Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]([CH3:34])[C:7]2[C:8]([CH3:33])=[C:9]([CH:23]=[C:24]([C:26]3[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH:31]=3)[CH:25]=2)[C:10]([NH:12][CH2:13][C:14]2[C:15](=[O:22])[NH:16][C:17]([CH3:21])=[CH:18][C:19]=2[CH3:20])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[Pd]>[CH:1]1([N:6]([CH3:34])[C:7]2[C:8]([CH3:33])=[C:9]([CH:23]=[C:24]([CH:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)[CH:25]=2)[C:10]([NH:12][CH2:13][C:14]2[C:15](=[O:22])[NH:16][C:17]([CH3:21])=[CH:18][C:19]=2[CH3:20])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C)CC3)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CCN(C)CC3)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Yield: 66.6 %

Procedure:
To a solution of 3-(cyclopentyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-5-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)benzamide (0.045 g, 0.097 mmol) in ethanol added 10% Pd/C and the reaction was stirred under H2 at bladder pressure. After complete consumption of the starting material reaction mixture was filtered through celite. The filtrate was concentrated and triturated in acetonitrile and filtered to provide the desired compound (0.030 g, 66%): LCMS: 465.40 (M+1)+; HPLC: 95.39% (@ 254 nm) (Rt; 3.884; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.44 (s, 1H), 7.98 (t, 1H), 7.00 (s, 1H), 6.77 (s, 1H), 5.85 (s, 1H), 4.25 (d, 2H, J=4.4 Hz), 3.42 (m, 1H), 2.84 (d, 2H, J=11.2 Hz), 2.47 (s, 3H), 2.37 (m, 1H), 2.18 (s, 6H), 2.15 (s, 3H), 2.10 (s, 3H), 1.93 (t, 2H, J=10.8 Hz), 1.70-1.55 (m, 8H), 1.48 (m, 2H), 1.38 (m, 2H).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].S(=O)(=O)(O)O.[CH3:14][C:15]([C:17]1[CH:18]=[CH:19][C:20]([OH:24])=[CH:21][C:22]=1[OH:23])=O>CO>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[NH:1][N:2]=[C:15]([C:17]1[CH:18]=[CH:19][C:20]([OH:24])=[CH:21][C:22]=1[OH:23])[CH3:14]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: NNc1ccccn1
Agent: O=S(=O)(O)O
Solvent: CO
Product: CC(=NNc1ccccn1)c1ccc(O)cc1O
Reaction time: 8 h
Yield: 46.9 %

