Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[C:8]([NH:12][C:13]1[N:14]=[C:15]2[CH2:37][CH2:36][NH:35][CH2:34][C:16]2=[N:17][C:18]=1[N:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[F:33])[CH2:21][CH2:20]1)([CH3:11])([CH3:10])[CH3:9].C(OC(=O)C)(=O)C.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[C:8]([NH:12][C:13]1[N:14]=[C:15]2[CH2:37][CH2:36][N:35]([C:2](=[O:1])[CH3:4])[CH2:34][C:16]2=[N:17][C:18]=1[N:19]1[CH2:20][CH2:21][CH:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[F:33])[CH2:23][CH2:24]1)([CH3:11])([CH3:9])[CH3:10].[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CNCC2
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N1CCc2nc(NC(C)(C)C)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2C1

Procedure:
A solution of N-(tert-butyl)-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (16 mg, 0.030 mmol), acetic anhydride (5.7 μL, 0.060 mmol), and DIPEA (15.8 μL, 0.090 mmol) in DCM (151 μL) was stirred at room temperature overnight. The crude reaction mixture was diluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR), and purified via HPLC Method A to give the title compound as a TFA salt (15 mg) as a clear oil. 1H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm 1.48 (s, 9H), 1.87-1.98 (m, 2H), 2.07-2.17 (m, 2H), 2.19 (s, 1.3H), 2.21 (s, 1.7H), 2.74 (t, J=5.9 Hz, 0.9H), 2.84 (t, J=5.9 Hz, 1.1H), 2.97 (ddd, J=12.4, 8.6, 3.3 Hz, 2H), 3.33-3.37 (m, 2H), 3.80 (t, J=5.9 Hz, 1.1H), 3.85 (t, J=5.9 Hz, 0.9H), 4.43-4.51 (m, 1H), 4.53 (d, J=1.3 Hz, 2H), 6.88 (ddddd, J=9.1, 8.1, 2.9, 1.9, 0.8 Hz, 1H), 6.95-7.02 (m, 1H), 7.18 (td, J=9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]+ 460.4.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.C(N(CC)CC)C.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>O1CCCC1>[C:25]([NH:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccccc2)CN1C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
Methyl (2S,4S)-4-amino-1-tert-butoxycarbonylpyrrolidine-2-carboxylate [product of Reference Example 5(3), 2.4 g] and triethylamine (2.0 mL) were dissolved in tetrahydrofuran (20 mL), and benzoyl chloride (1.1 mL) was added thereto. The mixture was stirred for 1 hr. The reaction mixture was added to water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution and dried. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography to give methyl (2S,4S)-4-benzoylamino-1-tert-butoxycarbonylpyrrolidine-2-carboxylate (1.63 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH2:17][CH2:18][C@@H:19]([C:21]([O:23][CH3:24])=[O:22])[N:20]=2)=[N:14][CH:15]=1.C(O)(=O)C.FC(F)(F)C(O)=O>C(OCC)(=O)C.[Pt]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C@@H:16]2[NH:20][C@H:19]([C:21]([O:23][CH3:24])=[O:22])[CH2:18][CH2:17]2)=[N:14][CH:15]=1
Reactant: COC(=O)[C@@H]1CCC(c2ccc(OCc3ccccc3F)cn2)=N1
Agent: [Pt]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CC[C@H](c2ccc(OCc3ccccc3F)cn2)N1
Reaction time: 4 h
Yield: 59.9 %

Procedure:
