Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.[CH:30]([C:33]1[N:37]=[C:36]([C:38](Cl)(Cl)Cl)[O:35][N:34]=1)([CH3:32])[CH3:31].CCN(C(C)C)C(C)C.C[OH:52]>>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:22])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([C:38]([C:36]4[O:35][N:34]=[C:33]([CH:30]([CH3:32])[CH3:31])[N:37]=4)=[O:52])[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: CC(C)c1noc(C(Cl)(Cl)Cl)n1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Reactant: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(C(=O)c5nc(C(C)C)no5)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (42 mg, 0.1 mmol), 3-isopropyl-5-(trichloromethyl)-1,2,4-oxadiazole (46 mg, 0.2 mmol) and DIEA (40 μL, 0.23 mmol) in MeOH (1 mL) was stirred at 70° C. overnight. The crude reaction mixture was purified by RP-HPLC to give (4-(4-(5-Chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)piperidin-1-yl)(3-isopropyl-1,2,4-oxadiazol-5-yl)methanone as a white solid; 1H NMR (400 MHz, CDCl3) δ 9.67 (br s, 2H), 8.50 (s, 1H), 8.07 (s, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.05 (d, J=12.4 Hz, 1H), 6.16 (s, 1H), 5.53 (s, 1H), 3.98 (d, J=13.2 Hz, 1H), 3.34 (dt, J=2.0, 2.8 Hz, 1H), 3.15 (m, 1H), 2.82 (m, 2H), 2.62 (t, J=4.8 Hz, 2H), 2.34 (s, 3H), 2.25 9s, 3H), 1.90 (m, 2H), 1.76 (2H); ESMS m/z 554.2 (M+H+).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:42])[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:41])[CH2:21][CH2:22][NH:23][C:24]([C:26]3[C:27]([C:37]([F:40])([F:39])[F:38])=[N:28][N:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:30]=3)=[O:25])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1>C1COCC1.CO.O>[C:31]1([N:29]2[CH:30]=[C:26]([C:24]([NH:23][CH2:22][CH2:21][C:20]([NH:19][C:16]3[CH:15]=[CH:14][C:13]([C@H:10]4[CH2:9][CH2:8][C@H:7]([CH2:6][C:5]([OH:42])=[O:4])[CH2:12][CH2:11]4)=[CH:18][CH:17]=3)=[O:41])=[O:25])[C:27]([C:37]([F:40])([F:39])[F:38])=[N:28]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3cn(-c4ccccc4)nc3C(F)(F)F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3cn(-c4ccccc4)nc3C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
NaOH (71.9 mg, 1.8 mmol) was added to trans-[4-(4-{3-[(1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)amino]propionylamino}phenyl)cyclohexyl]acetic acid methyl ester (100 mg, 0.18 mmol) dissolved in THF/MeOH/water (25 mL, 3:2:1). The reaction mixture was stirred at 25° C. for 5 hours and concentrated under vacuum. The residue was acidified with 1M HCl up to pH of 2 and extracted with ethyl acetate. The extract was washed with brine and dried with anhydrous sodium sulfate and concentrated under vacuum. Acetonitrile was added thereto and cooled to obtain a filtrate, and the filtrate was filtered and separated to obtain the desired compound (95 mg, 98%) as a white solid.
Reaction SMILES: [O:1]=[C:2]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)/[CH:3]=[CH:4]/[C:5]1[O:6][CH:7]=[CH:8][C:9](=[O:22])[C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C([BH-](CC)CC)C.[Li+]>O1CCCC1>[OH:1][CH:2]([CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)/[CH:3]=[CH:4]/[C:5]1[O:6][CH:7]=[CH:8][C:9](=[O:22])[C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CCCCCOc1c(/C=C/C(=O)CCc2ccccc2)occc1=O
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CCCCCOc1c(/C=C/C(O)CCc2ccccc2)occc1=O
Reaction time: 0.5 h
Yield: 28.2 %

Procedure:
To a solution, cooled under nitrogen to -78°, of 0.823 g (1.99 mmol) of 2-(3-oxo-5-phenyl-trans-1-pentenyl)-3-(5-carboethoxypentyloxy)-4-pyrone in 4 ml of tetrahydrofuran was added dropwise keeping the internal temperature at -70° to -75°, 1.89 ml (1.89 mmole) of lithium triethylborohydride. After being stirred for an additional 30 min the cold reaction was quenched by the addition of 2.0 ml of 40% aqueous acetic acid and then partially concentrated under reduced pressure. The residue was dissolved in methylene chloride and washed successively with aqueous sodium bicarbonate and brine solution. The organic solution was dried over magnesium sulfate and evaporated to give an oil. Chromatographic purification on silica gel eluting with ether furnished 0.233 g (28%) of 2-[(3RS)-3-hydroxy-5-phenyl-trans-1-pentenyl]-3-(5-carboethoxypentyloxy)-4-pyrone. NMR (CDCl3, 100 M Hz): δ1.26 (3H, t, J=7.0 Hz), 2.32 (2H, t, J=6 Hz).
