Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6].NC(C1N=NC(N[C:42]2[CH:47]=[C:46]([O:48]C)[C:45](OC)=[C:44](OC)[CH:43]=2)=NC=1)C.O(C1C=C(C=CC=1)C(O)=O)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[O:48]([C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6])[C:46]1[CH:47]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Reactant: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)c1cccc(Oc2ccccc2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Oc4ccccc4)c3)nn2)cc(OC)c1OC
Yield: 100 %

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (87 mg, 0.28 mmol), 3-phenoxybenzoic acid (80 mg, 0.37 mmol), diisopropylethylamine (0.13 mL, 0.75 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (140 mg, 0.37 mmol) in dimethylformamide (2 mL) gave 3-phenoxy-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (140 mg, 100%) as a yellow oil. MS m/z 501 (M+1).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:39][CH2:40][C:41]([N:43]([CH3:45])[CH3:44])=[O:42].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:39][CH2:40][C:41]([N:43]([CH3:45])[CH3:44])=[O:42])[N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Reactant: CN(C)C(=O)CCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)CCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Yield: 59.1 %

Procedure:
N-tert-Butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (100 mg, 188 μmol), 3-chloro-N,N-dimethylpropanamide (25.6 mg, 188 μmol) and cesium carbonate (184 mg, 565 mmol) in dimethylformamide (2 mL) were heated in a microwave at 150° C. for 30 min. The mixture was cooled, partitioned between ethyl acetate and water, washed with water 3 times, dried and concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-100% ethyl acetate in hexanes) gave N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-(dimethylamino)-3-oxopropyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (70 mg, 59%) as an off-white solid. MS (M+H)+=630; 1H NMR (CDCl3) δ: 9.19 (s, 1H), 8.41 (s, 1H), 8.25 (d, J=1.9 Hz, 1H), 8.08 (s, 1H), 7.67 (d, J=8.7 Hz, 1H), 7.31-7.37 (m, 1H), 6.22-6.78 (m, 1H), 5.72 (s, 2H), 4.79-4.88 (m, 2H), 3.53-3.63 (m, 2H), 3.11 (t, J=6.7 Hz, 2H), 2.95 (d, J=9.2 Hz, 6H), 1.61 (s, 9H), 0.87-1.01 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: IC.[C:3]([O-])([O-])=O.[K+].[K+].[Cl:9][C:10]1[C:11]([C:29]2[N:33]=[CH:32][NH:31][N:30]=2)=[C:12]([NH:15][C:16](=[O:28])[CH2:17][N:18]2[C:23](=[O:24])[CH:22]=[CH:21][N:20]3[N:25]=[CH:26][CH:27]=[C:19]23)[S:13][CH:14]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:9][C:10]1[C:11]([C:29]2[N:33]=[CH:32][N:31]([CH3:3])[N:30]=2)=[C:12]([NH:15][C:16](=[O:28])[CH2:17][N:18]2[C:23](=[O:24])[CH:22]=[CH:21][N:20]3[N:25]=[CH:26][CH:27]=[C:19]23)[S:13][CH:14]=1
Reactant: O=C(Cn1c(=O)ccn2nccc12)Nc1scc(Cl)c1-c1nc[nH]n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cnc(-c2c(Cl)csc2NC(=O)Cn2c(=O)ccn3nccc23)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Iodomethane (36 mg, 0.255 mmol) and K2CO3 (44 mg, 0.319 mmol) were added to a solution of N-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl)acetamide (80 mg, 0.212 mmol) in DMF (1 mL). The reaction mixture was stirred at room temperature for 30 minutes and was subsequently diluted with ethyl acetate and washed with brine. The organic phase was dried (Na2SO4), filtered, concentrated under vacuum and purified by preparative HPLC to give N-(4-chloro-3-(1-methyl-1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl)acetamide. Retention time (min)=3.00, method [7], MS(ESI) 390.1 (M+H); 1H NMR (300 MHz, CD3Cl) δ 8.25 (d, J=8.2 Hz, 1H), 7.90 (s, 1H), 7.76 (d, J=2.1 Hz, 1H), 6.79 (s, 1H), 6.22 (d, J=8.2 Hz, 1H), 5.97 (d, J=2.1 Hz, 1H), 5.36 (s, 2H), 3.99 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[F:27][CH2:28][CH2:29][N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1.C(=O)(O)[O-].[Na+].O1CCOCC1>CO.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>[F:27][CH2:28][CH2:29][N:30]1[CH:34]=[C:33]([C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]4[CH:17]=[C:16]([N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)[N:15]=[C:14]([NH2:25])[N:13]=4)[CH2:9]3)=[CH:4][CH:3]=2)[CH:32]=[N:31]1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CC1(C)OB(c2cnn(CCF)c2)OC1(C)C
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: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: CC1Cc2ccc(-c3cnn(CCF)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 23.3 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 1-(2-fluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.3 mg, 0.026 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol), and sodium bicarbonate (6.0 mg, 0.072 mmol) in a solution of 1,4-dioxane (0.2 mL) and water (0.1 mL) in a reaction vial was stirred at 90° C. overnight. After cooling it was diluted with methanol. After filtration the filtrate was purified with RP-HPLC (pH=10) to afford the desired product (2.1 mg). LCMS (M+H)+: m/z=451.2.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].CN(C=O)C.[H-].[Na+].Br[CH2:18][CH:19]=[CH2:20]>O>[CH2:20]([O:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5])[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: COC(=O)C(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOCC(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of methyl 3-hydroxy-2,2-dimethylpropanoate (5.59 g, 1 eq.) and DMF (42 ml) at 0° C. was slowly added NaH (60% in mineral oil, 1.69 g, 1 eq.). After 30 min, 3-bromoprop-1-ene (5.12 g, 1 eq.) was added. The reaction mixture was warmed to room temperature and stirred overnight. Water was carefully added. The resulting mixture was extracted with EtOAc, dried over MgSO4 and concentrated to yield a light-yellow oil to be used in the next step without purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([CH:15]1[CH2:17][CH2:16]1)=[O:14].[C:18]([O:22][C:23](=[O:38])[NH:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][N:32]=2)[CH2:26]1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23](=[O:38])[NH:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=4)[N:5]=[CH:4][C:3]=3[C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])=[CH:33][N:32]=2)[CH2:26]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: O=C(c1cnc2ccc(Cl)nc2c1Cl)C1CC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(N)cn2)C1
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Cl)nc34)cn2)C1
Yield: 76.5 %

