Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([CH2:6][OH:7])[CH2:2]1.C(Cl)(Cl)Cl.CCN(C(C)C)C(C)C.[CH3:21][CH:22]1[CH:27]([N:28]([CH3:48])[C:29]2[C:30]3[CH:37]=[CH:36][N:35]([S:38]([C:41]4[CH:47]=[CH:46][C:44]([CH3:45])=[CH:43][CH:42]=4)(=[O:40])=[O:39])[C:31]=3[N:32]=[CH:33][N:34]=2)[CH2:26][CH2:25][CH:24]([CH2:49][S:50](Cl)(=[O:52])=[O:51])[CH2:23]1>CN(C=O)C>[CH3:21][CH:22]1[CH:27]([N:28]([CH3:48])[C:29]2[C:30]3[CH:37]=[CH:36][N:35]([S:38]([C:41]4[CH:42]=[CH:43][C:44]([CH3:45])=[CH:46][CH:47]=4)(=[O:39])=[O:40])[C:31]=3[N:32]=[CH:33][N:34]=2)[CH2:26][CH2:25][CH:24]([CH2:49][S:50]([N:1]2[CH2:5][CH2:4][C@H:3]([CH2:6][OH:7])[CH2:2]2)(=[O:52])=[O:51])[CH2:23]1
Reactant: OC[C@H]1CCNC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)C4CCC(CS(=O)(=O)Cl)CC4C)ncnc32)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)C4CCC(CS(=O)(=O)N5CC[C@H](CO)C5)CC4C)ncnc32)cc1
Reaction time: 1 h

Procedure:
A mixture of (S)-pyrrolidin-3-ylmethanol (0.150 g, 1.5 mmol), CHCl3 (5 mL) and DIEA (0.5 mL, 3 mmol) was treated with a mixture of (3-methyl-4-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonyl chloride (0.208 g, 0.41 mmol), CHCl3 (3.0 mL), and DMF (1.5 mL). After 1 h, the mixture was concentrated and the resulting residue was chromatographed using 0→8% MeOH in CH2Cl2. The product fractions were pooled and concentrated to give ((3S)-1-((3-methyl-4-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methylsulfonyl)pyrrolidin-3-yl)methanol (0.126 g (54%). MS for C27H37N5O5S2 (ESI) (MH)+ m/z=576.
Reaction SMILES: [NH3:1].C(Cl)(Cl)Cl.[C:6]([N:11]=[C:12]=[O:13])(=[O:10])[C:7]([CH3:9])=[CH2:8]>ClCCCl>[C:6]([NH:11][C:12]([NH2:1])=[O:13])(=[O:10])[C:7]([CH3:9])=[CH2:8]
Reactant: C=C(C)C(=O)N=C=O
Reactant: N
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: C=C(C)C(=O)NC(N)=O

