Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH2:3][CH2:4][CH2:5][CH:6]1[O:11][CH:10]([OH:12])[CH2:9][CH2:8][CH2:7]1)=[O:2].CCN(CC)CC.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:1]([CH2:3][CH2:4][CH2:5][CH:6]1[O:11][CH:10]([O:12][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:9][CH2:8][CH2:7]1)=[O:2]
Reactant: O=CCCCC1CCCC(O)O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC1CCCC(CCCC=O)O1
Temperature: 0 °C
Yield: 80.8 %

Procedure:
In a 25 mL round bottomed flask was placed a solution of 6-(3-formylpropyl)-2-hydroxytetrahydropyran (153 mg, 0.89 mmol), DMAP (5 mg), and Et3N (0.4 mL) in CH2Cl2 (10 mL). The solution was cooled to 0° C., and tert-butyldimethylsilyl chloride (205 mg, 1.34 mmol) in CH2Cl2 (3 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature overnight, and then the solvent was removed under reduced pressure. Ether was added and the organic layer was washed with saturated NH4Cl twice followed by brine, dried over anhydrous magnesium sulfate, and then concentrated in vacuo. The residue was submitted to column chromatography on silica gel to afford 6-(3-formylpropyl)-2-(tert-butyldimethylsiloxy)tetrahydropyran as a clear yellow oil (206 mg, 90% yield): 1H NMR (CDCl3) δ 0.09 (s, 3H), 0.10 (s, 3H), 0.89 (s, 9H), 1.19-1.73 (m, 10H), 2.43 (m, 2H), 3.34 (t, 1H, J=5.7 Hz), 4.63 (d, 1H, J=9 Hz), 9.74 (s, 1H); 13C NMR (CDCl3) δ -4.0, 18.14, 18.41, 22.21, 25.81, 30.61, 33.83, 35.25, 43.70, 75.70, 97.26, 202.63. HRMS [CI (CH4)] calcd for C15H29O3Si: 285.1886 (M-H,)+. Found: 285.1890 (Δ-1.4 ppm).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].C(OC(=O)C)(=O)C.O[CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[CH:20][S:21][CH:22]=1)=[O:17].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[N+:1]([O:4][CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[CH:20][S:21][CH:22]=1)=[O:17])([O-:3])=[O:2]
Reactant: O=C(NCCO)c1cscn1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: O=C(NCCO[N+](=O)[O-])c1cscn1
Temperature: 5 °C

Procedure:
Fuming nitric acid (12.8 ml) was added dropwise to acetic anhydride (27.4 ml) with stirring and ice-sodium chloride cooling at 10° C. for 1 minute, and the mixture was stirred for 10 minutes at the same temperature. Continuously, a solution of N-(2-hydroxyethyl)-4-thiazolecarboxamide (25.0 g) in dry chloroform (35 ml) was added dropwise thereto with stirring and cooling at 5° C. for 10 minutes and the mixture was stirred for 1 hour at the same temperature. The reaction mixture was poured into a mixture of sodium bicarbonate (100 g) and ice-water (1.0 kg) and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was concentrated under reduced pressure and the residual solid was recrystallized from a mixture of diisopropyl ether and methanol (3:2) to give colorless crystals of N-(2-nitrooxyethyl)-4-thiazolecarboxamide (10.17 g).