Procedure:
Following general procedure I, 4,6-dichloro-1,5-naphthyridin-3-yl(cyclopropyl) methanone (400 mg, 1.5 mmol) was reacted with (R)-tert-butyl[1-(5-aminopyridin-2-yl) piperidine-3-yl]carbamate (550 mg, 1.9 mmol) to afford the product (600 mg, 76%) as an orange foam: ESI MS m/z 523 [M+H]+.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[C:5]1=[O:16])[CH:2]=[CH2:3].[CH:17](=[O:21])/C=C/C>>[CH3:15][O:14][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5](=[O:16])[CH:4]([CH2:1]/[CH:2]=[CH:3]/[CH:17]=[O:21])[CH2:13][CH2:12]2
Reactant: C=CCC1CCc2cc(OC)ccc2C1=O
Reactant: C/C=C/C=O
Product: COc1ccc2c(c1)CCC(C/C=C/C=O)C2=O

Procedure:
The title compound 54 is prepared according to the procedure reported in step C of Example 8 with tetralone 53 (1.1 g, 5.09 mmol) and crotonaldehyde (1.43 g, 20.34 mmol) as reactants. Purification by column chromatography on SiO2 (Petroleum/EtOAc=4:1) afford the title compound 54 as an off-white solid. (Yield 0.95 g, 76%).
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:20])[N:7]3[C:21]([CH3:24])=[N:22][N:23]=[C:6]3[N:5]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:4]=2[N:3]=1.[CH3:30][S:31]C.[Na].C(COC)OC>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:20])[N:7]4[C:21]([CH3:24])=[N:22][N:23]=[C:6]4[N:5]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:4]=3[N:3]=[C:2]2[S:31][CH3:30])=[CH:13][CH:14]=1
Reactant: CCCCCn1c2nc(Br)n(Cc3ccc(OC)cc3)c2c(=O)n2c(C)nnc12
Reactant: CSC
Agent: [Na]
Solvent: COCCOC
Product: CCCCCn1c2nc(SC)n(Cc3ccc(OC)cc3)c2c(=O)n2c(C)nnc12
Yield: 78.1 %