To a solution of methyl (2S)-5-(5-{[(2-fluorophenyl)methyl]oxy}-2-pyridinyl)-3,4-dihydro-2H-pyrrole-2-carboxylate (D85, 300 mg, 0.91 mmol) in ethyl acetate was added platinum on activated carbon (70 mg, 5 wt. % dry basis Degussa type F101 RAW) and the mixture was stirred under hydrogen atmosphere (P=1 atm) for 4 hours. After a further addiction of acetic acid (0.4 ml) and stirring for 12 hours the reaction wasn't complete. A further addiction of catalyst (70 mg) and trifluoroacetic acid was required before the reaction was complete. The catalyst was filtered off, the solvent removed under reduced pressure and the residue filtered on scx cartridge. The residue was purified by chromatography on silica gel using cyclohexane/ethyl acetate (7:3 to 6:4) to afford the title compound as a colourless oil (180 mg, 60%). Rt (HPLC): 3.69 min; MS: (ES/+) m/z: 331 [MH]+ C18H19FN2O3 requires 330; 1H NMR (400 MHz, CDCl3) δ (ppm): 8.27-8.43 (m, 1H); 7.45-7.56 (m, 1H); 7.38-7.44 (m, 1H); 7.31-7.38 (m, 1H); 7.24-7.31 (m, 1H); 7.15-7.23 (m, 1H); 7.08-7.15 (m, 1H); 5.18 (s, 2H); 4.32-4.41 (m, 1H); 3.98-4.05 (m, 1H); 3.79 (s, 3H); 2.19-2.31 (m, 2H); 2.04-2.13 (m, 1H); 1.77-1.90 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]Br.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[F:11])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Br)ccc1O
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: N#Cc1cc(Br)ccc1OCc1ccccc1F
Yield: 92 %

Procedure:
A solution of 5-bromo-2-hydroxybenzonitrile (3.31 g, 16.71 mmol), synthesized as described in J. Org. Chem. 1997, 13, 4504-4506, 2-fluorobenzylbromide (commercially available, 2.02 ml, 3.16 g, 16.71 mmol) and potassium carbonate (3.46 g, 25.06 mmol) was stirred overnight at room temperature. Then diethylether was added and the solution was washed with water, 1M NaOH and brine. The organic layer was dried (Na2SO4), filtered and evaporated to afford the title compound (4.74 g, 92%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.0 (M, 1H), 7.9 (m, 1H), 7.6 (m, 1H), 7.5-7.3 (m, 2H), 7.2 (m, 2H), 5.3 (s, 2H).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([S:8][CH2:9][C:10]2[N:15]=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[C:12]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:11]=2)=[N:5][N:4]=1)[CH3:2].[H-].[Na+].CS(O[CH2:37][C:38]1[CH:43]=[C:42]([N+:44]([O-:46])=[O:45])[CH:41]=[C:40]([CH3:47])[CH:39]=1)(=O)=O>CN(C)C=O.C(OCC)(=O)C>[C:19]([O:18][C:17]([N:16]([C:14]1[CH:13]=[C:12]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[CH:11]=[C:10]([CH2:9][S:8][C:6]2[S:7][C:3]([CH2:1][CH3:2])=[N:4][N:5]=2)[N:15]=1)[CH2:37][C:38]1[CH:43]=[C:42]([N+:44]([O-:46])=[O:45])[CH:41]=[C:40]([CH3:47])[CH:39]=1)=[O:23])([CH3:22])([CH3:20])[CH3:21]
Reactant: Cc1cc(COS(C)(=O)=O)cc([N+](=O)[O-])c1
Reactant: CCc1nnc(SCc2cc(N3CCOCC3)cc(NC(=O)OC(C)(C)C)n2)s1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1nnc(SCc2cc(N3CCOCC3)cc(N(Cc3cc(C)cc([N+](=O)[O-])c3)C(=O)OC(C)(C)C)n2)s1
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl N-[6-(5-ethyl-1,3,4-thiadiazol-2-ylthiomethyl)-4-morpholino-2-pyridyl]carbamate (200 mg) obtained in Example 1-(5) in dimethylformamide (2 ml), 60% sodium hydride (30 mg) was added under cooling with ice, followed by stirring at the same temperature for 30 minutes. A solution of 3-methyl-5-nitrobenzyl methanesulfonate (283 mg) in dimethylformamide (1 ml), was added to the reaction solution, followed by stirring at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with water and a saturated sodium hydrogen carbonate aqueous solution and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=1:1) to obtain the above identified compound (314 mg) as a pale yellow oily substance.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([OH:18])=O)=[CH:11][CH:10]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:56][C:57]1[C:58]([OH:68])=[N:59][C:60]([N:63]2[CH:67]=[CH:66][CH:65]=[N:64]2)=[N:61][CH:62]=1>CC#N>[OH:68][C:58]1[C:57]([NH:56][C:16](=[O:18])[CH:15]([C:12]2[CH:11]=[CH:10][C:9]([P:4](=[O:5])([O:6][CH2:7][CH3:8])[O:3][CH2:1][CH3:2])=[CH:14][CH:13]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:62][N:61]=[C:60]([N:63]2[CH:67]=[CH:66][CH:65]=[N:64]2)[N:59]=1
