Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].CC(C)(C)CCN.[O:17]=[C:18]1[C:26]2([CH2:30][O:29][C:28]3[CH:31]=[C:32]4[C:36](=[CH:37][C:27]2=3)[CH2:35][CH2:34][O:33]4)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]1[CH2:38][C:39](N)=[O:40]>>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:39](=[O:40])[CH2:38][N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26]2([CH2:30][O:29][C:28]3[CH:31]=[C:32]4[C:36](=[CH:37][C:27]2=3)[CH2:35][CH2:34][O:33]4)[C:18]1=[O:17]
Reactant: Cc1cccc(C)c1N
Reactant: NC(=O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Agent: CC(C)(C)CCN
Product: Cc1cccc(C)c1NC(=O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 12.49 and making non-critical variations using 2,6-dimethylaniline to replace 3,3-dimethylbutylamine, dimethylphenyl)-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3-indol]-1′(2′H)-yl)acetamide was obtained (67%) as a colorless solid: mp 261-262° C.; 1H NMR (300 MHz, DMSO-d6) δ9.66 (s, 1H), 7.30 (dd, J=7.7, 7.7 Hz, 1H), 7.16-6.98 (m, 6H), 6.51 (s, 1H), 6.37 (s, 1H), 4.75 (ABq, 2H), 4.67-4.52 (m, 2H), 4.49-4.40 (m, 2H), 2.90 (dd, J=8.6, 8.6 Hz, 2H), 2.12 (s, 6H); 13C NMR (75 MHz, DMSO-d6) δ177.7, 165.4, 161.5, 160.9, 143.0, 135.7, 135.0, 132.9, 128.9, 128.2, 127.1, 123.9, 123.4, 121.3, 120.2, 119.7, 109.3, 92.8, 80.2, 72.5, 57.4, 43.0, 28.8, 18.6, 15.6; MS (ES+) m/z 441.2 (M+1).
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=1.[I:24]I>CCOCC.C1COCC1>[Cl:16][C:17]1[C:22]([Cl:23])=[C:21]([I:24])[CH:20]=[CH:19][N:18]=1
Reactant: II
Reactant: Clc1cccnc1Cl
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Clc1nccc(I)c1Cl
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of n-butyllithium (27.6 ml, 69 mmol, 2.5 M in hexanes) in dry Et2O (150 ml) cooled at −78° C., under a nitrogen atmosphere, was added 2,2,6,6-tetramethylpiperidine (11.64 ml, 69 mmol), dropwise. The resulting reaction mixture was stirred at −78° C. for 10 min., and then a solution of 2,3-dichloropyridine (10 g, 67.57 mmol) in dry THF (75 ml) was added dropwise. The mixture was stirred at −78° C. for 30 min. and then a solution of iodine (25.38 g, 100 mmol) in dry THF (75 ml) was added. The mixture was allowed to warm to r.t. overnight, quenched with Na2S2O3 (aqueous sat. solution) and extracted twice with EtOAc. The combined organic extracts were washed with NaHCO3 (aqueous sat. solution), dried (Na2SO4) and concentrated in vacuo. The crude residue was precipitated with heptane, filtered off and dried to yield intermediate compound D10 (8.21 g, 44%) as a pale cream solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:17][CH:18]=2)[CH3:12])=[O:9])[CH:5]=[C:4]([CH3:25])[N:3]=1.[CH3:26][C:27]1[C:31]([CH3:32])=[C:30]([NH2:33])[O:29][N:28]=1>>[CH3:26][C:27]1[C:31]([CH3:32])=[C:30]([NH:33][C:2]2[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]3[CH:14]=[N:15][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:17][CH:18]=3)[CH3:12])=[O:9])[CH:5]=[C:4]([CH3:25])[N:3]=2)[O:29][N:28]=1
Reactant: Cc1cc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)nc(Cl)n1
Reactant: Cc1noc(N)c1C
Product: Cc1cc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)nc(Nc2onc(C)c2C)n1

