Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[CH2:8][CH2:9][CH2:10][NH:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].[CH2:17]1[O:19][CH2:18]1.[ClH:20]>C(O)C.CCOCC>[ClH:20].[OH:19][CH2:18][CH2:17][N:11]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[CH2:12]1
Reactant: C1CO1
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: O=[N+]([O-])c1ccc2c(c1)CN(CCO)CCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 8-nitro-2,3,4,5-tetrahydro-1H-2-benzazapine (5.08 g, 22.2 mmol) in ethanol (200 ml) at 0° C. was added 2.5M sodium hydroxide solution (10.0 ml). To this solution, in a pressure bottle, was added ethylene oxide (4.2 ml) and the bottle was capped and stirred at ambient temperature overnight. The solvent was concentrated in vacuo and the residue was partitioned between dichloromethane and dilute sodium hydroxide. The organic phase was dried (magnesium sulfate) and concentrated to give a yellow solid. This solid was taken up in ethanol and acidified with hydrochloric acid in ethanol. Addition of ether effected precipitation of the title salt as an orange solid (2.69 g, 44%), m.p. 193.5-4.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:10])[CH:6]=[CH:7][C:8]=1[Br:9].Br[CH2:12][C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:10][CH2:12][C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[CH:7][C:8]=1[Br:9]
Reactant: COc1cc(S)ccc1Br
Reactant: CCOC(=O)C(=O)CBr
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)C(=O)CSc1ccc(Br)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.2 %

Procedure:
3-Methoxy-4-bromobenzenethiol (D2) (9.6 g, 44 mmoles) in pyridine (30 ml) was treated with ethyl bromopyruvate (5.9 ml, 46 mmoles) and stirred at room temperature for 1 hr. Dilute hydrochloric acid (100 ml) was added and the product extracted into diethyl ether. The organics were washed with dilute hydrochloric acid then brine and dried (Na2SO4). Evaporation of the solvent followed by flash chromatography on TLC silica gel eluting with dichloromethane gave the title compound (D3) (3.7 g, 25%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[NH2:20])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].C(O[C:24]([CH2:26][C:27]1[NH:31][C:30]2[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:29]=2[N:28]=1)=O)C>C(Cl)Cl.C(O)C>[O:16]=[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14](=[O:15])[N:6]1[CH2:5][C:4]1[CH:17]=[CH:18][C:19]2[NH:20][C:24]([CH2:26][C:27]3[NH:31][C:30]4[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:29]=4[N:28]=3)=[N:1][C:2]=2[CH:3]=1
Reactant: Nc1ccc(CN2C(=O)c3ccccc3C2=O)cc1N
Reactant: CCOC(=O)Cc1nc2cc(C(=O)O)ccc2[nH]1
Solvent: ClCCl
Solvent: CCO
Product: O=C(O)c1ccc2[nH]c(Cc3nc4cc(CN5C(=O)c6ccccc6C5=O)ccc4[nH]3)nc2c1
Temperature: 185 °C
Reaction time: 1 h
Yield: 57.9 %

Procedure:
A finely ground mixture of 2-(3,4-diaminobenzyl)isoindole-1,3-dione (2.0 g, 7.5 mmol) and 2-ethoxycarbonylmethyl-1H-benzimidazole-5-carboxylic acid (0.93 g, 3.75 mmol) was heated 1 hour at 185° C. under nitrogen. The mixture was suspended in 1:1 methylene chloride/ethanol (20 mL) and stirred vigorously for 1 hour. The solids were collected by filtration, washed with 1:1 methylene chloride/ethanol (3×20 mL) and dried to provide 2-[5-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-1H-benzoimidazol-2-ylmethyl]-1H-benzoimidazole-5-carboxylic acid (0.98 g, 29% yield); 1H-NMR (300 Mhz, DMSO-d6): 12.45 (broad s, 1H), 8.07 (s, 1H), 7.80-7.83 (m, 6H), 7.51 (d, 1H, J=7.5 Hz), 7.43 (s, 1H), 7.11 (d, 1H, J=7.2 Hz), 4.82 (s, 2H), 4.48 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5](=[C:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)[NH:6][CH:7]=[O:8])[CH3:2].[SH:23][CH2:24][CH2:25][OH:26].C[O-].[Na+]>>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([C:9]1([S:23][CH2:24][CH2:25][OH:26])[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)[NH:6][CH:7]=[O:8])[CH3:2]
