Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([C:26]#[N:27])[CH:24]=[CH:25][C:20]=3[O:19][CH2:18][C:17]2=[O:28])[CH2:10][CH2:9]1)(C)(C)C.NC1CCN(CCN2C3C(=CC=C(C#N)C=3)C=CC2=O)CC1>>[NH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([C:26]#[N:27])[CH:24]=[CH:25][C:20]=3[O:19][CH2:18][C:17]2=[O:28])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2C(=O)COc3ccc(C#N)cc32)CC1
Agent: N#Cc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Product: N#Cc1ccc2c(c1)N(CC[C@H]1CC[C@H](N)CC1)C(=O)CO2

Procedure:
tert-Butyl{trans-4-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]cyclohexyl}carbamate (Intermediate 78) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([CH3:18])[CH:9]=2)[CH:5]=[C:4]([CH3:19])[N:3]=1.[Cl:20][C:21]1[CH:26]=[C:25](B(O)O)[CH:24]=[CH:23][N:22]=1>>[Cl:20][C:21]1[CH:26]=[C:25]([C:2]2[N:3]=[C:4]([CH3:19])[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([CH3:18])[CH:9]=3)[N:7]=2)[CH:24]=[CH:23][N:22]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(Cl)n1
Reactant: OB(O)c1ccnc(Cl)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(-c2ccnc(Cl)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(3-methyl-4-trifluoromethyl-phenyl)-6-methyl-pyrimidine (example A.40) (0.401 g, 1.4 mmol) and commercially available 2-chloro-pyridine-4-boronic acid (0.286 g, 1.82 mmol) according to the general procedure IVb. Obtained as a light brown solid (0.11 g, 22%). MS (ISP) 364.1 [(M+H)+]; mp 92° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][C:10](=O)[CH2:11][CH2:12][C:13](=O)[CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>CCCCCCC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:9])=[N:3][CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCCC
Product: Cc1ccc(C)n1-c1ccc(Br)cn1
Temperature: 20 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
2-Amino-5-bromopyridine (6.0 Kg, 34.7 mol), 2,5-hexanedione (4.35 Kg, 38.2 mol) and p-toluenesulfonic acid (12 g) were dissolved in heptane (36 L) and refluxed under Dean Stark conditions overnight. The equipment was set for distillation and heptane (18 L) was removed by distillation. The mixture was cooled to 20° C. for 60 minutes. Seed crystals were added and the mixture granulated at 20° C. for 2 hours and then at 5° C. overnight. The product was collected by filtration, washed with heptane (2×6 L) and dried at 45° C. under vacuum overnight. Yield=80% (7.0 Kg) δH (CDCl3 300 MHz) 2.20 (6H, s), 5.95 (2H, s), 7.15 (1H, d), 7.95 (1H, d), 8.70 (1H, s) ppm. MS m/z 253 (MH+, Br isotope).
Reaction SMILES: C(N(CC)CC)C.Cl[CH2:9][CH2:10][S:11](Cl)(=[O:13])=[O:12].[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[C:23]1[CH2:27][NH:26][CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=1>ClCCl>[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[C:23]1[CH2:27][N:26]([S:11]([CH:10]=[CH2:9])(=[O:13])=[O:12])[CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Fc1ccc(F)c(C2=CC(c3ccccc3)NC2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CS(=O)(=O)N1CC(c2cc(F)ccc2F)=CC1c1ccccc1
Reaction time: 1 h

