Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([CH:12]2[CH2:17][CH2:16][CH:15]([CH2:18]CCC=O)[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)(=O)C.Cl.[CH2:36]1C[O:39][CH2:38][CH2:37]1>>[CH2:1]([CH:6]1[CH2:7][CH2:8][CH:9]([CH:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH:38]([OH:39])[CH2:37][CH3:36])[CH2:14][CH2:13]2)[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: C1CCOC1
Reactant: CCCCCC1CCC(C2CCC(CCCC=O)CC2)CC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Product: CCCCCC1CCC(C2CCC(CC(O)CC)CC2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99 %

Procedure:
While keeping inside of a reaction system at a temperature of lower than 10° C., a solution of 5.0 g (16.3 mmol) of 4-(4-pentylcyclohexyl)-(oxobutyl)cyclohexane obtained in Example 1 and dissolved in 35 ml of THF was added dropwise to a mixture of 0.46 g (12.2 mmol) of LAH and 2.5 ml of THF and further stirred for 5 hours at a room temperature. Under cooled condition, 5 ml of ethyl acetate and then 100 ml of 6N hydrochloric acid were added to terminate the reaction. After extracted with 50 ml of ethyl acetate, the organic layer was washed with water twice and dried over anhydrous magnesium sulfate. After the magnesium sulfate was separated, the solvent was distilled off under a reduced pressure, and the residue thus obtained was recrystallized from 8 ml of hexane to obtain 5.0 g (yield 99%) of 4-(4-pentylcyclohexyl)-(2-hydroxybutyl)cyclohexane. Melting point: 130.9°-131.1° C.
Reaction SMILES: P([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:18]=[CH:17][C:15](=[O:16])[NH:14][C:12]2=[O:13])[C@H:8]([O:19][CH2:20][CH2:21][C:22]#[N:23])[C@@H:7]1[OH:24])(N)O>C(#N)C>[C:22]([CH2:21][CH2:20][O:19][C@@H:8]1[C@H:7]([OH:24])[C@@H:6]([CH2:5][OH:4])[O:10][C@H:9]1[N:11]1[CH:18]=[CH:17][C:15](=[O:16])[NH:14][C:12]1=[O:13])#[N:23]
Reactant: N#CCCO[C@@H]1[C@H](O)[C@@H](COP(N)O)O[C@H]1n1ccc(=O)[nH]c1=O
Solvent: CC#N
Product: N#CCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O

Procedure:
RNA synthesis program (condensation time: 10 min.) was carried out using anhydrous acetonitrile solution of 2′-O-cyanoethyluridine phosphoramidite unit (compound 7, 0.1M) by means of a DNA/RNA automatic synthesizer (Applied Bio System) provided with a long aminoalkyl chain CPG (1 μl) in which 2′-O-cyanoethyluridine was introduced via a succinyl linker by a conventional way (16 μl mol/g), which was filled into a socket for solid-phase synthesis. After the synthesis had been completed, the resulting oligonucleotide was excised from the solid phase by treatment with ammonia water (1 ml) for 20 min. After diluted appropriately with ammonium acetate buffer, the oligonucleotide was purified with a reverse phase column cartridge and an anion exchange HPLC. The oligonucleotide obtained by a desalting operation with the reverse phase column cartridge was lyophilized to give a titled compound with a yield of 21%. Analysis profile obtained in the anion exchange HPLC is shown in FIG. 1A.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:19]3[C:10]([C:11]4[CH:12]=[C:13]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[C:14]([C:20]5[CH:25]=[CH:24][C:23]([C:26]6([NH:30]C(=O)OC(C)(C)C)[CH2:29][CH2:28][CH2:27]6)=[CH:22][CH:21]=5)=[N:15][C:16]=4[CH:17]=[CH:18]3)=[N:9][N:8]=2)[N:4]=[CH:3]1.[ClH:44].CCOC(C)=O>CO.C(Cl)Cl>[ClH:44].[ClH:44].[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:19]3[C:10]([C:11]4[CH:12]=[C:13]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[C:14]([C:20]5[CH:21]=[CH:22][C:23]([C:26]6([NH2:30])[CH2:27][CH2:28][CH2:29]6)=[CH:24][CH:25]=5)=[N:15][C:16]=4[CH:17]=[CH:18]3)=[N:9][N:8]=2)[N:4]=[CH:3]1
Reactant: Cn1cnc(-c2nnc3c4cc(-c5ccccc5)c(-c5ccc(C6(NC(=O)OC(C)(C)C)CCC6)cc5)nc4ccn23)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: Cn1cnc(-c2nnc3c4cc(-c5ccccc5)c(-c5ccc(C6(N)CCC6)cc5)nc4ccn23)c1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl (1-{4-[3-(1-methyl-1H-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)carbamate (1-8) (2.52 g, 4.41 mmol) in MeOH (5 mL) and DCM (15 mL) was added a 4N solution of HCl in EtOAc (22 mL, 88 mmol). The sealed reaction mixture was permitted to stir at room temperature. After 4 hours the reaction mixture was concentrated in vacuo to give 1-{4-[3-(1-methyl-1H-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutanamine dihydrochloride (1-9) as a yellow solid. HRMS (M+H)+: observed=472.2249, calculated=472.2244.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:9][O:10][C:11]1[C:15](OC)=[N:14][S:13](=[O:18])[N:12]=1>CO>[CH3:9][O:10][C:11]1[C:15]([NH:1][CH2:2][C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)=[N:14][S:13](=[O:18])[N:12]=1
Reactant: COC1=NS(=O)N=C1OC
Reactant: NCc1cccnc1
Solvent: CO
Product: COC1=NS(=O)N=C1NCc1cccnc1