Reaction SMILES: [CH2:1]([N:3]1CCCCC1)[CH3:2].[CH2:9]([O:16][C:17]([NH:19][C@H:20]([C:22]([OH:24])=O)[CH3:21])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.ClC(OC(CC)C)=O.C(N)C>O1CCCC1>[CH2:1]([NH:3][C:22](=[O:24])[C@H:20]([CH3:21])[NH:19][C:17]([O:16][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:18])[CH3:2]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCN1CCCCC1
Agent: CCC(C)OC(=O)Cl
Agent: CCN
Solvent: C1CCOC1
Product: CCNC(=O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: -6 °C
Reaction time: 0.13 h

Procedure:
14 ml. of N-ethyl piperidine was added to a solution of 23.3 grams of benzyloxycarbonyl alanine in 100 ml. of tetrahydrofuran and, after cooling to -10 degrees C., 14 ml. of sec. butyl chlorformate was added. Next, the mixture was stirred for 8 minutes and cooled to -6 degrees C. Then 30 ml. of a 4.1 solution of ethylamine in tetrahydrofuran was added. After 30 minutes of stirring at 0 degrees C. and 2 hours of stirring at room temperature, the reaction solution was evaporated, gradually shaken with a 5% solution of sodium hydrogen carbonate, with water, dried with anhydrous sodium carbonate, and evaporated. The evaporation residue was crystallized from ethyl acetate (30 ml.) and petroleum ether. 18.1 g of a product having a melting point of 116 to 117 degrees C. was obtained.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH2:23])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH:24][CH2:25][C:26](=[CH2:31])[C:27]([O:29][CH3:30])=[O:28]>CO>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH:23][CH2:31][CH:26]([CH2:25][OH:24])[C:27]([O:29][CH3:30])=[O:28])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CN)ccc3c2)CC1
Reactant: C=C(CO)C(=O)OC
Solvent: CO
Product: COC(=O)C(CO)CNCc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compounds (6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methanamine (311 mg, 1.0 mmol, 1.0 eq.) and methyl 2-(hydroxymethyl)acrylate (116 mg, 1.0 mmol, 1.0 eq.) was dissolved in MeOH (5 mL). The mixture was stirred at r.t. for 2 h. Then the mixture was concentrated and purified by silica gel column chromatography using DCM/CH3OH (10/1) to give product (250 mg, 58%) as a slight yellow oil. ESI-MS (M+H)+: 428.3. HPLC: 90.18%. 1H NMR (400 MHz, CDCl3) δ 7.68 (t, 2H), 7.63 (s, 1H), 7.37 (dd, 1H), 7.14-7.11 (m, 2H), 4.27-4.25 (m, 1H), 4.01-3.96 (m, 2H), 3.91 (s, 2H), 3.71 (s, 3H), 3.18-2.93 (AB, 2H), 2.73-2.71 (m, 1H), 2.28-2.25 (m, 2H), 1.90-1.87 (m, 2H), 1.45-1.40 (m, 2H), 1.25-1.09 (m, 3H), 0.89 (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([NH:7][C:8](=[O:16])OC2C=CC=CC=2)[CH:4]=[C:3]2[CH2:17][CH2:18][CH2:19][C:2]=12.[CH3:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=[C:29]([C:35]([F:38])([F:37])[F:36])[N:28]=2)[CH2:23][CH2:22]1>CN(C=O)C.CN(C1C=CN=CC=1)C>[N:1]1[CH:6]=[C:5]([NH:7][C:8]([NH:34][CH2:33][C:32]2[C:27]([N:24]3[CH2:25][CH2:26][CH:21]([CH3:20])[CH2:22][CH2:23]3)=[N:28][C:29]([C:35]([F:38])([F:36])[F:37])=[CH:30][CH:31]=2)=[O:16])[CH:4]=[C:3]2[CH2:17][CH2:18][CH2:19][C:2]=12
Reactant: CC1CCN(c2nc(C(F)(F)F)ccc2CN)CC1
Reactant: O=C(Nc1cnc2c(c1)CCC2)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC1CCN(c2nc(C(F)(F)F)ccc2CNC(=O)Nc2cnc3c(c2)CCC3)CC1