Procedure:
Triethylamine (122 μL, 0.874 mmol, 5.00 equiv) and 2-chloroethanesulfonyl chloride (29 mg, 0.175 mmol, 1.00 equiv) were added sequentially to a solution of 4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole (2-4, 45 mg, 0.175 mmol, 1 equiv) in dichloromethane (10 mL) at 23° C., and the resulting mixture was stirred for 1 hour. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate and were concentrated to provide 4-(2,5-difluorophenyl)-2-phenyl-1-(vinylsulfonyl)-2,5-dihydro-1H-pyrrole (8-1) as a brown oil. LRMS m/z (M+H) 348.0 found, 348.1 required.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([O:17][C:18]([NH:20][C@H:21]([C:26]([NH:28][C:29]1[CH:34]=[C:33]([CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39](=[O:46])[NH:38][N:37]=2)[CH:32]=[CH:31][C:30]=1[F:47])=[O:27])[CH2:22][C:23]([OH:25])=O)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CC(N(C)C)=O>[CH2:10]([O:17][C:18]([NH:20][C@H:21]1[CH2:22][C:23](=[O:25])[N:28]([C:29]2[CH:34]=[C:33]([CH2:35][C:36]3[C:45]4[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:39](=[O:46])[NH:38][N:37]=3)[CH:32]=[CH:31][C:30]=2[F:47])[C:26]1=[O:27])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)C[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CC(=O)N(c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.9 %

Procedure:
O-Benzotriazol-1-yl-N,N,N′N′-tetramethyluronium tetrafluoroborate (0.289 g, 0.9 mmol) and diisopropylethylamine (0.193 g, 1.5 mmol) were added sequentially to a stirred solution of (S)-3-benzyloxycarbonylamino-N-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]succinamic acid (0.35 g, 0.68 mmol) in dimethylacetamide (3 ml), the mixture was stirred at ambient temperature for 24 hours, then it was added dropwise to stirred, ice-cold water (30 ml). The mixture was stirred for 1 hour, then the resulting solid was collected by filtration and dried in vacuo to give (S)-3-benzyloxycarbonylamino-1-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]pyrrolidine-2,5-dione (0.238 g) as an off white solid, m.pt. 121–127° C. (softens 102° C.); m/z (M+H)+. 501, 96% purity.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[Br:35][C:36]1[C:37]([F:46])=[C:38]2[C:44]([NH2:45])=[CH:43][NH:42][C:39]2=[N:40][CH:41]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:35][C:36]1[C:37]([F:46])=[C:38]2[C:44]([NH:45][C:10]([C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:12])=[CH:43][NH:42][C:39]2=[N:40][CH:41]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Agent: O=C([O-])[O-]
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
trans-2-Phenylcyclopropanecarboxylic acid (705 mg, 4.35 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (1107 mg, 4.35 mmol) and triethylamine (1100 mg, 10.9 mmol) were added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (500 mg, 2.17 mmol) in DCM (100 mL). The reaction was stirred at room temperature for 1 hour, and then 2N aqueous Na2CO3 was added (50 mL). The resulting suspension was filtered and the solid rinsed with DCM and water. After drying, trans-N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenylcyclopropanecarboxamide (503 mg, 61.8% yield) was obtained as a solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]1[N:12]=[C:13]([CH:22]2[O:27][CH2:26][CH2:25][NH:24][CH2:23]2)[NH:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl:28][C:29]1[CH:34]=[C:33](Cl)[N:32]=[C:31]([NH2:36])[N:30]=1>C(O)C>[Cl:28][C:29]1[CH:34]=[C:33]([N:24]2[CH2:25][CH2:26][O:27][CH:22]([C:13]3[NH:14][C:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[C:11]([CH3:10])[N:12]=3)[CH2:23]2)[N:32]=[C:31]([NH2:36])[N:30]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Cc1nc(C2CNCCO2)[nH]c1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1nc(C2CN(c3cc(Cl)nc(N)n3)CCO2)[nH]c1-c1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
A suspension of DIPEA (2.39 g, 18.50 mmol), 2-(4-methyl-5-phenyl-1H-imidazol-2-yl)morpholine (1.5 g, 6.17 mmol) and 4,6-dichloro-2-pyrimidinamine (1.011 g, 6.17 mmol) in ethanol (200 mL) was stirred at 100° C. overnight. The solvent was removed under reduced pressure, and the crude product was purified by silica gel chromatography, eluting with CH2Cl2/EtOAc (10:1) to afford the title compound (1.2 g) as a white solid. LC-MS (ES) m/z=371, 373 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH2:17][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.O1CCOCC1>CO>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH2:17][N:18]1[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCN3CCCC3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN3CCCC3)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.2 %