Reactant: CCOP(=O)(OCC)c1ccc(C(C(=O)O)c2ccccc2)cc1
Reactant: Nc1cnc(-n2cccn2)nc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOP(=O)(OCC)c1ccc(C(C(=O)Nc2cnc(-n3cccn3)nc2O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-(Diethoxyphosphoryl)phenyl)-2-phenylacetic acid, 14-f, (1.18 g, 3.4 mmol), HATU (1.86 g, 4.9 mmol) and triethylamine (989 mg, 9.8 mmol) in CH3CN (20 mL) was added 5-amino-2-(1H-pyrazol-1-yl)pyrimidin-4-ol (11-e, 577 mg, 3.30 mmol). The mixture was stirred at room temperature overnight and concentrated. The residue was taken up in EA and water. The aqueous layer was extracted with EA. The combined layers were washed with brine, dried over Na2SO4, and concentrated to give the crude product of 14-1 which was purified by pre-HPLC (766 mg, 45%). 1H NMR (300 MHz, DMSO-d6) δ1.18-1.23 (m, 6H), 3.92-4.03 (m, 4H), 6.64 (s, 1H), 7.25-7.35 (m, 6H), 7.47-7.51 (m, 2H), 7.64-7.71 (m, 2H), 7.97 (s, 1H), 8.61-8.52 (m, 1H), 8.63 (br s, 1H); LC-MS: (M+H)+ 508.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH:12]=[N:11][C:10]=2[C:18](NOCCOC=C)=[O:19])=[C:4]([F:27])[CH:3]=1.[CH3:28][C:29]1([CH3:37])[O:33][C@@H:32]([CH2:34][O:35][NH2:36])[CH2:31][O:30]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH:12]=[N:11][C:10]=2[C:18]([NH:36][O:35][CH2:34][C@H:32]2[CH2:31][O:30][C:29]([CH3:37])([CH3:28])[O:33]2)=[O:19])=[C:4]([F:27])[CH:3]=1
Reactant: CC1(C)OC[C@H](CON)O1
Reactant: C=COCCONC(=O)c1ncc2cncn2c1Nc1ccc(Br)cc1F
Product: CC1(C)OC[C@H](CONC(=O)c2ncc3cncn3c2Nc2ccc(Br)cc2F)O1

Procedure:
The desired compound was prepared in an analogous fashion to 5-(4-bromo-2-fluorophenylamino)-N-(2-(vinyloxy)ethoxy)-imidazo[1,5-a]pyrazine-6-carboxamide, using (R)—O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine as the starting material. LCMS (method D1): RT=0.954 min, [M+H]+=480/482.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[F:11][C:12]1[C:17]([F:18])=[CH:16][N:15]=[C:14]2[NH:19][CH:20]=[C:21]([NH2:22])[C:13]=12>N1C=CC=CC=1>[F:11][C:12]1[C:17]([F:18])=[CH:16][N:15]=[C:14]2[NH:19][CH:20]=[C:21]([NH:22][C:2](=[O:9])[C:3]3[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=3)[C:13]=12
Reactant: O=C(Cl)c1cccnc1
Reactant: Nc1c[nH]c2ncc(F)c(F)c12
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1c[nH]c2ncc(F)c(F)c12)c1cccnc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.6 %

Procedure:
Nicotinoyl chloride hydrochloride (0.70 g, 3.90 mmol) was added to 4,5-difluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.22 g, 1.30 mmol) in pyridine (5 mL). The reaction was stirred at room temperature for 10 minutes, and then the pyridine was removed. THF (5 mL) and 2N LiOH (3 mL) were added, and the reaction was stirred for 20 minutes. The THF was removed, and water (20 mL) was added. The solid formed was collected by filtration and dried to give N-(4,5-difluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (0.33 g, 92% yield) as a solid.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][C@H:8]([N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:19])[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])(=O)C.[OH-].[Na+]>C1COCC1.CO.CCOC(C)=O>[Si:11]([O:10][CH2:9][C@@H:8]([N:18]([CH3:19])[C:20](=[O:21])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:7][CH2:6][CH2:5][OH:4])([C:14]([CH3:16])([CH3:15])[CH3:17])([CH3:12])[CH3:13]