Temperature: 50 °C
Yield: 77.4 %

Procedure:
To a solution of phenyl 6,7-dihydro-5H-cyclopenta[b]pyridin-3-ylcarbamate (E) (80 mg, 0.31 mmol) in DMF was added DMAP (38 mg, 0.31 mmol) and (2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methanamine (F) (90 mg, 0.33 mmol) at room temperature. The reaction mixture was heated to 50° C. for 14 h. TLC showed complete consumption of starting material. The reaction mixture was diluted with water and extracted with EtOAc. The organic part was washed with water and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude was purified by column chromatography to give pure 1-(6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)urea (example compound I) (104 mg, 76%).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[N:15]=1.Cl([O-])(=O)(=O)=O.[CH2:26]1[C:33]2[CH2:32][CH2:31][CH2:30][N+:29]=2[CH2:28][CH2:27]1>C1COCC1>[F:13][C:14]1[C:19]([C:33]23[CH2:32][CH2:31][CH2:30][N:29]2[CH2:28][CH2:27][CH2:26]3)=[CH:18][CH:17]=[C:16]([F:20])[N:15]=1
Reactant: Fc1cccc(F)n1
Reactant: C1CC2=[N+](C1)CCC2
Agent: [Li]CCCC
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Fc1ccc(C23CCCN2CCC3)c(F)n1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 50.2 %

Procedure:
A solution of 2.5M nBuLi (675 μL, 1.7 mmol) in hexanes was added to diisopropylamine (220 μL, 1.6 mmol) in THF (4.5 mL) at ambient temperature. After 10 minutes of stirring, the reaction mixture was cooled to -78° C., 2,6-difluoropyridine (145 μL, 1.6 mmol) was introduced, and stirring was continued for 1 hour at -78° C. 1,2,3,5,6,7-hexahydropyrrolizinium perchlorate (500 mg, 2.4 mmol) was then added, and the cold bath was removed. After warming to ambient temperature, a solution of 2N HCl was added and the phases were separated after pouting the reaction mixture over EtOAc. The aqueous phase was basified with 15% NaOH solution and extracted with CH2Cl2 (2×). The CH2Cl2 extracts were combined, dried (MgSO4), concentrated and chromatographed (silica gel; CHCl3 /MeOH, 98:2) to afford a clear oil (180 mg, 50%). MS (CI/NH3) m/e: 225 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.5-1.63 (m, 2H), 1.78-1.89 (m, 2H), 1.92-2.10 (m, 4H), 2.63-2.70 (m, 2H), 3.08-3.12 (m, 2H), 6.72 (dd, J=8.1, 3.0 Hz, 1H), 8.33 (dd, J=18.0, 8.1 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][O:8][C:4]=2[CH:3]=1.C[O-].[Na+]>>[OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C@H:6]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C(O)Cc1coc2cc(O)ccc12
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)C[C@@H]1COc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.9 %

Procedure:
(6-Hydroxy-1-benzofuran-3-yl)acetic acid (0.050 g, 0.26 mmol) and dichloro[(+)-1,2-bis((2R,5R)-2,5-diisopropylphosphorano)benzene]ruthenium (II)-N,N-dimethylformamide complex (1.9 mg, 0.0026 mmol) and sodium methoxide (14.0 mg, 0.26 mmol) were charged, and purged with argon. Methanol (1 mL) was added thereto, and the mixture was stirred at room temperature for 12 hr under a hydrogen atmosphere (1.0 MPa). The obtained reaction mixture was analyzed by liquid chromatography to give the title compound (conversion ratio 99.9%, optical purity 84.1% ee(S)).
