Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:22][CH2:21][C@@H:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19]2)[C:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[S:8][C:6]=2[N:7]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:23][C@@H:20]1[CH2:21][CH2:22][N:18]([C:4]2[C:5]3[CH:10]=[C:9]([C:11]4[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=4)[S:8][C:6]=3[N:7]=[C:2]([NH2:1])[N:3]=2)[CH2:19]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2nc(N)nc3sc(-c4ccc(F)cc4)cc23)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(N2CC[C@@H](N)C2)c2cc(-c3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the compound of example 338 (66 mg, 0.15 mmol) in dichloromethane (6 ml) was added trifluoroacetic acid (3 ml). The solution was stirred at room temperature for 30 minutes. The solvents were evaporated in vacuo and co-evaporated with toluene. The residue was directly used for further reaction without any purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[N:8]=[CH:7]2.[H-].[Na+].[CH3:19]I>C1COCC1.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:19])[N:8]=[CH:7]2
Reactant: CI
Reactant: CC(C)(C)Nc1ncc2cccc(Br)c2n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(c1ncc2cccc(Br)c2n1)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
8-Bromo-N-(tert-butyl)quinazolin-2-amine (374a) (40 mg, 0.14 mmol) in THF (4 mL) at 0° C. was treated with NaH (60% dispersion in mineral oil, 8.6 mg, 0.21 mmol) and stirred at 0° C. for 30 min. MeI (10.71 μl, 0.17 mmol) was added and the solution was warmed to RT overnight (16 h). The reaction mixture was treated with brine and extracted with EtOAc (50 mL), dried over MgSO4, filtered and concentrated. Purification on a silica gel column (0-50% EtOAc in hexanes) afforded the title compound (34 mg, 0.12 mmol, 82% yield) as yellow viscous oil. m/z (ESI, +ve ion) 294.0/296.0 (M+H)+.
Reaction SMILES: O=[C:2]1[CH2:8][CH:7]2[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.C1(C)C=CC(S([CH2:26][N+:27]#[C-])(=O)=O)=CC=1.CC(C)([O-])C.[K+].C(O)C>COCCOC>[C:26]([CH:2]1[CH2:8][CH:7]2[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:4]([CH2:5][CH2:6]2)[CH2:3]1)#[N:27]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1C2CCC1CC(C#N)C2

Procedure:
tert-Butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate was reacted in the presence of p-toluenesulfonylmethylisocyanide, potassium tert-butoxide and ethanol in 1,2-dimethoxyethane to produce tert-butyl 3-cyano-8-azabicyclo[3.2.1]octane-8-carboxylate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.CCOC(C)=O>[CH:17]1[C:18]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:16]=1[C:2]1[N:3]=[CH:4][C:5]([OH:8])=[CH:6][CH:7]=1
Reactant: Oc1ccc(Br)nc1
Reactant: OB(O)c1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Oc1ccc(-c2ccc3ccccc3c2)nc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 16.9 %

Procedure:
To a solution of 2-bromo-5-hydroxypyridine (1.04 g, 6 mmol) in 25 mL anhydrous THF was added 2-naphthylboronic acid (1.03 g, 6 mmol) and 2 M aq. sodium carbonate (9 mL, 18 mmol). To this reaction mixture was added palladium tetrakistriphenylphosphine (0.7 g, 0.6 mmol) and the mixture was stirred at rt for 15 h under nitrogen. The reaction mixture was diluted with EtOAc, the organic layer was washed with water (50 mL), brine (50 mL) and dried over anhydrous Na2SO4. Removal of solvent gave a white powder which was purified by column chromatography (Silica Gel 230-400 mesh; 3% MeOH in DCM) to give 6-naphthalen-2-yl-pyridin-3-ol (0.225 g, 17%). MS (ES) m/z: 222.96 (M+1), 221.93 (M); Mp. 168-169° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[N:6][C:5]=1Cl.[CH:14]1([SH:19])[CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[N:6][C:5]=1[S:19][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc(OC)nc1Cl
Reactant: SC1CCCC1
Product: COC(=O)c1ccc(OC)nc1SC1CCCC1
Yield: 77 %