Reactant: CCOC(=O)C(NC=O)=C1CCN(Cc2ccccc2)CC1
Reactant: OCCS
Agent: C[O-]
Agent: [Na+]
Product: CCOC(=O)C(NC=O)C1(SCCO)CCN(Cc2ccccc2)CC1
Temperature: 80 °C

Procedure:
A mixture of ethyl(1-benzyl-4-piperidinylidene)(formylamino)acetate (3.0 g, 10.0 mmol), 2-mercaptoethanol (2.7 g, 35 mmol) and sodium methoxide (1 g) was heated at 80° C. for 8 h under nitrogen. The reaction mixture was then cooled to room temperature and quenched with saturated ammonium chloride solution. It was extracted with chloroform, washed twice with brine and dried over anhydrous Na2SO4, filtered and concentrated. The oily residue was purified by silica gel column chromatography eluting with 5% methanol:chloroform to provide ethyl{1-benzyl-4-[(2-hydroxyethyl)sulfanyl]-4-piperidinyl}(formylamino)acetate as a yellow oil; Yield: 2.8 g (73%); Electrospray Mass Spec: 381 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]O)=[CH:26][CH:25]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:30][C:27]5[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=5)=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: COc1ccc(CO)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1ccc(COc2ccn(-c3ccc4nc(C5CC5)n(C)c4c3)c(=O)c2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), (4-methoxy-phenyl)-methanol (98 mg) and tributylphosphine (320 μl) in THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (269 mg). The mixture was stirred under sonication at 50° C. for 1 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The crude residue was diluted with DCM (100 ml), and the DCM layer was washed with water (50 ml) and brine (30 ml), dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (45 mg) as an off-white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+]>CO>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cccc(CO)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(CO)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
A solution of methyl 3-(hydroxymethyl)benzoate (845 mg, 5.09 mmol) in methanol (15 mL) was treated with 1 M NaOH (aq) (15.300 mL, 15.30 mmol), and the reaction was stirred overnight at room temperature. The methanol was removed under reduced pressure, and the remaining aqueous solution was washed 3× with 10 mL of diethyl ether. The aqueous phase was acidified to pH 1 with concentrated HCl, then extracted 3× with 20 mL of ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated in-vacuo to yield the title compound (680 mg, 4.47 mmol, 88% yield) as a colorless powder. MS (ESI+)=153.10, (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([CH:9]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:11][C:12]1[CH:13]=[C:14]([C:28]2([O:34][CH3:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:15]=[C:16]([S:18][C:19]2[CH:27]=[CH:26][C:22]([CH2:23][O:24][NH2:25])=[CH:21][CH:20]=2)[CH:17]=1>>[F:11][C:12]1[CH:13]=[C:14]([C:28]2([O:34][CH3:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:15]=[C:16]([S:18][C:19]2[CH:27]=[CH:26][C:22]([CH2:23][O:24][N:25]=[CH:9][C:7]3[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[CH:21][CH:20]=2)[CH:17]=1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: COC1(c2cc(F)cc(Sc3ccc(CON)cc3)c2)CCOCC1