Procedure:
2-(Butyloxy)-8-(methyloxy)-9-[3-(1-pyrrolidinyl)propyl]-9H-purin-6-amine (49 mg, 0.141 mmol) was dissolved in methanol (5 ml) and 4M hydrogen chloride in 1,4-dioxane (0.879 ml, 3.52 mmol) was added and the mixture stirred at room temperature for 5 hours. The solvent was removed in vacuo to give a cream solid which was dissolved in methanol and loaded onto an aminopropyl SPE cartridge (2 g) and eluted with methanol. The solvent was evaporated to give the title compound as a white solid (43 mg).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].[F:13][C:14]([F:19])([F:18])[CH:15]1[O:17][CH2:16]1>>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[C:6]([NH:7][CH2:16][CH:15]([OH:17])[C:14]([F:19])([F:18])[F:13])[CH:8]=[CH:9][CH:10]=1
Reactant: Nc1cccc(OC(F)(F)F)c1
Reactant: FC(F)(F)C1CO1
Product: OC(CNc1cccc(OC(F)(F)F)c1)C(F)(F)F
Temperature: 80 °C
Yield: 88.5 %

Procedure:
EX-321A) 3-Trifluoromethoxyaniline (23.81 g, 134.4 mmol) and 3,3,3-trifluoro-1,2-epoxypropane (3.76 g, 33.6 mmol) were placed into a sealed tube and heated to 80° C. for 24 h. The excess aniline was removed by distillation (70° C. at 16.2 Torr) to give 8.6 g (88%) of the desired 3-[(3-trifluoromethoxyphenyl)amino]-1,1,1-trifluoro-2-propanol product as a light yellow oil. 1H NMR (CDCl3) δ 3.29-3.37 (m, 1H), 3.55 (dd, 1H), 4.20 (m, 1H), 6.48-6.63 (m, 3H), 7.12 (t, 1H). 19F NMR (CDCl3) δ −79.36 (s, 3F), −58.44 (s, 3F).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=2[O:16][CH2:17][C@@H:18]2[NH:22][CH2:21][C@H:20]([OH:23])[CH2:19]2)[N:9]=[CH:8][N:7]=1.[CH3:30][N:31]([CH3:36])[CH2:32][C:33](O)=[O:34]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=2[O:16][CH2:17][C@@H:18]2[N:22]([C:33](=[O:34])[CH2:32][N:31]([CH3:36])[CH3:30])[CH2:21][C@H:20]([OH:23])[CH2:19]2)[N:9]=[CH:8][N:7]=1
Reactant: CN(C)CC(=O)O
Reactant: COc1cc(OC[C@H]2C[C@@H](O)CN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Product: COc1cc(OC[C@H]2C[C@@H](O)CN2C(=O)CN(C)C)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Yield: 72 %

