Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].[CH2:28]([O:30][C:31]([C:33]1[CH:38]([C:39]2[CH:44]=[CH:43][C:42]([C:45](=[O:54])[NH:46][CH2:47][C:48]3[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=3)=[CH:41][CH:40]=2)[C:37]([C:55](=[O:57])[NH2:56])=[C:36]([CH2:58][CH:59]([CH3:61])[CH3:60])[NH:35][C:34]=1[CH2:62][CH2:63][C:64]1[CH:69]=[CH:68][C:67]([F:70])=[CH:66][CH:65]=1)=[O:32])[CH3:29].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH2:28]([O:30][C:31](=[O:32])[C:33]1[C:38]([C:39]2[CH:44]=[CH:43][C:42]([C:45](=[O:54])[NH:46][CH2:47][C:48]3[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=3)=[CH:41][CH:40]=2)=[C:37]([C:55](=[O:57])[NH2:56])[C:36]([CH2:58][CH:59]([CH3:61])[CH3:60])=[N:35][C:34]=1[CH2:62][CH2:63][C:64]1[CH:69]=[CH:68][C:67]([F:70])=[CH:66][CH:65]=1)[CH3:29]
Reactant: CCOC(=O)C1=C(CCc2ccc(F)cc2)NC(CC(C)C)=C(C(N)=O)C1c1ccc(C(=O)NCc2cccnc2)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(CCc2ccc(F)cc2)nc(CC(C)C)c(C(N)=O)c1-c1ccc(C(=O)NCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 5.6 %

Procedure:
An aqueous solution of CAN (1 M, 1 mL) was added to a solution of compound 12 (50 mg, 0.08 mmol) and trifluoroacetic acid (0.5 mL) in CHCl3 (30 mL). The resulting mixture was vigorously stirred for 10 min at r.t. The organic layer was separated, washed with water, dried over Na2SO4, and concentrated in vacuo to yield the crude product. Purification by preparative LCMS (PE SCIEX, C18, acetonitrile—water with 0.035% trifluoroacetic acid) yielded the title compound (2.6 mg, 95% purity by LCMS). 1H NMR (500 MHz, CDCl3): δ 8.16 (s, 1H), 8.00 (br. d, 1H), 7.87 (m, 3H), 7.35 (m, 2H), 7.18 (d, J=8.5 Hz, 1H), 7.08 (m, 2H), 6.90 (m, 2H), 6.03 (br. s, 1H), 5.60 (br. s, 1H), 4.75 (m, 3H), 3.94 (q, J=7.0 Hz, 2H), 3.07 (m, 5H), 2.77 (d, J=7.6 Hz, 1H), 1.27 (m, 1H), 0.94 (m, 3H), 0.88 (t, J=7.4 Hz, 6H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14](=[O:16])[CH3:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>>[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[CH:15][C:14]([C:12]2[S:13][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:1])[F:18])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)=[O:16])=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Product: O=C(C=Cc1ccc(O)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)s1

Procedure:
3-(4-Hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)prop-2-en-1-one is prepared from 1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)ethanone and 4-hydroxybenzaldehyde according to general procedure B. The evaporation residue is purified by silica-gel chromatography.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[C:10]([Cu])#[N:11]>CN1C(=O)CCC1.CCOCC>[C:10]([C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1)#[N:11]
Reactant: Oc1ccc(Br)cc1F
Reactant: N#C[Cu]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(O)c(F)c1
Temperature: 150 °C
Yield: 96.2 %