Reaction SMILES: [OH:1][C:2]1[C:10]([C:11](=[O:24])/[CH:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CS(C)=O>O1CCOCC1>[O:24]=[C:11]1[C:10]2[C:2](=[C:3]([C:4]([OH:6])=[O:5])[CH:7]=[CH:8][CH:9]=2)[O:1][C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=2)=[CH:12]1
Reactant: O=C(O)c1cccc(C(=O)/C=C/c2cccc(C(F)(F)F)c2)c1O
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: O=C(O)c1cccc2c(=O)cc(-c3cccc(C(F)(F)F)c3)oc12
Yield: 69.8 %

Procedure:
A mixture of (E)-2-hydroxy-3-(3-(3-(trifluoromethyl)phenyl)acryloyl)benzoic acid 34 (0.8 g, 2.4 mmol), SeO2 (0.79 g, 7.1 mmol) and DMSO (5 mL) in dioxane (150 mL) was heated at reflux for 1 h. The black solid was filtered and the dioxane was evaporated. The remaining oil was suspended in H2O, filtered and dried to give 35 (0.56 g, 76% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.N12CCN(CC1)CC2.[CH3:17][CH:18]([N:20]=[C:21]=[O:22])[CH3:19]>CN(C)C=O>[Cl:8][C:4]1[CH:3]=[C:2]([NH:1][C:21]([NH:20][CH:18]([CH3:19])[CH3:17])=[O:22])[CH:7]=[CH:6][N:5]=1
Reactant: CC(C)N=C=O
Reactant: Nc1ccnc(Cl)c1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Product: CC(C)NC(=O)Nc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2.6 grams (0.0203 mole) of 4-amino-2-chloropyridine, 0.53 gram (0.005 mole) of 1,4-diazabicyclo[2.2.2]octane (DABCO), and 3.9 ml (0.0305 mole) of (1-methylethyl)isocyanate in 20 ml of dry dimethylformamide was stirred at ambient temperature for five days. The dimethylformamide was removed under reduced pressure. The residue was taken up in 20 ml of ethanol and this was removed under reduced pressure. The procedure was repeated a second time using an additional 20 ml of ethanol. The residual oil was dried under reduced pressure at ambient temperature for 16 hours, then under reduced pressure at 60° C. for one hour. The resultant solid was triturated in hot water. The mixture was allowed to cool to ambient temperature then placed in a refrigerator where it stood for 60 hours. The solid was collected by filtration, washed with water and dried under reduced pressure for three hours at 40°-50° C. The yield of N-(2-chloro-4-pyridinyl)-N'-(1-methylethyl)urea was 4.1 grams, m.p. 142°-146.5° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[F:12].CN(CCN(CCN(C)C)C)C.C([Li])CCC.[CH:32](N1CCOCC1)=[O:33]>O.C1COCC1>[CH3:14][O:13][CH:3]([O:2][CH3:1])[C:4]1[C:5]([F:12])=[C:6]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH:32]=[O:33]
Reactant: O=CN1CCOCC1
Reactant: COc1ccc(F)c(C(OC)OC)c1
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C=O)c(F)c(C(OC)OC)c1
Temperature: -60 °C
Reaction time: 3 h

Procedure:
To 15 ml of a THF solution containing 3.665 g of 2-dimethoxymethyl-1-fluoro-4-methoxybenzene [CAS No. 883576-30-5] and 3.48 g of N,N,N′,N′,N″-pentamethyldiethylenetriamine, 7.1 ml of n-butyllithium (2.66 M, hexane solution) was added dropwise at −74° C. The resulting mixture was stirred at −60° C. for 3 hours, and then 3 ml of N-formylmorpholine was added thereto. The temperature of the reaction mixture was slowly allowed to rise to room temperature. Then, water was added to the reaction mixture while cooling on ice, and then the mixture was extracted with a mixture of hexane and t-butylmethyl ether and dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure to give a crude product of 3-dimethoxymethyl-2-fluoro-5-methoxybenzaldehyde.
Reaction SMILES: N[C:2](=[CH:20][C:21]([O:23][CH3:24])=[O:22])[CH:3]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)=[O:7])[CH3:4].C([O-])(=[O:27])C.[NH4+]>C(O)(=O)C>[CH3:24][O:23][C:21]([CH2:20][C:2](=[O:27])[CH:3]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)=[O:7])[CH3:4])=[O:22]
Reactant: CC(=O)[O-]
Reactant: COC(=O)C=C(N)C(C)OC(=O)c1ccc(-c2ccccc2)cc1
Agent: [NH4+]
Solvent: CC(=O)O
Product: COC(=O)CC(=O)C(C)OC(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
