Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:6]([C:7](OCC)=[O:8])[CH2:5][CH2:4][N:3]1[C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:32])([F:31])[F:30])[NH:18][C:19]2=[O:22])=[CH:14][CH:13]=1.[BH4-].[Na+].[Cl-].[Ca+2].[Cl-]>CO>[OH:8][CH2:7][CH:6]1[CH2:5][CH2:4][N:3]([C:12]2[CH:21]=[C:20]3[C:15]([CH:16]=[C:17]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:30])[F:31])[NH:18][C:19]3=[O:22])=[CH:14][CH:13]=2)[C:2]1=[O:1]
Reactant: CCOC(=O)C1CCN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C1=O
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CO
Product: O=C1C(CO)CCN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.7 %

Procedure:
The 2-oxo-1-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]pyrrolidin-3-carboxylic acid ethyl (11 mg, 0.025 mmol) prepared in step B of Example 1-45, sodium borohydride (9.5 mg, 0.25 mmol), and calcium chloride (27.7 mg, 0.25 mmol) were dissolved in methanol (5 ml), and the obtained solution was then stirred at a room temperature for 16 hours. Thereafter, the reaction solution was concentrated, and it was then purified using ODS cartridge 5 g (Mega Bond Elut (registered trademark) C18, manufactured by Varian; water methanol=1:0 to 0:1). The resultant was then preparatively separated by preparative HPLC (column: Combi ODS (φ: 28.0 mm×50 mm) manufactured by Wako; developing solvent: 0.05% trifluoroacetic acid-containing water: 0.05% trifluoroacetic acid-containing acetonitrile=90:10 to 5:95), so as to obtain 7-(3-hydroxymethyl-2-oxopyrrolidin-1-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (5 mg, 50%) in the form of a white amorphous substance.
Reaction SMILES: [OH:1][CH:2]([C:19]1[S:20][CH:21]=[CH:22][N:23]=1)[C:3]1[CH:4]=[C:5]([C:16]([OH:18])=O)[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:8]=1.Cl.Cl.[CH3:26][C:27]1[N:32]=[CH:31][C:30]([C@H:33]([NH2:35])[CH3:34])=[CH:29][CH:28]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:1][CH:2]([C:19]1[S:20][CH:21]=[CH:22][N:23]=1)[C:3]1[CH:4]=[C:5]([C:16]([NH:35][C@@H:33]([C:30]2[CH:31]=[N:32][C:27]([CH3:26])=[CH:28][CH:29]=2)[CH3:34])=[O:18])[CH:6]=[C:7]([C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[CH:8]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(O)c3nccs3)c2)cc1
Reactant: Cc1ccc([C@@H](C)N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3ccc(C)nc3)cc(C(O)c3nccs3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 5-(hydroxy(thiazol-2-yl)methyl)-4′-methylbiphenyl-3-carboxylic acid (31 mg, 0.095 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (50 mg, 0.24 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (100 mg, 0.26 mmol), and N,N-diisopropylethylamine (300 μL, 1.72 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford the final product as a light brown solid.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[N:9]1[C:15](=[O:35])[C:16]([C:18]1[CH:22]=[CH:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH:19]=1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CCOC(C)=O.CO>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[N:9]1[C:15](=[O:35])[CH:16]([C:18]1[CH:22]=[CH:21][N:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:27][CH:28]=2)[CH:19]=1)[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)C(=O)c1ccn(-c2ccc(-c3ccccc3)cc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)C(O)c1ccn(-c2ccc(-c3ccccc3)cc2)c1
Reaction time: 2.75 h
Yield: 99.2 %