Procedure:
Gaseous ammonia was blown into dry chloroform (50 g) to prepare a chloroform solution containing ammonia (0.18 g; 10.5 mmol). To the resultant solution, a solution of methacryloyl isocyanate (1.11 g; 10 mmol) in 1,2-dichloroethane (2 ml) was dropwise added under-nitrogen stream while cooling with ice. After completion of the addition, chloroform and 1,2-dichloroethane were evaporated under reduced pressure to give 1-methacryloylurea (1.28 g), which was recrystallized from a mixture of benzene and hexane to give colorless needles. M.P., 137°-138° C.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH:9]1([N:12]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13]2)[CH2:11][CH2:10]1.[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1>C1COCC1>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]([OH:27])[C:13]2[N:12]([CH:9]3[CH2:10][CH2:11]3)[CH:16]=[CH:15][C:14]=2[C:17]([O:19][CH3:20])=[O:18])=[CH:24][CH:23]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COC(=O)c1ccn(C2CC2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccn(C2CC2)c1C(O)c1ccc(Cl)cc1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
LDA (1.8M, 18.97 mL, 34.2 mmol) was added dropwise to a solution of methyl 1-cyclopropyl-1H-pyrrole-3-carboxylate (Step 240.6) (4.03 g, 24.40 mmol) in THF (80 mL) at −78° C. and the mixture was stirred for 30 min. A solution of 4-chlorobenzaldehyde (3.77 g, 26.8 mmol) in THF (20 mL) was added at −78° C. The mixture was allowed to warm to −50° C. over 2 hrs, quenched with a saturated aqueous solution of ammonium chloride, and taken up in EtOAc/saturated ammonium chloride solution. The aqueous layer was separated and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated. The crude material was purified by silica gel column chromatography (hexane/EtOAc 4:1) to afford the title compound (6.1 g, 79% yield) as a yellow solid. TLC (hexane/EtOAc 4:1): Rf=0.21.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[C:12](=[O:27])[NH:13][C:14](=[O:26])[N:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=4)[C:5]=3[C:4]=2[N:3]=1.[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33](OB(O)O)=[CH:32][N:31]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[C:12](=[O:27])[NH:13][C:14](=[O:26])[N:15]([C:16]5[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=5)[C:5]=4[C:4]=3[N:3]=2)=[CH:32][N:31]=1
Reactant: COc1ncc(OB(O)O)cn1
Reactant: O=c1[nH]c(=O)n(-c2cccc(C(F)(F)F)c2)c2c1cnc1ccc(Cl)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ncc(-c2ccc3ncc4c(=O)[nH]c(=O)n(-c5cccc(C(F)(F)F)c5)c4c3n2)cn1
Temperature: 25 °C
Yield: 41.8 %

Procedure:
9-chloro-1-(3-(trifluoromethyl)phenyl)pyrimidino[5,4-c][1,5]naphthyridine-2,4(1H,3H)-dione (300 mg, 0.77 mmol), (2-methoxypyrimidin-5-yl)boric acid (119 mg, 0.77 mmol), potassium carbonate (317 mg, 2.3 mmol) and tetrakis(triphenylphosphine)palladium(45 mg, 0.04 mmol) were added to 40 mL dioxane and 2 mL water. The resulting mixture was reacted under reflux in the nitrogen protection for 18 hrs, cooled to room temperature, filtered with Celite, and concentrated. 40 mL water was added. The resulting mixture was filtered to obtain a crude product, which was successively washed with ethyl acetate (30 mL) and methanol (10 mL) to produce 9-(2-methoxypyrimidin-5-yl)-1-(3-(trifluoromethyl)phenyl)pyrimidino[5,4-c][1,5]naphthyridine-2,4(1H,3H)-dione (150 mg).
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([NH:12][C:13]2[CH:14]=[C:15]([C:20]3[N:24]=[C:23]([C:25]4([NH:28]C(=O)OC(C)(C)C)[CH2:27][CH2:26]4)[O:22][N:21]=3)[CH:16]=[CH:17][C:18]=2[CH3:19])=[O:11])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl>O1CCOCC1>[NH2:28][C:25]1([C:23]2[O:22][N:21]=[C:20]([C:15]3[CH:16]=[CH:17][C:18]([CH3:19])=[C:13]([NH:12][C:10]([C:3]4[N:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]5=[N:1][CH:2]=4)=[O:11])[CH:14]=3)[N:24]=2)[CH2:26][CH2:27]1
Reactant: Cc1ccc(-c2noc(C3(NC(=O)OC(C)(C)C)CC3)n2)cc1NC(=O)c1cnc2ccccn12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(-c2noc(C3(N)CC3)n2)cc1NC(=O)c1cnc2ccccn12
Reaction time: 0.5 h

