Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:12]=[C:13]([C:19](=O)[CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=1)[O:8][C:7]([CH3:22])=[CH:6][C:5]2=[O:23].[NH2:24][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:26][C:27]#[N:28].CC(C)([O-])C.[K+]>CC(O)C>[C:27]([C:26]1[CH:12]([C:10]2[CH:11]=[C:2]([F:1])[CH:3]=[C:4]3[C:9]=2[O:8][C:7]([CH3:22])=[CH:6][C:5]3=[O:23])[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:19]([CH3:20])[NH:24][C:25]=1[C:29]([F:32])([F:31])[F:30])#[N:28]
Reactant: CCOC(=O)C(=Cc1cc(F)cc2c(=O)cc(C)oc12)C(C)=O
Reactant: N#CC=C(N)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CCOC(=O)C1=C(C)NC(C(F)(F)F)=C(C#N)C1c1cc(F)cc2c(=O)cc(C)oc12

Procedure:
A solution of 230 mg (0.72 mmol) of ethyl 2-[(6-fluoro-2-methyl-4-oxo-4H-chromen-8-yl)-methylene]-3-oxobutanoate in 10 ml of 2-propanol is mixed with 98.34 mg (0.72 mmol) of 3-amino-4,4,4-trifluorobut-2-enenitrile [preparation in analogy to K. Krespan, J. Org. Chem. 34, 42-45 (1969)] and 12.2 mg (0.11 mmol) of potassium tert-butoxide and stirred under reflux for 12 h. After cooling, the mixture is concentrated. The residue is purified on an Analogix cartridge (F12M) (mobile phase: cyclohexane/ethyl acetate 2:1). The resulting crystals are purified further by preparative HPLC. 27.4 mg (8.69% of theory) of the title compound are obtained as yellow crystals.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[OH:20])O)=[CH:8][CH:7]=1)=[O:5]>[Pd].CO>[CH3:2][O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[OH:20])=[CH:10][CH:11]=1)=[O:5]
Reactant: COC(=O)c1ccc(C(O)c2ccncc2O)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc(Cc2ccncc2O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 94.9 %

Procedure:
Next, a mixture of (4-methoxycarbonylphenyl)-(3-hydroxypyridin-4-yl)-methanol hydrochloride (1.87 g, 5.50 mmol), methanol (50 ml) and 10% palladium/carbon (0.94 g) was stirred under a hydrogen atmosphere at room temperature for 3 days. After filtration to remove the insoluble materials, the filtrate was concentrated under reduced pressure and the resulting residue was poured into saturated aqueous NaHCO3 and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crystal was recrystallized from diethyl ether to give the titled compound (1.27 g, 95%).
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[CH:2].[C:10]1([CH3:19])[CH:15]=[CH:14][CH:13]=[C:12]([N:16]=[C:17]=[O:18])[CH:11]=1.C(Cl)Cl.CO.C(Cl)Cl>C1COCC1.C(OCC)(=O)C>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:17]([NH:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([CH3:19])[CH:11]=2)=[O:18])=[CH:5][CH:4]=1)#[CH:2]
Reactant: Cc1cccc(N=C=O)c1
Reactant: C#Cc1ccc(N)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1ccc(NC(=O)Nc2cccc(C)c2)cc1

Procedure:
A solution of 4-ethynylaniline (1.308 g, 11.18 mmol, 1 eq) and m-tolyl isocyanate (1.684 mL, 1.2 eq) in anhydrous THF (20 mL) was stirred under nitrogen atmosphere at room temperature for three hours. The yellow solution was diluted with ethyl acetate, washed sequentially with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, brine, and lastly dried with anhydrous sodium sulfate. The clear solution was decanted, concentrated under reduced pressure to a lesser amount, and an off-white solid was obtained upon filtration. This solid was subject to a gradient column chromatography (EtOAc-Hex 1:100 to 1:4) followed by another column chromatography (from DCM to MeOH-DCM 1:10). 1-(4-ethynylphenyl)-3-(3-methylphenyl)urea was obtained as an off-white powder in amount of 2.134 g.
Reaction SMILES: [ClH:1].[NH2:2][N:3]=[CH:4][C:5]1[CH:27]=[CH:26][C:8]([CH2:9][CH2:10][C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][C:13](O)=[O:14])=[CH:7][CH:6]=1.Cl.[CH3:29][O:30][C:31](=[O:34])[CH2:32][NH2:33].F[B-](F)(F)F.C(CCOC(C=NOC(N(C)C)=[N+](C)C)=O)#N.C(N1CCOCC1)C>CN(C)C=O>[ClH:1].[CH3:29][O:30][C:31](=[O:34])[CH2:32][NH:33][C:13](=[O:14])[CH2:12][C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([CH:4]=[N:3][NH2:2])=[CH:27][CH:26]=1
Reactant: COC(=O)CN
Reactant: CCOC(=O)C(CCc1ccc(C=NN)cc1)(CC(=O)O)C(=O)OCC
Agent: CCN1CCOCC1
Agent: CN(C)C(ON=CC(=O)OCCC#N)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCc1ccc(C=NN)cc1)(CC(=O)NCC(=O)OC)C(=O)OCC
Reaction time: 24 h

