Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3C(OCC3C=CC=CC=3)=O)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:25])[NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.Br.C(O)(=O)C>O>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][C:14]([C:17]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:25])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c([C@@H]3CCCN3C(=O)OCc3ccccc3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Reaction time: 1 h
Yield: 58.3 %

Procedure:
To (S)-benzyl 2-(8-amino-1-(4-(pyridin-2-ylcarbamoyl)phenyl)imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (0.146 mmol, 78 mg) was added a 33% hydrobromic acid/acetic acid solution (11.26 mmol, 2 ml) and the mixture was left at room temperature for 1 hour. The mixture was diluted with water and extracted with dichloromethane. The aqueous phase was neutralized using 2N sodium hydroxide solution, and then extracted with dichloromethane. the organic layer was dried over magnesium sulfate, filtered and evaporated to give 34 mg of (S)-4-(8-Amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide (58%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH:17]([CH3:32])[CH2:18][CH2:19][NH:20][C:21](=[O:31])[C:22]2[C:27]([CH3:28])=[CH:26][C:25]([Cl:29])=[N:24][C:23]=2[CH3:30])[CH2:13][CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:33][N:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[CH:39]=O.[BH4-].[Na+].[NH4+].[Cl-]>CO>[Cl:29][C:25]1[CH:26]=[C:27]([CH3:28])[C:22]([C:21]([NH:20][CH2:19][CH2:18][CH:17]([N:14]2[CH2:15][CH2:16][CH:11]([NH:10][C@H:3]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:2][NH:1][CH2:39][C:35]3[N:34]([CH3:33])[CH:38]=[CH:37][CH:36]=3)[CH2:12][CH2:13]2)[CH3:32])=[O:31])=[C:23]([CH3:30])[N:24]=1
Reactant: Cn1cccc1C=O
Reactant: Cc1cc(Cl)nc(C)c1C(=O)NCCC(C)N1CCC(N[C@@H](CN)c2ccccc2)CC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cc(Cl)nc(C)c1C(=O)NCCC(C)N1CCC(N[C@@H](CNCc2cccn2C)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 79.6 %

Procedure:
A solution of N-{3-[4-((R)-2-Amino-1-phenyl-ethylamino)-piperidin-1-yl]-butyl}-6-chloro-2,4-dimethyl-nicotinamide (60 mg, 0.13 mmol) and 1-Methyl-1H-pyrrole-2-carbaldehyde (15 mg, 0.13 mmol) in CH3OH (2 ml) was stirred at rt for 2 h. The mixture was then cooled to 0° C. NaBH4 (8 mg, 0.2 mmol) was added. The mixture was stirred at this temperature for 20 min. NH4Cl (aq. Sat. 1 ml) was then added and the mixture was extracted with CH2Cl2 (3×10 ml). The organic layer was dried and concentrated. Purification of the residue by chromatography on silica gel (CH2Cl2/MeOH, 9:1) afforded 6-chloro-2,4-dimethyl-N-[3-(4-{(R)-2-[(1-methyl-1H-pyrrol-2-ylmethyl)-amino]-1-phenyl-ethylamino}-piperidin-1-yl)-butyl]-nicotinamide (57 mg, 79%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:32])[CH:17]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)[CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[N:13][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[CH:19]1([CH2:18][CH:17]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)[C:16]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][N:13]=2)=[O:32])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(Nc1ccc(OCc2ccccc2)cn1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: [Pd]
Solvent: CO
Product: O=C(Nc1ccc(O)cn1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