Procedure:
2-Chloro-6-methoxy-nicotinic acid methyl ester (54 mg, 0.26 mmol) and cyclopen-tanethiol were reacted in the same manner as in Step A of Preparation Example 16 to obtain the title compound (55 mg, 77%).
Reaction SMILES: C([C:5]1[CH:6]=[C:7]([CH:13]=[C:14](C(C)(C)C)[C:15]=1O)[CH:8]=[CH:9][C:10]([OH:12])=O)(C)(C)C.[CH2:21]([O:23][C:24]([CH2:26][S:27][CH2:28][CH2:29][NH:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:25])[CH3:22].Cl.C(N=C=NCCCN(C)C)C.ClCCl>O>[CH2:21]([O:23][C:24]([CH2:26][S:27][CH2:28][CH2:29][N:30]([CH2:31][CH2:32][CH2:33][CH3:34])[C:10](=[O:12])[CH:9]=[CH:8][C:7]1[CH:6]=[CH:5][CH:15]=[CH:14][CH:13]=1)=[O:25])[CH3:22]
Reactant: CC(C)(C)c1cc(C=CC(=O)O)cc(C(C)(C)C)c1O
Reactant: CCCCNCCSCC(=O)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCCCN(CCSCC(=O)OCC)C(=O)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 105 %

Procedure:
First, 5.53 g of 3,5-di-t-butyl-4-hydroxycinnamic acid, 4.4 g of N-ethoxycarbonylmethylthioethyl-n-butylamine, and 4.0 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) were added to 100 ml of dichloromethane and the mixture was agitated for 3 hours at room temperature. Then, this reaction mixture was poured into water, and after chloroform extraction the chloroform layer was dehydrated with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue so obtained was separated and purified by column chromatography on silica gel with chloroform, after which hexane was added and crystallization yielded 7.34 g of an N-ethoxycarbonylmethylthioethyl-N-n-butylcinnamamide derivative (yield 79.5%) in the form of white crystals.
Reaction SMILES: Br[C:2](=[CH2:23])[CH2:3][CH2:4][O:5][Si:6]([C:19]([CH3:22])([CH3:21])[CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[Cl:31]>C1(C)C=CC=CC=1>[Cl:24][C:25]1[CH:26]=[C:27]([C:2](=[CH2:23])[CH2:3][CH2:4][O:5][Si:6]([C:19]([CH3:22])([CH3:21])[CH3:20])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: C=C(Br)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: C=C(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 64.7 %

Procedure:
[(3-Bromo-3-buten-1-yl)oxy](1,1-dimethylethyl)diphenylsilane (P12, 3.50 g) and (3,4-dichlorophenyl)boronic acid (2.06 g) were dissolved in toluene (45 mL), the stirred solution was degassed, then tetrakis(triphenylphosphine)palladium(0) (0.363 g) and ethanol (33 mL) were added and the mixture was degassed again. A 2N aqueous solution of Na2CO3 (24 mL) was added and the mixture was heated to 80° C. and stirred under nitrogen atmosphere for 3 h at this temperature. After cooling to RT, the reaction mixture was extracted with ethyl ether, the organic phase was washed with brine, dried over Na2SO4 and the solvent removed under reduced pressure. The crude product was purified by flash chromatography (eluting with cy/EA from 100/0 to 95/5) to give the title compound (2.65 g) as a colourless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[OH:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH:16]=[O:17])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=Cc1cccc(O)c1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Temperature: 85 °C
Reaction time: 8 h
Yield: 37.6 %

