5 mL of water and extracted three times with 5 mL each of dichloromethane. The combined organics were dried (Na2SO4), filtered and concentrated in vacuo. Chromatography (10 g silica gel, 20% ethyl acetate/hexanes) afforded 0.2 g (75%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[N+:16]([O-])=O)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=1>CO.[C].[Pd]>[NH2:16][C:15]1[CH:14]=[CH:13][C:4]([O:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=2)=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(Oc2ccnc(N)c2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(Oc2ccnc(N)c2)ccc1N
Temperature: 25 °C
Reaction time: 14.5 h
Yield: 53.1 %

Procedure:
To a solution of 4-(3-methyl-4-nitrophenoxy)pyridin-2-ylamine (1.64 g, 6.69 mmol) in methanol (75 ml) was added 10% palladium carbon (300 mg), followed by stirring under a hydrogen atmosphere at room temperature 14.5 hrs. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under a reduced pressure to give a residue, which was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:2, ethyl acetate, then ethyl acetate:methanol=20:1 to 10:1) to provide the titled compound (765 mg, 53.1%) as a brown solid.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]4[N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:27]=[CH:28][C:21]=34)[CH:17]=[N:16]2)[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].[ClH:37].O1CCOCC1.CCOCC>C(OCC)(=O)C>[CH3:35][Si:33]([CH3:34])([CH3:36])[CH2:32][CH2:31][O:30][CH2:29][N:26]1[C:22]2=[N:23][CH:24]=[CH:25][C:20]([C:18]3[CH:17]=[N:16][N:15]([C:4]4([CH2:3][C:1]#[N:2])[CH2:5][NH:6][CH2:7]4)[CH:19]=3)=[C:21]2[CH:28]=[CH:27]1.[ClH:37]
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3ccnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ccnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl 3-(cyanomethyl)-3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (0.85 g, 1.7 mmol) was dissolved in ethyl acetate (2 mL). To the solution was added 4.0 M hydrogen chloride in 1,4-dioxane (2.0 mL, 8.0 mmol). The mixture was stirred at room temperature for 3 hours. Ether was added, the mixture was centrifuged, and then the solvents were decanted. The residue was dried under vacuum to afford the desired product as HCl salt which was directly used in next step reaction without further purification. LCMS (M+H)+: m/z=409.2
Reaction SMILES: N1C=CN=C1.Cl.[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[C:8]1[CH:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1C)[N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.S(Cl)([Cl:31])=O.O1C2C=CC=CC=2C=C1C(C1C=CC=CC=1)O>C(#N)C>[ClH:31].[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[C:8]1[CH:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccccc1C(c1cc2ccccc2o1)n1ccnc1
Agent: Cl
Agent: OC(c1ccccc1)c1cc2ccccc2o1
Agent: c1c[nH]cn1
Solvent: CC#N
Product: c1ccc(C(c2cc3ccccc3o2)n2ccnc2)cc1
Reaction time: 1 h

Procedure:
To 0.08 moles of imidazole in 70 ml of acetonitrile, at the temperature of 10 C., 0.02 moles of thionylchloride are added, followed by 1 hour rest, and then 0.02 moles of (benzofuran-2-yl)phenylmethanol are added in 20 ml of acetonitrile. The reaction admixture is kept 24 hours at ambient temperature and then concentrated to dryness. The residue is taken up with ethylether, washed first with 2% sodium hydrate solution and then with water: the hydrochloride is obtained from the ethereal solutions using 5% hydrochloric acid, then an oil is obtained by alkalinization with 5% NaOH, which is extracted with ethylether. The ethereal extract is washed, made anhydrous and saturated with gaseous HCl: the precipitate thus obtained is crystallized from isopropanol: m.p. 205°-207° C. (dec.).
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[CH:9]=[CH:8][C:7]([N:10]=O)=[CH:6][CH:5]=1)[CH3:2].[C:14]1([C:20]2[CH:24]=[C:23]([NH2:25])[N:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(=O)C>[CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[CH:9]=[C:8]2[C:7]([N:10]=[C:24]3[C:20]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)=[N:21][N:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[C:23]3=[N:25]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCN(CC)c1ccc(N=O)cc1
Reactant: Nc1cc(-c2ccccc2)nn1-c1ccccn1
Solvent: CC(=O)O
Product: CCN(CC)c1ccc2nc3c(-c4ccccc4)nn(-c4ccccn4)c3nc2c1
Yield: 33 %