A solution of N-(5-benzyloxy-pyridin-2-yl)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionamide (145.3 mg, 0.3 mmol) in methanol (5.1 mL) was treated with 10% palladium on activated carbon. The reaction mixture was stirred under hydrogen gas at 25° C. for 16 h. The catalyst was then filtered off through a pad of celite, which was washed well with ethyl acetate. The resulting filtrate was concentrated in vacuo to give 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-hydroxy-pyridin-2-yl)-propionamide (92.2 mg, 78.5%) as a tan solid: mp 79-81° C.; EI-HRMS m/e calcd for C19H20Cl2N2O2 (M+) 378.0896, found 378.0890.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:47][C:48]1[CH:53]=[CH:52][C:51]([N:54]2[C:58]([CH2:59]O)=[CH:57][N:56]=[C:55]2[S:61][CH2:62][C:63]2[C:68]([F:69])=[CH:67][CH:66]=[C:65]([F:70])[C:64]=2[F:71])=[CH:50][CH:49]=1>C1COCC1.C(OCC)(=O)C.O>[F:47][C:48]1[CH:53]=[CH:52][C:51]([N:54]2[C:58]([CH2:59][N:5]3[C:1](=[O:11])[C:2]4[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4]3=[O:6])=[CH:57][N:56]=[C:55]2[S:61][CH2:62][C:63]2[C:68]([F:69])=[CH:67][CH:66]=[C:65]([F:70])[C:64]=2[F:71])=[CH:50][CH:49]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phthalimide (783 mg, 5.32 mmol), di-tert-butylazodicarboxylate (1.23 g, 5.32 mmol) and triphenyl phosphine (1.4 g, 5.32 mmol) were added to a solution of (1-(4-fluorophenyl)-2-((2,3,6-trifluorobenzyl)thio)-1H-imidazol-5-yl)methanol (28) (980 mg, 2.66 mmol) in THF (30 mL) and the reaction was stirred overnight at room temperature. An additional equivalent of phthalimide, di-tert-butylazodicarboxylate and triphenyl phosphine was added and stirred overnight. Water and ethyl acetate were added and the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0-100% EtOAc in hexanes) to afford 2-((1-(4-fluorophenyl)-2-((2,3,6-trifluoro benzyl)thio)-1H-imidazol-5-yl)methyl)isoindoline-1,3-dione (29) as an oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[C:7]([CH3:38])=[C:8]([C:27]2[CH:28]=[N:29][N:30]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[CH:31]=2)[C:9]([O:25][CH3:26])=[C:10]([CH:12]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH2:23])=[C:17]3[C:16]([CH3:24])=[N:15]2)[CH3:13])[CH:11]=1.C(N(C(C)C)CC)(C)C.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([N:35]1[CH2:34][CH2:33][CH:32]([N:30]2[CH:31]=[C:27]([C:8]3[C:9]([O:25][CH3:26])=[C:10]([CH:12]([N:14]4[C:18]5=[N:19][CH:20]=[N:21][C:22]([NH2:23])=[C:17]5[C:16]([CH3:24])=[N:15]4)[CH3:13])[CH:11]=[C:6]([Cl:5])[C:7]=3[CH3:38])[CH:28]=[N:29]2)[CH2:37][CH2:36]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1cnn(C2CCNCC2)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1cnn(C2CCN(C(C)=O)CC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 11.2 %

Procedure:
Acetyl chloride (2.4 μL, 0.033 mmol) was added to a solution of 1-{1-[5-chloro-2-methoxy-4-methyl-3-(1-piperidin-4-yl-1H-pyrazol-4-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (8.0 mg, 0.017 mmol, chiral intermediate from Example 181, Step 2) and N,N-diisopropylethylamine diisopropylethylamine (14 μL, 0.083 mmol) in methylene chloride (0.3 mL) at 0° C. and the reaction was stirred at room temperature for 15 min. The crude was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (1.0 mg, 7.8%). The product was isolated as a single enantiomer. LCMS calculated for C26H32ClN8O2 (M+H)+: m/z=523.2; Found: 523.2.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=2)=[CH:5][C:4]=1[CH:22]([CH3:24])[CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:44]N1C(=O)CCC1=O>>[Br:44][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=2)=[CH:5][C:4]=1[CH:22]([CH3:24])[CH3:23]
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(CO)c(C(C)C)c2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)Cc1ccc(C#Cc2ccc(CBr)c(C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of methyl [4-(4-hydroxymethyl-3-isopropyl-phenylethynyl)-phenyl]-acetate (Compound 123, 180.0 mg, 0.56 mmol) and triphenylphosphine (190.0 mg, 0.73 mmol) in 5 mL CH2C2 was cooled to 0° C. and N-bromosuccinimide (130.0 mg, 0.73 mmol) was added in 5 portions over 20 minutes. The solution was warmed to 25° C. and stirred for 17 hours. The reaction was quenched by the addition of dilute aqueous NaHCO3. The resulting mixture was extracted with Et2O and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (Na2SO4) and concentrated under reduced pressure. The title compound, 212.0 mg (98%), was isolated by column chromatography (5-10% EtOAc-hexanes) as a pale-yellow oil.