Procedure:
To a solution of 1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-[1-(biphenyl-4-yl)-1H-pyrrol-3-yl)ethane-1,2-dione (250 mg, 0.54 mmol) in EtOAc (6 mL) and MeOH (2 mL) at 0° C. was added NaBH4 (20 mg, 0.54 mmol). After 2.75 hours at 0° C., more NaBH4 (20 mg, 0.54 mmol) was added. After 1.25 hours at 0° C., the reaction was quenched with HOAc (few drops) and H2O (2 mL). The pH was adjusted to 5 (by pH paper) with HOAc and partitioned between H2O (25 mL) and EtOAc (25 mL). The organic layers were dried over Na2SO4 and concentrated to provide 0.25 g (99%) of 1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-[1-(biphenyl-4-yl)1H-pyrrol-3-yl]-2-hydroxy-ethanone as a crisp foam. 1HNMR: δ 7.65 (d, 2H, J=8.5 Hz), 7.59 (d, 2H, J=7.4Hz), 7.48-7.19 (m, 10H), 7.14 (t, 1H, J=2.0 Hz), 7.06 (t, 1H, J=2.6 Hz), 6.31 (t, 1H, J=2.4 Hz), 5.11 (d, 1H, J=7.4 Hz), 4.29 (d, 1H, J=6.6 Hz), 3.99-3.95 (m, 1H), 3.76 (d, 1H, J=9.2 Hz), 3.60 (dd, 1H, J=5.0, 8.6 Hz), 3.08-3.02 (m, 1H), 2.90 (dd, 1H, J=10.5, 13.4 Hz), 1.82 (s, 3H), 1.60 (s, 3H). Anal. Calculated for C30H30N2O3.0.4 H2O: C, 76.05; H, 6.55; N, 5.91. Found: C, 76.17; H, 6.66; N, 5.74.
Reaction SMILES: [F:1][C:2]1[C:3]([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[C:14]([O:19][CH3:20])[C:13]=3[C:12]([C:21]3[CH:22]=[N:23][N:24](COCC[Si](C)(C)C)[CH:25]=3)=[N:11]2)=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[F:1][C:2]1[C:3]([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[C:14]([O:19][CH3:20])[C:13]=3[C:12]([C:21]3[CH:25]=[N:24][NH:23][CH:22]=3)=[N:11]2)=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: COc1nccc2c1c(-c1cnn(COCC[Si](C)(C)C)c1)nn2-c1c(F)cccc1C#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1nccc2c1c(-c1cn[nH]c1)nn2-c1c(F)cccc1C#N
Temperature: 25 °C
Reaction time: 5 h
Yield: 40 %

Procedure:
To a solution of 3-fluoro-2-(4-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzonitrile (400 mg) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL), and the mixture was stirred at room temperature for 5 hr. To the reaction mixture was added aqueous sodium carbonate solution. The organic layer was separated, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether) to give the title compound (115 mg).
Reaction SMILES: C(OC(C)(C)C)(=O)C=C.[CH2:10]1[C:14]2=[C:15]([CH:22]=O)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[N:13]2[CH2:12][CH2:11]1.[CH3:24][N:25]1C2C(=CC=CC=2)C(C)=C1C=O>>[CH3:24][NH:25][CH2:22][C:15]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=2[N:13]2[CH2:12][CH2:11][CH2:10][C:14]=12
Reactant: O=Cc1c2n(c3ccccc13)CCC2
Reactant: Cc1c(C=O)n(C)c2ccccc12
Agent: C=CC(=O)OC(C)(C)C
Product: CNCc1c2n(c3ccccc13)CCC2
Yield: 54 %

Procedure:
According to the procedure of Preparation 13 (c), except substituting 2,3-dihydro-1H-3a-azacyclopenta[α]indene-8-carboxaldehyde (0.17 g, 0.92 mmole) for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (0.1 g, 54%) was prepared as a yellow oil: MS (ES) m/e 201 (M+H)+.
Reaction SMILES: C(O[CH:4](OCC)[C:5](=[NH:16])[NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)C>S(=O)(=O)(O)O>[CH3:15][O:14][C:11]1[CH:10]=[C:9]2[C:8](=[CH:13][CH:12]=1)[CH:7]=[N:6][C:5]([NH2:16])=[CH:4]2
Reactant: CCOC(OCC)C(=N)NCc1ccc(OC)cc1
Agent: O=S(=O)(O)O
Product: COc1ccc2cnc(N)cc2c1
Yield: 2.9 %