Procedure:
The title compound is prepared from 2-chloro-6-methyl-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carb oxamide (20 mg, 0.05 mmol, Step-1, single enantiomer) and 3,4-dimethylisoxazol-5-amine (12 mg, 0.1 mmol) according to the procedure similar to that described in Step-4 of Example 445.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1.[C:16](=O)(OC1C=CC=CN=1)[O:17]C1C=CC=CN=1.C(N(CC)CC)C>ClCCl>[N:14]([C:12]1[CH:11]=[N:10][N:9]([CH2:8][C:7]2[C:3]([CH3:2])=[N:4][O:5][C:6]=2[CH3:15])[CH:13]=1)=[C:16]=[O:17]
Reactant: O=C(Oc1ccccn1)Oc1ccccn1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1noc(C)c1Cn1cc(N=C=O)cn1

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (400 mg, 2.08 mmol), dipyridin-2-yl carbonate (450 mg, 2.08 mmol) and triethylamine (0.290 mL, 2.08 mmol) were stirred in dichloromethane (7 mL) for 12 hours at room temperature. The reaction was concentrated under vacuum to afford 4-((4-isocyanato-1H-pyrazol-1-yl)methyl)-3,5-dimethylisoxazole as an off-white solid in quantitative yield. Ethanol (1 mL) was added along with methyl 2-amino-3-(3-methoxyphenyl)propanoate (68 mg, 0.327 mmol) and triethylamine (0.064 mL, 0.461 mmol). The reaction was stirred at reflux for 12 hours, then allowed to cool to room temperature. The solvent was removed under a stream of nitrogen. The crude product was re-suspended in MeOH (1 mL) and purified by reversed phase HPLC (5 to 95% acetonitrile in H2O: 16 minutes gradient). The pure fractions were combined and solvent removed under vacuum to afford 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5-(3-methoxybenzyl)imidazolidine-2,4-dione as a white solid yield: 50% 1H NMR (CDCl3, 400 MHz): δ 2.19 (s, 3 H), 2.41 (s, 3H), 3.34-3.33 (d, J=3.2 Hz, 1H), 3.31-3.29 (d, J=8 Hz, 1H), 3.76 (s, 3H), 4.33-4.30 (m, 1H), 5.05 (s, 2H), 5.95 (bs, 1H), 7.25-7.21 (t, 1H), 6.82-6.78 (m, 3H), 7.85 (s, 1H), 7.99 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.13 μM.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].P(Cl)(Cl)Cl.[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[N:27]1[CH2:32][CH2:31][N:30]([CH:33]([CH3:40])[CH2:34][CH2:35][CH2:36][C:37](O)=[O:38])[CH2:29][CH2:28]1>N1C=CC=CC=1>[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[N:27]1[CH2:28][CH2:29][N:30]([CH:33]([CH3:40])[CH2:34][CH2:35][CH2:36][C:37]([NH:1][C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=2[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:38])[CH2:31][CH2:32]1
Reactant: CC(CCCC(=O)O)N1CCN(c2ccc3ccccc3n2)CC1
Reactant: CCOC(=O)C1=C(N)CCCC1
Solvent: ClP(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(NC(=O)CCCC(C)N2CCN(c3ccc4ccccc4n3)CC2)CCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.1 %

Procedure:
To a solution of 170 mg of ethyl 2-aminocyclohex-1-enecarboxylate as synthesized in Step 7-1-B in 5 ml of pyridine, 70 mg of phosphorus trichloride was added under cooling with ice, followed by 15 minutes' stirring. Raising the temperature to room temperature, 327 mg of 5-(4-quinoline-2-ylpiperazin-1-yl)hexanoic acid as synthesized in above Step 7-14-C was added to the solution and stirred for 3 hours. Distilling the pyridine off under reduced pressure, the residue was extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified on silica gel column chromatography (ethyl acetate) to provide 182 mg (38%) of ethyl 2-[5-(4-quinolin-2-ylpiperazin-1-yl)hexanoylamino]cyclohex-1-enecarboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][N:13]=NN=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:15]1([C:21](Cl)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>N1C=CC=CC=1>[CH:15]1([C:21]2[O:22][C:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)=[N:14][N:13]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: O=[N+]([O-])c1ccc(-c2nnn[nH]2)cc1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(-c2nnc(C3CCCCC3)o2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 69.8 %