Procedure:
The procedure described in Example 32 was repeated using (3R,5R)-5-[({4-[3-chloro-4-fluoroanilino]-7-methoxyquinazolin-5-yl}oxy)methyl]pyrrolidin-3-ol (209 mg) with N,N-dimethylglycine (57 mg) to give the title compound as a white solid in 72% yield; NMR spectrum (DMSO-d6) 10.03 (s, 1H), 8.46 (s, 1H), 8.19 (dd, 1H), 7.76-7.71 (m, 1H), 7.43 (t, 1H), 6.83 (d, 1H), 6.75 (d, 1H), 5.27-5.26 (m, 1H), 4.72-4.67 (m, 1H), 4.61-4.56 (m, 1H), 4.41-4.40 (m, 1H), 4.34-4.29 (m, 1H), 3.93 (s, 3H), 3.78 (dd, 1H), 3.52 (br d, 1H), 3.14 (d, 1H), 2.99 (d, 1H), 2.26-2.17 (m, 7H), 1.95-1.90 (m, 1H); Mass spectrum MH+ 504.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH2:23]([O:30][N:31]1[C:37](=[O:38])[N:36]2[CH2:39][C@H:32]1[CH2:33][CH2:34][C@H:35]2[C:40]([NH:42][NH:43][C:44]([CH:46]1[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH2:47]1)=O)=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:23]([O:30][N:31]1[C:37](=[O:38])[N:36]2[CH2:39][C@H:32]1[CH2:33][CH2:34][C@H:35]2[C:40]1[S:10][C:44]([CH:46]2[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH2:47]2)=[N:43][N:42]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)s2)CC1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
Lawesson's reagent (0.16 g, 6 mol) was added to a solution of tert-butyl 4-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinecarbonyl)piperidine-1-carboxylate (0.16 g, 0.319 mmol) in THF (20 mL). The reaction mixture was stirred at 70° C. for 0.5 h. The solution was cooled to room temperature and sat. NaHCO3 was added. The organic layer was separated and the aqueous layer was exacted with EtOAc (2×). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (gradient elution 20%-50% EtOAc/petroleum ether) to give tert-butyl 4-(5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate (90 mg, 50%) as a white solid. ESI-MS (EI+, m/z): 500.2 [M+H]+. 1H NMR (500 MHz, DMSO-d6): δ 7.48-7.37 (m, 5H), 4.99-4.94 (m, 2H), 4.77 (d, J=7.0 Hz, 1H), 3.99 (d, J=11 Hz, 2H), 3.69 (s, 1H), 3.39-3.35 (m, 1H), 2.88-2.85 (m, 3H), 2.68 (d, J=12 Hz, 1H), 2.44 (dd, J=7.5, 5.5 Hz, 1H), 2.05-1.96 (m, 4H), 1.79-1.77 (m, 1H), 1.62-1.55 (m, 2H), 1.40 (s, 9H).
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([S:8]([NH:11][C:12]2[S:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:2]=1.N1C=CC=CC=1.[Cl:23][CH:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25](Cl)=[O:26]>C(Cl)Cl>[Cl:23][CH:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25]([NH:7][C:6]1[CH:1]=[CH:2][C:3]([S:8](=[O:10])(=[O:9])[NH:11][C:12]2[S:16][CH:15]=[CH:14][N:13]=2)=[CH:4][CH:5]=1)=[O:26]
Reactant: O=C(Cl)C(Cl)c1ccccc1
Reactant: Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(S(=O)(=O)Nc2nccs2)cc1)C(Cl)c1ccccc1

Procedure:
Synthesized according to general procedure 1: N′-(2-thiazolyl)sulfanilamide (5.60 g, 22 mmol), pyridine (3.6 mL, 44 mmol), 2-chloro-2-phenyl acetylchloride (3.8 mL, 26.4 mmol, 1.2 equiv) in DCM (400 mL). Yield: 6.73 g (75%) of a white solid. 1H-NMR (DMSO-d6) δ 10.85 (s, 1H), 7.78-7.72 (m, 4H), 7.60-7.57 (m, 2H), 7.45-7.37 (m, 3H), 7.25 (d, J=4.6 Hz, 1H), 6.82 (d, J=4.6 Hz, 1H), 5.77 (s, 1H). LC/MS (10-99%) M/Z: M+1 obs=408.1; tR=2.61 min.
Reaction SMILES: [CH2:1]([C:3]1[C:7]2[C:8]([O:12][C:13]3[N:18]=[CH:17][C:16]([NH:19][C:20]([C@H:22]([NH:25]C(=O)OC(C)(C)C)[CH2:23][CH3:24])=[O:21])=[CH:15][CH:14]=3)=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][N:4]=1)[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[NH2:25][C@H:22]([CH2:23][CH3:24])[C:20]([NH:19][C:16]1[CH:17]=[N:18][C:13]([O:12][C:8]2[C:7]3[C:3]([CH2:1][CH3:2])=[N:4][O:5][C:6]=3[CH:11]=[CH:10][CH:9]=2)=[CH:14][CH:15]=1)=[O:21]
Reactant: CCc1noc2cccc(Oc3ccc(NC(=O)[C@@H](CC)NC(=O)OC(C)(C)C)cn3)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1noc2cccc(Oc3ccc(NC(=O)[C@H](N)CC)cn3)c12
Reaction time: 2 h

