Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:10](=[O:13])[CH:11]=[CH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([OH:13])[CH:11]=[CH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: C=C[C@@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
A solution of the resultant compound of Example 30 (3.25 g, 14.4 mmol) in anhydrous tetrahydrofuran was cooled to -78° C. and treated slowly along the side of the reaction vessel with 57 ml (57 mmol) of diisobutylaluminum hydride (1M in tetrahydrofuran). The solution was stirred at -78° C. for 0.5 h, quenched cautiously with methanol, allowed to warm to ambient temperature, and partitioned between ether and aqueous Rochelle salts. The organic phase was washed sequentially with water and brine, dried over MgSO4, and concentrated in vacuo. Chromatography on silica gel using 4:1 hexane:ethyl acetate provided 0.77 g (22%) of the desired compound (10:1 ratio of (3S,4S):(3R:4S) isomers). 1H NMR (CDCl3) δ 0.91 (d, J=7 Hz 3 H), 0.94 (d, J=7 Hz, 3 H), 1.26 (br t, J=7 Hz, 2 H), 1.44 (s, 9 H), 1.67 (nonet J=7 Hz, 1 H), 2.96 (br d, J=5 Hz, 1 H), 3.82 (m, 1 H), 4.18 (m, 1 H), 4.50 (br d, 1 H), 5.23 (dt, J=11, 1.5 Hz, 1 H), 5.33 (dt, J=17, 1.5 Hz, 1 H), 5.84 (ddd, J=17, 11, 6 Hz, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][SH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:17][N:16]=1>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][S:11][C:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:17][N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1cc(-c2ccccc2)on1
Reactant: CC(C)(C)OC(=O)NCCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCSc1cc(-c2ccccc2)on1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 24.3 %

Procedure:
2-(N-tert-Butoxycarbonylamino)ethanethiol (300 mg) was dissolved in dimethylformamide (3.0 ml), and the mixture was cooled to 5° C., followed by addition of sodium hydride [>55% (oil), 73 mg]. The resulting mixture was stirred at the same temperature for 30 minutes. Then, 3-chloro-5-phenylisoxazole (300 mg) was added to the reaction mixture, followed by stirring of the mixture at the same temperature for 30 minutes and further at room temperature for 3 days. At the end of this time, the reaction mixture was added to ice-cold water (40 ml) and extracted with ethyl acetate (40 ml×2), and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=4/1) to obtain the title compound (130 mg, 24%) as colorless crystals.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C:5]1[C:10]2=[C:11]([C:29]3[S:30][C:31]4[C:37]([O:38][CH3:39])=[CH:36][C:35]([CH3:40])=[CH:34][C:32]=4[CH:33]=3)[C:12]([CH2:21][N:22]3[CH2:27][CH2:26][NH:25][C:24](=[O:28])[CH2:23]3)=[C:13]([CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[N:9]2[N:8]=[CH:7][N:6]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:47](Cl)(=[O:49])[CH3:48]>ClCCl.C1COCC1>[C:47]([N:18]1[CH2:17][CH2:16][N:15]([CH2:14][C:13]2[N:9]3[C:10]([C:5]([NH2:4])=[N:6][CH:7]=[N:8]3)=[C:11]([C:29]3[S:30][C:31]4[C:37]([O:38][CH3:39])=[CH:36][C:35]([CH3:40])=[CH:34][C:32]=4[CH:33]=3)[C:12]=2[CH2:21][N:22]2[CH2:27][CH2:26][NH:25][C:24](=[O:28])[CH2:23]2)[CH2:20][CH2:19]1)(=[O:49])[CH3:48]
Reactant: COc1cc(C)cc2cc(-c3c(CN4CCNC(=O)C4)c(CN4CCNCC4)n4ncnc(N)c34)sc12