Procedure:
The crude 2,2-diethoxy-N-(4-methoxybenzyl)acetimidamide (23 g) was added dropwise to conc. sulfuric acid (200 mL) at 20˜25° C. with stirring. The mixture was stirred at room temperature for 48 hours and then quenched with ice (1 Kg). 12 N NaOH solution (400 mL) was added to give a final pH of 9˜10. The resulting suspension was extracted with CH2Cl2 (5×2 L). The organic layers were combined, washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The crude material was further purified by silica gel chromatography (EtOAc/Hexane=1/1) and afforded the title compound (430 mg, 2.9% yield based on p-methoxybenzylamine) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): 8.62 (s, 1H), 7.66 (d, J=9 Hz, 1H), 6.86 (d, J=2.4, 1H), 6.75 (dd, J=2.4 and 9 Hz, 1H), 6.52 (s, 1H), 5.83 (s, 1H), 3.83 (s, 3H); MS: m/z 175.1 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:12]=[CH:11][N:10]=1)[CH:15]=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccnc(OCc2ccccc2)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1ccnc(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
A suspension of [2-(benzyloxy)-4-pyridyl]methanol (6.0 g) and activated manganese dioxide (30 g) in chloroform (180 mL) was heated under reflux for 2.5 hours. After the reaction solution was allowed to cool to room temperature, the manganese dioxide was filtered off and washed with ethyl acetate. The filtrate was concentrated to give the title compound as a pale brown oil (5.34 g).
Reaction SMILES: C(Cl)Cl.[F:4][C:5](F)(F)[C:6]([C:16]([F:19])([F:18])[F:17])=[C:7](F)[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].CCN(CC)CC.[CH3:29][NH:30][NH2:31]>O>[CH3:29][N:30]1[C:5]([F:4])=[C:6]([C:16]([F:19])([F:18])[F:17])[C:7]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])=[N:31]1
Reactant: CNN
Reactant: FC(=C(C(F)(F)F)C(F)(F)F)C(F)(F)C(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In a 3-kneck flask equipped with condenser, thermometer, and a dropping funnel 130 ml methylene chloride and perfluoro-2-methyl-2-pentene (19.6 g, 0.065 mol) was placed and then 15 ml water were added. The mixture was cooled to 0° C. and Et3N (16.4 g, 0.16 mol) was added at a temperature ranging from 0° C. to 5° C. The mixture was stirred at this temperature for 15 min and 40% solution of methylhydrazine in water (7.4 g) was slowly added to this mixture at 0° C. The reaction mixture was stirred for 1 h at 5° C. and finally for 1.5 h at 20° C. The mixture was washed with water (3×50 ml), the organic layer was dried over Na2SO4 and the solvent was distilled off under atmospheric pressure. The crude product was purified via vacuum distillation. The yield of N-methyl-3-pentafluoroethyl-4-trifluoromethyl-5-fluoro-1H-pyrazole was 13.9 g. (75%), boiling point 62-65° C. at 17 mbar.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[CH2:10][OH:11].ClCCl>O1CCCC1.[O-2].[O-2].[Mn+4]>[NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[CH:10]=[O:11]
Reactant: Cc1cc(Cl)cc(CO)c1N
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(C=O)c1N
Temperature: 40 °C
Reaction time: 16 h
Yield: 72.9 %