Reactant: CC(=O)OCCC[C@@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C(=O)OC(C)(C)C)[C@@H](CCCO)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a solution of (S)-4-(tert-butoxycarbonyl(methyl)amino)-5-(tert-butyldimethylsilyloxy)pentyl acetate (0.124 mol) in THF (200 mL) and MeOH (50 mL) was added sodium hydroxide (2 N, 93 mL, 0.186 mol) at RT The reaction was stirred at RT for 2 h and LC-MS indicated the reaction was completed. The reaction mixture was diluted with EtOAc and the organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on silica gel column using a mixture of hexanes and EtOAc to give (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)-5-hydroxypentan-2-yl(methyl)carbamate (37.9 g, 88%). LRMS (M+H+-Boc) m/z 248.2.
Reaction SMILES: N[C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]([NH:18][CH3:19])=[O:17])[CH:13]=[CH:14][CH:15]=2)[C:5]([C:20]#[N:21])=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][OH:31])=[CH:24][CH:23]=2)[C:3]=1[C:32]#[N:33].[ClH:34].N([O-])=O.[Na+]>O>[Cl:34][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]([NH:18][CH3:19])=[O:17])[CH:13]=[CH:14][CH:15]=2)[C:5]([C:20]#[N:21])=[C:4]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][OH:31])=[CH:26][CH:27]=2)[C:3]=1[C:32]#[N:33]
Reactant: CNC(=O)c1cccc(CSc2nc(N)c(C#N)c(-c3ccc(OCCO)cc3)c2C#N)c1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CNC(=O)c1cccc(CSc2nc(Cl)c(C#N)c(-c3ccc(OCCO)cc3)c2C#N)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2 g (4.35 mmol) of 3-[({6-amino-3,5-dicyano-4-[4-(2-hydroxyethoxy)phenyl]pyridin-2-yl}-sulfanyl)methyl]-N-methylbenzenecarboxamide Example 8 were dissolved in ice-cooled conc. hydrochloric acid. 0.9 g (13.06 mmol) of sodium nitrite was added, and the mixture was then stirred at 0° C. for 1 h. After 30 min, a barely stirrable solution had formed. 200 ml of water were added to the reaction mixture. The precipitate was filtered off and purified by column chromatography on silica gel 60 (mobile phase: dichloromethane/methanol 50/1→20/1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[C:16]3[NH:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[C:4]2[N:3]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CCN(CC)CC>O1CCOCC1>[CH:9]1([NH:8][C:6]2[N:5]3[N:12]=[CH:13][C:14]([CH:15]=[C:16]4[NH:20][C:19](=[O:21])[NH:18][C:17]4=[O:22])=[C:4]3[N:3]=[C:2]([N:32]3[CH2:33][CH2:34][N:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=4)[CH2:30][CH2:31]3)[CH:7]=2)[CH2:11][CH2:10]1
Reactant: O=C1NC(=O)C(=Cc2cnn3c(NC4CC4)cc(Cl)nc23)N1
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C1NC(=O)C(=Cc2cnn3c(NC4CC4)cc(N4CCN(c5ccccn5)CC4)nc23)N1
Temperature: 120 °C
Yield: 27.4 %

Procedure:
To 5-((5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (30 mg, 0.09 mmol) in 1,4-dioxane was added 1-(pyridin-2-yl)piperazine (58 μL, 4.10 mmol) and Et3N (13 μL, 0.09 mmol). Reaction was then heated 120° C. for 35 minutes in microwave. Solvent was removed under reduced pressure, and mixture was dissolved in methanol. Solid was isolated by filtration, then air dried to yield 11 mg (26% yield) 5-((7-(cyclopropylamino)-5-(4-(pyridin-2-yl)piperazin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=446)