Procedure:
10.5 g of 4-[4-(aminoiminomethyl)benzyl]-3,3-bisethoxycarbonylbutyric acid hydrochloride are dissolved in 500 ml of dimethylformamide. 3.75 g of glycine methyl ester hydrochloride, 9.83 g of O-[(cyanoethoxycarbonylmethylene)amino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU) and 11.5 ml of N-ethylmorpholine are then added successively. The mixture is stirred for 24 h and the solvent is then stripped off in vacuo. The oily residue is chromatographed on silica gel using dichloromethane/methanol/water/acetic acid (100:10:1:1). The fractions containing the product are combined and concentrated.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[N:14]([S:26]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:28])=[O:27])[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1cc2[nH]ccc2cc1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: COc1cc2c(ccn2S(=O)(=O)c2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Yield: 84 %

Procedure:
To 5-benzyloxy-6-methoxyindole (5.0 g, 20 mmol), benzenesulfonyl chloride (5.2 g, 30 mmol) and tetrabutylammonium hydrogen sulfate (2.0 g, 6 mmol) DCM (200 mL) and 4M NaOH (50 mL) were added. The reaction mixture was allowed to stir at room temperature over night. The organic layer was collected and the aqueous phase was washed with DCM (2×30 mL). The combined organic layers were then washed with brine (2×50 mL). Drying, (MgSO4), filtration and evaporation afforded a brown oil. The product precipitated when adding diethyl ether. Recrystallization from MeOH afforded the title compound in 84% yield (6.55 g) as light yellow crystals. MS (ESI+) for C22H19NO4S m/z 394 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:23][CH3:24])=[CH:12][CH:11]=2)=[O:9])[CH:2]=1.ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH+:7]([O-:33])[C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:23][CH3:24])=[CH:12][CH:11]=2)=[O:9])[CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(C(=O)Nc2cccnc2)c2c1oc1ccccc12
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)[NH+]([O-])c2cccnc2)c2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.9 %

Procedure:
A suspension of N-(pyrid-3-yl)-4-methoxy dibenzo[b,d]furan-1-carboxamide (50 mg, 0.15 mmol) (example 8) and m-chloroperbenzoic acid (50-55%) (135 mg, 0.78 mmol) in chloroform (10 ml) was stirred at room temperature for 16 h. Chloroform was evaporated and the resulting solid was washed with saturated sodium bicarbonate solution, water, dried and then purified by column chromatography using 20% acetone-chloroform as the eluent to give 15 mg of N-(pyrid-3-yl)-4-methoxy dibenzo[b,d]furan-1-carboxamide-N1-oxide as white solid; mp: 239-241° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22](OC)=[O:23])=[CH:4][N:5]([S:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:14])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].C([Al+]CC(C)C)C(C)C.O.C(OCC)(=O)C>O1CCCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]([CH:22]=[O:23])=[CH:4][N:5]([S:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:14])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1cn(S(=O)(=O)c2cccnc2)c(-c2ccccc2)c1F
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=Cc1cn(S(=O)(=O)c2cccnc2)c(-c2ccccc2)c1F
Temperature: 0 °C
Yield: 67.1 %