Procedure:
The (2-amino-5-chloro-3-methylphenyl)methanol (10.8 g, 63.1 mmol) was dissolved in tetrahydrofuran (20 mL). Dichloromethane (50 mL) was added along with activated carbon (16.3 g). Activated manganese dioxide (16.8 g, 189 mmol) was added and the solution stirred at 40° C. for 16 h. The solution was cooled to room temperature and vacuum filtered through a celite. The solvent was removed at reduced pressure and the 2-amino-5-chloro-3-methylbenzaldehyde (7.90 g, 46.0 mmol) obtained by recrystallization from diethyl ether/hexanes (1:10, 100 mL). HRMS m/z 169.0280; calcd 169.0294.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:9]=1[NH2:10].[CH3:16][CH2:17][CH2:18][C:19]#[C:20][CH2:21][CH2:22][CH3:23]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.[Fe+2].CN1C(=O)CCC1>[CH2:18]([C:19]1[NH:10][C:9]2[C:8]([C:20]=1[CH2:21][CH2:22][CH3:23])=[CH:14][C:13]([F:15])=[CH:12][CH:11]=2)[CH2:17][CH3:16]
Reactant: CCCC#CCCC
Reactant: Nc1ccc(F)cc1Br
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN1CCCC1=O
Product: CCCc1[nH]c2ccc(F)cc2c1CCC
Temperature: 130 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
A 50 mL three neck flask was charged with palladium acetate (22.4 mg, 0.1 mmol), dtbpf (94 mg, 0.2 mmol), potassium carbonate (690 mg, 5 mmol), 2-bromo-4-fluoroaniline (380 mg, 2 mmol), 4-octyne (264 mg, 2.4 mmol) and NMP (10 ml). The mixture was purged with argon and heated to 130° C. After 1 hr, the reaction mixture was cooled to rt. Ethyl acetate and water were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic phases were washed with water, brine and dried with MgSO4. Removal of the solvents and purification of the crude by column chromatography afforded the desired product as yellow oil (355 mg, containing 4.3 wt % AcOEt). The corrected yield was 77.6%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[CH:28][N:27]=[C:26](Cl)[N:25]=3)[CH:19]=2)[CH2:15][CH3:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([Cl:41])[CH:35]=1>>[Cl:41][C:36]1[CH:35]=[C:34]([CH2:33][CH2:32][NH:31][C:26]2[N:25]=[C:24]([C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([CH2:17][N:14]([CH2:15][CH3:16])[CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:19]=3)[CH:29]=[CH:28][N:27]=2)[CH:39]=[CH:38][C:37]=1[OH:40]
Reactant: NCCc1ccc(O)c(Cl)c1
Reactant: CCN(Cc1cccc(-c2ccnc(Cl)n2)c1)C1CCN(C(=O)OC(C)(C)C)CC1
Product: CCN(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1)C1CCNCC1

Procedure:
Intermediate 84 was coupled with 4-(2-amino-ethyl)-2-chloro-phenol following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 467. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.27 (m, 2H), 7.69 (m, 2H), 7.26 (d, 1H), 7.19 (m, 1H), 7.04 (s, 1H), 7.01 (d, 1H), 6.80 (d, 1H), 4.48 (m, 2H), 3.53 (m, 4H), 3.09 (m, 4H), 2.85 (t, 2H), 2.39 (d, 2H), 2.03 (m, 3H), 1.32 (t, 3H).
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]([NH:16][C:17]([C:19]3([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[CH2:21][CH2:20]3)=[O:18])[N:10]=2)=[CH:5][C:4]=1[CH3:30].[Si](I)(C)(C)C>C(#N)C.ClCCl>[CH3:29][O:28][C:24]1[CH:23]=[C:22]([C:19]2([C:17]([NH:16][C:11]3[CH:12]=[CH:13][C:14]([CH3:15])=[C:9]([C:6]4[CH:5]=[C:4]([CH3:30])[C:3](=[O:2])[NH:8][CH:7]=4)[N:10]=3)=[O:18])[CH2:20][CH2:21]2)[CH:27]=[CH:26][CH:25]=1
Reactant: COc1cccc(C2(C(=O)Nc3ccc(C)c(-c4cnc(OC)c(C)c4)n3)CC2)c1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Solvent: CC#N
Product: COc1cccc(C2(C(=O)Nc3ccc(C)c(-c4c[nH]c(=O)c(C)c4)n3)CC2)c1
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
To a solution of N-(6′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)-1-(3-methoxyphenyl)cyclopropanecarboxamide (41 mg, 0.10 mmol) in acetonitrile (2 mL) was added TMS-Iodide (28.0 μL, 0.20 mmol). The reaction was stirred at 50° C. for 20 min. The reaction solution was diluted with dichloromethane and washed with saturated NaHSO3 (2×), brine, dried over MgSO4 and concentrated. The crude product was dissolved in DMSO (1 mL) and purified by reverse phase HPLC (Gilson, 10-99% CH3CN in water) to yield the desired product. ESI-MS m/z calc. 389.4. found 390.5 (M+1)+. Retention time 1.41 minutes.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]([OH:20])[C@@H:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][O:9][CH2:10][CH:11]=[CH2:12])(=[O:3])[CH3:2].N1C(C)=CC=CC=1C.[Si:29](OS(C(F)(F)F)(=O)=O)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[C:1]([O:4][CH2:5][C@@H:6]([O:20][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[C@@H:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][O:9][CH2:10][CH:11]=[CH2:12])(=[O:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C=CCOC[C@H](C(=O)OC(C)(C)C)[C@H](O)COC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C=CCOC[C@H](C(=O)OC(C)(C)C)[C@@H](COC(C)=O)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The crude material from Step 2 (0.090 g) was dissolved in CH2Cl2 (3 mL) and cooled to 0° C. To the cooled solution, was added 2,6-lutidine (0.10 mL, 0.90 mmol) followed by TBSOTf (0.10 mL, 0.4 mmol). The mixture was stirred at 0° C. for 2 h then diluted with H2O and sat'd NaHCO3. The aqueous phase was extracted with CH2Cl2 (3×20 mL) and the organic extracts dried (Na2SO4), filtered, and conc in vacuo. Purification on SiO2 (5-20% EtOAc/Hexanes) gave the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=2)=[N:7][CH:8]=1)[CH3:2].[F:24][C:25]([F:36])([F:35])[O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1>>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]([CH2:31][C:30]2[CH:33]=[CH:34][C:27]([O:26][C:25]([F:24])([F:35])[F:36])=[CH:28][CH:29]=2)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(NCCc2ccc(OC)c(C(F)(F)F)c2)nc1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Product: CCc1cnc(N(CCc2ccc(O)c(C(F)(F)F)c2)Cc2ccc(OC(F)(F)F)cc2)nc1