Procedure:
A mixture of 7-bromo-6-(4-methoxybenzyl)-3-methyl-9-pentyl-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (271 mg, 0.6 mmol) and sodium methyl sulfide (45.5 mg, 0.65 mmol) in dimethoxyethane (13.4 ml, 129 mmol) was refluxed for 2 h. The reaction was quenched with water. The solid formed was filtered and dried to yield the desired product (200 mg, 79.5%). LCMS calculated for C21H27N6O2S (M+H): 427.2. Found 427.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[NH:6]1)C.Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:10]=[C:7]1[N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:5]([C:4]([O:3][CH3:1])=[O:11])[CH2:9][CH2:8]1
Reactant: CCOC(=O)[C@H]1CCC(=O)N1
Reactant: Brc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)[C@@H]1CCC(=O)N1c1ccccc1
Temperature: 25 °C
Yield: 28 %

Procedure:
D-pyroglutamic acid ethyl ester (0.200 g, 1.27 mmol) was dissolved in dioxane (5 ml) and treated with tris(dibenzylideneacetone)dipalladium (0) (0.058 g, 0.06 mmol), bromobenzene (0.351 ml, 1.53 mmol), cesium carbonate (0.621 g, 1.91 mmol) and Xantphos™ (0.110 g, 0.19 mmol). The resulting mixture was heated at reflux overnight and then allowed to cool to room temperature. The mixture was diluted with methanol and filtered. The filtrate was evaporated in vacuo and then partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate. The aqueous layer was extracted with more dichloromethane (3 aliquots) and then the combined organic layers were washed with brine and dried over magnesium sulphate. Evaporation of the solvent gave a bright yellow residue which was purified by flash silica column chromatography, eluting with a gradient of 0-50% ethyl acetate in hexane, to give methyl 5-oxo-1-phenylprolinate (0.078 g) as a yellow oil. This was used in the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C@H:4]([CH2:7][C@H:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:9]([OH:11])=O)[CH2:3]1.C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[CH:33]=[CH:32][N:31]([CH2:34][C:35]([CH3:38])([OH:37])[CH3:36])[N:30]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[OH:37][C:35]([CH3:38])([CH3:36])[CH2:34][N:31]1[CH:32]=[CH:33][C:29]([NH:28][C:9](=[O:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH2:7][C@H:4]2[CH2:5][CH2:6][C:2](=[O:1])[CH2:3]2)=[N:30]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C1CC[C@H](C[C@@H](C(=O)O)c2cccc(C(F)(F)F)c2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](C[C@H]2CCC(=O)C2)c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
(R)-3-((R)-3-Oxo-cyclopentyl)-2-(3-trifluoromethyl-phenyl)-propionic acid (prepared in Example 118, 90 mg, 0.30 mmol) was dissolved in methylene chloride (3 mL) and N,N-dimethylformamide (three drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 160 μL, 0.32 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (3 mL) and added dropwise into a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 47 mg, 0.30 mmol), 2,6-lutidine (70 μL, 0.60 mmol) and methylene chloride (3 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 1 h. After this time, the reaction was quenched with a small amount of methanol and diluted with methylene chloride and then concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 50% ethyl acetate/hexanes to 100% ethyl acetate) to afford (R)—N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-((R)-3-oxo-cyclopentyl)-2-(3-trifluoromethyl-phenyl)-propionamide (84 mg) which still contained impurities. This material was then cleaned up by using reverse phase HPLC. The purified material was then concentrated in vacuo then dissolved in ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution and then brine, dried over sodium sulfate and concentrated in vacuo to afford pure (R)—N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-((R)-3-oxo-cyclopentyl)-2-(3-trifluoromethyl-phenyl)-propionamide (53 mg, 40%) as a white foam: [α]29589=−67.5° (c=0.12, methanol); ES-HRMS m/e calcd for C22H26N3O3F3 (M+H)+ 438.1999, observed 438.1999; 1H NMR (300 MHz, DMSO-d6) δ 1.03 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.50 (m, 1H, CH), 1.73-2.30 (m, 8H, 4×CH2), 3.87 (s, 2H, NCH2), 3.95 (m, 1H, ArCHCO), 4.64 (s, 1H, OH), 6.46 (d, J=2.2 Hz, 1H, Ar), 7.50 (d, J=2.2 Hz, 1H, Ar), 7.60 (m, 2H, Ar), 7.69 (brd, 1H, Ar), 7.73 (brs, 1H, Ar), 10.79 (s, 1H, NH).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:24](B(O)O)[CH:25]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[C:24]([C:2]2[CH:14]=[CH:13][C:5]([C:6]([N:8]3[CH2:12][CH2:11][CH2:10][CH2:9]3)=[O:7])=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=2)[CH:25]=1
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccccc1
Reactant: O=C(c1ccc(Br)cc1C(F)(F)F)N1CCCC1
Product: O=C(c1ccc(-c2cc(Cl)ccc2OCc2ccccc2)cc1C(F)(F)F)N1CCCC1