Reaction SMILES: [CH:1](=[CH:8][C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].[CH2:14]1[CH2:18]OC[CH2:15]1>[Cu]I>[CH3:18][C:14](=[CH2:15])[CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:8][C:9](=[O:11])[CH3:10]
Reactant: C1CCOC1
Reactant: CC(=O)C=Cc1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Product: C=C(C)C(CC(C)=O)c1ccccc1
Reaction time: 2 h

Procedure:
The organo magnesium compound is then added to a solution of 10 g (0.068 mole) of benzalacetone and 7% (0.97 g) of CuI in 250 ml of THF. The mixture rapidly assumes a brown colouring. After addition, it is left for a few minutes at reflux and then 12 hours at ambient temperature. Hydrolyzing takes place by the addition of the reaction mixture to crushed ice and ammonium chloride, accompanied by very vigorous stirring. After 2 hours, the mixture assumes a blue lavender shade. Extraction takes place with ether and the product is dried on sodium sulphate.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:23][CH2:22][C:10]2[C:11]3[C:12]([CH:19]4[CH2:21][CH2:20]4)(O)[CH2:13][CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:23][CH2:22][C:10]2[C:11]3[CH:12]([CH:19]4[CH2:20][CH2:21]4)[CH2:13][CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)C(O)(C1CC1)CC3
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)N1CCc2ccc3c(c2CC1)C(C1CC1)CC3
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The product from step (a) was dissolved in DCM (20 ml) and cooled to 0° C. To the stirred solution triethylsilane (943 μL, 5.85 mmol) was added, followed by borontrifluoride etherate (456 μL, 3.66 mmol). After 1 hour, additional borontrifluoride etherate (456 μL, 3.66 mmol) was added and the reaction mixture was stirred for an additional hour at 0° C. The reaction was quenched with saturated aqueous NaHCO3 (50 ml) and the aqueous layer was extracted with DCM (3×). The combined DCM extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo. The residue was purified by silica gel chromatography (gradient elution: 0 to 20% EtOAc in hexane) to give the sub-title compound as a colorless oil (103 mg). 1H NMR (CDCl3) δ 7.01-6.93 (m, 2H); 4.16 (q, J=7.2 Hz, 2H); 3.75-3.68 (m, 2H); 3.52-3.43 (m, 2H); 3.11-2.99 (m, 4H); 2.80-2.72 (m, 2H); 2.25-2.14 (m, 1H); 2.06-1.99 (m, 1H); 1.29 (t, J=6.9 Hz, 3H); 0.88-0.77 (m, 1H); 0.55-0.41 (m, 2H); 0.34-0.26 (m, 1H); 0.20-0.13 (m, 1H); MS: ESI (positive): 300, (M+1).