Procedure:
Under a nitrogen atmosphere, a solution of methyl 4-fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate (200 mg) in tetrahydrofuran (10 mL) was cooled to −78° C., and a 1.5 mol/L solution (1.85 mL) of diisobutylaluminum hydride in toluene was added with stirring. After stirring at the same temperature for 15 min, the mixture was raised to 0° C. over 1.5 hr. Water (20 mL) was added, and the mixture was stirred at the same temperature for 5 min. After stirring, ethyl acetate (20 mL) was added, and the mixture was stirred for 15 min, and then stirred at room temperature for 20 min. The reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL), manganese dioxide (75% chemically treated product, 1.0 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→1:2) to give the title compound as a colorless solid (yield 123 mg, 67%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:19][O:20][C:21]1[C:22](=[O:49])[C:23]([CH3:48])=[C:24]([CH2:30][C:31]2[C:32]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34](O)=[O:35])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]>C(Cl)Cl>[CH3:19][O:20][C:21]1[C:22](=[O:49])[C:23]([CH3:48])=[C:24]([CH2:30][C:31]2[C:32]([O:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:35])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2OCc2ccccc2)=C(C)C1=O
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)N3CCOCC3)c2OCc2ccccc2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 63.2 %

Procedure:
Morpholine (0.033 g, 0.38 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.109 g, 0.57 mmol) were added to a methylene chloride solution (10 ml) of 3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-benzyloxybenzoic acid (0.080 g, 0.19 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:1) to obtain the titled compound (0.057 g, 0.12 mmol, 61%).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:26]=[C:25]([O:27][C@@H:28]3[CH2:32][C@H:31]([OH:33])[C@@H:30]([OH:34])[C@H:29]3[OH:35])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[OH:35][C@@H:29]1[C@H:30]([OH:34])[C@@H:31]([OH:33])[CH2:32][C@H:28]1[O:27][C:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([N:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)[N:26]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2nc(O[C@@H]3C[C@H](O)[C@@H](O)[C@H]3O)c3ccccc3n2)CC1
Agent: [Pd]
Solvent: CO
Product: O[C@@H]1[C@H](O)[C@@H](O)C[C@H]1Oc1nc(N2CCNCC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 14.5 h
Yield: 88.5 %

Procedure:
To a solution of 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(1R,2R,3R,4S)-(2,3,4-trihydroxycyclopentan-1-yl)oxy]quinazoline (854 mg) in methanol (15 ml) is added 10% palladium/carbon (200 mg), and the mixture is stirred under hydrogen atmosphere and under atmospheric pressure at room temperature for 14.5 hours. The reaction mixture is filtered, and the filtrate is evaporated to dryness under reduced pressure to give 4-[(1R,2R,3R,4S)-(2,3,4-trihydroxycyclopentan-1-yl)oxy]-2-(1-piperazinyl)quinazoline (545 mg) as foam.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([NH2:22])=[C:20]([CH3:23])[CH:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.O.C1C[O:31][CH2:30]C1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([CH3:23])=[C:21]3[NH:22][C:30]2=[O:31])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: Cc1ccnc(Nc2ccc(OCc3ccccc3)cc2)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccnc2c1[nH]c(=O)n2-c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of N2-[4-(benzyloxy)phenyl]-4-methylpyridine-2,3-diamine (91.0 g) in THF (850 mL) was added N,N′-carbonylimidazol (90.8 g) at room temperature. The mixture was stirred at room temperature for 17 h. To the mixture was added 1 N NaOH (300 mL) over 10 min in ice bath, and the mixture was stirred for 15 min. To the mixture was added 1 N HCl (460 mL) under ice cooling, and then the mixture was stirred for 15 min. To the mixture was added water (90 mL) at room temperature, and then the mixture was stirred for 20 min. The precipitate was collected by filtration, washed with water (1.3 L), and dried in air blowing for 30 min. The precipitate was washed with IPE (1.5 L) and dried in vacuo at 55° C. for 2.5 h. The precipitate was suspended in IPE (500 mL), and the mixture was stirred at room temperature for 1 h. The precipitate was collected by filtration, washed with IPE (500 mL), and dried in vacuo to give 3-[4-(benzyloxy)phenyl]-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (86 g) as a purple solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.C[Mg+].[Br-].[CH3:19]COCC>Cl[Ni]Cl.C1COCC1>[CH3:19][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1
Reactant: CCOCC
Reactant: COc1cc2ncc(Cl)nc2cc1OC
Agent: Cl[Ni]Cl
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cc2ncc(C)nc2cc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The title compound is prepared using an adaptation of the published method of Tamao, et al. Tetrahedron, 1982, 38, 3347-3354. To a THF solution under argon is added 2-Chloro-6,7-dimethoxyquinoxaline (5 g, 26 mmol) and NiCl2 (dppp) (0.14 g, 0.26 mmol). The reaction mixture is cooled to 0° C., and a 3 M solution of MeMgBr in Et2O (13 mL, 39 mmol) is added portionwise. The reaction mixture is allowed to warm to room temperature, stirred for 1 hours then refluxed for 1.5 hours. The mixture is cooled, quenched with 10% HCl, stirred 10 minutes, then made basic with 5% NaOH. CH2Cl2 and H2O are added to the reaction, and the mixture stirred overnight. Additional CH2Cl, H2O, and NaCl are then added and the mixture is filtered. The resulting solution is poured into a separatory funnel, and the aqueous layers are washed 3× with CH2Cl2. The organic layers are combined, washed with brine, dried (MgSO4), concentrated onto silica gel, and chromatographed (50%-80% EtOAc/hexanes) to provide a orange solid (49% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[N+:17]([C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23])([O-:19])=[O:18]>O1CCCC1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[N+:17]([O-:19])=[O:18])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1Cl
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1cc(Br)cnc1Cl)c1ccccc1[N+](=O)[O-]
Reaction time: 24 h