Reaction SMILES: C([C:3]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)#N.[N-:24]=[N+:25]=[N-:26].[Na+]>CS(C)=O>[N:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]1[NH:26][N:25]=[N:24][C:3]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(C#N)=Cc2ccccn2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2nn[nH]c2-c2ccccn2)CC1
Temperature: 110 °C

Procedure:
To a stirred solution of tert-butyl 4-(1-cyano-2-(pyridin-2-yl)vinyl)piperazine-1-carboxylate (2.5 g), sodium azide (0.4 g) were taken in dry DMSO (4 ml) and heated to 110° C. overnight. The reaction mixture was carefully quenched with water (10 ml) and the reaction mixture was extracted with dichloromethane (3×10 ml). The combined organic layer was washed with brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using methanol:chloroform (1:9) as an eluent to afford tert-butyl 4-(5-(pyridin-2-yl)-1H-1,2,3-triazol-4-yl)piperazine-1-carboxylate as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([NH:28][C:14]([C:12]1[S:13][C:9]([S:8][C:7]2[C:6]([Cl:20])=[CH:5][N:4]=[CH:3][C:2]=2[Cl:1])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=1)=[O:16])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCc1ccccc1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (39 mg, 0.11 mmol) and benzylamine (13 mg, 0.12 mmol). The title product was obtained as a yellow solid (15 mg, 28% yield). 1H NMR (300 MHz, d6-DMSO) δ: 8.72 (1H, s), 8.71 (1H, s), 8.35-8.39 (3H, m), 7.31 (2H, m), 7.27 (2H, m), 2.6 (2H, m). MS m/z: 439.85, 441.80 [M+H]+.
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][CH:14]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[C@H:2]([C:7](O)=[O:8])CCCC.[CH3:27][C:28]1C=CC(C(N)C2C=CC=CC=2)=C[CH:29]=1.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.Cl.C1C=CC2N(O)N=NC=2C=1.CC(N=C=NC(C)C)C.N(C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)CC(O)=O>C(Cl)Cl.CN(C=O)C.CN(C=O)C.CN(C1C=CN=CC=1)C>[NH:1]([C:10]([O:12][CH2:13][CH:14]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[CH2:2][C:7]([CH2:29][CH:28]=[CH2:27])=[O:8]
Reactant: Cc1ccc(C(N)c2ccccc2)cc1
Reactant: CCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: C=Cc1ccc(C=C)cc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: C=Cc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCC(=O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 0.5 h

Procedure:
0.848 g Fmoc-Nle (2.4 mmol) was coupled to 2.0 g MBHA resin (1.6 mmol) with 0.367 g HOBt (2.4 mmol) and 0.373 mL DIPCDI (2.4 mmol) in 20 mL DCM-DMF (1:1) for 2.3 h. The resin was washed 3 times with DMF, deprotected with 20 mL piperidine-DMF (1:1) for 30 min, and washed 3 times with DMF. 1.82 g allyl linker (3.2 mmol) was coupled to the resin with 0.489 g HOBt (3.2 mmol) and 0.497 mL DIPCDI (3.2 mmol) in 20 mL DMF for 18.5 h. The resin was washed 1 time with DMF and 2 times with DCM, deprotected twice with 20 mL TFA-DCM (9:1), first for 20 min, then for 10 min, washed 3 times with DCM, neutralized with 20 mL DIEA-DCM (1:9) for 15 min, and washed 1 time with DCM and 2 times with DMF. 1.43 g Fmoc-Gly (4.8 mmol) was esterified to the allyl resin with 0.735 g HOBt (4.8 mmol), 0.746 mL DIPCDI (4.8 mmol), and 0.059 g DMAP (0.48 mmol) in 20 mL DMF for 6.5 h. The resin was washed 1 time with DMF and 2 times with DCM and stored under vacuum overnight.