Procedure:
To a vial was added tert-butyl (1-(3-(3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)cyclopropyl)carbamate (F67) (275 mg, 0.6 mmol) and 4N HCl in 1,4-dioxane (3 mL). The reaction was stirred for 30 minutes. The solvent was concentrated and placed under high vacuum. The solid was taken in water/acetonitrile and the pH was adjusted to neutral with an aqueous solution of ammonium carbonate and lyophilized to afford N-(5-(5-(1-aminocyclopropyl)-1,2,4-oxadiazol-3-yl)-2methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (156). MS m/z 375.1 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:14])=[CH:4][C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH3:15][NH2:16].C(OCC)(=O)C>O1CCCC1.C(N(CC)CC)C.ClC(OCC)=O>[CH3:15][NH:16][C:7](=[O:8])[C:6]1[CH:10]=[C:2]([Br:1])[C:3]([CH3:14])=[CH:4][C:5]=1[O:11][CH2:12][CH3:13]
Reactant: CCOc1cc(C)c(Br)cc1C(=O)O
Reactant: CN
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOc1cc(C)c(Br)cc1C(=O)NC
Reaction time: 1 h

Procedure:
After dissolving 5-bromo-2-ethoxy-4-methylbenzoic acid in tetrahydrofuran (80 ml), triethylamine (3.5 ml) and ethyl chloroformate (2.4 ml) were added while cooling on ice, the mixture was stirred for 1 hour, and then a 40% methylamine aqueous solution (3.5 ml) was added. The reaction mixture was stirred for 1 hour, ethyl acetate was added and the mixture was washed with brine, after which the organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The crystals of the residue were washed with hexane and filtered to yield the title compound (5.08 g) as white crystals.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[C@H:19]([CH2:20][OH:21])[CH2:18][CH2:17][C:12]2(OCC[O:13]2)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+]>C(O)(=O)C.O.CO>[CH2:1]([O:8][CH2:9][C@H:10]1[C@H:19]([CH2:20][OH:21])[CH2:18][CH2:17][C:12](=[O:13])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[C@@H]1CCC2(C[C@H]1COCc1ccccc1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: O=C1CC[C@@H](CO)[C@H](COCc2ccccc2)C1
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
A solution composed of {(7R,8R)-7-[(benzyloxy)methyl]-1,4-dioxaspiro[4.5]dec-8-yl}methanol (33.6 g, 115 mmol) in a mixture of acetic acid (220 mL) and water (80 mL) was heated at 85° C. for 2 h. The solvents were removed by rotary evaporation under reduced pressure and the residue was partitioned between water and ethyl acetate. The aqueous phase was extracted with an additional portion of ethyl acetate and the combined organics were washed with saturated aqueous NaHCO3 and NaCl solutions, and dried over a mixture of Na2SO4 and MgSO4. Concentration in vacuo afforded a yellow syrup that was taken up in methanol (250 mL) and treated with K2CO3 (20 g, 150 mmol) with stirring at rt for 30 min. The methanol was then evaporated and the residue was taken up in ethyl acetate and washed with water, saturated aqueous NaCl solution, and dried a mixture of Na2SO4 and MgSO4. Concentration in vacuo provided (3R,4R)-3-[(benzyloxy)methyl]-4-(hydroxymethyl)cyclohexanone as a thick, yellow syrup. 1H NMR (500 MHz, d6-acetone) δ 7.36 (4H, m), 7.30 (1H, m), 4.56-4.50 (2H, m), 3.70 (1H, m), 3.66-3.60 (2H, m), 3.56 (1H, dd, J= 5.4, 9.3 Hz), 3.54-3.48 (1H, dd, J= 4.0, 9.3 Hz), 2.44-2.26 (4H, m), 2.13-2.07 (2H, m), 1.91 (1H, m), 1.67 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:33][CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]([CH3:32])([O:24][Si](CC)(CC)CC)[CH3:23])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].O1CCCC1.C(O)(=O)C>O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:33][CH:34]2[CH2:35][CH2:36][CH2:37][CH2:38]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]([OH:24])([CH3:32])[CH3:23])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CC[Si](CC)(CC)OC(C)(C)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Yield: 61 %