Procedure:
A total of 33.8 g (0.309 mol) of 2-hydrazinopyridine and 2 L of methanol were charged into a four-neck flask with a capacity of 3 L equipped with a reflux condenser, a thermometer, and a stirrer, and 1 mL of concentrated sulfuric acid was then dropwise added at room temperature under stirring. Then, 44.0 g (0.289 mol) of 2,4-dihydroxyacetophenone was charged and a reaction was conducted for 8 h at 40° C. under stirring. The precipitated crystals were taken out by filtration, washed with methanol and water and dried at 60° C. to obtain 33.0 g of 4-{1-[(2-pyridine-2-yl)hydrazono]ethyl}benzene-1,3-diol in the form of light-yellow crystals. The yield was 50%. GC/MS, 1H-NMR, and IR measurements were performed with respect to the obtained crystals. The results are shown below.
Reaction SMILES: N[C:2]1[S:3][C:4]2[C:9]([NH2:10])=[N:8][CH:7]=[N:6][C:5]=2[N:11]=1.[OH-].[Na+].N([O-])=O.[Na+].[ClH:18].[Li+].[Cl-]>O>[NH2:10][C:9]1[C:4]2[S:3][C:2]([Cl:18])=[N:11][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: Cl
Reactant: Nc1nc2ncnc(N)c2s1
Agent: O=N[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Product: Nc1ncnc2nc(Cl)sc12
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a suspension of 2,7-diaminothiazolo[4,5-d]pyrimidine (27: 16.3 g, 97.3 mmol) in water (200 mL) at 55° C. was added enough 1N NaOH (about 100 mL) to dissolve the starting material and sodium nitrite (8.0 g) was then added. This solution was then added dropwise over 30 min. to a solution containing con HCl (400 mL), water (100 mL) and LiCl (60 g) at 30° C. The resulting mixture was warmed to 45° C. for 15 min. and then hot water (1 L, 90°) was added. The reaction mixture was stirred overnight at room temperature, filtered to remove unreacted starting material and the filtrate was neutralized with solid NaOH to pH 4. The resulting solid was filtered off, washed with water and dried to yield 28: 5.38 g, 34%: recrystallization from water gave an analytical sample- mp >234° C. decomp.: UV λmax (pH 1) 228 nm (ε), 296 (): UV λmax (pH 7) 232 nm (ε), 298 (): UV λmax (pH 119 227 nm (ε), 300 (): 1H NMR (DMSO-d6) δ7.82 (b, 2H, NH2, exchanges with D2O), 8.41 (s, 1H, C5H). Anal. Calcd. for C5H3N4SCl.0.1H2O: C, 31.87: H, 1.71: N, 29.74: S, 17.02: Cl, 18.82. Found: C, 31.71: H, 1.50: N, 29.35: S, 16.92: Cl, 19.54.
Reaction SMILES: [CH2:1]([C:4]1([CH2:29][CH2:30][O:31][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:5]1=[O:28])[CH:2]=C.I([O-])(=O)(=O)=[O:43].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[Cl:16][C:12]1[CH:11]=[C:10]([C@@H:8]2[C@@H:7]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:6]([CH2:24][CH:25]3[CH2:26][CH2:27]3)[C:5](=[O:28])[C:4]([CH2:1][CH:2]=[O:43])([CH2:29][CH2:30][O:31][Si:32]([CH:33]([CH3:35])[CH3:34])([CH:39]([CH3:40])[CH3:41])[CH:36]([CH3:38])[CH3:37])[CH2:9]2)[CH:15]=[CH:14][CH:13]=1
Reactant: C=CCC1(CCO[Si](C(C)C)(C(C)C)C(C)C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](OCCC1(CC=O)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O)(C(C)C)C(C)C
Reaction time: 0.42 h

Procedure:
To a solution of 1.28 g (2.08 mmol) of (5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-(2-(triisopropylsilyloxy)ethyl)piperidin-2-one (Example 69, Step A, mixture of diastereomers) in THF (50 mL) and water (17.5 mL) was added a catalytic amount of osmium tetroxide. After 25 min, 1.34 g (6.25 mmol) of sodium periodate was added. The resulting light brown slurry was stirred for 19 h and then was filtered through a fitted funnel. The filtrate was partially concentrated under reduced pressure, then was diluted with water and extracted with ethyl acetate (2×). The combined organic layers were washed with saturated aqueous sodium thiosulfate and then saturated aqueous sodium chloride. The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated. The crude title compound (mixture of C-3 epimers) was used directly in the next step.
Reaction SMILES: CC1NC(C2C=C(C=CC=2C)C(O)=O)=C(C)N=1.[CH3:18][C:19]1[CH:28]=[C:27]([CH3:29])[C:26]([C:30]2[NH:34][C:33]([CH:35]3[CH2:38][O:37][CH2:36]3)=[N:32][C:31]=2[CH3:39])=[CH:25][C:20]=1[C:21]([O:23]C)=[O:22].CC1NC(C2C=C(C=CC=2C)C(OC)=O)=C(C)N=1>>[CH3:18][C:19]1[CH:28]=[C:27]([CH3:29])[C:26]([C:30]2[NH:34][C:33]([CH:35]3[CH2:38][O:37][CH2:36]3)=[N:32][C:31]=2[CH3:39])=[CH:25][C:20]=1[C:21]([OH:23])=[O:22]
Reactant: COC(=O)c1cc(-c2[nH]c(C3COC3)nc2C)c(C)cc1C
Agent: COC(=O)c1ccc(C)c(-c2[nH]c(C)nc2C)c1
Agent: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Product: Cc1cc(C)c(-c2[nH]c(C3COC3)nc2C)cc1C(=O)O