Procedure:
To a solution of DMF (50 mL) was added 1-bromo-2-nitro-4-chloro-benzene (10.0 g, 42.2 mmol), 3-hydroxybenzaldehyde (5.2 g, 42.2 mmol), and K2CO3 (11.5 g, 84.6 mmol). The solution was heated to 85° C. and stirred overnight. The reaction was poured into distill water and extracted with ethyl acetate. The combined organic layers were washed with distilled water, brine, and dried over Na2SO4, filtered and concentrated under vacuum giving the crude title compound. This solid was purified by silica gel column chromatography eluting with hexanes/ethyl acetate (4:1) to give the title compound (4.4 gm, 41%).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4].O.O.[C:14]1([S:20]([O-:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na+].O>CS(C)=O>[C:14]1([S:20]([CH2:2][C:3]([O:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)=[O:4])(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S([O-])c1ccccc1
Reactant: O=C(CBr)OC1CCCCC1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(CS(=O)(=O)c1ccccc1)OC1CCCCC1
Temperature: 60 °C
Reaction time: 6 h
Yield: 76.9 %

Procedure:
To a solution of cyclohexyl bromoacetate (15.6 g, 0.0705 mole) in dimethylsulfoxide (120 ml), sodium benzenesulfinate dihydrate (15 g, 0.075 mole) was added in a small portion at 20°-40° C., and reacted with stirring at 60° C. for 6 hours. After cooling, the reaction mixture was poured into cold H2O (1.5 liter). The precipitate was filtered, washed with H2O and dried to give 15.3 g of cyclohexyl benzenesulfonylacetate as a white crystals having a melting point of 35°-38° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:21][C:22]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[CH2:18][NH:17][CH2:16][C:15](=[O:19])[NH:14][C:13]=3[CH:20]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:40][CH2:41][C:42]([F:45])([F:44])[F:43]>C(O)CCC>[Cl:1][C:2]1[C:3]([NH:21][C:22]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[CH2:18][N:17]([CH2:40][CH2:41][C:42]([F:45])([F:44])[F:43])[CH2:16][C:15](=[O:19])[NH:14][C:13]=3[CH:20]=2)=[N:6][CH:7]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CNC3)ncc1Cl
Reactant: FC(F)(F)CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CN(CCC(F)(F)F)C3)ncc1Cl
Yield: 25.7 %

Procedure:
A solution of 2-[5-chloro-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide (50 mg, 0.11 mmol), potassium carbonate (31 mg, 0.22 mmol) and 1-iodo-3,3,3-trifluoropropane (58 mg, 0.25 mmol) was heated at 115° C. in butanol (3 mL) for 24 hours. After evaporated solvent, chromatography of the crude solid on a TLC plate with methylene chloride and methanol (25:1) to give 15.6 mg of 2-{5-chloro-2-[2-oxo-4-(3,3,3-trifluoro-propyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino]-pyrimidin-4-ylamino}-3-fluoro-N-methyl-benzamide in 14% yield: 1H NMR (300 MHz, CDCl3) δ 8.82 (s, 1H), 8.2 (s, 1H), 7.6 (m, 2H), 7.43 (m, 2H), 7.24 (s, 1H), 7.15 (d, 1H), 6.9 (d, 1H), 6.43 (d, 1H), 3.85 (s, 2H), 3.53 (s, 2H), 3.07 (d, 3H), 2.97 (m, 2H), 2.46 (m, 2H); MS (m/e): 552.2 (M+1).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[CH:7][C:6]=2[CH:5]=[C:4]([OH:18])[CH:3]=1.C[O-].[Na+].Cl.C[CH2:24][O:25]C(C)=O>CN(C=O)C>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[O:9][C:10]3[C:2]([O:25][CH3:24])=[CH:3][C:4]([OH:18])=[CH:5][C:6]=3[CH:7]=2)=[CH:12][CH:13]=1
Reactant: CCOC(C)=O
Reactant: Oc1ccc(-c2cc3cc(O)cc(Br)c3o2)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Temperature: 160 °C