Procedure:
In a flask containing 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-methyl-2-triethylsilanyloxy-propyl)-1H-pyrazol-3-yl]-propionamide (80 mg, 0.14 mmol) was added tetrahydrofuran (2 mL), water (500 μL) and acetic acid (2 mL) and was stirred at 25° C. until complete by thin layer chromatography. It was then diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The organics were than combined and washed with a saturated aqueous solution of sodium bicarbonate (10 mL) and dried over magnesium sulfate, filtered and concentrated. Purification by AnaLogix Intelliflash system (4 g silica gel column, 15% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (40 mg, 63%) as a white foam: [α]31589=−8.2° (c=0.11, methylene chloride); ES-HRMS m/e calcd for C22H30N3O4SCl (M+H)+ 468.1719, observed 468.1717; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.06-1.20 (m, 2H, CH2), 1.35-1.84 (m, 8 H, 4×CH2), 2.00-2.17 (m, 1H, CH), 3.34 (s, 3H, SO2CH3), 3.86 (s, 2H, NCH2), 3.92 (dd, J=8.3, 6.8 Hz, 1H, ArCH), 4.65 (s, 1H, OH), 6.45 (d, J=2.3 Hz, 1H, Ar), 7.51 (d, J=2.3 Hz, 1H, Ar), 7.59 (dd, Jo=8.3 Hz, Jm=1.6 Hz, 1H, Ar), 7.70 (d, Jm=1.6 Hz, 1H, Ar), 8.01 (d, Jo=8.3 Hz, 1H, Ar), 10.81 (s, 1H, NH).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][CH:18]1[CH2:20][O:19]1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:17][CH:18]2[CH2:20][O:19]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCC1CO1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Product: c1ccc(COc2ccc(OCC3CO3)cc2)cc1
Yield: 79 %

Procedure:
Alkylation of 4-(benzyloxy)phenol with 2-(bromomethyl)oxirane (76) as in Example 2A, followed by chromatography of the product on silica gel, eluting with 0-25% CH2Cl2/petroleum ether (foreruns) and then with 25% CH2Cl2/petroleum ether, gave 2-{[4-(benzyloxy)phenoxy]methyl}oxirane (78) (reported by Kopka et al., 2003 using epichlorohydrin) (79%) as a white solid: mp (CH2Cl2/pentane) 61-62° C.; 1H NMR (CDCl3) δ 7.44-7.28 (m, 5H), 6.90 (dt, J=9.3, 2.8 Hz, 2H), 6.85 (dt, J=9.3, 2.8 Hz, 2H), 4.16 (dd, J=11.1, 3.3 Hz, 1H), 3.92 (dd, J=11.1, 5.6 Hz, 1H), 3.32 (m, 1H), 2.89 (dd, J=4.8, 4.3 Hz, 1H), 2.73 (dd, J=5.0, 2.7 Hz, 1H).
Reaction SMILES: [CH2:1]([N:8]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:9]1[C:10]([F:29])=[C:11]([C:16](=O)[C:17](=[C:24]2[S:27]CS2)[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[C:12]([F:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:38][NH2:39]>C(O)C>[CH2:30]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[C:10]([F:29])=[C:11]([C:16]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:24]([SH:27])[NH:38][N:39]=2)[C:12]([F:15])=[CH:13][CH:14]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(C(=C1SCS1)c1ccncc1)c1c(F)ccc(N(Cc2ccccc2)Cc2ccccc2)c1F
Reactant: NN
Solvent: CCO
Solvent: O
Product: Fc1ccc(N(Cc2ccccc2)Cc2ccccc2)c(F)c1-c1n[nH]c(S)c1-c1ccncc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
1-(3-Dibenzylamino-2,6-difluoro-phenyl)-2-[1,3]dithietan-2-ylidene-2-pyridin-4-yl-ethanone (1.26 g, 2.44 mmol) was suspended in absolute ethanol (10 mL). Hydrazine monohydrate (0.473 mL, 9.755 mmol, 4 eq) was added dropwise and the mixture was stirred at 60° C. for 2 hours. The suspension was concentrated under reduced pressure, taken up with toluene (2×20 mL) and evaporated to dryness. The crude product (1.35 g) was used in the following step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](Cl)(=[O:27])[C:24](Cl)=[O:25].C(=O)(O)[O-].[Na+]>CCOCC>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)[C:24](=[O:25])[C:23]2=[O:27])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(NC2CCN(Cc3ccccc3)CC2)c1
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: COc1ccc2c(c1)N(C1CCN(Cc3ccccc3)CC1)C(=O)C2=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.3 %