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:25]2[CH2:29][CH2:28][CH2:27][S:26]2(=[O:31])=[O:30])[CH:3]=1.[O:32]1[CH2:36][CH:35]=[N:34][C:33]1=[O:37]>>[O:30]=[S:26]1(=[O:31])[CH2:27][CH2:28][CH2:29][N:25]1[C:4]1[CH:3]=[C:2]([N:34]2[CH2:35][CH2:36][O:32][C:33]2=[O:37])[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: O=C1N=CCO1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Yield: 81.7 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (507 mg) described in Preparation Example 180 and oxazolin-2-one (104 mg), the title compound (419 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[C:7]([CH3:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:19]Br.CC1C(C)=NC2C(C=1)=CC=CC=2>ClC1C=CC=CC=1Cl.O>[Br:19][CH2:12][C:11]1[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]2[C:10]=1[N:9]=[CH:8][C:7]([CH3:13])=[CH:6]2
Reactant: BrBr
Reactant: Cc1cnc2c(C)c(Cl)ccc2c1
Agent: CC(=O)[O-]
Agent: Cc1cc2ccccc2nc1C
Agent: [Na+]
Solvent: O
Solvent: Clc1ccccc1Cl
Product: Cc1cnc2c(CBr)c(Cl)ccc2c1

Procedure:
9.6 g of 7-chloro-3,8-dimethylquinoline are dissolved in 850 g of 1,2-dichlorobenzene, 6.2 g of sodium acetate, dissolved in 150 ml of water, and then 8 g of bromine are added, and the mixture is exposed to a 150 watt low pressure mercury lamp for from 5 to 6 hours at 15° C. The yield, determined chromatographically, is 80% of theory, based on converted dimethylquinoline. The selectivity of the reaction is 88% at a conversion of 91%. Table 1 summarizes the result of varying the reaction conditions.
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:14].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C>[CH2:22]([O:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:14])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc2c(c1O)CCNC2=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: COc1ccc2c(c1OCc1ccccc1)CCNC2=O

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-one (700 mg, 3.62 mmol, 1.00 equiv), Cs2CO3 (2.36 g, 7.22 mmol, 2.00 equiv), ethanol (20 mL) and (bromomethyl)benzene (740 mg, 4.35 mmol, 1.20 equiv). The resulting solution was heated to reflux for 1 hr. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 1 g (97%) of 5-(benzyloxy)-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-one as a gray solid. 1H NMR (300 MHz, DMSO-d6) δ: 2.70-2.75 (t, 2H), 3.19-3.23 (t, 2H), 3.90 (s, 3H), 4.95 (s, 2H), 7.05-7.08 (m, 1H), 7.33-7.42 (m, 5H), 7.62-7.64 (m, 1H), 7.70 (S, 1H); MS (ESI) m/z 284 ([M+H]+).
Reaction SMILES: [CH:1]1[CH:6]=[C:5](Cl)[CH:4]=[C:3]([C:8]([O:10]O)=[O:9])[CH:2]=1.[OH-].[Na+]>C(Cl)Cl>[C:8]([OH:10])(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:1][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A solution of Example 349G in CH2Cl2 was treated with mCPBA and stirred at room temperature for seven hours. The mixture was then treated with 2M NaOH and the organic layer was separated, dried (Na2SO4), filtered through a pad of silica and concentrated. The resulting solid was crystallized from EtOH/H2O to afford a white solid contaminated with benzoic acid. The solid was dissolved in hot DMSO/EtOH and precipitated with water to afford the title compound (0.84 mg). HPLC Rt=4.03 min. m/z=412 (M+H+).