Procedure:
Similarly prepared from 5-ethyl-N-{2-[4-methoxy-3-(trifluoromethyl)phenyl]ethyl}pyrimidin-2-amine and 4-trifluoromethoxy benzyl bromide.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[N+:6]([C:9]1[O:13][C:12]([C:14]2[C:18]([CH:19]=[N+](C)C)=[CH:17][N:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:15]=2)=[CH:11][CH:10]=1)([O-:8])=[O:7].C([O-])(=O)C.[Na+].[C:34]([O:38][CH2:39][CH3:40])(=[O:37])[NH:35][NH2:36].CN(C)C=O>O>[CH2:39]([O:38][C:34]([NH:35][N:36]=[CH:19][C:18]1[C:14]([C:12]2[O:13][C:9]([N+:6]([O-:8])=[O:7])=[CH:10][CH:11]=2)=[N:15][N:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:17]=1)=[O:37])[CH3:40]
Reactant: CCOC(=O)NN
Reactant: C[N+](C)=Cc1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)NN=Cc1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
Add 2.0 g of [3-(5-nitro-2-furyl)-1-phenylpyrazol-4-ylmethylene]dimethylammonium perchlorate, 0.4 g. of anhydrous sodium acetate and 0.63 g of ethyl carbazate to 10.5 ml of dimethylformamide. Stir the resulting admixture for 30 minutes before adding 30 ml of water dropwise thereto to obtain a 95% yield of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxaldehyde-ethoxycarbonylhydrazone [m.p. 200° to 201° C].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.ClC1C=C(C=CC=1)C(OO)=[O:17]>C(Cl)Cl.CCOC(C)=O>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N+:10]([O-:17])=[CH:9][CH:8]=[CH:7]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cccc2cccnc12
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cccc2ccc[n+]([O-])c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.5 %