Reaction SMILES: CS[C:3](=N)[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[OH:18][CH2:19][CH2:20][NH:21][CH:22]([CH3:26])[CH:23]([CH3:25])[NH2:24]>C(O)C>[CH3:25][CH:23]1[CH:22]([CH3:26])[N:21]([CH2:20][CH2:19][OH:18])[C:3](=[N:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[NH:24]1
Reactant: CC(N)C(C)NCCO
Reactant: CSC(=N)Nc1ccccc1N1CCOCC1
Solvent: CCO
Product: CC1NC(=Nc2ccccc2N2CCOCC2)N(CCO)C1C

Procedure:
A mixture of 2-methyl-1-(2-morpholinophenyl)-2-thiopseudourea (12.5 g) and N-(2-hydroxyethyl)-1,2-dimethylethylenediamine (8 g) in dry ethanol (150 ml) was heated under reflux at 90°-95° C. for 6 days to give a dark brown oil which was purified by column chromatography on neutral alumina (250 g) using a 1:9 mixture of dichloromethane and hexane to give 4-{2-[4,5-dimethyl-1-(2-hydroxyethyl)-2-imidazolidinylideneamino]phenyl}morpholine as a colourless solid (m.p. 108°-109° C.) which was recrystallised from hexane.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6](=[O:40])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][N:23]=[C:22]([CH3:25])[C:21]=3[NH:26][C:27]([O:29][CH:30]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=3[F:39])[CH3:31])=[O:28])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)C.Cl>CO.O>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH:30]([O:29][C:27]([NH:26][C:21]2[C:22]([CH3:25])=[N:23][O:24][C:20]=2[C:17]2[CH:18]=[CH:19][C:14]([C:11]3[CH:12]=[CH:13][C:8]([CH2:7][C:6]([OH:40])=[O:5])=[CH:9][CH:10]=3)=[CH:15][CH:16]=2)=[O:28])[CH3:31])=[C:33]([F:39])[CH:34]=1
Reactant: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccc(Cl)cc3F)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1noc(-c2ccc(-c3ccc(CC(=O)O)cc3)cc2)c1NC(=O)OC(C)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Excess lithium hydroxide was added to a solution of (4′-{4-[1-(4-chloro-2-fluoro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-acetic acid ethyl ester (0.100 g, 0.19 mmol) in methanol and water, and the reaction was stirred at room temperature overnight. The mixture was acidified with 1N aqueous HCl and extracted with EtOAc, and the combined organic layers were dried, filtered, and concentrated. The residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[F:14][C:15]([F:43])([F:42])[C:16]1[CH:17]=[C:18]([C@H:26]2[O:30][C:29](=[O:31])[N:28]([CH2:32][C:33]3[C:38]([Br:39])=[CH:37][CH:36]=[C:35](Cl)[N:34]=3)[C@H:27]2[CH3:41])[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1.O1CCOCC1>C(OCC)(=O)C>[F:25][C:22]([F:23])([F:24])[C:20]1[CH:19]=[C:18]([C@H:26]2[O:30][C:29](=[O:31])[N:28]([CH2:32][C:33]3[C:38]([Br:39])=[CH:37][CH:36]=[C:35]([N:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)[N:34]=3)[C@H:27]2[CH3:41])[CH:17]=[C:16]([C:15]([F:14])([F:42])[F:43])[CH:21]=1
Reactant: C1COCCN1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(Cl)ccc1Br
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(N2CCOCC2)ccc1Br
Temperature: 140 °C
Yield: 82.1 %

Procedure:
Triethylamine (3.23 mL, 23.18 mmol), morpholine (1.683 mL, 19.32 mmol), (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 24, 2 g, 3.86 mmol) and 1,4-dioxane (10.0 mL) were mixed in a 20 mL microwave vial, capped and heated at 140° C. for 6 hours in microwave with monitoring by TLC and LCMS. Once the reaction was determined to be complete, the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous NaHCO3, water and brine. The organic phase was dried with Na2SO4, filtered and the filtrate concentrated. The crude was purified by silica gel chromatography in 30% ethyl acetate/hexanes to give the titled compound (1.8 g, 3.17 mmol, 82% yield) as white solid. LCMS (M+H)+: 569.9. 1H NMR (CDCl3, 500 MHz): δ 7.93 (s, 1H), 7.80 (s, 2H), 7.63 (dd, 1H), 6.52 (d, 1H), 5.75 (d, 1H), 4.91 (d, 1H), 4.32 (d, 1H), 4.28 (t, 1H), 3.87-3.84 (t, 4H), 3.57-3.48 (m, 4H), 0.83 (d, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]2[NH2:13])[CH2:3]1.[C:14](N1C=CN=C1)(N1C=CN=C1)=O.[Cl:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[Cl:36])[C:30](O)=[O:31]>>[CH3:14][N:13]([CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[N:4]1[CH2:5][CH2:6][CH:2]([OH:1])[CH2:3]1)[C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:35]([Cl:36])=[C:27]([Cl:26])[CH:28]=1