Procedure:
1-Benzyl-4-(3-methoxyphenyl)aminopiperidine (1.88 g) synthesized in accordance with the method of Referential Example 1 of JP-B 40-6347 was dissolved in ether (38 ml). Into the resultant solution was added dropwise oxalyl chlori de (1.62 g) over 30 min at room temperature followed by heating under reflux for 3.5 hr. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. Into a suspension of aluminum chloride (5.9 g) in methylene chloride (20 ml) was added dropwise a solution of the resulting residue in methylene chloride (100 ml) at 0° C. over 30 min. After the completion of the addition, the resultant mixture was stirred at room temperature for additional 1.5 hr. After the completion of the reaction, the reaction solution was poured into ice and neutralized by adding an aqueous solution of sodium bicarbonate thereto. The resulting precipitate was filtered off and the filtrate was extracted with methylene chloride. After removing the solvent, the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate system) to give 1-(1-benzylpiperidin-4-yl)-6-methoxyindoline-2,3-dione (1.63 g) (yield: 73%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Oc1ccc(I)cc1
Product: CC(C)(C)OC(=O)COc1ccc(I)cc1

Procedure:
The subject compound was prepared starting from 4-iodophenol and t-butyl bromoacetate in the same manner as Reference example 6-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:43]=[CH:44][CH:45]=1)[CH2:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:23])=[C:17]([C:30](=[O:34])[N:31]([CH3:33])[CH3:32])[CH:16]=3)[CH:13]=2)[N:8](COC(=O)C(C)(C)C)[N:7]=1.[OH-].[Na+]>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:43]=[CH:44][CH:45]=1)[CH2:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)=[O:23])=[C:17]([C:30](=[O:34])[N:31]([CH3:32])[CH3:33])[CH:16]=3)[CH:13]=2)[NH:8][N:7]=1
Reactant: CN(C)C(=O)c1cc(-c2cnc3c(c2)c(Cc2cccc(Cl)c2)nn3COC(=O)C(C)(C)C)ccc1NC(=O)N1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc(-c2cnc3[nH]nc(Cc4cccc(Cl)c4)c3c2)ccc1NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.2 %

Procedure:
2,2-Dimethyl-propionic acid 3-(3-chloro-benzyl)-5-{3-dimethylcarbamoyl-4-[(morpholine-4-carbonyl)-amino]-phenyl}-pyrazolo[3,4-b]pyridin-1-ylmethyl ester (180 mg, 0.284 mmol) was dissolved in tetrahydrofuran (10 ml). 1 M sodium hydroxide in methanol (3.0 ml) was added to the mixture, and the reaction was stirred for 2 hours at room temperature. The reaction was quenched with sodium bicarbonate solution and extracted with dichloromethane. The organic layer was dried, filtered, and concentrated. The crude material was purified by mass-triggered reverse-phase HPLC to give 18 mg (12%) of morpholine-4-carboxylic acid {4-[3-(3-chloro-benzyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-2-dimethylcarbamoyl-phenyl}-amide. 1H-NMR (250 MHz, DMSO-d6) δ 13.48 (s, 1H), 8.82 (d, J=2.0 Hz, 1H), 8.77 (s, 1H), 8.46 (d, J=2.0 Hz, 1H), 7.79-7.71 (m, 2H), 7.64 (s, 1H), 7.47 (s, 1H), 7.34-7.20 (m, 3H), 4.35 (s, 2H), 3.66-3.56 (m, 4H), 3.43-3.35 (m, 4H), 2.98 (s, 6H); MS: m/z 519.2 (M+H+).
Reaction SMILES: I[C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][CH:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N[C@@H]1CCCC[C@H]1N>[Cu]I.C(OCC)(=O)C.O1CCOCC1>[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:30][C:2]2[CH:22]=[CH:21][C:5]([O:6][C:7]3[C:12]([C:13]4[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=4)=[CH:11][CH:10]=[CH:9][N:8]=3)=[CH:4][CH:3]=2)=[O:29])=[CH:26][CH:25]=1
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(I)cc2)n1
Reactant: NC(=O)c1ccc(N)cc1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)c3ccc(N)cc3)cc2)n1
Temperature: 25 °C