Procedure:
To a solution of 5-bromo-2-chloropyridine-3-amine (3.9 g, 18.9 mmol) and triethylamine (5.3 mL, 37.9 mmol) in tetrahydrofuran (60 mL) was added 2-nitrobenzoylchloride (2.49 mL, 18.9 mmol). The reaction was stirred for 24 hours. The reaction mixture was diluted with ethyl acetate (200 mL) and saturated aqueous sodium bicarbonate (60 mL). The organic layer was separated and washed with water (50 mL), brine (50 mL), dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. The crude product was purified by flash chromatography (SiO2, 25% ethyl acetate in hexanes). The N-(5-bromo-2-chloropyridin-3-yl)-2-nitrobenzamide was obtained as a yellow solid (1.5 g). LCMS [M+H]: 356.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:9]([O:16][CH2:17][C:18]1([CH2:32][OH:33])[O:23][C:22]2[CH:24]=[CH:25][C:26]([N+:28]([O-:30])=[O:29])=[CH:27][C:21]=2[NH:20][C:19]1=[O:31])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>>[Si:1]([O:33][CH2:32][C:18]1([CH2:17][O:16][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:11])[O:23][C:22]2[CH:24]=[CH:25][C:26]([N+:28]([O-:30])=[O:29])=[CH:27][C:21]=2[NH:20][C:19]1=[O:31])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)[Si](C)(C)OCC1(CO)Oc2ccc([N+](=O)[O-])cc2NC1=O
Product: CC(C)(C)[Si](C)(C)OCC1(CO[Si](C)(C)C(C)(C)C)Oc2ccc([N+](=O)[O-])cc2NC1=O