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(C)cc2cc(-c3c(CN4CCNC(=O)C4)c(CN4CCN(C(C)=O)CC4)n4ncnc(N)c34)sc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of Example 49 (310 mg, 522 μmol) in dichloromethane/THF (2.5:1, 9.64 ml) was treated with sodium carbonate (442 mg, 4.17 mmol) and stirred at rt for 30 min. Acetyl chloride (74 μl, 1.04 mmol) was added, and the resulting mixture was stirred at rt for 2 h. After quenching with methanol, the mixture was evaporated, and the residue was purified by preparative RP-HPLC (Reprosil C18, gradient 10-95% acetonitrile/0.1% aq. formic acid) affording 133 mg (45% of th.) of the title compound.
Reaction SMILES: [C:1](OCC)(=O)CC(OCC)=O.[Na].Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1>C1(C)C=CC=CC=1>[CH3:1][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: Cc1ccccc1
Product: Cc1ccc([N+](=O)[O-])cn1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A slurry of diethyl malonate (42 mL) and sodium (4.71 g) was warmed slowly to 90° C. and stirred at 90° C. for 2 hours and 120° C. for 30 min. before being cooled to room temperature. Toluene (200 mL) and 2-chloro-5-nitropyridine (25.0 g) were added and the mixture was heated at 110° C. for 1.5 hours and ambient temperature for 17 h. After removal of the volatiles in vacuo, 6 N HCl (200 mL) was added and the mixture heated to reflux for 4 h and cooled to room temperature. The solution was neutralized with solid sodium carbonate, extracted with ethyl acetate (6×100 mL), dried over solid magnesium sulfate, and concentrated to a dark solid. This material was purified by flash chromatography using 20% ethyl acetate in petroleum ether as the eluent. Concentration in vacuo of the product-rich fractions afforded 2-methyl-5-nitropyridine. A mixture of 2-methyl-5-nitropyridine (13.0 g) and 10% Pd on activated carbon (0.1 g) in 1,4-dioxane (150 mL) was hydrogenated at 50 psi for 24 hours and filtered over celite. Removal of the volatiles in vacuo provided 2-methyl-5-aminopyridine. A solution of this compound (9.90 g) was dissolved in 6 N HCl (100 mL), cooled to 0° C., and vigorously stirred throughout the procedure. Sodium nitrite (6.32 g) in water (50 mL) was added. After 30 min, tin (II) chloride dihydrate (52.0 g) in 6 N HCl (100 mL) was added and the reaction slurry was stirred at 0° C. for 3 hours. The pH was adjusted to pH 14 with 40% aqueous potassium hydroxide solution and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and removal of the volatiles in vacuo provided hydrazine XC. A solution of XC (8.0 g) and 4,4-dimethyl-3-oxopentanenitrile (10.0 g) in ethanol (200 mL) and 6 N HCl (6 mL) was refluxed for 17 hours and cooled to room temperature. Solid sodium hydrogen carbonate was added to neutralize the solution. The slurry was filtered and removal of the volatiles in vacuo provided a residue which was purified by column chromatography using ethyl acetate as the eluent. Concentration in vacuo of the product-rich fractions afforded XCI, which was reacted with LXXXIX (Example 8) according to Method B to provide 9, m.p. 121-123° C.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25](Br)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:29]1[O:33][N:32]=[C:31]2[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:30]=12>>[N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([C:35]3[CH:36]=[CH:37][C:30]5[C:31]([CH:34]=3)=[N:32][O:33][N:29]=5)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(Br)cccc2[nH]1
Reactant: OB(O)c1ccc2nonc2c1
Product: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(-c3ccc4nonc4c3)cccc2[nH]1