Procedure:
4-Bromo-2-fluorophenol (10 ml, 91 mmol) and 9.85 g (0.11 mol) of CuCN were combined in 75 ml of NMP with stirring under nitrogen, and the mixture was heated at 150° C. for 5 h. The mixture was diluted with 200 ml of ether, stirred, and decanted. The residue was diluted again with 200 ml of ether, heated, and decanted. The combined decantates were washed with water, 1N HCl solution, water, and brine, and dried over magnesium sulfate. The organic solution was concentrated in vacuo to provide 12 g of a white solid which was triturated in carbon tetrachloride and filtered to afford 7.29 g (72.1%) of the title compound.
Reaction SMILES: [Li+].[OH-].[Cl:3][C:4]1[CH:8]=[C:7]([C:9]([NH:11][CH2:12][CH2:13][OH:14])=[O:10])[NH:6][C:5]=1[C:15]([O:17]C)=[O:16]>C1COCC1.CO>[Cl:3][C:4]1[CH:8]=[C:7]([C:9]([NH:11][CH2:12][CH2:13][OH:14])=[O:10])[NH:6][C:5]=1[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1[nH]c(C(=O)NCCO)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NCCO)c1cc(Cl)c(C(=O)O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
LiOH (2 mL, 2 mmol) was added to a solution of methyl 3-chloro-5-{[(2-hydroxyethyl)amino]carbonyl}-1H-pyrrole-2-carboxylate (0.082 g, 0.33 mmol) in THF (2 mL) and methanol (2 mL). The solution was stirred at RT overnight. The solvent was evaporated and the residue partitioned between EtOAc and 1 N HCl. The organic layer was separated, dried over MgSO4, filtered and evaporated to afford very little solid. The aqueous layer was evaporated to a residue and the salts extracted with methanol. The methanol was evaporated to afford the title compound (0.042 g, 54%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.16 (br. s., 1H), 8.40 (t, 1H), 6.61-7.10 (m, 1H), 3.45 (t, 2H), 3.26 (q, 2H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[N:22]([CH3:39])[C:23](=[O:38])[C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[F:15][C:13]1[CH:12]=[CH:11][C:10]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N:22]([CH3:39])[C:23](=[O:38])[C:24]2[CH:25]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=2)=[C:9]([OH:8])[CH:14]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccc(F)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccc(F)cc1O
Yield: 83.2 %

Procedure:
A solution of N-[4-(2-benzyloxy-4-fluoro-phenyl)-pyridin-3-yl]-N-methyl-3,5-bis-trifluoromethyl-benzamide (65 mg, 0.118 mmol, example 43) in MeOH (10 mL) was purged with argon for 20 minutes before 10% Pd—C (10 mg) was added. The resulting reaction mixture was hydrogenated under balloon pressure hydrogen at 25° C. for 16 hours. The reaction mixture was filtered through a bed of celite and the residue was further washed with EtOAc. The combined filtrate was concentrated in vacuo, and the crude material thus obtained was purified by column chromatography over silica gel (25-35% EtOAc in n-hexane) to give 45 mg of the desired compound. Off-white solid (60%). MS (ESI): m/z=459.0 [M+H]+.
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.[CH:38]12[N:44]([C:45](=O)[CH2:46]Br)[CH:41]([CH2:42][CH2:43]1)[CH2:40][CH2:39]2>>[CH:38]12[N:44]([CH2:45][CH2:46][O:10][C:8]3[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]4[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=4[C@@H:12]4[CH2:21][CH2:20][C:19]5[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=5[CH2:13]4)=[CH:6][CH:7]=3)[CH:41]([CH2:42][CH2:43]1)[CH2:40][CH2:39]2
Reactant: O=C(CBr)N1C2CCC1CC2
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN3C4CCC3CC4)cc2)c1
Yield: 152.4 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 1-(7-azabicyclo[2.2.1]hept-7-yl)-2-bromoethanone (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (12 mg) was obtained.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:21])[CH2:13][CH2:14][NH:15][S:16]([CH2:19][CH3:20])(=[O:18])=[O:17].[H-].[Na+]>>[CH3:11][N:12]([CH3:21])[CH2:13][CH2:14][N:15]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[S:16]([CH2:19][CH3:20])(=[O:18])=[O:17]
Reactant: CCS(=O)(=O)NCCN(C)C
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Product: CCS(=O)(=O)N(CCN(C)C)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 1-fluoro-4-nitro-benzene, N-(2-dimethylamino-ethyl)-ethanesulphonamide and sodium hydride as base
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[C:7](Cl)(=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>>[C:7]([NH:1][C@H:2]([CH3:3])[C:4]([OH:6])=[O:5])(=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCC(=O)Cl
Reactant: C[C@@H](N)C(=O)O
Product: CCCCCC(=O)N[C@H](C)C(=O)O

Procedure:
D-alanine (20 mmol) and hexanoyl chloride (22 mmol) were reacted using the method as described in Example 1 Part B to give the title compound as a white crystalline material (2.45 g, 65.5%) after recrystallization from isopropyl ether (20 ml), m.p. 82°-95° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:29])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)=[CH:23][C:22]=1[C:30]([F:31])([F:32])[F:33]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Product: NC(=O)c1[nH]c2ncccc2c1-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
29.8 mg of solid white 3-{4-[3-(4-chloro-3-trifluoromethylphenyl)ureido]-phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and 4-chloro-3-trifluoromethylphenyl isocyanate.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O.[N+:14]([CH2:17][CH3:18])([O-:16])=[O:15].C(N)CCC>>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:7]=[C:17]([N+:14]([O-:16])=[O:15])[CH3:18])[CH:9]=[CH:10][CH:11]=1
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Reactant: CC[N+](=O)[O-]
Solvent: CCCCN
Product: CC(=Cc1cccc(OC(F)(F)F)c1)[N+](=O)[O-]
Yield: 70 %