Procedure:
To a solution of 8-methylquinoline (1.00 g, 6.98 mmol) in DCM (21 ml) was added 3-chlorobenzoperoxoic acid (2.35 g, 10.5 mmol), and the reaction was stirred for 16 hours at ambient temperature. The reaction was diluted with EtOAc and washed with 20% sodium sulfite, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified on the silica gel eluting with a gradient of 1-10% MeOH/DCM to yield the desired compound (0.440 g, 2.76 mmol, 39.6% yield).
Reaction SMILES: Br[C:2]1[C:15]2=[N:16][O:17][C:13]3=[C:14]2[C:5]([C:6](=[O:18])[C:7]2[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:4]([NH:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)[CH:3]=1.C(N(CC)CC)C.[CH:36]1([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.CC(OC)(C)C>CS(C)=O.CO>[CH:36]1([N:42]2[CH2:47][CH2:46][N:45]([C:2]3[C:15]4=[N:16][O:17][C:13]5=[C:14]4[C:5]([C:6](=[O:18])[C:7]4[C:12]5=[CH:11][CH:10]=[CH:9][CH:8]=4)=[C:4]([NH:19][C:20]4[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=4)[CH:3]=3)[CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: C1CCC(N2CCNCC2)CC1
Reactant: O=C(O)c1ccc(Nc2cc(Br)c3noc4c3c2C(=O)c2ccccc2-4)cc1
Solvent: CS(C)=O
Solvent: CO
Solvent: COC(C)(C)C
Product: O=C(O)c1ccc(Nc2cc(N3CCN(C4CCCCC4)CC3)c3noc4c3c2C(=O)c2ccccc2-4)cc1
Temperature: 65 °C
Reaction time: 2.5 h

Procedure:
Dissolving 4-((3-bromo-6-oxo-6H-anthra[1,9-cd]isoxazol-5-yl)amino)benzoic acid in DMSO, then adding triethylamine and 1-cyclohexyl piperazine (2a) into the solution. Raising temperature to 60-70° C. After 2-3 hours, slowly adding MTBE and MeOH solution and cooling to room temperature. Isolation and washing of the wet cake with MTBE and MeOH followed by filtering provided 4-((3-(4-cyclohexylpiperazin-1-yl)-6-oxo-6H-anthra[1,9-cd]isoxazol-5-yl)amino)benzoic acid (Intermediate 6) as a solid.
Reaction SMILES: C1(OC)C=CC=CC=1.C(OC([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][O:23][CH2:24][CH:25]([NH:32][C:33]([C:35]2[CH:43]=[C:42]3[C:38]([C:39]([Cl:44])=[CH:40][NH:41]3)=[CH:37][CH:36]=2)=[O:34])[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH2:18][CH2:17]1)=O)(C)(C)C>>[Cl:44][C:39]1[C:38]2[C:42](=[CH:43][C:35]([C:33]([NH:32][CH:25]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)[CH2:24][O:23][CH2:22][CH:19]3[CH2:18][CH2:17][NH:16][CH2:21][CH2:20]3)=[O:34])=[CH:36][CH:37]=2)[NH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COCC(NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccncc2)CC1
Solvent: COc1ccccc1
Product: O=C(NC(COCC1CCNCC1)c1ccncc1)c1ccc2c(Cl)c[nH]c2c1
Yield: 101.4 %

Procedure:
Using deprotection method B, but without addition of anisole, 4-{2-[(3-chloro-1H-indole-6-carbonyl)amino]-2-(4-pyridinyl)ethoxymethyl}piperidine-1-carboxylic acid tert-butyl ester (83 mg, 0.16 mmol) afforded 67 mg (100%) of the title compound as a crude residue, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[C:13]([O:14][Si](CCCC)(CCCC)CCCC)=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCCC[Si](CCCC)(CCCC)Oc1cccnc1C(=O)c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1)c1ncccc1O
Reaction time: 2 h
Yield: 89.6 %

Procedure:
A solution of 2-(4-fluorobenzoyl)-3-(tributylsilyloxy)pyridine (3.75 g, 11.3 mmol) in tetrahydrofuran (17 ml) was cooled to 0° C. and tetrabutylammonium fluoride (17 ml, 1.0 M in tetrahydrofuran) was added. After 2 h, the reaction mixture was diluted with ethyl acetate. The organic layer was separated, washed with sodium bicarbonate and brine, and dried over sodium sulfate. The organics were removed in vacuo and the residue was purified on a silica gel column using ethyl acetate-hexane (2:8) as the eluant to give 2-(4-fluorobenzoyl)-3-hydroxypyridine (2.2 g).