Procedure:
A solution consisting of 58 (1.5 g, 4.9 mmol) in DMF (25 mL) was treated with CulBr (1.0 g, 6.5 mmol) and NaOMe (6 mL, 4.4 N in MeOH, 27 mmol) and heated to 160° C. for approximately 1 hour. The reaction mixture was allowed to cool and then worked up by adding 2 N HCl and EtOAc. The EtOAc layer was washed with NaHCO3 aq, brine and dried over MgSO4. The solution was concentrated and chromatographed on silica gel (1:4 EtOAc/hexanes to 3:7 EtOAc/hexanes) to yield 0.47 g of pdt: p=167-168° C., 1H NMR (DMSO-d6) δ 9.84 (br s, 1 H), 9.18 (br s, 1 H), 7.67 (d, 2 H, J=8.6 Hz), 6.99 (s, 1H), 6.86 (d, 2 H, J=8.7 Hz), 6.46 (d, 1 H, J=2.1 Hz), 6.34 (d, 1 H, J=2.1 Hz), 3.89 (s, 3 H); MS 257 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:14])[C:8](=[O:13])[N:9]2[OH:12])=[CH:4][CH:3]=1.[N+:15]([O-])([O-:17])=[O:16].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:14])[C:8](=[O:13])[N:9]2[OH:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c2ccc(F)cc2n(O)c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc([N+](=O)[O-])c(F)cc2n(O)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
In 20 ml of sulfuric acid was dissolved 1.34 g of 7-fluoro-1-hydroxyquinoxaline-2,3-(1H,4H)-dione followed by addition of 0.76 g of potassium nitrate under ice-cooling. The mixture was cooled to at room temperature, and after 1 hour, the reaction mixture was poured in ice-water. The resulting crystals were recovered by filtration, rinsed with water and recrystallized from ethanol-water to provide 0.82 g (50%) of 7-fluoro-1-hydroxy-6-nitroquinoxaline-2,3-(1H,4H)-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[S:27]1[CH:31]=[CH:30][C:29]([CH:32]([NH2:34])[CH3:33])=[CH:28]1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:14])([F:13])[F:15])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:34][CH:32]([C:29]1[CH:30]=[CH:31][S:27][CH:28]=1)[CH3:33]
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CC(N)c1ccsc1
Product: CC(Nc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)c1ccsc1
Yield: 52.8 %

Procedure:
Use a method similar to the General Procedure 5-3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 0.47 mmol) with (±)-1-thiophen-3-yl-ethylamine (prepared as described in J. Heterocycl. Chem. 1988, 25, 1571-1581) (90 mg, 0.70 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 9:1 and 4:1) to give (±)-7-chloro-6-(1-thiophen-3-yl-ethylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (100 mg, 53%).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:20]([SH:22])[CH3:21]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([S:22][CH2:20][CH3:21])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCS
Reactant: CCCCOC(=O)c1nc(Cl)c2ccccc2c1O
Product: CCCCOC(=O)c1nc(SCC)c2ccccc2c1O
Temperature: 70 °C
Reaction time: 48 h

Procedure:
52 mg of 1-Chloro-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester, Example D-20c, was dissolved in 2 ml of ethanethiol and heated in a sealed tube at 70° C. for 24 h, and 1000 C for 48 h. The resultant solution was concentrated under vacuum and the residue (54 mg) was purified by chromatography on silica gel using a gradient of 0 to 20 percent ethyl acetate in hexanes to elute the product. 25 mg of product was obtained; MS (+): m/z 306.06 (M+1)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=2)[CH:7]=1.[C:15]([C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19])#[CH:16]>>[C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:16]#[C:15][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[NH2:19])=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: C#Cc1ccccc1N
Reactant: CC(C)(C)c1cc2ncc(Br)cn2n1
Product: CC(C)(C)c1cc2ncc(C#Cc3ccccc3N)cn2n1