Procedure:
32 g (0.17 mol) of 3-trifluoromethoxy-benzaldehyde, 32 ml of nitro-ethane and 2 ml of n-butylamine are introduced into a 100 ml flask surmounted by a condenser. The mixture is heated for 20 hours at the reflux temperature and then rectified. 29 g (70% yield) of 1-(3'-trifluoromethoxy-phenyl)-2-nitro-1-propene are collected as a yellow oil b.p. 90°-110° C./2mm. Hg.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Br:12][CH2:13][CH2:14]Br>>[Br:12][CH2:13][CH2:14][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Oc1cccc2ncccc12
Reactant: BrCCBr
Product: BrCCOc1cccc2ncccc12
Yield: 11 %

Procedure:
Following the same procedure as in Example 32-(a), reaction and treatment were carried out using 1.05 g of 5-hydroxyquinoline and 2.04 g of 1,2-dibromoethane to obtain 0.2 g of 5-(2-bromoethoxy)quinoline.
Reaction SMILES: [C:1](=[O:3])=O.[N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11]C=2)[CH:7]=[CH:6][CH:5]=1>>[OH:3][C:1]1[CH:13]=[C:8]([CH2:7][CH2:6][C:5]#[N:4])[CH:9]=[CH:10][CH:11]=1
Reactant: c1ccc2ncccc2c1
Reactant: O=C=O
Product: N#CCCc1cccc(O)c1
Reaction time: 2.5 h
Yield: 69 %

Procedure:
A 300 ml. flask equipped with a magnetic stirrer, cold water condenser, CO2 outlet and bubbler, and a heated oil bath was charged with 21 g. of crude α-cyano-m-hydroxydihydrocinnamic acid (above) and freshly redistilled quinoline (10 ml.). The acid underwent smooth decarboxylation at an oil bath temperature of 150°C with CO2 evolution ceasing after about 2.5 hr. For workup, the cooled mixture was treated with 200 ml. of 5N HCl and extracted thoroughly with several portions of diethyl ether totalling 350 ml. The ether was washed with water (1 × 100 ml.), saturated NaHCO3 (4 × 50 ml.), brine (1 × 100 ml.), and dried over anhydrous Na2SO4. Concentration of the ether solution gave 11.15 g. (69% yield) of β-(m-hydroxyphenyl)propionitrile as a pale yellow solid. Recrystallization from ethyl acetate/hexane gave the pure compound as light yellow crystals, m.p. 64°-66°C.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[H-].[Na+].Br[CH:21]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C1COCC1.CCOCC>[CH:21]1([N:15]2[C:13]3=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]3[N:17]=[CH:16]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: BrC1CCCCCC1
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Oc1ccc2ncn(C3CCCCCC3)c2n1
Temperature: 25 °C
Yield: 17.3 %

Procedure:
5-(Benzyloxy)-3H-imidazo[4,5-b]pyridine (2.00 g, 8.88 mmol) was dissolved in THF and NaH (0.18 g, 14.7 mmol) was added portionwise. The resulting mixture was heated in a sealed tube for 1 h and then cooled to room temperature. Bromocycloheptane (3.14 g, 17.8 mmol) was added and the reaction was heated to 70° C. overnight. The solution was then diluted with ether and washed with water. The aqueous layer was back extracted with additional ether and the combined organic portions were washed with brine, dried over MgSO4 and purified by preparative HPLC. The resulting 5-(benzyloxy)-3-cycloheptyl-3H-imidazo[4,5-b]pyridine was then dissolved in MeOH with catalytic amount of 5% Pd/C and excess ammonium formate. The reaction mixture was heated to 80° C. until the reaction was complete. The solvent was removed under reduced pressure and the residue purified via preparative HPLC to give the title compound (0.356 g). LCMS m/z=232.1 [M+H]+; 1H NMR (400 MHz, acetonitrile-d3) δ ppm 1.55-1.80 (m, 6H), 1.80-1.90 (m, 2H), 2.05-2.20 (m, 4H), 4.50-4.60 (m, 1H), 6.57 (d, J=8.6 Hz, 1H), 7.85 (d, J=8.6 Hz, 1H), 7.96 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].[Cl-].[Al+3].[Cl-].[Cl-].[Br:17]Br>CCOCC>[Br:17][CH2:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 69 %