Procedure:
The sub-title compound was prepared by the method of Example 11 step b) using the product of step b) and [5-chloro-2-(phenylmethoxy)phenyl]boronic acid. M.p. 143-4° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C)C=O>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10])[CH3:24]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 76.7 %

Procedure:
To a solution of 4-bromo-2-nitro-phenol (3.28 g, 15.0 mmol, 1 equiv) in dimethylformamide (40 mL) at 23° C. was added potassium carbonate (4.14 g, 30 mmol, 2 equiv) followed by ethyl bromoacetate (1.84 mL, 16.6 mmol, 1.1 equiv). The resulting mixture was warmed to 60° C. (oil bath) for 90 min then cooled to 23° C. The reaction mixture was partitioned between ethyl acetate:heptane (1:1) and water (100 mL each). The organic layer was separated and washed successively with water, saturated brine solution (100 ml, each) then dried (MgSO4), filtered and concentrated to give 4.50 g (11.5 mmol, 77%) of the product as a yellow oil.
Reaction SMILES: C(O)=O.C(N(CC)CC)C.[CH:11]([CH:13]1[CH2:18][O:17][CH2:16][CH2:15][N:14]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=O.[CH3:26][C:27]1(C)[O:34]C(=O)CC(=O)[O:28]1>[OH-].[Na+]>[C:22]([O:21][C:19]([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH:13]1[CH2:11][CH2:26][C:27]([OH:34])=[O:28])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCOCC1C=O
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O=CO
Product: CC(C)(C)OC(=O)N1CCOCC1CCC(=O)O
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 40.3 %

Procedure:
A mixture of formic acid (2.26 mL, 58.9 mmol) and triethylamine (3.36 mL, 24.11 mmol) was stirred for 5 minutes in an ice bath. To the mixture were added tert-butyl 3-formylmorpholine-4-carboxylate (0.47 g, 2.2 mmol) and Meldrum's acid (0.32 g, 2.2 mmol) in turn at 0° C. The reaction mixture was heated at 100° C. for 5 hours, and cooled down in an ice bath. To the resulting mixture was added aqueous NaOH solution (2 mol/L, 40 mL). The aqueous layer was extracted with EtOAc (50 mL×3) and the organic layer was discarded. To the aqueous layer was added EtOAc (80 mL), and the mixture was adjusted to pH 4-5 with HCl (1 mol/L) under stirring. The aqueous layer was extracted with EtOAc (80 mL). The organic layer was dried over anhydrous Na2SO4, then filtered and the filtrate was concentrated in vacuo to give the title compound as a white solid (0.23 g, 40%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.Br[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:27][C:26]([NH2:28])=[N:25][N:24]=2)=[C:19]([Cl:29])[CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[Cl:29][C:19]1[CH:18]=[C:17]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[CH:22]=[CH:21][C:20]=1[C:23]1[S:27][C:26]([NH2:28])=[N:25][N:24]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1nnc(-c2ccc(Br)cc2Cl)s1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2ccc(-c3nnc(N)s3)c(Cl)c2)cn1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 47 %