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.7, except methyl 2,4-dimethyl-5-(4-methyl-2-(oxetan-3-yl)-1H-imidazol-5-yl)benzoate (compound 180.3) was used in place of methyl 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 5.6). m/z (ES+) 287 (M+H)+.
Reaction SMILES: O.[NH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([SH:10])[N:4]=1.[Cl:11][C:12]1[C:13]([F:20])=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Br>>[NH2:2][C:3]1[N:4]=[C:5]([S:10][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[C:12]([Cl:11])[C:13]=2[F:20])[NH:6][C:7](=[O:9])[CH:8]=1
Reactant: Fc1c(Cl)cccc1CBr
Reactant: Nc1cc(O)nc(S)n1
Solvent: O
Product: Nc1cc(=O)[nH]c(SCc2cccc(Cl)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure of Example 1 step i) treating 4-amino-6-hydroxy-2-mercaptopyrimidine monohydrate (8.4 g) with 3-chloro-2-fluorobenzyl bromide (11.0 g) to afford the subtitle compound as a white solid. Yield: 14.1 g.
Reaction SMILES: [CH2:1]([N:4]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]=[CH:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=3)[N:21]=2)=[CH:16][CH:15]=1)C(=O)OC(C)(C)C)[CH:2]=[CH2:3].C(=O)(O)[O-].[Na+]>>[F:35][C:32]([F:33])([F:34])[O:31][C:28]1[CH:27]=[CH:26][C:25]([N:22]2[CH:23]=[N:24][C:20]([C:17]3[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][NH:4][CH2:1][CH:2]=[CH2:3])=[CH:15][CH:16]=3)=[N:21]2)=[CH:30][CH:29]=1
Reactant: C=CCN(CCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1