Procedure:
Another experiment using 3 equiv. of TBS-Cl with 1.02 g of 2,2-bis(hydroxymethyl)-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one, gave the pure product (0.62 g, 32% yield), followed by the product with TBS-Cl (0.8 g), followed by mono-silylated material-2-(((tert-butyldimethylsilyl)oxy)methyl)-2-(hydroxymethyl)-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (0.56 g, 38%)
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[O:1]=[C:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (58.50 g) in CH2Cl2 was added Dess-Martin agent (174.10 g) in portions at 0° C. The reaction mixture was stirred for 2 h at room temperature, and quenched with water. The resulted mixture was extracted with CH2Cl2 (200 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 3:1 (v/v) PE/EA) to give the title compound as a white solid (52.00 g, 90.00%), HPLC: 97.50%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 200.5 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.42 (s, 9H), 2.78 (m, J=6.4 Hz, 2H), 3.56 (t, J=6.4 Hz, 2H), 4.28 (t, J=6.4 Hz, 2H), 4.50 (s, 2H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH:7]2[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8]2)[N:3]=1.Br[C:19]1[C:20](=[O:27])[N:21]([CH3:26])[N:22]=[C:23]([Cl:25])[CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C(OCC)(=O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:25][C:23]1[CH:24]=[C:19]([NH:1][C:2]2[CH:6]=[CH:5][N:4]([CH:7]3[CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10]3)[N:3]=2)[C:20](=[O:27])[N:21]([CH3:26])[N:22]=1
Reactant: CC(C)(C)OC(=O)N1CC(n2ccc(N)n2)C1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cn1nc(Cl)cc(Nc2ccn(C3CN(C(=O)OC(C)(C)C)C3)n2)c1=O
Temperature: 25 °C
Yield: 73.4 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with 105b (677 mg, 2.84 mmol), 103a (635 mg, 2.84 mmol), cesium carbonate (1.85 g, 5.68 mmol) and 1,4-dioxane (14 mL). After bubbling nitrogen through the resulting suspension for 30 min, Xantphos (246 mg, 0.426 mmol) and tris(dibenzylideneacetone)dipalladium(0) (260 mg, 0.284 mmol) were added. A reflux condenser was attached to the flask, and the reaction mixture was heated at reflux for 2.5 h. After this time, the mixture was cooled to room temperature and diluted with ethyl acetate (200 mL) and water (75 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (50 mL), and the combined organic layers were dried over sodium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography (silica, 95:5 methylene chloride/methanol) to afford a 73% yield of 105c (794 mg) as an amorphous white solid: mp 154-156° C.; 1H NMR (500 MHz, CDCl3) δ 7.95 (s, 1H), 7.60 (s, 1H), 7.43 (d, J=2.5 Hz, 1H), 6.01 (d, J=2.5 Hz, 1H), 5.00-4.95 (m, 1H), 4.39-4.32 (m, 4H), 3.79 (s, 3H), 1.48 (s, 9H); MS (ESI+) m/z 403.1 (M+Na).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)=[N:15][N:16]4[C:21](Cl)=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OCC)(=O)C.[CH:38]1([NH2:41])[CH2:40][CH2:39]1>>[Cl:23][C:19]1[CH:20]=[C:21]([NH:41][CH:38]2[CH2:40][CH2:39]2)[N:16]2[N:15]=[C:14]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:13]([C:11]3[CH:10]=[CH:9][N:8]=[C:7]([NH:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[N:12]=3)=[C:17]2[CH:18]=1
Reactant: COc1ccc(-c2nn3c(Cl)cc(Cl)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Reactant: NC1CC1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nn3c(NC4CC4)cc(Cl)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Yield: 71 %

Procedure:
N-Cyclopentyl-4-[5,7-dichloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine (271 mg, 0.60 mmol) in cyclopropylamine (5 mL) was heated at 100° C. for 11 hours in a steel bomb. Cooled to room temperature. Ethyl acetate was added to the reaction mixture. The solution was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration followed by purification with flash chromatography (4:1 hexanes/ethyl acetate) gave N-{4-[5-chloro-7-(cyclopropylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-cyclopentylamine (201 mg, yield 71%) as a yellow foam. 1H NMR (CDCl3) δ 8.02 (d, 1H), 7.96 (s, 1H), 7.56 (d, 2H), 7.01 (d, 2H), 6.42 (s, 1H), 6.37 (d, 1H), 6.32 (d, 1H), 5.12 (d, 1H), 4.15 (m, 1H), 3.91 (s, 3H), 2.70 (m, 1H), 2.08 (m, 2H), 1.82–1.59 (m, 6H), 0.95 (m, 2H), 0.80 (m, 2H); MS m/z 475 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-:19])=[O:18])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][NH:11][C:10](=[O:16])[CH:9]=2)[CH:7]=1.Br[CH:21]([CH3:25])[C:22]([OH:24])=[O:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-:19])=[O:18])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:21]([CH3:25])[C:22]([OH:24])=[O:23])[C:10](=[O:16])[CH:9]=2)[CH:7]=1
Reactant: CC(Br)C(=O)O
Reactant: COc1c[nH]c(=O)cc1-c1cc(Cl)ccc1[N+](=O)[O-]
Product: COc1cn(C(C)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
115 mg (purity 85%, 0.35 mmol) of 4-(5-chloro-2-nitrophenyl)-5-methoxypyridin-2(1H)-one and 1.5 eq. of 2-bromopropanoic acid (racemate) were reacted according to General Method 4A at 50° C. Yield: 43 mg (35% of theory)