Procedure:
1,1-dimethylethyl {(1R)-1-[({6-[(3-ethyl-1,2-benzisoxazol-4-yl)oxy]-3-pyridinyl}amino)carbonyl]propyl}carbamate (Intermediate 34, 4.4 mg) was dissolved in dichloromethane (1.0 ml) and, at 0° C., TFA (0.100 ml, 1.3 mmol) was added. The reaction mixture was stirred at that temperature for 2 hours. After removal of the volatiles, the residue was charged on a SCX cartridge and eluted with DCM/MeOH/NH3 (2.0 M in MeOH) to afford the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].[Li].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1.[Cl-].[NH4+]>O1CCCC1.C1CCCCC1>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]([OH:14])[CH2:2][C:1]([O:4][CH2:5][CH3:6])=[O:3])=[CH:11][CH:10]=1
Reactant: CCOC(C)=O
Reactant: O=Cc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)c1ccc(Br)cc1
Reaction time: 0.25 h
Yield: 80 %

Procedure:
Ethyl acetate (5.8 ml) was dissolved in tetrahydrofuran (80 ml), to which was then added 1.5M lithium diisoprypylamide/cyclohexane solution (43 ml) in nitrogen atmosphere at −70° C., and then the mixture was stirred for 15 min. 4-Bromobenzaldehyde (10.151 g)/tetrahydrofuran (10 ml) solution was added to the reaction mixture, which was then stirred for 30 min. A saturated aqueous solution of ammonium chloride was added thereto, and then it was extracted with in ethyl acetate. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by (NH) silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a yellow oil (11.906 g, yield; 80%).
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][N:2]1[CH2:14][C:15]1[S:19][C:18](/[CH:20]=[CH:21]/[C:22](O)=[O:23])=[CH:17][CH:16]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:46][O:47][CH:48]1[CH2:53][CH2:52][CH2:51][CH2:50][O:49]1>C(Cl)Cl.CCN(C(C)C)C(C)C>[CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][N:2]1[CH2:14][C:15]1[S:19][C:18](/[CH:20]=[CH:21]/[C:22]([NH:46][O:47][CH:48]2[CH2:53][CH2:52][CH2:51][CH2:50][O:49]2)=[O:23])=[CH:17][CH:16]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1ccc(CN2CCc3c([nH]c4ccccc34)C2)s1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C/c1ccc(CN2CCc3c([nH]c4ccccc34)C2)s1)NOC1CCCCO1
Reaction time: 3 h