Product: COC1(c2cc(F)cc(Sc3ccc(CON=Cc4ccc([N+](=O)[O-])o4)cc3)c2)CCOCC1
Yield: 58 %

Procedure:
Using an analogous procedure to that described in Example 6, 5-nitrofuran-2-carboxaldehyde was reacted with O-{4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]benzyl}hydroxylamine to give 5-nitrofuran-2-carboxaldehyde O-{4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]benzyl}oxime as a gum in 58% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][S:18]([C:15]1[CH:14]=[CH:13][C:12]([O:11][CH3:10])=[CH:17][CH:16]=1)(=[O:20])=[O:19])#[N:5]
Reactant: N#Cc1ccccc1N
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)Nc2ccccc2C#N)cc1
Yield: 63.7 %

Procedure:
Using 2-aminobenzonitrile (1.03 g, 8.55 mmol) and 4-methoxybenzenesulfonyl chloride (1.78 g, 8.55 mmol), the procedure of Reference Example 2 was repeated to obtain 1.57 g (63.7%) of the title compound in the form of colorless solid.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[OH:19][C@H:20]1[CH2:24][CH2:23][C@H:22]([NH:25]C2C3N(C=CC=3)N=CC=2C(N)=O)[C:21]1([CH3:39])[CH3:38].C(=O)(O)[O-].[Na+]>ClCCl>[OH:19][C@@H:20]1[CH2:24][CH2:23][C@H:22]([NH:25][C:9](=[O:10])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:21]1([CH3:39])[CH3:38]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC1(C)[C@@H](Nc2c(C(N)=O)cnn3cccc23)CC[C@@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)[C@H](O)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 10.1 %

Procedure:
Triethylamine (6.69 mL, 48.0 mmol) and benzyl chloroformate (4.22 g, 24.71 mmol) were added to a solution of 3-amino-2,2-dimethylcyclopentanol (3.10 g, 23.99 mmol, from Step 3 of Intermediates 15 and 16) in dichloromethane (100 mL) at 0° C. The resulting mixture was stirred at room temperature for 15 h, treated with saturated sodium bicarbonate (50 mL) and extracted with dichloromethane (3×150 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated. Silica gel chromatography, eluting with 0 to 40% ethyl acetate in hexanes, gave separation of the two major components. The first eluted product was found to be benzyl cis-3-hydroxy-2,2-dimethylcyclopentylcarbamate (cis-isomer B, 640 mg, 10% yield). 1H NMR (400 MHz, methanol-d4) δ ppm 7.13-7.53 (5 H, m), 5.06 (2 H, s), 3.53-3.86 (2 H, m), 1.81-2.05 (2 H, m), 1.36-1.71 (2 H, m), 0.86-1.07 (3 H, m), 0.78 (3 H, s); MS (ES+) m/z: 264.2 (M+H); HPLC retention time: 2.32 min (analytical HPLC Method A). The second eluted product was benzyl trans-3-hydroxy-2,2-dimethylcyclopentylcarbamate (trans-isomer A, 1.77 g, 28% yield). 1H NMR (400 MHz, methanol-d4) δ ppm 7.21-7.51 (5 H, m), 5.06 (2 H, s), 3.91 (1 H, t, J=8.25 Hz), 3.64-3.79 (1 H, m), 1.99-2.20 (2 H, m), 1.33-1.62 (2 H, m), 0.94 (3 H, s), 0.79 (3 H, s); MS (ES+) m/z: 264.3 (M+H); HPLC retention time: 2.29 min (analytical HPLC Method A).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:11]1[C:23]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([Cl:24])[C:14]=2[N:13]=[C:12]1[CH2:25][O:26][CH2:27][CH3:28])[CH:9]=[CH2:10].[OH:29][N:30]=[C:31](Cl)[CH3:32]>ClCCl>[Cl:24][C:15]1[C:14]2[N:13]=[C:12]([CH2:25][O:26][CH2:27][CH3:28])[N:11]([CH2:8][CH:9]3[O:29][N:30]=[C:31]([CH3:32])[CH2:10]3)[C:23]=2[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1