Procedure:
This compound is synthesized from compound 194 (see example 156) and benzo[1,2,5]oxadiazol-5-yl-boronic acid analogously to the method described in Example 156.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.Cl[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22]>ClCCl>[C:8]([C:4]1[CH:3]=[C:2]([NH:1][C:21](=[O:22])[O:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:7]=[CH:6][CH:5]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cccc(N)c1
Reactant: CCCCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCOC(=O)Nc1cccc(C(C)=O)c1
Yield: 89.5 %

Procedure:
A mixture of 27.03 g of m-aminoacetophenone, 25.85 g of diisopropylethylamine, 27.32 g of n-butyl chloroformate and 300 ml of dichloromethane was reacted as described in Example 1, giving 42.10 g of (3-acetylphenyl)carbamic acid, butyl ester, mp 59°-60° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[NH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1>C(O)C.C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)NC=C2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc2c(cc1OC)CC(=O)NCC2
Reaction time: 22 h

Procedure:
At ambient temperature, 35 g (159.6 mmol) of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one are dissolved in a mixture of 525 mL of ethanol and 175 mL of ethyl acetate. There are then added 7 g (20% by weight) of palladium-on-carbon 10% and hydrogenation is carried out at 65° C. and 3.5 bars for 22 hours. The catalyst is filtered off over Celite; rinsing with a mixture of ethanol/ethyl acetate and evaporation to dryness are carried out to yield the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:22][N:23](C=O)C>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.[C-]#N.[C-]#N.[Zn+2]>[C:22]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)#[N:23]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Br)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(C#N)cc2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A mixture of tert-butyl 4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylate (compound 13.1, 36 g, 101 mmol), Pd(PPh3)4 (11.7 g, 10.1 mmol), and Zn(CN)2 (17.9 g, 152.4 mmol) in DMF (400 mL) under nitrogen was stirred overnight at 80° C. The mixture was cooled to ambient temperature, then the reaction was quenched by the addition of 600 mL of FeSO4 (aq., sat.) and diluted with ethyl acetate. The resulting mixture was stirred vigorously then filtered through Celite® and washed with 1 M FeSO4, water, and ethyl acetate. The layers were separated and the aqueous phase was extracted with ethyl acetate (2×300 mL). The combined organic layers were washed with potassium carbonate (aq., sat., 200 mL), followed by brine (200 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:200-1:5) as the eluent to yield 23 g (75%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]2)[CH:5]=[C:4]([Cl:16])[C:3]=1[CH:17]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:18](N)=[O:19].Cl.C(O)(=[O:31])C>>[Cl:16][C:4]1[CH:5]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]2)[CH:7]=[C:2]([Cl:1])[C:3]=1[CH:17]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:18]([OH:31])=[O:19]
Reactant: CC(=O)O
Reactant: NC(=O)C(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Agent: Cl
Product: O=C(O)C(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Yield: 27.8 %

Procedure:
A mixture of 13.2 parts of 2,6-dichloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetamide, 648 parts of concentrated hydrochloric acid and 200 parts of acetic acid was stirred and refluxed for 224 hours. The resulting product was filtered off, washed with water and taken up to 100 parts of water. After treatment with a sodium hydroxide solution, the resulting solution was acidified with concentrated hydrochloric acid. The product was filtered off and purified by column chromatography over silica gel using a mixture of methylbenzene, tetrahydrofuran and acetic acid (70:30:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 3.8 parts (27.8%) of 2,6-dichloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetic acid; mp. 219.5° C. (intermediate 29).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([C:16]([O:18]C)=[O:17])[C:12](=[O:15])[NH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.Cl.C(O)(=O)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[NH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1cc(-c2cccc(OC)c2)c[nH]c1=O
Agent: Cl
Solvent: CC(=O)O
Product: COc1cccc(-c2c[nH]c(=O)c(C(=O)O)c2)c1

Procedure:
Methyl 1,2-dihydro-5-(3-methoxyphenyl)-2-oxo-3-pyridinecarboxylate is treated with 1:1 hydrochloric acid-acetic acid to give 1,2-dihydro-5-(3-methyoxyphenyl)-2-oxo-3-pyridinecarboxylic acid. This product is boiled in quinoline to afford 5-(3-methoxyphenyl)-2(1H)-pyridinone as the product. Treatment of this product with phosphorus oxychloride provides 2-chloro-5-(3-methoxyphenyl)pyridine. The preceding product is treated with hydrazine to produce 2-hydrazino-5-(3-methoxyphenyl)pyridine. Treatment of this product with ethyl orthoacetate yields 6-(3-methoxyphenyl)-3-methyl-1,2,4-triazolo[4,3-a]pyridine. Hydrogenation of the above product gives the product of the Example.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][C:12]#[N:13])[CH:8]=2)[CH:3]=[CH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][CH2:12][NH2:13])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: N#CCC(c1ccccc1)c1ccc2cc[nH]c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCC(c1ccccc1)c1ccc2cc[nH]c2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 60.4 %

Procedure:
To a 0° C. solution of 3-(1H-indol-6-yl)-3-phenyl-propionitrile XIII (1.1 g, 4.5 mmol) in THF (35 ml) was slowly added a suspension of LiAlH4 (0.51 g, 13 mmol) in THF (10 ml). The mixture was stirred 10 min at 0° C. and 10 minutes at room temperature, then it was refluxed for 1.5 hours. The reaction mixture was cooled to 0° C., quenched by the careful addition of freshly ground Na2SO4.10H2O (25 g), filtered, and the solid was washed with EtOAc. The filtrate was concentrated and purified via flash chromatography (DCM/MeOH/NH4OH) affording 3-(1H-indol-6-yl)-3-phenyl-propylamine XIV as a colorless oil (0.68 g, 62% yield).
Reaction SMILES: [CH3:1][C:2]([S:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Br:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][C:15]3([CH2:21][CH2:20]3)[C:16]2=O)=[CH:11][CH:10]=1.CO.C([O-])(O)=O.[Na+]>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC.CCOC(C)=O>[Br:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][C:15]3([CH2:21][CH2:20]3)[C:16]2=[N:7][S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])=[CH:11][CH:10]=1
Reactant: CC(C)(C)S(N)=O
Reactant: O=C1c2cc(Br)ccc2CCC12CC2
Agent: [Ti+4]
Agent: CC[O-]
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)S(=O)N=C1c2cc(Br)ccc2CCC12CC2
Reaction time: 4 h
Yield: 39.9 %