A mixture of biphenyl-4-carboxylic acid 2-amino-3-methoxycarbonyl-1-methyl-allyl ester (566 g, 1.74 mol, 1 eq) and ammonium acetate (283 g, 3.67 mol) in glacial acetic acid (11.3 L) was heated at reflux for 2 h, cooled, and concentrated. The residue was coevaporated with toluene (2×2.5 L) and EtOAc (2.5 L). The mixture was diluted with EtOAc (6.6 L) and transferred with EtOAc (2.2 L) to a bottom outlet separation flask. The mixture was washed twice with water (2.2 L), saturated aqueous NaHCO3 (1.1 L), and brine (2×2.2 L). The organic layer was dried (Na2SO4, 550 g), filtered with the aid of EtOAc (1.1 L), and concentrated. The residue was dissolved in isopropanol (2 L) at 50° C. and allowed to cool overnight at room temperature. The mixture was kept at 0° C. to 5° C. for 1 h. The precipitated solid was broken up and collected by filtration. The solid was washed with cold isopropanol (4×0.55 L) and dried overnight in a vacuum oven at 50° C. to yield 428 g of the title compound (72% from Step 2).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.B(O)(O)[C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[C:16]1([CH3:19])[CH:17]=[CH:18][C:13]([C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:14][CH:15]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: FC(F)(F)c1cccnc1Cl
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: [Na+]
Solvent: COCCOC
Product: Cc1ccc(-c2ncccc2C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a de-gassed mixture of 2-chloro-3-(trifluoromethyl)-pyridine (70.1 mmol), p-tolylboronic acid (70.6 mmol), and 2M Na2CO3 (175.0 mmol) in DME (200 mL) under nitrogen, add Pd(PPh3)4 (2.8 mmol). Stir the mixture at 80° C. overnight, concentrate, and extract with EtOAc. Dry over Na2SO4, concentrate under vacuum, and pass through a silica gel pad to give 2-p-tolyl-3-trifluoromethyl-pyridine.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([C:53]2[CH:54]=[C:55]3[CH:61]=[CH:60][N:59]([CH3:62])[C:56]3=[N:57][CH:58]=2)[C:16]([C:18]2[CH:19]=[C:20]([C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][C:28]=3[C:34]([N:36]3[C@H:45]([CH2:46][N:47]4[CH2:52][CH2:51][O:50][CH2:49][CH2:48]4)[CH2:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH2:37]3)=[O:35])[N:21]3[C:26]=2[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:17])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:83][C:84]([N:86]1[CH2:91][CH2:90][CH2:89][CH2:88][CH2:87]1)=[O:85].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([C:53]2[CH:54]=[C:55]3[CH:61]=[CH:60][N:59]([CH3:62])[C:56]3=[N:57][CH:58]=2)[C:16]([C:18]2[CH:19]=[C:20]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:83][C:84](=[O:85])[N:86]4[CH2:91][CH2:90][CH2:89][CH2:88][CH2:87]4)=[CH:29][C:28]=3[C:34]([N:36]3[C@H:45]([CH2:46][N:47]4[CH2:48][CH2:49][O:50][CH2:51][CH2:52]4)[CH2:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH2:37]3)=[O:35])[N:21]3[C:26]=2[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:17])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(CO)N1CCCCC1
Reactant: Cn1ccc2cc(N(C(=O)c3cc(-c4ccc(O)cc4C(=O)N4Cc5ccccc5C[C@H]4CN4CCOCC4)n4c3CCCC4)c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cnc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cn1ccc2cc(N(C(=O)c3cc(-c4ccc(OCC(=O)N5CCCCC5)cc4C(=O)N4Cc5ccccc5C[C@H]4CN4CCOCC4)n4c3CCCC4)c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cnc21
Temperature: 50 °C
Reaction time: 1 h

Procedure:
The compound of Step D (3.0 g, 2.9 mmol) is dissolved in 100 mL of toluene. 1.53 g (5.8 mmol) of triphenylphosphine and 0.62 g (4.3 mmol) of 2-hydroxy-1-(1-piperidyl)ethanone are added thereto. The mixture is heated to 50° C., and then 1.01 g (4.3 mmol) of di-tert-butyl azodicarboxylate are added. The reaction mixture is stirred at 50° C. for 1 hour and is then allowed to return to ambient temperature before adding 1 mL of trifluoroacetic acid. After stirring overnight at ambient temperature, the mixture is successively washed with water, saturated NaHCO3 and brine solution. The combined aqueous phases are extracted with ethyl acetate. The resulting organic phases are dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product obtained is purified by chromatography over silica gel (dichloromethane/ethanol 98/2) to yield the expected compound.