Procedure:
A solution of (2E)-3-[5-(1,3,4,9-tetrahydro-2H-b-carbolin-2-ylmethyl)thien-2-yl]acrylic acid in DCM (2 mL) and DIEA (0.11 mL) was sequentially treated with HOBT (32 mg), EDCI (64 mg) and NH2OTHP (40 mg). After three hours, the solvent was evaporated and the residue purified by flash chromatography on silica gel eluting with EtOAc. (2E)-3-[5-(1,3,4,9-Tetrahydro-2H-b-carbolin-2-ylmethyl)thien-2-yl]-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide was obtained as a yellow oil (37 mg), m/e=438 (M+1).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:19]=[C:18]2[C:9]([O:10][CH2:11][CH2:12][N:13]3[C:17]2=[N:16][C:15]([C:20]2[N:24]([CH:25]([CH3:27])[CH3:26])[N:23]=[CH:22][N:21]=2)=[CH:14]3)=[CH:8][CH:7]=1)=[O:5].[CH3:29][Mg]Cl>C1COCC1>[CH3:27][CH:25]([N:24]1[C:20]([C:15]2[N:16]=[C:17]3[N:13]([CH:14]=2)[CH2:12][CH2:11][O:10][C:9]2[C:18]3=[CH:19][C:6]([C:4](=[O:5])[CH3:29])=[CH:7][CH:8]=2)=[N:21][CH:22]=[N:23]1)[CH3:26]
Reactant: C[Mg]Cl
Reactant: CON(C)C(=O)c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
To a solution of N-methoxy-N-methyl-4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene-13-carboxamide (800 mg, 2.09 mmol) in THF (80 mL) was added methylmagnesium chloride (3.5 mL, 10.5 mmol) dropwise at 0° C. The mixture was further stirred at 0° C. for 1 h. After being quenched with aqueous NH4Cl (20 mL), most of THF was removed by rotate evaporate. The residue was extracted with ethyl acetate (3×20 mL), washed with water (3×20 mL), and sat. NaCl (20 mL). The organic phase was dried and concentrated to give the crude product, which was purified by silica gel chromatography eluting with EtOAc/petroleum ether (1:1) to give 1-{4-[1-(Propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-13-yl}ethan-1-one (560 mg, 80% yield) as a white solid. LCMS (ESI) m/z: 338.2 [M+H+]
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:23]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][C:24]=2[C:25](O)=[O:26])[N:6]([CH3:22])[C:7](=[O:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:65]([NH:68][NH2:69])(=[O:67])[CH3:66]>CN(C)C=O>[C:65]([N:68]([C:25](=[O:26])[C:24]1[CH:28]=[C:29]([C:32]#[N:33])[CH:30]=[CH:31][C:23]=1[CH:5]1[C:4]([C:1](=[O:3])[CH3:2])=[C:9]([CH3:10])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=2)[C:7](=[O:21])[N:6]1[CH3:22])[NH2:69])(=[O:67])[CH3:66]
Reactant: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1C(=O)O
Reactant: CC(=O)NN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1C(=O)N(N)C(C)=O
Reaction time: 0.08 h

Procedure:
2-[5-Acetyl-3,6-dimethyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrimidin-m 4-yl]-5-cyano-benzoic acid (intermediate 6) (47.0 mg, 0.10 mmol)) and triethylamine (35.8 μL, 0.26 mmol) are suspended in N,N-dimethylformamide (2 mL), stirred for 5 min and O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (41.0 mg, 0.11 mmol) is added. The mixture is stirred for 10 min and acetic acid hydrazide (12.2 mg, 0.16 mmol) is added. The mixture is stirred overnight at room temperature. Another equivalent of acetic acid hydrazide is added to bring the reaction to completion. The crude product is purified by reversed phase HPLC. Yield 15 mg; ESI mass spectrum [M+H]+=514; Retention time HPLC: 0.95 min (HPLC method Z018_S04).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1>C(P[Pd](PC(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(PC(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)PC(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)C>[C:10]1([C:2]2[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1ccc(Br)cn1
Reactant: OB(O)c1ccccc1
Agent: c1ccc(C(P[Pd](PC(c2ccccc2)(c2ccccc2)c2ccccc2)(PC(c2ccccc2)(c2ccccc2)c2ccccc2)PC(c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: N#Cc1ccc(-c2ccccc2)cn1
Yield: 136.7 %

Procedure:
A mixture comprising 5-bromopyridine-2-carbonitrile (0.09 g, 0.49 mmol), phenyl boronic acid (0.12 g, 0.98 mmol), 2M sodium carbonate ((0.98 mL, 1.96 mmol), tetrakis(tritylphosphanyl)palladium (0.06 g, 0.049 mmol), benzene (2 mL) and ethanol (2 mL) was heated at reflux for 1 hour and then partitioned between ethyl acetate and water. The organic layer was separated, washed with water, dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography (25% ethyl acetate/hexanes) to provide 5-phenylpyridine-2-carbonitrile (0.12 g, 0.67 mmol). MS (CI), Calculated for C12H8N2, 180.2, Found (MH+): 182.