Procedure:
A solution of 3-aminomethylpyridine (2.02 g; 18.7 mmoles) in 80 ml of methanol was added dropwise over 40 minutes to a partial suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (3.03 g; 18.7 mmoles) in 150 ml of methanol, to produce a methanol solution of the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([CH:8]([CH2:18][CH2:19][CH3:20])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:23][C:24]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]2[C:25]=1[CH:26]=[N:27][C:28]([CH3:35])=[N:29]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([CH:8]([CH2:18][CH2:19][CH3:20])[CH2:9][C:10]([C:13]([F:16])([F:14])[F:15])([OH:17])[CH:11]=[N:23][C:24]2[CH:33]=[C:32]([F:34])[CH:31]=[C:30]3[C:25]=2[CH:26]=[N:27][C:28]([CH3:35])=[N:29]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ncc2c(N)cc(F)cc2n1
Reactant: CCCC(CC(O)(C=O)C(F)(F)F)c1cccc(F)c1OC
Agent: [Ti+4]
Agent: CC[O-]
Product: CCCC(CC(O)(C=Nc1cc(F)cc2nc(C)ncc12)C(F)(F)F)c1cccc(F)c1OC

Procedure:
In the same way as in Example 61, 228 mg (0.71 mmol) of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)heptanal, 150 mg (0.85 mmol) of 5-amino-7-fluoro-2-methylquinazoline and 0.5 ml of titanium tetraethoxide are reacted to give 4-(3-fluoro-2-methoxyphenyl)-1-[(7-fluoro-2-methylquinazolin-5-yl)imino]-2-(trifluoromethyl)heptan-2-ol. 185 mg of imine purified by column chromatography (silica gel, hexane/ethyl acetate 0-25%) are cyclized in the same way as in Example 61 at −20° C. with 3 ml (3 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 0-65%) yields 27 mg of product and 38 mg of the corresponding 5α,6α,8α) compound (Example 64).
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.O=[C:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1.[NH4+].[Cl-]>C1COCC1>[CH2:2]=[C:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C1CCC(C(=O)OCC)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of MePh3PBr (37.1 g, 104 mmol) in THF (500 mL) at 0° C. was added slowly LDA (1.2 eq) over 1 h. The resulting orange solution was stirred for 30 min before ethyl 4-oxocyclohexanecarboxylate (16.1 g, 94.4 mmol) was added dropwise. The resulting suspension was warmed to rt and stirred overnight (may not necessary). A saturated NH4Cl (aq) was added and THF was removed. The aqueous residue was extracted with EtOAc (100*3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by passing through a short silica gel plug (hexanes/EtOAc 7:1). After being concentrated, ethyl 4-methylenecyclohexanecarboxylate was obtained as pale yellow oil (12.1 g, 76%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10](O)[CH2:11][O:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[F:44]C(F)(C(F)(F)F)C(F)(F)C(F)(F)S(F)(=O)=O>C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][C@H:10]([F:44])[CH2:11][O:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@H](COCc1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: F[C@@H](COCc1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 3 h