Procedure:
The title compound was prepared from tert-butyl allyl(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)carbamate (CB65), neutralized with aqueous sodium bicarbonate, and isolated as a yellow solid (0.124 g, 90%): mp 110-120° C.; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 8.14-8.07 (m, 2H), 7.81-7.73 (m, 2H), 7.42-7.34 (m, 2H), 7.34-7.28 (m, 2H), 5.92 (ddt, J=16.9, 10.2, 6.6 Hz, 1H), 5.43-5.22 (m, 2H), 3.49 (dt, J=6.6, 1.2 Hz, 2H), 3.19-2.92 (m, 5H); 19F NMR (376 MHz, CDCl3) δ −58.04; ESIMS m/z 389 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:13]1[C:22]2[C:17](=[C:18]([C:23]3[N:27]=[C:26]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH:35]([CH3:37])[CH3:36])=[C:30]([C:38]#[N:39])[CH:29]=4)[O:25][N:24]=3)[CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1)[CH2:9][C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=[CH:47][CH:48]=[CH:49][C:44]=2[N:43]=N1.C(Cl)CCl.N1CCCC1>CN(C=O)C.C([O-])(O)=O.[Na+]>[C:38]([C:30]1[CH:29]=[C:28]([C:26]2[O:25][N:24]=[C:23]([C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:17]=3[CH2:16][CH2:15][CH2:14][C@@H:13]4[N:8]([CH2:9][C:10](=[O:11])[N:43]3[CH2:44][CH2:49][CH2:48][CH2:47]3)[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[N:27]=2)[CH:33]=[CH:32][C:31]=1[O:34][CH:35]([CH3:37])[CH3:36])#[N:39]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@@H]4N(CC(=O)O)C(=O)OC(C)(C)C)no2)cc1C#N
Reactant: On1nnc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCNC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@@H]4N(CC(=O)N3CCCC3)C(=O)OC(C)(C)C)no2)cc1C#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
Prepared using General Procedure 12. To a stirring solution of (S)-2-((tert-butoxycarbonyl)(5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)amino)acetic acid INT-24 (30 mg, 0.06 mmol) in DMF (0.5 mL) were added N-hydroxybenzotriazole (15.21 mg, 0.11 mmol) and EDC (21.63 mg, 0.11 mmol). After 10 min, pyrrolidine (46 μL, 0.56 mmol) was added and the reaction mixture was stirred 18 h at room temperature. The crude reaction was diluted with sat NaHCO3 added extracted with EA. The combined organic layers were dried over Na2SO4 and purified by preparative HPLC to give 26.9 mg (82%) of (S)-tert-butyl (5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)(2-oxo-2-(pyrrolidin-1-yl)ethyl)carbamate. LCMS-ESI (m/z) calculated for C33H39N5O5: 585.7; found 358.1 [M−tert-butyl (2-oxo-2-(pyrrolidin-1-yl)ethyl)carbamate]+, tR=4.18 min.
Reaction SMILES: CC([CH:5]1[CH2:10][N:9]([CH2:11][CH:12]2[C:21]3[C:16](=[C:17]([O:24][CH3:25])[C:18]([C:22]#[N:23])=[CH:19][CH:20]=3)[CH2:15][CH2:14][O:13]2)[CH2:8][CH2:7][N:6]1C([O-])=O)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:25][O:24][C:17]1[C:18]([C:22]#[N:23])=[CH:19][CH:20]=[C:21]2[C:16]=1[CH2:15][CH2:14][O:13][CH:12]2[CH2:11][N:9]1[CH2:10][CH2:5][NH:6][CH2:7][CH2:8]1
Reactant: COc1c(C#N)ccc2c1CCOC2CN1CCN(C(=O)[O-])C(C(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(C#N)ccc2c1CCOC2CN1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1,1-dimethylethyl-4-{[6-cyano-5-(methyloxy)-3,4-dihydro-1H-isochromen-1-yl]methyl}piperazine-1-carboxylate (30 mg, 0.08 mmol) in 5 mL of DCM was added 5 mL of TFA was stirred at room temperature for 1 hours, and the reaction was concentrated. The resulting crude 5-(methyloxy)-1-(piperazin-1-ylmethyl)-3,4-dihydro-1H-isochromene-6-carbonitrile was directly used in next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7](B(O)O)[CH:8]=1.Br[C:13]1[CH:18]=[C:17]([F:19])[C:16]([C:20]([N:22]2[CH2:26][CH2:25][CH2:24][C@H:23]2[CH2:27][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:21])=[C:15]([F:33])[CH:14]=1>>[F:19][C:17]1[CH:18]=[C:13]([C:7]2[CH:6]=[N:5][CH:4]=[C:3]([O:2][CH3:1])[CH:8]=2)[CH:14]=[C:15]([F:33])[C:16]=1[C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[CH2:27][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:21]
Reactant: COc1cncc(B(O)O)c1
Reactant: O=C(c1c(F)cc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Product: COc1cncc(-c2cc(F)c(C(=O)N3CCC[C@H]3CN3CCCC3)c(F)c2)c1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure WW starting from 3-methoxypyridine-5-boronic acid and (4-bromo-2,6-difluoro-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone to give 20 mg (19%). MS (ES+) 402 m/z
Reaction SMILES: [OH:1][CH:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH:4]=[CH:3]1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C(Cl)Cl.CCOCC.O>[Si:18]([O:1][CH:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH:4]=[CH:3]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)N1CC=CC(O)C1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)N1CC=CC(O[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
To a solution of Compound 239C (16 g, 93.5 mmol) in 150 mL of dry CH2Cl2 at 0° C. was added imidazole (9.5 g, 140.0 mmol) and t-butyldimethylsilylchloride (15.5 g, 102.8 mmol) and the mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with ether (500 mL) and water (1 L) at 0° C. The organic phase was separated and washed with 10% LiCl (150 mL×3), dried over anhydrous MgSO4. Concentration in vacuo followed by flash chromatography (hexane-EtOAc: 15:1 to 10:1) afforded 25.2 g (Yield: 94.4%) of 239D as an oil.
Reaction SMILES: Br[C:2]1[N:3]([CH3:27])[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[NH:19][C:18]3=[O:26])[CH2:13][CH2:12]1)[N:7]=[CH:6][N:5]=2.[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1.C(N(C(C)C)CC)(C)C.[H-].[Na+]>C(O)C>[N:28]1([C:2]2[N:3]([CH3:27])[C:4]3[C:9]([N:10]=2)=[C:8]([N:11]2[CH2:12][CH2:13][CH:14]([N:17]4[C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[NH:19][C:18]4=[O:26])[CH2:15][CH2:16]2)[N:7]=[CH:6][N:5]=3)[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: c1c[nH]cn1
Reactant: Cn1c(Br)nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc21
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(-n2ccnc2)nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc21
Temperature: 100 °C
Yield: 48.1 %