Procedure:
Titanium ethoxide (5.9 mL, 28.7 mmol), 2-methyl-2-propanesulfinamide (2.61 g, 21.5 mmol) and 7′-bromo-3′,4′-dihydro-1′H-spiro[cyclopropane-1,2′-naphthalen]-1′-one (Intermediate 6, 3.6 g, 14.3 mmol) in dry 2-Me THF (80 mL) were heated to 100° C. to give an azeotrope. In total 100 mL 2-Me THF was removed and replaced by new 2-Me THF in 50 mL portions over a period of 4 h. The mixture was refluxed overnight. The azeotropic distillation was continued for 9 h and then more 2-methyl-2-propanesulfinamide (2.61 g, 21.5 mmol) and titanium ethoxide (5.9 mL, 28.7 mmol) were added. In total 90 mL 2-Me THF were removed and replaced by new 2-Me THF in 50 mL portions. The mixture was refluxed overnight and the azeotropic distillation was continued for 6 h. The cooled reaction mixture was added to a mixture of MeOH (105 mL), sat. aq. NaHCO3 (41 mL) and EtOAc (430 mL). The resulting slurry was stirred for 2 h and was then filtered through a mixture of diatomaceous earth and Na2SO4 and concentrated. Some material crystallized from the mixture. The solid was triturated with EtOAc/n-heptane and collected by filtration. The mother liquor was purified by flash silica gel chromatography using CHCl3/MeOH 50:1 as eluent and the obtained product was recrystallized from EtOAc/n-heptane. Combining the obtained solids gave 2.02 g (40% yield) of the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.06 (d, 2 H), 1.14 (s, 9 H), 1.40 (d, 2 H), 1.64-1.84 (m, 2 H), 2.83 (m, 2H), 7.36 (d, 1 H), 7.69 (dd, 1 H), 8.16 (d, 1 H); MS (ES+) m/z 354.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[N:23][C:24]=3[NH2:26])[N:19]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[N:18]=2)[CH:6]=[CH:7][C:8]=1[NH:9][CH2:10][C:11]1[O:12][C:13]([CH3:16])=[CH:14][CH:15]=1.[CH3:33][N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[N:23][C:24]=3[NH2:26])[N:19]([CH:27]3[CH2:32][CH2:31][N:30]([CH2:39][C:35]4[N:34]([CH3:33])[CH:38]=[CH:37][N:36]=4)[CH2:29][CH2:28]3)[N:18]=2)[CH:6]=[CH:7][C:8]=1[NH:9][CH2:10][C:11]1[O:12][C:13]([CH3:16])=[CH:14][CH:15]=1
Reactant: COc1cc(-c2nn(C3CCNCC3)c3ncnc(N)c23)ccc1NCc1ccc(C)o1
Reactant: Cn1ccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1cc(-c2nn(C3CCN(Cc4nccn4C)CC3)c3ncnc(N)c23)ccc1NCc1ccc(C)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
A mixture 3-(3-methoxy-4-{[(5-methyl-2-furyl)methyl]amino}phenyl)-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.045 g, 0.0001 mol), 1-methyl-2-imidazole carboxaldehyde (0.011 g, 0.00011 mol), and acetic acid (0.018 g, 0.0003 mol) in dichloroethane (4 mL) was stirred at room temperature under an atmosphere of nitrogen for 1.5 hrs. Sodium triacetoxyborohydride (0.064 g, 0.0003 mol) was added into the mixture and the mixture was stirred at ambient temperature under an atmosphere of nitrogen for 18 hours. The reaction was quenched with an aqueous 5 N solution of sodium hydroxide. The solvents were removed under reduced pressure, and the residue was partitioned between water and dichloromethane. The organic layer was washed with water and brine. The solvents were removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield 3-(3-methoxy-4-{[(5-methyl-2-furyl)methyl]amino}phenyl)-1-{1-[(1-methyl-1H-2-imidazolyl)methyl]-4-piperidyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.03 g, 0.00006 mol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[O:14][C:13]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH:27](C(O)=O)[C:28]([OH:30])=[O:29])=[CH:20][CH:19]=3)=[O:16])=[N:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]>CC(O)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[O:14][C:13]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:20][CH:19]=3)=[O:16])=[N:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(Nc1ccc(CCCC(C(=O)O)C(=O)O)cc1)c1nnc(Nc2ccc(F)c(F)c2)o1
Solvent: CC(=O)O
Product: O=C(O)CCCCc1ccc(NC(=O)c2nnc(Nc3ccc(F)c(F)c3)o2)cc1
Reaction time: 4 h
Yield: 55.2 %