Procedure:
A mixture of 5-(4-nitro-phenyl)-1H-tetrazole (0.5 g, 2.62 mmol) and cyclohexane carbonyl chloride (0.35 ml, 2.62 mmol) in 3 ml anhydrous pyridine was stirred at room temperature under nitrogen for 20 min, then heated to 60° C. for 1 hr and finally heated to 100° C. for 2 h. The reaction mixture was cooled to room temperature then poured onto ice (30 g) and the aqueous mixture was extracted with 30 ml ethyl acetate. The ethyl acetate solution was washed sequentially with 30 ml water, 30 ml 1N aqueous hydrochloric acid solution and 30 ml brine, dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The crude produce was purified by flash column chromatography (silica gel, 40 g), eluting with 4:1 hexane/ethyl acetate to yield the title compound as a yellowish solid (0.5 g, 100% yield). MS: 274.2 (M+1)
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:8].[N-:9]=[N+:10]=[N-:11].[Na+].O>CN(C)C=O>[N:9]([CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:8])=[N+:10]=[N-:11]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1NCCCC1Br
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1CCCNC1=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
To a solution of 2.0 g of 3-bromopiperidin-2-one in 30 ml of N,N-dimethylformamide was added 5.9 g of sodium azide, followed by stirring at 60° C. overnight. After cooling down to room temperature, water was added to the reaction mixture and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 890 mg of the title compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[C:29]([C:33]1[NH:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1)([CH3:32])([CH3:31])[CH3:30]>>[C:29]([C:33]1[N:34]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:20])[CH3:21])[CH2:15][CH2:14]4)[N:8]3[CH3:11])=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:3]=2)[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)c1nc2ccccc2[nH]1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(C(C)(C)C)nc4ccccc43)nc21

Procedure:
2-(1-((2-Chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (0.3 g) was reacted with tert-butylbenzimidazole via General Procedure I for Buchwald coupling to give 94.3 mg 462 following reverse phase purification. MS (Q1) 547.3 (M)+
Reaction SMILES: Br[C:2]1[N:3]([CH:24]([CH3:26])[CH3:25])[C:4]2[C:9]([N:10]=1)=[C:8]([C:11]1[CH:12]=[N:13][C:14]([NH2:17])=[N:15][CH:16]=1)[N:7]=[C:6]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:5]=2.[CH3:27][Zn]C.CO>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:24]([N:3]1[C:2]([CH3:27])=[N:10][C:9]2[C:4]1=[N:5][C:6]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[N:7][C:8]=2[C:11]1[CH:12]=[N:13][C:14]([NH2:17])=[N:15][CH:16]=1)([CH3:26])[CH3:25]
Reactant: C[Zn]C
Reactant: CC(C)n1c(Br)nc2c(-c3cnc(N)nc3)nc(N3CCOCC3)nc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nc2c(-c3cnc(N)nc3)nc(N3CCOCC3)nc2n1C(C)C
Yield: 47 %