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC1CCCCC1N1CCC(O)C1
Product: CN(C(=O)c1ccc(Cl)c(Cl)c1)C1CCCCC1N1CCC(O)C1

Procedure:
Following the procedure of Example 1a, using trans-N-methyl-N-[2-(3-hydroxy-1-pyrrolidinyl)cyclohexylamine, carbonyldiimidazole] and 3,4-dichlorobenzoic acid there is obtained N-methyl-N-[2-(3-hydroxy-1-pyrrolidinyl)cyclohexyl]-3,4-dichlorobenzamide.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:14])[N:5]([CH3:13])[C:6](=[O:12])[NH:7]2.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:13][N:5]1[C:4](=[O:14])[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[NH:7][C:6]1=[O:12]
Reactant: Cn1c(=O)[nH]c2cccc(Br)c2c1=O
Reactant: C#C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(=O)[nH]c2cccc(C#C[Si](C)(C)C)c2c1=O
Temperature: 70 °C
Reaction time: 4 h
Yield: 45.9 %

Procedure:
To a degassed solution of 5-bromo-3-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline (1.0 g, 4.0 mmol) in 20 ml of DMF and 20 ml of triethylamine was added trimethylsilylacetylene (1.6 ml, 12 mmol), 50 mg of triphenylphosphine, 20 mg of palladium(II)acetate, and 1 mg of cuprous(I)iodide. The mixture was stirred under nitrogen, at 70° C. After 7 h additionally 0.4 ml of trimethylsilylacetylene was added and heating continued for 4 h. Then the mixture was evaporated in vacuo and the residue extracted with 100 ml of dichloromethane and 100 ml of water. The organic layer was washed twice with 100 ml of water, dried over anhydrous sodium sulfate, treated with charcoal, filtered through a pad of celite, and evaporated. The residue was triturated with ether/petroleum ether (1:1) and filtered off and dried giving 0.50 g (46%) of 1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-5-trimethylsilylethynyl-quinazoline.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([NH:20][C:21](=O)OC(C)(C)C)[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.[Cl:28][C:29]1[CH:30]=[CH:31][C:32]2[O:36][C:35](C=O)=[CH:34][C:33]=2[CH:39]=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]2[O:36][C:35]([CH:21]=[N:20][N:17]3[CH2:16][CH2:15][N:14]([CH2:13][C@:2]4([CH3:1])[O:6][C:5]5=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]5[CH2:3]4)[CH2:19][CH2:18]3)=[CH:34][C:33]=2[CH:39]=1
Reactant: O=Cc1cc2cc(Cl)ccc2o1
Reactant: CC(C)(C)OC(=O)NN1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@]1(CN2CCN(N=Cc3cc4cc(Cl)ccc4o3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
To a mixture of tert-butyl (S)-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]carbamate prepared in Example 503 (0.20 g, 0.523 mmol) and 5-chlorobenzofuran-2-carbaldehyde (0.113 g, 0.628 mmol) and methylene chloride (4 ml), trifluoroacetic acid (0.4 ml) was added followed by stirring at room temperature for 2 hours. To the reaction mixture, a saturated sodium hydrogencarbonate solution was added followed by extraction with methylene chloride. The organic phase was washed with a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=4/1) to afford (S)-N-(5-chlorobenzofuran-2-ylmethylene)-N-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]amine (0.137 g, yield 59%) as a light yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][N:8]=[C:7]([C:10]3[N:11]([CH3:15])[CH:12]=[CH:13][CH:14]=3)[C:6]=2[CH:16]=1.CN(C)[CH:19]1[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH2:22][C:21](=[O:29])[O:20]1>C(O)(=O)C>[CH3:15][N:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[C:7]1[C:6]2[CH:16]=[C:2]([N:1]3[C:21](=[O:29])[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[NH:24][C:19]3=[O:20])[CH:3]=[CH:4][C:5]=2[S:9][N:8]=1
Reactant: Cn1cccc1-c1nsc2ccc(N)cc12
Reactant: CN(C)C1N=C(C(F)(F)F)CC(=O)O1
Solvent: CC(=O)O
Product: Cn1cccc1-c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.3 %

Procedure:
To a mixture of 5-amino-3-(1-methylpyrrol-2-yl)-1,2-benzisothiazole(1.05 g, 4.59 mmol) and acetic acid is added 2-(dimethylamino)-4-(trifluoromethyl)-5H-1,3-oxazin-6-one (0.960 g, 4.60 mmol). The resultant mixture is stirred at reflux for two hours, cooled to room temperature, diluted with ice water and stirred vigorously for approximately 15 minutes. Filtration and drying affords the title compound as a gray solid (1.50 g, 83.3%, mp 125-130° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].[C:17](Cl)(=[O:19])[CH3:18]>C(Cl)Cl>[C:17]([C:11]1[CH:10]=[C:9]([C:5]([CH3:6])([CH3:7])[CH3:8])[CH:14]=[CH:13][C:12]=1[OH:15])(=[O:19])[CH3:18].[C:17]([C:13]1[CH:14]=[C:9]([C:5]([CH3:8])([CH3:6])[CH3:7])[CH:10]=[CH:11][C:12]=1[O:15][CH3:16])(=[O:19])[CH3:18]