Procedure:
To a stirred solution of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (197 mg, 0.946 mmol) and 5-(4-bromo-2-chlorophenyl)-1,3,4-thiadiazol-2-amine (250 mg, 0.860 mmol) in dioxane (8 mL) was added Pd(PPh3)4 (50 mg, 0.043 mmol) followed by a solution of Na2CO3 (274 mg, 2.58 mmol) in water (2 mL). The reaction mixture was purged with nitrogen, sealed, and heated at 80° C. for 1 hour under microwave irradiation, then for an additional 2.5 hours at an increased temperature of 120° C. The reaction mixture was diluted with DCM (40 mL) and washed with saturated NaHCO3(aq) (40 mL). A few mLs of saturated NaCl(aq) were added to clear the resulting slight emulsion and the organic phase separated, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo to afford the crude product as a yellow solid. The crude material was pre-absorbed onto silica gel and purified by flash chromatography using a 24 g silica cartridge running a MeOH/DCM gradient to afford the title compound as a pale yellow solid (118 mg, 47% yield). LC-MS: Rt 0.83 min; MS m/z 292.0 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.31 (s, 1H), 7.97-8.03 (m, 2H), 7.83 (d, J=1.52 Hz, 1H), 7.65 (dd, J=8.34, 1.77 Hz, 1H), 7.41 (s, 2H), 3.87 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:9]2[N:10]=[C:11]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=[C:13]([C:14](O)=[O:15])[C:8]=2[C:7]([CH3:21])=[N:6]1)([CH3:4])[CH3:3].[NH2:22][CH2:23][C:24]1[C:25](=[O:32])[NH:26][C:27]([CH3:31])=[CH:28][C:29]=1[CH3:30].CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CS(C)=O>[CH3:1][C:2]([N:5]1[C:9]2[N:10]=[C:11]([C:17]([CH3:20])([CH3:18])[CH3:19])[CH:12]=[C:13]([C:14]([NH:22][CH2:23][C:24]3[C:25](=[O:32])[NH:26][C:27]([CH3:31])=[CH:28][C:29]=3[CH3:30])=[O:15])[C:8]=2[C:7]([CH3:21])=[N:6]1)([CH3:3])[CH3:4]
Reactant: Cc1nn(C(C)(C)C)c2nc(C(C)(C)C)cc(C(=O)O)c12
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: On1nnc2cccnc21
Solvent: CS(C)=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: Cc1cc(C)c(CNC(=O)c2cc(C(C)(C)C)nc3c2c(C)nn3C(C)(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 109 using 1,6-bis(1,1-dimethylethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (70 mg, 0.242 mmol), DMSO (2 mL), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (68.5 mg, 0.363 mmol), N-methylmorpholine (0.106 mL, 0.968 mmol), 1-hydroxy-7-azabenzotriazole (65.9 mg, 0.484 mmol) and EDC (93 mg, 0.484 mmol). The final product was collected as 91 mg (87%). LCMS E-S (M+H)=424.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (s, 9 H), 1.74 (s, 9 H), 2.12 (s, 3 H), 2.23 (s, 3 H), 2.35 (s, 3 H), 4.35 (d, J=4.80 Hz, 2 H), 5.88 (s, 1 H), 7.15 (s, 1 H), 8.61 (t, J=4.93 Hz, 1 H), 11.52 (s, 1 H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([N:16]3[C:24]4[C:23]5[CH:25]=[C:26]([NH:29][C:30]([C:32]6[C:37]([Cl:38])=[CH:36][CH:35]=[C:34](Cl)[N:33]=6)=[O:31])[CH:27]=[CH:28][C:22]=5[CH2:21][CH2:20][C:19]=4[C:18]([C:40]([NH2:42])=[O:41])=[N:17]3)=[CH:15][C:10]=2[O:9][CH2:8]1.CCO>CC(N(C)C)=O>[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([N:16]3[C:24]4[C:23]5[CH:25]=[C:26]([NH:29][C:30]([C:32]6[C:37]([Cl:38])=[CH:36][CH:35]=[C:34]([N:1]7[CH2:6][CH2:5][O:4][CH2:3][CH2:2]7)[N:33]=6)=[O:31])[CH:27]=[CH:28][C:22]=5[CH2:21][CH2:20][C:19]=4[C:18]([C:40]([NH2:42])=[O:41])=[N:17]3)=[CH:15][C:10]=2[O:9][CH2:8]1
Reactant: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(NC(=O)c3nc(Cl)ccc3Cl)cc1-2
Reactant: C1COCCN1
Solvent: CC(=O)N(C)C
Solvent: CCO
Product: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(NC(=O)c3nc(N4CCOCC4)ccc3Cl)cc1-2
Reaction time: 36 h

Procedure:
The title compound was synthesized from 0.27 g of morpholine and the title compound of Example 216 (0.522 g) by the same procedure used for Example 207 except that EtOH was replaced by 0.5 ml of DMA. The reaction was carried out at 80° C. for 36 hours. The title compound, isolated by preparative HPLC, is a white solid (0.30 g, 52%), m.p. 260-262° C. (decomposition). Its structure was confirmed by 1H NMR and LC/MS: 1H NMR (CDCl3) δ 2.96 (m, 2H), 3.15 (m, 2H)), 3.48 (m, 4H), 3.86 (m, 4H), 5.41 (s, 1H), 6.74-6.86 (m, 2H), 6.90-7.04 (m, 2H), 7.16 (d, 1H, J=1 Hz), 7.28-7.35 (m, 2H), 7.54-7.22 (m, 2H), 9.32 (s, 1H). ESI mass spectrum for C29H26ClN6O5+: 573 (M+1).