Reaction SMILES: O[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:4]=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26](=[O:60])[N:27]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][C:36]3[N:37]=[CH:38][N:39](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:40]=3)=[CH:31][N:30]=2)[CH:28]=1.CCN(C(C)C)C(C)C.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>C(Cl)Cl>[Cl:22][C:23]1[CH:24]=[CH:25][C:26](=[O:60])[N:27]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][C:36]3[N:37]([CH2:2][C:3]4[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[CH:4]=4)[CH:38]=[N:39][CH:40]=3)=[CH:31][N:30]=2)[CH:28]=1
Reactant: O=c1ccc(Cl)cn1-c1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cn1
Reactant: N#Cc1ccc(CO)cc1OCCCCc1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)cc1OCCCCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled solution (-78° C.) of 4-hydroxymethyl-2-(4-phenyl-butoxy)-benzonitrile from step 2 (100 mg, 0.36 mmol) and 5-chloro-5'-(1-trityl-1H-imidazol-4-ylmethyl)-[1,2']bipyridinyl-2-one from Example 23 Step 5 (188 mg, 0.36 mmol) in CH2Cl2 (2 ml) was added DIEA (136 μl, 0.78 mmol) followed immediately by the addition of Tf2O (90 μl, 0.53 mmol). The reaction mixture stirred at -78° C. for 1 hour and was then transferred to an ice bath and stirred at 0° C. for another hour. The solvent was removed in vacuo. The residue was then dissolved in MeOH (2 ml) and heated to 60° C. for several hours. The MeOH was then removed in vacuo and the residue treated with saturated NaHCO3 (5 mL) and extracted with CH2Cl2 (2×10 mL). The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography [4% MeOH(5% NH4OH)/CH2Cl2 ] to yield the final product.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.Cl[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:21]4[CH:22]=[CH:23][C:24]([O:27][CH2:30][CH2:31][N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[CH:25][CH:26]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4ccc(O)cc4)nc23)cc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4ccc(OCCN5CCOCC5)cc4)nc23)cc1
Temperature: 70 °C

Procedure:
A suspension of 4-[8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenol (50.0 mg, 0.131 mmol), 4-(2-chloroethyl)-morpholine hydrochloride (27.0 mg, 0.145 mmol) and potassium carbonate (36.0 mg, 0.260 mmol) in acetonitrile (1 mL) was heated at 70° C. for 18 hours. The mixture was cooled to room temperature, diluted with acetonitrile (10 mL), filtered through a plug of diatomaceous earth and evaporated to an orange resin. The residue was purified via chromatography utilizing an ISCO automated purification apparatus with silica gel column (12 g) and 0%→10% methanol:dichloromethane solvent gradient. The title compound, [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-amine, was isolated as a yellow foam (0.047 g, 72%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.47 (d, J=6.5 Hz, 1H), 8.23 (d, J=8.4 Hz, 2H), 8.07 (d, J=8.3 Hz, 2H), 7.64 (d, J=7.4 Hz, 1H), 7.51-7.46 (m, 2H), 7.00 (t, J=7.0 Hz, 1H), 6.96-6.90 (m, 2H), 6.73 (s, 1H), 4.12 (t, J=5.8 Hz, 2H), 3.77-3.72 (m, 4H), 3.10 (s, 3H), 2.80 (t, J=5.6 Hz, 2H), 2.62-2.55 (m, 4H). MS=494 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=[C:5]([CH3:19])[N:6]2[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>CC#N>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([O:20][C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][S:36]([CH3:35])(=[O:38])=[O:37])[N:6]([CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[C:5]=2[CH3:19])=[CH:26][CH:25]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(Oc2ccc(Cl)cc2)c2c(N)cccc2n1CC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(Oc2ccc(Cl)cc2)c2c(NS(C)(=O)=O)cccc2n1CC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of the product from step (iv) (70 mg) in MeCN (1 ml) was added triethylamine (50 ul) and methanesulfonyl chloride (24 ul) and the reaction stirred at 50° C. for 3 h. The residue was partitioned between diethylether/water, the organics were separated, washed with aq potassium hydrogensulfate solution, brine, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 5-30% ethylacetate/iso-hexane.