Procedure:
To a solution of 5-(8-bromo-9-isopropyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylamine, (30 mg, 0.072 mmol) and Pd(dppf)Cl2, (3 mg, 5% mmol) in 3 ml of anhydrous dioxane, was added slowly dimethyl zinc (210 μl, 1.0 M in heptane solution) in a sealed tube. The mixture was heated to about 65′C. MeOH was added drop wise and the solvents removed in vacuo. EtOAc was added to the residue and the resulting solution washed with 1 M HCl, water, brine and then dried over Na2SO4. The solvent was removed and the crude mixture was subjected to flash chromatography on silica gel to obtain 5-(9-isopropyl-8-methyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylamine 8 mg in a yield of 47%. 1H NMR, MeOD: 9.40 (s, 2H), 4.81 (m, 1H), 3.89 (m, 4H), 3.82 (s, 4H), 3.71 (s, 3H), 1.73 (d, 6H). m/z: 355.16 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C[O:13]C(OC)N(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:13])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Cc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4-chloro-2-nitrotoluene (514.8 mg, 3.000 mmol) and dimethylformamide dimethylacetal (1.200 ml, 1074 mg, 9.000 mmol) in DMF (1.2 ml) was heated at 135° C. in a sealed tube for 15 h. The reaction mixture was cooled to rt and added dropwise to a 20° C. solution of NaIO4 (1926 mg, 9.000 mmol) in water (6.18 ml) and DMF (3.09 ml). After 3 h, the mixture was treated with water (20 ml) and extracted with EtOAc (3×15 ml). The extracts were washed with water (3×15 ml) and brine (15 ml), and dried over MgSO4. After the solid was filtered off and the solvent was removed in vacuo, a brown solid of 4-chloro-2-nitrobenzaldehyde was obtained (J. Org. Chem. 2003, 68, 4104-4107). NMR (CDCl3, 400 MHz) δ 7.74-7.78 (m, 1 H), 7.94-7.96 (m, 1 H), 8.11-8.12 (m, 1 H), 10.39 (s, 1 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].[N:13]1[C:22]2[C:21](=O)[CH2:20][CH2:19][CH2:18][C:17]=2[CH:16]=[CH:15][CH:14]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:21]1[C:22]2[N:13]=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:18][CH2:19][CH2:20]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=C1CCCc2cccnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCNC1CCCc2cccnc21

Procedure:
Using General Procedure B, reaction of (3-amino-propyl)-carbamic acid tert-butyl ester, 6,7-dihydro-5H-quinolin-8-one and NaBH(OAc)3 in CH2Cl2 gave [3-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-propyl]-carbamic acid tert-butyl ester as a light brown oil plus ˜15% impurity. 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.77 (m, 4H), 2.00 (m, 2H), 2.80 (m, 4H), 3.24 (m, 2H), 3.74 (t, 1H, J=7.5 Hz), 5.36 (br, 1H(NH)), 7.06 (m, 1H), 7.37 (d, 1H, J=7.5 Hz), 8.39 (d, 1H, J=4.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH2:19][CH2:20][NH:21][CH2:22]4)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C([O-])([O-])=O.[K+].[K+].Br[CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH2:19][CH2:20][N:21]([CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:22]4)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)CCBr
Reactant: CC(C)Oc1ccc(-c2noc(-c3cccc4c3CCNC4)n2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2noc(-c3cccc4c3CCN(CCC(=O)OC(C)(C)C)C4)n2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.3 %