Procedure:
1.78 g N,N-diethyl-p-nitrosoaniline and 2.67 g 3-phenyl-1-(2-pyridyl)-5-aminopyrazole were refluxed for 2 hrs in acetic acid. The mixture was concentrated to half volume. Water was added to get a precipitate, then filtered. The solid was purified by chromatograph column on silica gel. After removing the solvent, 1.3 g pure 7-diethylamino-3-phenyl-1-(2-pyridyl)-1H-pyrazolo[3,4-b]quinoxaline (DEPPPQ) was obtained as brown-red solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:4][O:5][CH:6]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[F:32][C:33]([F:56])([F:55])[CH2:34][CH2:35][C@@H:36](OS(C(F)(F)F)(=O)=O)[C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38]>C1COCC1>[CH3:1][C:2]1[C:3]([C@H:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:36]([CH2:35][CH2:34][C:33]([F:32])([F:55])[F:56])[C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])=[N:4][O:5][CH:6]=1
Reactant: O=C(OCc1ccccc1)[C@@H](CCC(F)(F)F)OS(=O)(=O)C(F)(F)F
Reactant: Cc1conc1CC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1conc1[C@H](C(=O)OC(C)(C)C)[C@@H](CCC(F)(F)F)C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To tert-butyl 2-(4-methylisoxazol-3-yl)acetate (25 mg, 0.127 mmol) (S7C) in a 10 mL round bottomed flask at room temperature was added THF (Ratio: 4.00, Volume: 0.8 mL). The solution was colorless. The solution was stirred at −78° C. 10 min. Next, 0.5 M KHMDS in toluene (0.317 mL, 0.158 mmol) was added slowly. The color of the solution turned to light orange. The mixture was stirred at −78° C. for 10 min and then placed in a room temperature water bath. After 10 minutes, the reaction mixture was put into a −78° C. bath for 20 min. (R)-Benzyl 5,5,5-trifluoro-2-(trifluoromethylsulfonyloxy)pentanoate, Intermediate S5D (65.0 mg, 0.165 mmol) in THF (Ratio: 1.000, Volume: 0.2 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 4 h. The reaction was quenched with saturated aqueous NH4Cl at −78° C. The mixture was placed in a room temperature water bath and diluted with brine. After 5 minutes, the mixture was extracted with EtOAc. The organic layer was separated and washed with brine, dried over MgSO4, filtered and concentrated to give a crude material as Intermediate S7D.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH2:25]([O:24][C:16]([CH:17]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:23])[CH3:26]
Reactant: BrCCCCCCOCc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)C(CCCCCCOCc1ccccc1)C(=O)OCC
Yield: 60 %

Procedure:
Ethyl 2-ethoxycarbonyl-8-benzyloxyoctanoate was prepared from 6-benzyloxyhexyl bromide (3.52 g, 13 mmol) and diethyl malonate (2.29 g, 14 mmol) according to the general procedure given above. Yield 60%, bp 152-158° C./0.15 torr. 1H-NMR: 1.24 (t, 6H), 1.2-1.9 (m, 10H), 3.43 (t, 2H), 4.18 (q, 4H), 4.45 (s, 2H), 7.27 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])[C:3]=1[CH:20]([OH:24])[C:21](=[O:23])[CH3:22].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])[C:3]=1[C:20](=[O:24])[C:21](=[O:23])[CH3:22]
Reactant: CC(=O)C(O)c1c(F)cccc1Oc1cnc2c(F)cccc2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(=O)C(=O)c1c(F)cccc1Oc1cnc2c(F)cccc2c1
Reaction time: 3 h
Yield: 57.5 %