Procedure:
The title compound, light yellow solid, MS: m/e=291.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 2-ethynylaniline.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:8]([N:10]2[CH:14]([C:15](O)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.CN1CCOCC1.[CH2:50]([C:52]1[N:57]=[C:56]([NH2:58])[CH:55]=[CH:54][CH:53]=1)[CH3:51]>C(#N)C>[CH:1]1([CH2:6][C@@H:7]([C:8]([N:10]2[CH:14]([C:15]([NH:58][C:56]3[CH:55]=[CH:54][CH:53]=[C:52]([CH2:50][CH3:51])[N:57]=3)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1cccc(N)n1
Reactant: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CCc1cccc(NC(=O)C2CC=NN2C(=O)[C@@H](CC(=O)OC(C)(C)C)CC2CCCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of 1-{(2R)-2-(cyclopentylmethyl)-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoyl}-4,5-dihydro-1H-pyrazole-5-carboxylic acid (352 mg, 1.0 mmol) in acetonitrile (10 mL) at 0° C. was added 4-[4,6-bis(methyloxy)-1,3,5-triazin-2-yl]-4-methylmorpholin-4-ium (656 mg, 2.0 mmol) and N-methylmorpholine (0.28 mL, 2.5 mmol). The reaction mixture was stirred for 2 hours. After this time, 6-ethyl-2-pyridinamine (159 mg, 1.3 mmol) was added to the mixture, which was then allowed to warm to room temperature and stirred for 3 hours. The solvent was removed under reduced pressure, and water (5 mL) and DCM (15 mL) were added to the resulting residue. The phases were separated. The aqueous phase was extracted twice with DCM (15 mL), and the combined organic phases were dried over sodium sulfate and concentrated. The crude product residue was purified by Combiflash silica gel chromatography (0-100% EtOAc in hex) to provide 1,1-dimethylethyl (3R)-3-(cyclopentylmethyl)-4-(5-{[(6-ethyl-2-pyridinyl)amino]carbonyl}-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoate (359 mg, 0.79 mmol, 79% yield) as a clear oil. MS: 457 ([M+H]+).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]=[N:42][CH:43]=[C:44]([CH3:46])[N:45]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:56])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]=[N:42][CH:43]=[C:44]([CH3:46])[N:45]=5)=[O:56])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nncc(C)n4)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nncc(C)n4)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 72.8 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(5-methyl-1,2,4-triazin-3-yl)methylthio]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.67 g) was suspended in dichloromethane (100 ml). The suspension was cooled to −78° C. A solution of 3-chloroperbenzoic acid (0.38 g) in dichloromethane (7 ml) was added dropwise to the suspension. The mixture was stirred for 1.5 hours at −78° C. To the mixure was added sodium thiosulfate solution, and the mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane) to give crude crystals, which were recrystallized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(5-methyl-1,2,4-triazin-3-yl)methylsulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 39) (0.50 g) as yellow crystals.
Reaction SMILES: [CH:1]1([C:7]2([OH:20])[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:23]I>CN(C=O)C>[CH:1]1([C:7]2([O:20][CH3:23])[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C2CCCCC2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(C2CCCCC2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C

Procedure:
To a solution of tert-butyl 4-cyclohexyl-4-hydroxy-1-piperidinecarboxylate (7.26 g) in DMF (70 ml) was added sodium hydride (60% in oil) (2.05 g) with stirring under ice-cooling. The mixture was stirred at ambient temperature for 1 hour. To the suspension was added methyl iodide (4.79 ml) and the mixture was stirred at ambient temperature overnight. The reaction mixture was poured into ice-water (300 ml) and extracted three times with ethyl acetate (200 ml). The extracts were collected, washed twice with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (400 ml) eluting with a mixture of n-hexane and ethyl acetate (4:1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give tert-butyl 4-cyclohexyl-4-methoxy-1-piperidinecarboxylate (6.77 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])[N:8]=1)(=O)=O.[C:28]([CH2:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)#[N:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([F:25])[C:18]=1[N:9]1[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=2[C:7]([C:34]2[CH:35]=[CH:36][C:31]([CH2:30][C:28]#[N:29])=[CH:32][CH:33]=2)=[N:8]1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2-c1c(F)cccc1F
Reactant: N#CCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nccc2c1c(-c1ccc(CC#N)cc1)nn2-c1c(F)cccc1F
Temperature: 130 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
To a solution of 1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (150 mg) obtained in Step C of Example 35 in DMF (4 mL)/water (0.40 mL) were added (4-(cyanomethyl)phenyl)boronic acid (156 mg), tetrakis(triphenylphosphine)palladium(0) (42.4 mg) and potassium carbonate (101 mg). The reaction mixture was stirred under microwave irradiation at 130° C. for 1 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (107 mg).