Procedure:
3-(3-chloro-4-isopropoxyphenyl)-5-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1,2,4-oxadiazole (0.1088 g, 0.294 mmol) in DMF (2.94 ml) (briefly heated to 40° C. for complete dissolution). K2CO3 (0.081 g, 0.588 mmol) and tert-butyl 3-bromopropanoate (0.046 ml, 0.276 mmol) was added and the mixture stirred at ambient temperature for 2 hrs. Additional tert-butyl 3-bromopropanoate (0.053 ml, 0.315 mmol) was added and the reaction was stirred at 60° C. over the weekend. Additional tert-butyl 3-bromopropanoate (0.053 ml, 0.315 mmol) was added and the reaction continued heated at 60° C. overnight. Additional K2CO3 (0.041 g, 0.294 mmol) was added, followed by tert-butyl 3-bromopropanoate (0.053 ml, 0.315 mmol). The reaction was heated at 60° C. overnight. The reaction mixture was filtered and the filtrate concentrated in vacuo to give ˜179 mg of crude yellow oil. The crude residue was purified via Analogix system using RediSep RS 12 g column, with a gradient of 0-45% EtOAc/Heptane over 35 min. at 15 mL/min. Fractions 23-28 were combined and concentrated to yield tert-butyl 3-(5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propanoate (91 mg, 0.183 mmol) as light yellow oil. LCMS (Table 1, Method c) Rt=3.39 min, m/z 500.72 (M+H)+.
Reaction SMILES: [C:1]([C:3]1([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5][CH2:4]1)#[CH:2].C#CCCCCCC.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:37][CH:38]2[CH2:43][CH2:42][CH:41]3[CH2:44][CH:39]2[C:40]3([CH3:46])[CH3:45])(=[O:36])=[O:35])=[CH:30][CH:29]=1.IC1C=C2C(=CC=1)CN(C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C2>>[C:14]([O:13][C:12](=[O:18])[NH:11][C:3]1([C:1]#[C:2][C:28]2[CH:29]=[CH:30][C:31]([S:34](=[O:35])(=[O:36])[NH:37][CH:38]3[CH2:43][CH2:42][CH:41]4[CH2:44][CH:39]3[C:40]4([CH3:45])[CH3:46])=[CH:32][CH:33]=2)[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5][CH2:4]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC1(C)C2CCC(NS(=O)(=O)c3ccc(Br)cc3)C1C2
Reactant: C#CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1
Agent: C#CCCCCCC
Agent: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Product: CC(C)(C)OC(=O)NC1(C#Cc2ccc(S(=O)(=O)NC3CCC4CC3C4(C)C)cc2)COC(C)(C)OC1
Yield: 46 %

Procedure:
When tert-butyl 5-ethynyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate was substituted for 1-octyne and the product of Step A was substituted for 5-iodo-2-tritylisoindoline in Example 2, Step D, the similar process afforded the title compound in 46% yield, as a creamy paste. 1H-NMR (CDCl3) 0.85 (s, 3H); 1.1 (s, 3H); 1.44 (s, 3H); 1.46 (s, 9H); 1.48 (s, 3H); 1.63-1.65 (m, 2H); 1.79-1.86 (m, 5H); 2.05-2.08 (m, 1H); 2.27-2.32 (m, 1H); 2.89 (tr, 2H, J=6.59 Hz); 4.0-4.13 (m, 4H); 4.6 (broad s, 1H); 5.23 (s, 1H); 7.52 (d, 2H, J=8.25 Hz); 7.75 (d, 2H, J=8.46 Hz).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:28]4[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:28]4[CH:29]=[CH:30][C:31]([O:34][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:32][CH:33]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]5[CH2:24][CH2:25][CH2:26][CH2:27]5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)COc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Yield: 71.5 %