Reactant: COc1ccc(C(C)(C)C)cc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(C(C)(C)C)ccc1O
Product: COc1ccc(C(C)(C)C)cc1C(C)=O
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To 7.40 g of aluminum chloride suspended in 100 ml of methylene chloride were added, under nitrogen, 8.20 g of 4-tert-butylanisole (prepared in Reference Example 1) dissolved in 50 ml of methylene chloride at 0° C. followed by dropwise addition of 3.92 ml of acetyl chloride dissolved in 50 ml of methylene chloride at the same temperature. The mixture was stirred at 20° C. for 30 minutes. The reaction mixture was concentrated at reduced pressure and poured into 200 ml of ice-water and extracted with diethyl ether. The extract was washed with water and saturated brine successively, dried over magnesium sulfate anhydride and concentrated at reduced pressure. The residue was chromatographed on silica gel column using a mixed solvent of methylene chloride and cyclohexane (1:2) as an eluting agent to give 5.30 g of the title compound and 3.79 g of 2-acetyl-4-tert-butylanisole. The physical properties of each compound are as follows.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]([F:30])([CH:27]([F:29])[F:28])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH:25]=[N:24][NH:23][C:22]2=[O:26])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C(OCC)(=O)C.O.CN(C)C=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:23]2[C:22](=[O:26])[N:21]([C:18]3[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:12]([F:11])([F:30])[CH:27]([F:28])[F:29])=[CH:20][CH:19]=3)[CH:25]=[N:24]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=c1[nH]ncn1-c1ccc(OCC(F)(F)C(F)F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1n(-c2ccc(OCC(F)(F)C(F)F)cc2)cnn1-c1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
A mixture of 4-fluoronitrobenzene (3.1 g), 4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone (5.8 g), potassium carbonate (13.8 g) and N,N-dimethylformamide (60 ml) was stirred at 80° C. for 2 hours. The resultant was cooled and poured into water (500 ml). The mixture was neutralized with hydrochloric acid and the precipitated crystals were collected by filtration. The crystals thus obtained were dissolved in ethyl acetate (300 ml) and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate and diisopropyl ether to give 2-(4-nitrophenyl)-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone (5.5 g, 67%) as yellow crystalline powders.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:19][CH2:20][O:21][CH2:22][CH3:23])[C:7]2=[O:24])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:39]=[N:40][C:41]([NH2:44])=[CH:42][CH:43]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>C1(C)C=CC=CC=1>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:39]=[N:40][C:41]([NH:44][C:13]3[N:14]=[CH:15][C:10]4[CH:9]=[C:8]([CH2:19][CH2:20][O:21][CH2:22][CH3:23])[C:7](=[O:24])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:11]=4[N:12]=3)=[CH:42][CH:43]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOCCc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Solvent: Cc1ccccc1
Product: CCOCCc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Yield: 20.3 %

Procedure:
8-Cyclopentyl-6-(2-ethoxy-ethyl)-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.0 g 2.86 mmol) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.10 g, 3.95 mmol) were heated to reflux in toluene (10 mL) for 16 hours. The mixture was cooled to room temperature and purified by silica gel chromatography to give 4-{6-[8-cyclopentyl-6-(2-ethoxy-ethyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester as an orange solid (0.328 g, 20.4%). 1H NMR δ(400 MHz, CDCl3) 8.54 (s, 1H), 8.26 (d, J=9.0 Hz, 1H), 7.98 (d, J=2.9 Hz, 1H), 7.45 (s, 1H), 7.38 (dd, J=2.9, 9.3 Hz, 1H), 5.90 (m, 1H), 3.70 (t, J=6.3, 1H), 3.61 (m, 4H), 3.51 (q, J=7.1, 1H), 3.11 (m, 4H), 2.84 (t, J=5.9, 1H), 2.33 (m, 2H), 2.08 (m, 2H), 1.87 (m, 2H), 1.69 (m, 2H), 1.48 (s, 9H), 1.19 (t, J=7.1, 1H).