Procedure:
1-[1-(8-Bromo-9-methyl-9H-purin-6-yl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one (50 mg, 0.12 mmol) was dissolved in ethanol (1 mL). To this solution was added imidazole (24 mg, 0.35 mmol) and diisopropylethylamine (39 μL, 0.23 mmol). This mixture was irradiated in the microwave at 180° C. for 6 hours. The ethanol was removed in vacuo and replaced by DMA (1 mL). To this solution was added 1 equiv. of sodium hydride. After heating to 100° C. for 1 hour, the mixture was filtered and purified by prep HPLC to obtain 24 mg of the desired product. 1H NMR (400 MHz, DMSO-d6): δ 10.85 (s, 1H), 8.39-8.28 (m, 1H), 8.27-8.16 (m, 1H), 7.78 (m, 1H), 7.18 (m, 1H), 7.14 (m, 1H), 6.99-6.82 (m, 3H), 5.47 (s, 1H), 4.63-4.40 (m, 1H), 3.67 (s, 3H), 3.22 (m, 3H), 2.42-2.20 (m, 2H), 1.80 (m, 2H). EI (MS) for C21H21N9O, found 416 (MH+).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:4]=1[C:19]([O:21]C)=[O:20])#[N:2].[OH-].[Li+].O>CO.Cl>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:4]=1[C:19]([OH:21])=[O:20])#[N:2]
Reactant: COC(=O)c1c(C#N)c2ccccc2n1-c1cccc(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#Cc1c(C(=O)O)n(-c2cccc(F)c2)c2ccccc12
Yield: 97.3 %

Procedure:
Methyl 3-cyano-1-(3-fluorophenyl)-1H-indole-2-carboxylate (0.13 g, 0.44 mmol) was treated with 1.0 M lithium hydroxide in water (0.66 mL, 0.66 mmol) in methanol (3 mL) at room temperature for 3 hours. The reaction was diluted with 1 N HCl and extracted with EtOAc. The extracts were combined, washed with brine, dried over MgSO4 and concentrated to give the desired acid (0.12 g, 97%). LCMS calculated for C16H10FN2O2(M+H)+: m/z=281.1. Found: 281.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:19])([CH3:18])[CH2:14][N:15]([CH3:17])[CH3:16])[C:10](=[O:20])[C@@H:9]([CH2:21][C:22](O)=[O:23])[O:8][C@H:7]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[C:6]=2[CH:35]=1.C(N1C=CN=C1)([N:38]1C=CN=C1)=O.C(=O)(O)[O-].[NH4+]>CN(C)C=O.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:19])([CH3:18])[CH2:14][N:15]([CH3:17])[CH3:16])[C:10](=[O:20])[C@@H:9]([CH2:21][C:22]([NH2:38])=[O:23])[O:8][C@H:7]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[C:6]=2[CH:35]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(C)CC(C)(C)CN1C(=O)[C@@H](CC(=O)O)O[C@H](c2cccc3ccccc23)c2cc(Cl)ccc21
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CN(C)CC(C)(C)CN1C(=O)[C@@H](CC(N)=O)O[C@H](c2cccc3ccccc23)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.2 %

Procedure:
Trans-7-chloro-5-(1 -naphthyl)-1 -(2,2-dimethyl-3-dimethylamino-propyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid (1.16 g, 2.35 mmol) and 1,1'-carbonyldiimidazole (1.91 g, 11.8 mmol) were dissolved in dimethylformamide (75 ml). Stirring for 1 h at room temperature was followed by addition of ammonium bicarbonate (1.86 g, 23.5 mmol) in one portion to the reaction mixture, which was stirred for further 18 hours at room temperature. The solvent was concentrated under reduced pressure and the residue flash chromatographed directly (dichloromethane/methanol/aqueous ammonia 99:1:0.1 to 98:2:0.2). The solid was taken up in dichloromethane and a stoichiometric amount of 1N HCl in ether was added. Removal of the solvent provided a solid which was dissolved in ethanol and precipitated with ether to give the title compound (0.42 g, 36%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].O.[C:13]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:13][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:11]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)c1cc(Br)ccc1F
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(Br)ccc1F
Yield: 91.9 %