Procedure:
4-Nitroacetophenone (25 g) in ether (250 ml) was treated with aluminium chloride (catalytic amount) followed by bromine (7.77 ml) for 10 minutes and the reaction was stirred for 30 minutes. The reaction was quenched with aqueous NaHCO3, the ether layer was separated, dried using Na2SO4 and concentrated. The residue was dissolved in EtOAc, dried using Na2SO4, and concentrated to get off white solid which was crystallized in EtOAc/Pet ether to yield 25.5 gm (69%) of the title compound. 1HNMR (CDCl3, 300 MHz): δ 8.19 (d, 2H), 8.36 (d, 2H), 4.47 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([N:8]([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.[Li+].CC([N-]C(C)C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:10])[CH3:11])=[O:7])=[C:15]([B:17]([OH:22])[OH:18])[CH:16]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)N(C(=O)c1ccc(Br)cc1)C(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)N(C(=O)c1ccc(Br)cc1B(O)O)C(C)C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-N,N-diisopropylbenzamide (1.0 g, 35 mmol) and triisopropyl borate (0.79 g, 4.2 mmol) in THF (20 mL) was added a freshly prepared solution of LDA in THF (4.6 mL, 4.6 mmol) dropwise at 20° C. over a 1 hour period under nitrogen. The reaction mixture was stirred overnight, quenched with saturated aqueous NH4Cl solution (20 mL), and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated to afford {5-bromo-2-[(diisopropylamino)carbonyl]phenyl}boronic acid that was used without further purification.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([C:12]2([CH2:18][CH2:19][N:20]3[CH:25]4[CH2:26][CH2:27][CH:21]3[CH2:22][CH:23]([N:28]3[C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=5[N:30]=[C:29]3[CH3:37])[CH2:24]4)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1)[CH3:4].C(N(CC)CC)C.[CH3:45][C:46]([CH3:51])([CH3:50])[C:47](Cl)=[O:48]>ClCCl>[CH3:45][C:46]([CH3:51])([CH3:50])[C:47]([N:15]1[CH2:16][CH2:17][C:12]([CH2:18][CH2:19][N:20]2[C@H:21]3[CH2:27][CH2:26][C@@H:25]2[CH2:24][CH:23]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[CH3:37])[CH2:22]3)([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:3][CH3:4])[CH:7]=2)[CH2:13][CH2:14]1)=[O:48]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOc1cccc(C2(CCN3C4CCC3CC(n3c(C)nc5ccccc53)C4)CCNCC2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1cccc(C2(CCN3[C@@H]4CC[C@H]3CC(n3c(C)nc5ccccc53)C4)CCN(C(=O)C(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
A mixture of 1-(8-{2-[4-(3-ethoxyphenyl) piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole dihydrochloride (0.2 g, 0.39 mmol), triethylamine (0.11 mL, 0.78 mmol) and trimethylacetyl chloride (0.053 mL, 0.43 mmol) in dichloromethane (4 mL) was stirred at rt for 1 h before the reaction mixture was quenched with saturated sodium bicarbonate solution. The organic layer was separated, dried, concentrated and purified by chromatography on silica gel eluting with a dichloromethane to 1:9 methanol:dichloromethane gradient to give 1-((1R,5S)-8-{2-[1-(2,2-dimethylpropanoyl)-4-(3-ethoxyphenyl) piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole as a foam (0.14 g, 65%). 1H NMR (400 MHz, CDCl3) δ 7.65 (m, 1H), 7.28 (m, 2H), 7.16 (m, 2H), 6.86 (m, 2H), 6.76 (m, 1H), 4.63 (m, 1H), 4.04 (m, 2H), 3.94 (m, 2H), 3.29 (m, 4H), 2.59 (s, 3H), 2.40 (m, 2H), 2.19 (m, 2H), 1.66-1.95 (m, 12H), 1.43 (t, 3H), 1.26 (s, 9H). HRMS C35H48N4O2 m/z 557.3856 (M+H)Cal., 557.3840 (M+H)Obs..
Reaction SMILES: [CH:1]([C:3]1[CH:32]=[CH:31][C:6]([NH:7][C:8]2[N:9]=[C:10]3[C:16]([C:17]([NH:19][CH:20]([CH3:22])[CH3:21])=[O:18])=[CH:15][N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:11]3=[N:12][CH:13]=2)=[CH:5][CH:4]=1)=O.[O:33]1[CH2:38][CH2:37][N:36]([C:39](=[O:43])[CH2:40][C:41]#[N:42])[CH2:35][CH2:34]1.N1CCCCC1>C(Cl)Cl>[C:41]([C:40]([C:39]([N:36]1[CH2:35][CH2:34][O:33][CH2:38][CH2:37]1)=[O:43])=[CH:1][C:3]1[CH:32]=[CH:31][C:6]([NH:7][C:8]2[N:9]=[C:10]3[C:16]([C:17]([NH:19][CH:20]([CH3:22])[CH3:21])=[O:18])=[CH:15][N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[C:11]3=[N:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:42]