Procedure:
To a solution of 4-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenol (100 mg, 0.22 mmol) in acetone (10 mL) was added ethyl α-bromoacetate (49 μL, 0.44 mmol) and potassium carbonate (304 mg, 2.2 mmol). The mixture was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature and water was added. The solution was extracted with ethyl acetate. The organics were dried (magnesium sulfate), filtered and concentrated, followed by purification with flash chromatography (1:1 ethyl acetate:hexanes) to give ethyl (4-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenoxy)acetate (85 mg, 71%) as a brown oil. 1H NMR (CDCl3): δ 7.94 (d, 1H), 7.70 (d, 1H), 7.55 (d, 2H), 7.23 (t, 1H), 6.95 (d, 2H), 6.25 (d, 1H), 5.98–5.95 (m, 2H), 5.13 (d, 1H), 4.62 (s, 2H), 4.31–4.21 (m, 3H), 3.94 (m, 1H), 2.07–1.99 (m, 4H), 1.75–1.46 (m, 12H), 1.28 (t, 3H); MS m/z 541 (M+1).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:9](O)(=[O:13])[C:10]([CH3:12])=[O:11].N1C=CC=CC=1.COC(Cl)Cl>C(Cl)Cl>[C:9]([O:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=1)(=[O:13])[C:10]([CH3:12])=[O:11]
Reactant: CC(=O)C(=O)O
Reactant: Cc1ccc(O)cc1
Agent: COC(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)C(=O)Oc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
p-Tolyl pyruvate was prepared as follows. p-cresol (540 mg, 5 mmol) and pyruvic acid (440 mg, 5 mmol) were dissolved in methylene chloride (30 mL) and cooled on an ice bath. Pyridine (790 mg. 1 mL, 12.4 mmol) was added, followed by addition of 1,1-dichloromethyl methyl ether (690 mg, 0.53 mL, 6 mmol). The reaction mixture was stirred for 1 h on an ice bath, warmed to room temperature and washed with 30 mL of 5% aqueous HCl and 30 mL of saturated aqueous NaHCO3. The organic layer was dried over anhydrous MgSO4, filtered and solvent removed on a rotary evaporator. The residue was purified by flash silica gel chromatography (20:1→15:1 hexanes-ethyl acetate) to give 450 mg of p-tolyl pyruvate as a clear oil. 1H NMR (400 MHZ, CDCl3) δ 7.21 (d, J=4 Hz, 2H), 7.05 (d, J=4 Hz, 2H), 2.59 (s, 3H), 2.36 (s, 2H). 13C NMR (100 MHZ, CDCl3) δ 191.3, 159.5, 148.1, 136.6, 130.4, 120.8, 27.0, 21.1. HRMS (ESI-12 Tesla FT-MS) [M+H]+ calcd. 179.0708, found 179.0709.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)=[CH:5][CH:4]=1.[OH:15][C:16]1[CH:27]=[CH:26][C:19]([CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:18][CH:17]=1>>[N:21]1([CH2:20][C:19]2[CH:26]=[CH:27][C:16]([O:15][CH2:2][C:3]3[CH:14]=[CH:13][C:6]([CH2:7][N:8]4[CH:12]=[CH:11][CH:10]=[CH:9]4)=[CH:5][CH:4]=3)=[CH:17][CH:18]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Oc1ccc(CN2CCCC2)cc1
Reactant: ClCc1ccc(Cn2cccc2)cc1
Product: c1ccn(Cc2ccc(COc3ccc(CN4CCCC4)cc3)cc2)c1

Procedure:
The title compound was prepared starting from 1-(4-chloromethyl-benzyl)-pyrrole and 4-hydroxybenzyl-pyrrolidine by the same method described in Example 19. 1H NMR (400 MHz, MeOD-d4)δ7.18 (m, 2 H), 6.99 (m, 2 H), 6.59 (t, J=2.1 Hz, 2 H), 5.97 (t, J=2.1 Hz, 2 H), 4.99 (s, 2 H), 3.55 (s, 2 H), 2.41 (m, 4 H), 1.70 (m, 4 H).
Reaction SMILES: C1(CCC(Cl)=O)CCCC1.[CH:11]1([CH2:16][CH2:17][C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12]1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[O:31][C:32]1[C:41]2[C:36](=[CH:37][C:38]([O:44][CH3:45])=[C:39]([O:42][CH3:43])[CH:40]=2)[N:35]=[CH:34][CH:33]=1)[NH2:27].C1(C)C=CC=CC=1>C(O)C>[CH:11]1([CH2:16][CH2:17][C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15]1.[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:21]([NH:20][C:18](=[O:19])[CH2:17][CH2:16][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)=[S:22])[CH:28]=[CH:29][C:30]=1[O:31][C:32]1[C:41]2[C:36](=[CH:37][C:38]([O:44][CH3:45])=[C:39]([O:42][CH3:43])[CH:40]=2)[N:35]=[CH:34][CH:33]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(CCC1CCCC1)N=C=S
Agent: O=C(Cl)CCC1CCCC1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)CCC4CCCC4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
3-Cyclopentylpropanoyl isothiocyanate was prepared using commercially available 3-cyclopentylpropanoyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Cyclopentylpropanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (68 mg, yield 88%).