Reactant: CC(Cl)=NO
Reactant: C=CCn1c(COCC)nc2c(Cl)nc3ccccc3c21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2c(Cl)nc3ccccc3c2n1CC1CC(C)=NO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
Triethylamine (1.04 mL, 7.46 mmol) was added to a 0° C. solution of 1-allyl-4-chloro-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline (1.50 g, 4.97 mmol) and N-hydroxyethanimidoyl chloride (581 mg, 6.21 mmol) in dichloromethane (80 mL). The reaction solution was allowed to warm slowly to room temperature and stir overnight under a nitrogen atmosphere. After 20 hours, the solution was washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, elution with 98:2 dichloromethane/methanol) to yield 4-chloro-2-(ethoxymethyl)-1-[(3-methyl-4,5-dihydroisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinoline (1.34 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)=[O:4].[Li][CH2:19]CCC.CI>O1CCCC1>[CH3:1][C:2]([CH3:17])([CH3:16])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:13])([F:14])[F:15])[C:7]=1[CH3:19])=[O:4]
Reactant: [Li]CCCC
Reactant: CC(C)(C)C(=O)Nc1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(NC(=O)C(C)(C)C)cccc1C(F)(F)F
Temperature: 5 °C
Yield: 80 %

Procedure:
A solution of 2,2-dimethyl-3'-trifluoromethyl-propionanilide (6.1 g, 25 mmol) in 100 ml dry tetrahydrofuran was cooled to 0° C. under nitrogen atmosphere and a solution of n-BuLi (1.6M in hexane, 50 ml, 75 mmol) was added dropwise in such a rate that the internal temperature did not rise above 10° C. (about 20 min.) and it was stirred at that temperature for 10 more minutes during which time a grayish turbidity appeared. The cooling bath was removed and the reaction mixture was stirred at room temperature for 2.5 hours. It was cooled to about 5° C. again and a solution of methyl iodide (4.258 g, 30 mmol) in tetrahydrofuran (10 ml.) was slowly transferred via a canula. It was stirred at room temperature for 4 hours and then quenched with water. The solution was concentrated in vacuo and then diluted with water and acidified with dilute HCl. It was then extracted with ether, and the ethereal extracts were washed with water followed by brine. The ether extract was dried with MgSO4 and concentrated to give a light yellow creamy solid (6.2 g., 95%). This was purified by crystallization from dichloromethane and petroleum ether mixture to afford colorless needles of 2,2,2'-trimethyl-3'-trifluoromethyl-propionanilide (80-85%, m.p. 122.5° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].[Li+].CC([N-]C(C)C)C.[O:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:32]=[N:33][C:34]3[C:39]([N:40]=2)=[CH:38][C:37]([CH:41]=[O:42])=[CH:36][CH:35]=3)[CH2:27][CH2:26]1>C1COCC1>[F:1][C:2]1[C:7]([CH:41]([OH:42])[C:37]2[CH:38]=[C:39]3[C:34](=[CH:35][CH:36]=2)[N:33]=[CH:32][C:31]([N:28]2[CH2:29][CH2:30][O:25][CH2:26][CH2:27]2)=[N:40]3)=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10][C:11](=[O:16])[C:12]([CH3:13])([CH3:15])[CH3:14]
Reactant: O=Cc1ccc2ncc(N3CCOCC3)nc2c1
Reactant: CC(C)(C)C(=O)Nc1cc(F)c(F)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1cc(F)c(F)c(C(O)c2ccc3ncc(N4CCOCC4)nc3c2)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