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=O)cc3)nc12
Reactant: N#CCC(=O)N1CCOCC1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=C(C#N)C(=O)N4CCOCC4)cc3)nc12
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a 20 ml vial 2-(4-formylanilino)-N-isopropyl-5-(2-trimethylsilylethoxymethyl)-pyrrolo[2,3-b]pyrazine-7-carboxamide (50 mg, 0.11 mmol), 3-morpholino-3-oxopropanenitrile (33.99 mg, 0.22 mmol) and piperdine (0.02 ml, 0.22 mmol) were mixed and stirred overnight. The residues was dissolved in minimum CH2Cl2, loaded on silica gel column, and eluted with EtOAc:hexane, 0, 50, 80, 100% to get 60 mg of 2-[4-(2-cyano-3-morpholino-3-oxo-prop-1-enyl)anilino]-N-isopropyl-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-carboxamide as a white solid.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl[CH2:15][C:16](Cl)=[O:17]>O1CCCC1.O>[CH2:10]([O:9][C:1]1[O:8][CH2:15][C:16](=[O:17])[C:2]=1[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(Cl)CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1=C(OCC)OCC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Diethyl malonate (8.0 mL, 0.052 mol) was added dropwise to a solution of sodium hydride (60% w/w in oil, 4.2 g, 0.11 mol) in anhydrous tetrahydrofuran (130 mL) that cooled with ice bath. The mixture was refluxed for 7 min. The reaction mixture was cooled with ice bath, chloroacetyl chloride (4.2 mL, 0.052 mol) was added dropwise to the reaction mixture and stirred for 1 h then stirred at 45° C. for 1 h. Cooled to ambient temperature, the reaction mixture was diluted with water, and extracted with chloroform for 4 times. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel(chloroform/methanol) to afford ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (5.0 g, y. 48%).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=2)[N:9]=[N:8][C:7]=1[C:22]([NH:24][CH:25]1[CH2:27][CH2:26]1)=[O:23])#[N:2].C[Si]([N:32]=[N+:33]=[N-:34])(C)C>C1(C)C=CC=CC=1>[CH:25]1([NH:24][C:22]([C:7]2[N:8]=[N:9][N:10]([C:11]3[CH:12]=[CH:13][C:14]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:16]=3)[C:6]=2[CH2:5][CH2:4][CH2:3][C:1]2[NH:34][N:33]=[N:32][N:2]=2)=[O:23])[CH2:26][CH2:27]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCC#N)cc1
Solvent: Cc1ccccc1
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCc2nnn[nH]2)cc1
Yield: 26.9 %

Procedure:
A solution of 5-(3-cyanopropyl)-N-cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxamide (183 mg, 0.5 mmol) obtained in Example 1207, trimethylsilyl azide (58 mg, 0.5 mmol) and di-N-butyltin oxide (12.5 mg, 0.05 mmol) in toluene (5 ml) was boiled under reflux for 24 hr and the solvent was evaporated. Methanol (5 ml) was added to the residue, and the solvent was evaporated again. Ethyl acetate (10 ml) and 6% aqueous sodium bicarbonate solution (10 ml) were added to the residue and, after partitioning, the aqueous layer was adjusted to pH 4-5 with 1N hydrochloric acid, and the precipitated crystals were collected by filtration and dried to give the title compound as a colorless powder (55 mg, 27%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([N:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)=[N:24][CH:25]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[CH:12]=2)[CH:8]=[N:7]1>Cl.CCOCC>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[N:24][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(Cl)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc32)cc1
Agent: Cl
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(Cl)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Yield: 161.1 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(5-(3-(1-(3-chlorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazine-1-carboxylate (185 mg, 0.25 mmol) was deprotected in HCl in ether (10 ml) to afford 133 mg (78.8% yield) of the titled compound.