Procedure:
In a manner analogous to that described in Klappars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7727, 4-(2-(4-iodophenoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine (202 mg, 0.500 mmol), 4-aminobenzamide (102 mg, 0.750 mmol), finely ground CuI (4.8 mg, 0.0250 mmol, 5 mol %), and anhydrous potassium phosphate (212 mg, 1 mmol) were added into a screw cap test tube. The tube was purged with argon for 5 minutes. Then trans-1,2-diaminocyclohexane (15.0 mL, 0.100 mmol, 10 mol %) and dioxane were added into the reaction mixture via syringe. The tube was sealed and placed in a preheated oil bath at 110° C. After a day, the reaction was cooled to room temperature. The reaction mixture was passed through a pad of celite with the aid of ethyl acetate. The filtrate was concentrated under reduced pressure. The product was purified by column chromatography using 10:90 Hex:EtOAc. 4-Amino-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)benzamide was obtained as an off-white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:27][CH3:28])=[C:10]([CH2:19][NH:20][C:21](=[O:26])[CH2:22][C:23]([OH:25])=O)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:29][C:30]1[CH:31]=[C:32]([CH2:38][NH2:39])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[Br:29][C:30]1[CH:31]=[C:32]([CH2:38][NH:39][C:23](=[O:25])[CH2:22][C:21]([NH:20][CH2:19][C:10]2[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]3[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]3=[N:8][C:9]=2[CH2:27][CH3:28])=[O:26])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)O
Reactant: COc1ccc(CN)cc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1ccc(OC)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
A mixture of 3-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-3-oxopropanoic acid (0.6 g, 1.541 mmol), 1-[3-bromo-4-(methyloxy)phenyl]methanamine (0.389 g, 1.8 mmol), HATU (0.760 g, 2.0 mmol), and triethylamine (0.599 ml, 4.3 mmol) in dichloromethane (40 mL) was stirred overnight at room temperature to give a pale yellow solution. The reaction mixture was diluted with DCM, washed with saturated NaHCO3 and then saturated NaCl. The organic layer was dried over Na2SO4, evaporated to dryness which gave viscous syrup. The viscous syrup was chromatographed on an 80 g Combi-Flash Column in silica with DCM-MeOH (0-8%). The product from this purification was placed on a Chromatotron Plate (2000μ) silica eluting with DCM-MeOH (3.5%) to give N-{[3-bromo-4-(methyloxy)phenyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}propanediamide (800 mg, 88%). LC-MS m/z 587.3 (M+H)+, 0.83 min (ret time).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][OH:7])[CH2:2][CH3:3].[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:4]([CH2:5][CH2:6][OH:7])[S:14]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:16])=[O:15])[CH2:2][CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCCNCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(CCO)S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
At 0° C., 5.16 g (50 mmol) of N-propylethanolamine were introduced into 70 ml of methylene chloride, and 9.7 g (55 mmol) of benzenesulfonyl chloride and 7.6 g (75 mmol) of triethylamine were added successively. After 2 hours of stirring at 0° C., the mixture was allowed to warm to room temperature, stirring was continued for a further hour and the mixture was then extracted with 1M hydrochloric acid and subsequently with 2M aqueous sodium hydroxide solution. The organic phase was dried over Na2SO4, filtered, concentrated and the resulting residue (13.2 g) was chromatographed over silica gel (methylene chloride/methanol 19:1). Yield: 7.4 g as an oil which was directly reacted further.