Procedure:
After 0.14 g of 1-[2-fluoro-6-(8-fluoroquinolin-3-yloxy)-phenyl]-1-hydroxy-propan-2-one was dissolved in 10 ml of dichloromethane, 0.91 g of Dess-Martin reagent was added thereto at 0° C. After 3 hours of stirring, the reaction solution was concentrated and purified by silica gel column chromatography to obtain 0.08 g of 1-[2-fluoro-6-(8-fluoroquinolin-3-yloxy)-phenyl]-propane-1,2-dione (Compound Number 396).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[C:13]([O:20][CH3:21])(=[O:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16].N1CCCCC1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=[C:14]([C:13]([O:20][CH3:21])=[O:19])[C:15]([O:17][CH3:18])=[O:16]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: COC(=O)CC(=O)OC
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COC(=O)C(=Cc1ccc(OC)cc1OC)C(=O)OC
Temperature: 25 °C
Yield: 105.8 %

Procedure:
2,4-Dimethoxybenzaldehyde (10.0 g, 0.060 mol), dimethyl malonate (9.5 g, 0.072 mol), piperidine (1.5 g, 0.017 mol), benzoic acid (1.8 g, 0.015 mol) and 100 mL of toluene are stirred at reflux for 5.5 hours under a Dean Stark trap to remove water. After cooling to room temperature, the reaction mixture is partitioned between ethyl acetate and water. The organic layer is washed with 10% hydrochloric acid, water and brine. The resulting solution is dried over anhydrous magnesium sulfate and then concentrated to yield 17.8 g of an orange syrup which is purified by chromatography on silica gel (2:1, heptane:ethyl acetate) to provide 12.8 g of the title compound as a pale yellow solid melting at 71–73° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:40])=[C:14]([C:35](OCC)=[O:36])[C:15](=[O:34])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]([CH3:33])[C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:41]([O:43][CH2:44][CH2:45][NH2:46])[CH3:42]>>[CH2:41]([O:43][CH2:44][CH2:45][NH:46][C:35]([C:14]1[C:15](=[O:34])[N:16]([CH2:19][CH2:20][CH2:21][N:22]([CH3:33])[C:23](=[O:24])[O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:17]2[C:12]([C:13]=1[OH:40])=[N:11][CH:10]=[C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH:18]=2)=[O:36])[CH3:42]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN(C)C(=O)OCc2ccccc2)c1=O
Reactant: CCOCCN
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN(C)C(=O)OCc2ccccc2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[3-(methyl{[(phenylmethyl)oxy]carbonyl}amino)propyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-(ethyloxy)ethanamine using conditions similar to Step 5 from Example 497 and obtained as a white solid: ES+ MS: 591 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])([O-:3])=[O:2].C[O-].[Na+].C([O-])(=O)C.[Na+].Cl.[NH2:21][OH:22]>CO.O.C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7](=[N:21][OH:22])[NH2:8])([O-:3])=[O:2]
Reactant: NO
Reactant: N#Cc1cccc([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: C[O-]
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: NC(=NO)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.5 %

Procedure:
In a 500-ml flask, place 30.6 g (0.21 m) of 3-nitrobenzonitrile (3a; R2=3-nitrophenyl) and 150 ml of methanol and stir to absolution. Add 48 g (0.22 m) of 25 wt. % sodium methoxide in methanol slowly and stir at room temperature for 1.5 hrs. Add 22.5 ml of acetic acid to make pH of reaction mixture around 6. Add 18.1 g (0.22 m) of sodium acetate and 22 g (0.32 m) of hydroxylamine hydrochloride. After a few minutes with stirring, the reaction mixture becomes thick yellow slurries. Stir the slurries at room temperature for 1 hr. Add 130 ml of water and stir for 15 min. Collect solid, wash with water and dry in air to give 30.5 g (80%) of 3-nitrobenzamidoxime (9a; R=3-nitrophenyl).