Reaction SMILES: C([O:8][C:9](=[O:46])[CH:10]([O:43][CH2:44][CH3:45])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19](=[O:35])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:23][CH:22]=2)=[C:14]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:13]=1)C1C=CC=CC=1.CCO>CCOC(C)=O>[CH2:36]([C:14]1[CH:13]=[C:12]([CH2:11][CH:10]([O:43][CH2:44][CH3:45])[C:9]([OH:46])=[O:8])[CH:17]=[CH:16][C:15]=1[O:18][C:19](=[O:35])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])=[CH:23][CH:22]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCOC(Cc1ccc(OC(=O)Cc2ccc(NC(=O)OC(C)(C)C)cc2)c(Cc2ccccc2)c1)C(=O)OCc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(Cc1ccc(OC(=O)Cc2ccc(NC(=O)OC(C)(C)C)cc2)c(Cc2ccccc2)c1)C(=O)O

Procedure:
The title compound was prepared from 3-{3-benzyl-4-[2-(4-tert-butoxycarbonylamino-phenyl)-acetoxy]-phenyl}-2-ethoxy-propionic acid benzyl ester (0.06 g, 0.096 mmol) in the same manner as described for example 1 with the difference that EtOH was used as the solvent instead of EtOAc. The crude product was purified by column chromatography using DCM/MeOH (9:1) as the eluent and the title compound was obtained as an oil (0.047 g, 24.2%). 1H NMR (400 MHz, CDCl3): δ 9.28 (s, 1H), 7.38-7.29 (d, 2H), 7.02-7.21 (m, 9H), 6.88-6.91 (d, 1H), 3.79 (s, 2H), 3.50-3.55 (m, 1H), 3.15-3.19 (m, 1H), 2.85-2.87 (dd, 1H), 2.64-2.69 (m, 1H), 2.48-2.50 (m, 1H), 1.45 (s, 9H), 0.91-0.95 (t, 3H). Mass spectrum: M−H+ 531.93.
Reaction SMILES: O.O.[O:3]=[C:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:14]([O-:17])(=O)=[O:15])[CH:10]=2)[NH:5]1.[Na+].O=P(Cl)(Cl)[Cl:21].S1(CCCC1)(=O)=O>O>[O:3]=[C:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:14]([Cl:21])(=[O:17])=[O:15])[CH:10]=2)[NH:5]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1Nc2ccc(S(=O)(=O)[O-])cc2C1=O
Agent: [Na+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: O=C1Nc2ccc(S(=O)(=O)Cl)cc2C1=O
Temperature: 60 °C
Yield: 81.7 %

Procedure:
A suspension of sodium 2,3-dioxoindoline-5-sulfonate dihydrate (5.0 g, 17.53 mmol) and POCl3 (8.17 ml, 88 mmol) in sulfolane (25 ml, 264 mmol) was heated at 60° C. for 3 hours. The solution was cooled to 0° C. and water (60 ml) was added drop wise; the green precipitate was filtered and washed with a small amount of water. The solid was dissolved in ethyl acetate and washed three times with water; the organic phase was then dried over sodium sulfate and evaporated to give a crude solid that was purified by crystallization from hexane/ethyl acetate 1:1 to give 2,3-dioxoindoline-5-sulfonyl chloride (3.52 g, 14.33 mmol, 82% yield).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:23][NH:24][O:25][CH3:26]>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([C:8]([N:24]([O:25][CH3:26])[CH3:23])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: CNOC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)c1cccc(Br)n1
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a slurry of 6-bromopicolinic acid (5.44 g, 26.93 mmol) in DCM (100 mL) was added a solution of CDI (5.67 g, 34.97 mmol) in DCM (70 mL) drop-wise over 15 minutes under nitrogen. The solution cleared a little during the addition but remained cloudy and after 1 hour at rt the mixture was treated drop-wise over 15 minutes with N,O-dimethylhydroxylamine [solution in DCM prepared by treating N,O-dimethylhydroxylamine hydrochloride (5.35 g, 53.82 mmol) with aqueous NaOH (2M, 100 mL) and extracting with DCM (2×100 mL)]. The mixture cleared during the addition and the resulting clear pale yellow solution was left to stir under nitrogen for 20 hours. The mixture was then reduced under vacuum and the residue partitioned between EtOAc (125 mL) and saturated aqueous NaHCO3 (125 mL). The layers were then separated and the organic layer washed with brine (125 mL), dried (MgSO4), filtered and reduced to give the title compound as a yellow oil (5.29 g).