Reaction SMILES: [N:1]1[C:9]([NH:10][C@H:11]([C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[C:16]3[CH:31]=[CH:32][CH:33]=[CH:34][C:15]=3[N:14]=2)[CH3:12])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:21]1[CH2:22][CH2:23][CH:18]([N:17]2[C:16]3[CH:31]=[CH:32][CH:33]=[CH:34][C:15]=3[N:14]=[C:13]2[C@@H:11]([NH:10][C:9]2[N:1]=[CH:2][N:3]=[C:4]3[C:8]=2[N:7]=[CH:6][NH:5]3)[CH3:12])[CH2:19][CH2:20]1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To a solution of 4-{2-[(S)-1-(9H-purin-6-ylamino)ethyl]benzoimidazol-1-yl}piperidine-1-carboxylic acid tertbutyl ester 112 (101 mg, 0.218 mmol) in DCM (3 mL) was added TFA (1 mL) and the mixture was stirred at RT for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-20% 2M NH3/MeOH in DCM) affording 113 as a white solid (68 mg, 86%). LCMS: RT 1.65 min [M+H]+ 363.1. 1H NMR (CDCl3, 400 MHz): δ 8.34 (1H, s), 7.88 (1H, s), 7.75-7.65 (3H, m), 7.27-7.19 (3H, m), 6.01 (1H, br), 4.80-4.70 (1H, m), 3.39-3.38 (1H, m), 3.37-3.30 (1H, m), 3.19-3.09 (1H, m), 2.89-2.38 (3H, m) 1.99-1.70 (6H, m)
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[C:43]([CH2:47][CH2:48][O:49]S(C)(=O)=O)[CH:44]=[CH:45][CH:46]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:54][NH:55][CH3:56].C1C[O:60]CC1>>[CH:48]([OH:49])=[O:60].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][CH2:48][N:55]([CH3:56])[CH3:54])[CH:42]=2)[N:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CNC
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(CCOS(C)(=O)=O)c4)c4ccccc43)cn12
Reactant: C1CCOC1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(CCN(C)C)c4)c4ccccc43)cn12
Product: O=CO

Procedure:
A solution of Intermediate 131d (44.5 mg, 0.06 mmol) and dimethylamine solution (2M in THF, 0.6 mL, 1.2 mmol) in THF (1 mL) was stirred at 60° C. for 20 h in a sealed tube. The mixture was concentrated in vacuo and the residue purified by MDAP (Method 7). The title product was isolated as an off-white solid (18 mg, 41%). LCMS (Method 5): Rt 3.63 min, m/z 690.6 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.3 Hz), 1.28 (9H, s), 1.47-1.55 (2H, m), 1.63-1.71 (2H, m), 1.75-1.97 (4H, m), 2.00-2.16 (2H, m), 2.19 (6H, s), 2.53 (2H, t, J=8.1 Hz), 2.78 (2H, t, J=7.6 Hz), 2.90 (1H, ddd, J=12.2, 9.0, 4.0 Hz), 3.16 (1H, dt, J=12.1, 4.2 Hz), 3.31 (1H, m), 4.82 (1H, td, J=8.6, 5.5 Hz), 5.52 (1H, t, J=4.3 Hz), 6.33 (1H, s), 7.09 (1H, d, J=8.6 Hz), 7.19 (1H, dd, J=9.8, 2.2 Hz), 7.24-7.42 (8H, m), 7.64 (1H, dd, J=9.8, 0.8 Hz), 7.69 (1H, d, J=2.1 Hz), 8.12 (1H, s), 8.19 (1H, s).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:12]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:24]=[C:25]=[O:26])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:25]([NH:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:26]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C=Nc1ccccc1-c1ccccc1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1ccccc1-c1ccccc1
Yield: 19.4 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-phenylphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-phenyl phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.22 g, 19%). EI-MS m/z 350(M+H)+