To a solution of N-(2,4,5-trifluorophenyl)pivalamide (550 mg, 2.4 mmol, 1.2 eq.) in THF (30 mL) cooled at −78° C. was added LDA (4.1 mL, 4.8 mmol, 2.4 eq.) dropwise. The resulting mixture was stirred at −78° C. for 1 h, then a solution of 3-morpholinoquinoxaline-6-carbaldehyde (486 mg, 2.0 mol, 1.0 eq.) in THF (20 mL) was added dropwise. The resulting mixture was stirred at −78° C. for 1 h, then quenched by the addition of NH4Cl solution. The mixture was extracted with EA (20 mL×3) and the combined organic layers were dried over Na2SO4 and concentrated. The resulting residue was purified by flash column chromatography (MeOH/DCM=1/50, v/v) to afford N-(2,4,5-trifluoro-3-(hydroxy(3-morpholinoquinoxalin-6-yl)methyl)phenyl)pivalamide (620 mg, 65.2%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([OH:12])=O)=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:44][O:45][C:46]1[CH:74]=[C:73]([O:75][CH3:76])[CH:72]=[CH:71][C:47]=1[CH2:48][NH:49][CH:50]([CH2:53][CH2:54][CH2:55][C:56]1[CH:61]=[CH:60][C:59]([O:62][CH2:63][C@@H:64]2[CH2:68][O:67][C:66]([CH3:70])([CH3:69])[O:65]2)=[CH:58][CH:57]=1)[CH2:51][NH2:52]>CN(C=O)C>[CH3:44][O:45][C:46]1[CH:74]=[C:73]([O:75][CH3:76])[CH:72]=[CH:71][C:47]=1[CH2:48][NH:49][CH:50]([CH2:53][CH2:54][CH2:55][C:56]1[CH:57]=[CH:58][C:59]([O:62][CH2:63][C@H:64]2[CH2:68][O:67][C:66]([CH3:70])([CH3:69])[O:65]2)=[CH:60][CH:61]=1)[CH2:51][NH:52][C:10]([C:3]1[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=1)=[O:12]
Reactant: Nc1nc(N)c(C(=O)O)nc1Cl
Reactant: COc1ccc(CNC(CN)CCCc2ccc(OC[C@@H]3COC(C)(C)O3)cc2)c(OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1ccc(CNC(CCCc2ccc(OC[C@H]3COC(C)(C)O3)cc2)CNC(=O)c2nc(Cl)c(N)nc2N)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid (161 mg, 0.86 mmol) and HATU (325 mg, 0.86 mmol) in DMF (10 mL) is added N-methylmorpholine (0.38 mL, 3.42 mmol) followed by N*2*-(2,4-dimethoxy-benzyl)-5-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-pentane-1,2-diamine (391 mg, 0.86 mmol) and the mixture is stirred at RT overnight. The solvent is removed in vacuo. To the crude residue is added water (10 mL), which is then decanted off to leave an orange solid that is washed with diethyl ether (10 mL) and dried in vacuo at 50° C. to afford the title compound. [M+H]+ 629.
Reaction SMILES: [Li]CCCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([C:40]2[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=2)=[O:39])[CH:33]=1>C1COCC1>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:38]([C:34]3[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=3)([C:40]3[CH:41]=[CH:42][C:43]([C:46]([F:47])([F:48])[F:49])=[CH:44][CH:45]=3)[OH:39])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: O=C(c1ccc(C(F)(F)F)cc1)c1cccnc1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccc(C(F)(F)F)cc3)c3cccnc3)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 0.07 mL, 0.175 mmol) was added dropwise by syringe to a solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (75.9 mg, 0.177 mmol, Intermediate 10) in dry THF (3 mL) in a dry ice-acetone bath. After 1.5 minutes, a solution of pyridin-3-yl(4-(trifluoromethyl)phenyl)methanone (48.0 mg, 0.191 mmol, Intermediate 91: step b) in dry THF (0.2 mL) was added dropwise. The reaction mixture was stirred for 5 minutes in a dry ice-acetone bath, then the reaction flask was placed into an ice-water bath. After 10 minutes, the mixture was warmed to room temperature and the reaction was quenched with methanol and water. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 10-50% EtOAc-Hexanes) to provide the title compound as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 8.51 (d, J=2.2 Hz, 1H), 8.48 (dd, J=4.8, 1.4 Hz, 1H), 8.02 (d, J=2.1 Hz, 1H), 7.83 (d, J=2.4 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.66 (d, J=1.6 Hz, 1H), 7.66-7.63 (m, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.5 Hz, 2H), 7.49 (dd, J=8.8, 2.2 Hz, 1H), 7.46 (d, J=8.3 Hz, 2H), 7.34 (d, J=8.5 Hz, 2H), 7.26-7.23 (m, 1H), 6.42 (t, J=2.1 Hz, 1H), 4.29 (s, 2H), 4.08 (s, 3H); MS m/e 602.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=3)[O:20][CH2:21][C:22]([OH:24])=O)[N:9]=2)=[CH:4][CH:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=3)[O:20][CH2:21][C:22]([N:32]3[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]3)=[O:24])[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)COc1cccc(-n2nc(-c3ccc(F)cc3)c3cccnc32)c1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)COc2cccc(-n3nc(-c4ccc(F)cc4)c4cccnc43)c2)CC1

Procedure:
By conducting reactions and treatments in the same manner as in Examples 36 and 37, using 3-[3-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl]phenoxyacetic acid and 4-methylpiperazine, there was obtained 1-{3-[3-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl]phenoxyacetyl}-4-methylpiperazine, m.p. 132°-135° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:19]=1)[C:7]([N:9]=[S@@:10]([CH3:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[C:20]([C:22]1[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=1)[C:25]([NH:27][O:28][CH3:29])=[O:26])#[CH:21]>>[CH3:29][O:28][NH:27][C:25]([C:24]1[CH:23]=[C:22]([C:20]#[C:21][C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:19]=2)[C:7]([N:9]=[S@@:10]([CH3:18])(=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH:32]=[CH:31][CH:30]=1)=[O:26]
Reactant: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Reactant: C#Cc1cccc(C(=O)NOC)c1
Product: CONC(=O)c1cccc(C#Cc2cncc(C(=O)N=[S@@](C)(=O)c3ccccc3)c2)c1

Procedure:
In a manner similar to that described in Example 460 (step 2), (S)-5-bromo-N-[methyl(oxido)phenyl--sulfanylidene]nicotinamide (0.100 g, 0.295 mmol) and 3-Ethynyl-N-methoxy-benzamide (0.106 g, 0.442 mmol) were reacted to give the title compound yield (0.126 g, 86%).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Br:11])[N:3]=1.C(N(CC)CC)C.[CH2:19]([NH:26][CH2:27][C@H:28]([OH:30])[CH3:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[CH2:19]([N:26]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Br:11])[N:3]=1)[CH2:27][C@H:28]([OH:30])[CH3:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[C@@H](O)CNCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Br)nc1Br
Solvent: CCO
Solvent: CCN(CC)CC
Product: C[C@@H](O)CN(Cc1ccccc1)c1nc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 17 h
Yield: 89.3 %

Procedure:
2,6-Dibromo-3-nitropyridine (2.59 g, 9.20 mmol) and triethylamine (2.70 mL, 19.37 mmol) were added to a solution of (R)-1-(benzylamino)propan-2-ol (1.6 g, 9.68 mmol) in ethanol (35 mL). The solution was stirred at rt for 17 h and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution (25 mL). The layers were separated, and the organic layer was washed with 5% aqueous sodium chloride solution (25 mL). The ethyl acetate layer was concentrated under reduced pressure to afford an orange syrup. The crude product was purified by column chromatography on silica gel (eluting with 5:1 hexanes-ethyl acetate followed by 3:1 hexanes-ethyl acetate) to afford (R)-1-(benzyl(6-bromo-3-nitropyridin-2-yl)amino)propan-2-ol (3.01 g, 85%) as a bright yellow syrup. MS (ESI, pos. ion) m/z 388, 390 [M+Na]+.