Reaction SMILES: [C:1]1([C@H:7]2[C:12](=[O:13])[O:11][CH2:10][CH2:9][N:8]2[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[F:35][C:36]([F:51])([F:50])[C:37]1[CH:38]=[C:39]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[C:40](Cl)=[O:41]>C1COCC1>[F:35][C:36]([F:50])([F:51])[C:37]1[CH:38]=[C:39]([CH:43]=[C:44]([C:46]([F:49])([F:47])[F:48])[CH:45]=1)[C:40]([O:13][C@H:12]1[O:11][CH2:10][CH2:9][N:8]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@H:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:41]
Reactant: O=C1OCCN(Cc2ccccc2)[C@H]1c1ccccc1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O[C@H]1OCCN(Cc2ccccc2)[C@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.75 h
Yield: 79.7 %

Procedure:
A solution of 2.67 g (10.0 mmol) of 3-(S)-phenyl-4-benzyl-2-morpholinone (from Example 14) in 40 mL of dry THF was cooled to −78° C. The cold solution was treated with 12.5 mL of 1.0 M L-Selectride®, solution in THF, maintaining the internal reaction temperature below −70° C. The resulting solution was stirred cold for 45 minutes and the reaction was charged with 3.60 mL (20.0 mmol) of 3,5-bis(trifluoro-methyl)benzoyl chloride. The resulting yellow mixture was stirred cold for 30 minutes and the reaction was quenched with 50 mL of saturated aqueous sodium bicarbonate solution. The quenched mixture was partitioned between 300 mL of ether and 50 mL of water and the layers were separated. The organic layer was dried over magnesium sulfate. The aqueous layer was extracted with 300 mL of ether; the extract was dried and combined with the original organic layer. The combined organics were concentrated in vacuo. Flash chromatography on 150 g of silica gel using 37:3 v/v hexanes/ether as the eluant afforded 4.06 g (80%) of the title compound as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:16][C:17]([C:18]([NH:20][C@@H:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:22]([OH:24])=[O:23])=[O:19])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.O[NH:58][C:59](=[NH:61])[CH3:60]>C(Cl)Cl>[NH2:61]/[C:59](=[N:58]\[O:23][C:22](=[O:24])[C@@H:21]([NH:20][C:18]([C:17]1[N:16]=[C:15]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:11]2[CH2:12][CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][C:10]=12)=[O:19])[C:25]([CH3:27])([CH3:28])[CH3:26])/[CH3:60]
Reactant: CC(C)(C)OC(=O)N1CCCn2c(-c3ccccc3)nc(C(=O)N[C@H](C(=O)O)C(C)(C)C)c2C1
Reactant: CC(=N)NO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: C/C(N)=N/OC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CCC2)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 2 mL dichloromethane solution of Compound 515 (320 mg, 0.68 mmol) was added to a dichloromethane solution of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (209 mg, 1.09 mmol) and 1-hydroxybenzotriazole hydrate (167 mg, 1.09 mmol). The solution was stirred for 15 minutes at ambient temperature. N-hydroxyacetamidine (76 mg, 1.02 mmol) was added in one portion as a solid, and the mixture was stirred overnight. After diluting with additional DCM, the reaction mixture was washed with saturated aqueous NaHCO3 solution and brine, dried over anhydrous Na2SO4, and concentrated to a pale yellow foaming solid (Intermediate 49A). LCMS (+ESI) m/z 527.2 [M+H]+.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([N+:24]([O-:26])=[O:25])=[C:19]([CH:21]([OH:23])[CH3:22])[CH:20]=1>CC(C)=O>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([N+:24]([O-:26])=[O:25])=[C:19]([C:21](=[O:23])[CH3:22])[CH:20]=1
Reactant: CC(O)c1cc(Br)ccc1[N+](=O)[O-]
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CC(=O)c1cc(Br)ccc1[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 76.6 %

Procedure:
Jones Reagent (2.67 M, 2.54 mL, 6.79 mmol) was added dropwise to 1-(5-bromo-2-nitrophenyl)-ethanol (1.67 g, 6.79 mmol) in acetone (34 mL) at 0° C., then the reaction mixture was stirred for 10 minutes. Any excess Jones reagent was quenched by the addition of iso-propanol, then the reaction mixture was neutralized with saturated sodium bicarbonate, and the acetone was removed by evaporation. Water was added and the solution was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 1:9 ethyl acetate:hexanes to give 1.27 g (77%) of 1-(5-bromo-2-nitrophenyl)-ethanone as a solid. 1H NMR (400 MHz, d6-DMSO): δ 8.05 (d, J=5 Hz, 1H), 8.04 (s, 1H), 7.96 (dd, J=9, 2 Hz, 1H), 2.57 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][NH:11]2)=[C:7]([NH:14][C@H:15]([CH2:23][OH:24])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:6]=1)=[O:4].[H-].[Na+].[OH:27][C@@H:28]1[CH2:32][CH2:31][C@H:30](OC(=O)C)[CH2:29]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.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]>[CH3:1][O:2][C:3]([C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:31]2[CH2:32][C@H:28]([OH:27])[CH:29]=[CH:30]2)=[C:7]([NH:14][C@H:15]([CH2:23][OH:24])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:6]=1)=[O:4]
Reactant: CC(=O)O[C@H]1CC[C@@H](O)C1
Reactant: COC(=O)c1nc(N[C@H](CO)Cc2ccccc2)c2nc[nH]c2n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [H-]
Solvent: C1CCOC1
Product: COC(=O)c1nc(N[C@H](CO)Cc2ccccc2)c2ncn([C@H]3C=C[C@@H](O)C3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-((S)-1-Hydroxymethyl-2-phenyl-ethylamino)-9H-purine-2-carboxylic acid methyl ester (1.05 eq.) is suspended in THF (deoxygenated & dry). NaH (1.05 eq.) is added over 5 minutes and the reaction mixture is stirred at RT over 30 minutes. A solution of acetic acid (1S,3R)-3-hydroxy-cyclopentyl ester (1 eq.), triphenylphosphane (0.15 eq.) and tris(dibenzylideneacetone)dipalladium(0) in THF (deoxygenated & dry) is added to reaction. The reaction mixture is reflux for 6 hours. The reaction mixture is reduce in vacuo and columned to give the title compound.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]4[CH:37]=[C:36]5[C:31]([CH2:32][CH2:33][N:34]([CH3:38])[CH2:35]5)=[CH:30][CH:29]=4)[N:22]=3)=[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N:14]3[N:13]=2)[CH:7]=1)=O.O[Li].O>O1CCCC1.O.C(Cl)Cl>[NH2:5][C:6]1[CH:7]=[C:8]([C:12]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]4[CH:37]=[C:36]5[C:31]([CH2:32][CH2:33][N:34]([CH3:38])[CH2:35]5)=[CH:30][CH:29]=4)[N:22]=3)=[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N:14]3[N:13]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CN1CCc2ccc(Nc3nccc(-c4c(-c5cccc(NC(=O)C(F)(F)F)c5)nn5ccccc45)n3)cc2C1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN1CCc2ccc(Nc3nccc(-c4c(-c5cccc(N)c5)nn5ccccc45)n3)cc2C1
Temperature: 50 °C
Yield: 92 %

Procedure:
To a solution of 2,2,2-trifluoro-N-[3-(3-{2-[(2-methyl-1,2,3,4-tetrahydro-7-isoquinolinyl)amino]-4-pyrimidinyl}pyrazolo[1,5-a]pyridin-2-yl)phenyl]acetamide (290 mg, 0.53 mmol) in tetrahydrofuran (2 mL) and deionized water (2 mL) was added LiOH.H2O (34 mg, 0.80 mmol). The reaction was heated to 50° C. for 3 h, and then diluted with 10 mL DCM. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over Na2SO4, filtered, and concentrated to generate the title compound in 92% yield (219 mg, 0.49 mmol). 1H NMR (400 MHz, d6-DMSO) δ 9.41 (s, 1H), 8.79 (d, J=6.8 Hz, 1H), 8.52 (bd, 1H), 8.21 (d, J=5.3 Hz, 1H), 7.53 (s, 1H), 7.41-7.46 (m, 2H), 7.08-7.15 (m, 2H), 7.00 (d, J=8.2 Hz, 1H), 6.80 (s, 1H), 6.67 (t, J=7.7 Hz, 1H), 6.49 (d, J=5.3 Hz, 1H), 5.25 (s, 2H), 3.42 (s, 2H), 2.76 (t, J=5.7 Hz, 2H), 2.58 (t, J=5.7 Hz, 2H), 2.32 (s, 3H). MS (ESI) m/z=448 [M+H]+.