Procedure:
Heat a solution of 5-bromo-2-fluorobenzoic acid (20 g, 92 mmol) and p-toluenesulfonic acid monohydrate (52 g, 275 mmol) in methanol (200 mL) at reflux overnight. Concentrate and dissolve the residue in ethyl acetate, wash twice with an aqueous saturated solution of sodium bicarbonate, once with an aqueous saturated solution of sodium chloride, dry (sodium sulfate), filter and concentrate to give the title compound as a clear liquid (19.7 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[CH:14][C:15]([O:17]CC)=[CH:16][C:8]=3[NH:7][C:6]=2[CH:20]=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:8]=3[NH:7][C:6]=2[CH:20]=1
Reactant: CCOc1ccc2c(c1)Nc1cc(Cl)ccc1C(=O)N2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1Nc2ccc(O)cc2Nc2cc(Cl)ccc21
Reaction time: 8 h

Procedure:
A mixture of Example 506C (1.87 g, 6.5 mmol) in dichloromethane (50 mL) at −78° C. was treated dropwise with a 1.0M solution of BBr3 in dichloromethane, stirred overnight and allowed to reach room temperature, quenched with a saturated solution of ammonium chloride, concentrated under vacuum, and extracted with ethyl acetate. The extracts were combined, washed with brine, dried (MgSO4), filtered, and concentrated under vacuum to provide the desired product.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15]1)[N:7]=[CH:6]2.B(Br)(Br)Br.O=S(Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH2:13][N:14]1[CH2:15][CH2:16][CH:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:19]1)[N:7]=[CH:6]2
Reactant: COC(=O)C1CCN(Cc2ncc3cc(OC)ccc3n2)CC1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1CCN(Cc2ncc3cc(O)ccc3n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.4 %

Procedure:
To a solution of methyl 1-((6-methoxyquinazolin-2-yl)methyl)piperidine-4-carboxylate (3.0 g, 9.5 mmol) in DCM (15 mL) was added BBr3 (9.5 mmol, 1.0 eq) at 0° C. under N2. The reaction was stirred at room temperature for 16 h. After the removal of solvent, SOCl2 (2.8 g, 0.238 mol, 1.5 eq) and MeOH (20 mL) was added at 0° C. The mixture was refluxed at 80° C. for 3 h, poured into the NaHCO3 aqueous solution and extracted with DCM (100 mL*3). The combined extracts were dried over anhydrous Na2SO4 and evaporated to dryness in vacuum. The crude product was purified by chromatography (eluting with DCM/MeOH=25/1) to give methyl 1-((6-hydroxyquinazolin-2-yl)methyl)piperidine-4-carboxylate (1.7 g, yield: 77%) as a yellow solid. 1HNMR (400 MHz, DMSO-d6) δ: 10.36 (s, 1H), 9.35 (s, 1H), 7.84 (d, J=9.2 Hz, 1H), 7.51 (dd, J=9.2, 2.4 Hz, 1H), 7.25 (d, J=2.4 Hz, 1H), 3.74 (s, 2H), 3.57 (s, 3H), 2.86˜2.84 (m, 2H), 2.27 (m, 1H), 2.16 (m, 2H), 1.77 (m, 2H), 1.56 (m, 2H); ESI-MS: m/z 302.1 ([M+1]+).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[N:3]=[C:4]3[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2cnc3[nH]cc(C(=O)C(C)(C)C)c3n2)cc1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 47.7 %

Procedure:
A mixture of 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one (60 mg, 0.21 mmol), 4-methoxyphenyl boronic acid (33 mg, 0.22 mmol), potassium carbonate (69 mg, 0.5 mmol), Pd(dppf)Cl2CH2Cl2 (13 mg, 0.016 mmol), 1.7 mL dioxane and 0.4 mL water was stirred at 150° C. in a microwave for 30 min. The resulting mixture was partitioned between ethyl acetate and water. The combined organic layers were dried over Na2SO4 and concentrated to give a dark brown solid. The crude product was purified by preparative thin layer chromatography using 90:9.5:0.5 CH2Cl2:MeOH:conc NH4OH as eluant. The resultant brown solid was washed with ethyl ether to provide 31 mg (50%) of 1-[2-(4-methoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as a brown solid. MP 207-208° C., M+H 310.