Procedure:
A solution of (3-{4-[({5-[(3,4-difluorophenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]phenyl}propyl)malonic acid (Example 506) (40 mg, 0.087 mmol) in AcOH (4 mL) was heated under reflux with stirring for 4 h. The reaction mixture was concentrated in vacuo and the solid filtered and washed with water then Et2O to give the title compound (20 mg, 55%) as a solid; 1H NMR δ 1.50-1.60 (4H, m), 2.24 (2H, t), 2.55 (2H, t), 7.15-7.20 (2H, m), 7.35-7.37 (1H, m), 7.48-7.52 (1H, m), 7.68-7.73 (3H, m), 10.97 (1H, s); MS m/e MH+ 417.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8]/[C:7]/1=[N:16]\[NH2:17])[CH2:2][CH2:3][CH2:4][CH3:5].[F:18][C:19]([F:24])([F:23])[C:20](O)=O>>[CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[N:8]2[C:20]([C:19]([F:24])([F:23])[F:18])=[N:17][N:16]=[C:7]12)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]cnc21
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(C(F)(F)F)nnc12
Yield: 60.2 %

Procedure:
The mixture of (2E)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone (200 mg, 0.85 mmol) in trifluoroacetic acid (10 mL) was refluxed overnight. The reaction mixture was concentrated and purified by preparative LCMS to yield the desired product (160 mg, 60.2%). LCMS calculated for C12H14F3N6O(M+H): 315.1; found 315.0.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([O:33][CH3:34])=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[CH:19]=[C:18]2[NH:24][C:25]1[C:30]([Cl:31])=[CH:29][N:28]=[CH:27][C:26]=1[Cl:32]>>[Cl:32][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([Cl:31])[C:25]=1[NH:24][C:18]1[C:17]2[C:22](=[C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:14]([O:33][CH3:34])=[CH:15][CH:16]=2)[O:21][C:20](=[O:23])[CH:19]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCBr
Reactant: C1CCNC1
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCN1CCCC1

Procedure:
The title compound was prepared from pyrrolidine and 8-(5-bromopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 28) following the procedure outlined in Example 52. 1H NMR (400 MHz, DMSO-d6): δ 9.58 (br s, 1H), 8.50 (s, 2H), 7.83 (d, 1H), 7.02 (d, 1H), 4.12 (br s, 1H), 3.97 (t, 2H), 3.87 (s, 3H), 2.87 (br, 6H), 1.80 (m, 4H), 1.70 (m, 4H), 1.53 (m, 2H); MS (ESI): 491.9.
Reaction SMILES: [N+:1]([C:4]1[CH:31]([CH3:32])[CH:8]2[CH2:9][C:10]([CH2:13][C:14]3[CH2:15][CH2:16][N:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH:30]=[CH:29][N:28]=[CH:27]5)=[CH:22][CH:21]=4)[CH2:18][CH:19]=3)([CH3:12])[O:11][C:7]2=[C:6]([CH3:33])[C:5]=1[CH3:34])([O-])=O.C(O)C.Cl.[OH-].[Na+]>O>[NH2:1][C:4]1[CH:31]([CH3:32])[CH:8]2[CH2:9][C:10]([CH2:13][C:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:21]=[CH:22][C:23]([N:26]5[CH:30]=[CH:29][N:28]=[CH:27]5)=[CH:24][CH:25]=4)[CH2:16][CH:15]=3)([CH3:12])[O:11][C:7]2=[C:6]([CH3:33])[C:5]=1[CH3:34]
Reactant: CC1=C2OC(C)(CC3=CCN(c4ccc(-n5ccnc5)cc4)CC3)CC2C(C)C([N+](=O)[O-])=C1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1=C(N)C(C)C2CC(C)(CC3=CCN(c4ccc(-n5ccnc5)cc4)CC3)OC2=C1C
Yield: 82.9 %

Procedure:
To 1.2 g of 4-(±)-(5-nitro-2,4,6,7-tetramethyldihydrobenzofuran-2-ylmethyl)-1-(4-imidazol-1-ylphenyl)-1,2,3,6-tetrahydropyridine, 30 ml of ethanol was added and 3.6 g of stannous chloride-dihydrate and 15 ml of concentrated hydrochloric acid were added, followed by heating at reflux for 8 hours. The reaction solution was poured into water, neutralized with a 1N sodium hydroxide solution and then extracted with chloroform. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration and concentrating under reduced pressure, the residue was subjected to silica gel column chromatography (chloroform:methanol=20:1) to obtain 0.93 g of the objective product (mp: 161-163° C.).