Procedure:
After dissolving (R)-1-benzyloxy-3-trityloxypropan-2-ol (CAS 83526-68-5) (10.45 g) in toluene (50 ml), nonafluoro-1-butanesulfonyl fluoride (7.95 ml) was added and the mixture was cooled on ice. Next, 1,8-diazabicyclo[5.4.0]undeca-7-ene (6.63 ml) was added dropwise while stirring. The mixture was stirred for 30 minutes on ice, and then for 3 hours and 30 minutes at room temperature. The reaction mixture was directly purified by silica gel column chromatography to obtain the title compound (7.52 g).
Reaction SMILES: [OH:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[N:20][N:19]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:16]3=[N:17][CH:18]=2)[CH:8]=1)([CH3:6])[C:3](O)=[O:4].[CH3:38][NH:39][CH3:40].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C1COCC1>[OH:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[N:20][N:19]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:35])[CH3:36])[C:16]3=[N:17][CH:18]=2)[CH:8]=1)([CH3:6])[C:3]([N:39]([CH3:40])[CH3:38])=[O:4]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(C)(O)C(=O)O)c3)cc12
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(C)(O)C(=O)N(C)C)c3)cc12
Temperature: 60 °C

Procedure:
To a solution of 2-hydroxy-2-{3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-propionic acid (100 mg, 0.19 mmol), dimethylamine (2 N in THF, 0.143 mL, 0.29 mmol), and diisopropylethylamine (37 mg, 0.29 mmol) in THF (2 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (110 mg, 0.29 mmol.). The resulting suspension was heated to 60° C. with stirring until all was dissolved. The solvent was evaporated and the residue was used in next step without purification. MS: m/z 547 (M+H+).
Reaction SMILES: [N:1]([CH:4]([C:6]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[C:20]([F:22])[CH:21]=2)=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1)[CH3:5])=[N+]=[N-].CP(C)C.C(OCC)(=O)C>O1CCCC1.O>[F:22][C:20]1[CH:21]=[C:16]([C:15]2[C:6]([CH:4]([NH2:1])[CH3:5])=[CH:7][CH:8]=[C:9]3[C:14]=2[N:13]=[CH:12][CH:11]=[CH:10]3)[CH:17]=[N:18][CH:19]=1
Reactant: CC(N=[N+]=[N-])c1ccc2cccnc2c1-c1cncc(F)c1
Agent: CP(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(N)c1ccc2cccnc2c1-c1cncc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 7-(1-azidoethyl)-8-(5-fluoropyridin-3-yl)quinoline (0.147 g, 0.500 mmol) in tetrahydrofuran (1 mL) and water (0.360 mL) was added 1.00 M trimethylphosphine in tetrahydrofuran (0.60 mL, 0.60 mmol) at room temperature and the mixture was stirred at room temperature for 1 hour. To the mixture was added ethyl acetate and the mixture was extracted with 1 N HCl twice. The combined extracts were neutralized with solid sodium bicarbonate, and then extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue showed two peaks by LCMS with the same desired mass and was used directly in next step (112 mg, 84%). LCMS calculated for C16H15FN3(M+H)+: m/z=268.1; found: 268.0.
Reaction SMILES: [CH:1]12[O:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[CH:2]2[C:3](=[O:12])[CH2:4][C:5]1=[O:11].[CH3:13]O>[Pd]>[CH3:13][C:7]12[O:10][CH:1]([CH2:9][CH2:8]1)[CH:2]1[CH:6]2[C:5](=[O:11])[CH2:4][C:3]1=[O:12]
Reactant: O=C1CC(=O)C2C3C=CC(O3)C12
Reactant: CO
Agent: [Pd]
Product: CC12CCC(O1)C1C(=O)CC(=O)C12

Procedure:
The 10-oxa-tricyclo[5.2.1.0*2,6*]dec-8-ene-3,5-dione (10.5 g) is dissolved in methanol (700 ml). The methanol solution is passed at a rate of 1.5 ml/min through a Thalis H-cube apparatus (from Thalis nanotec) set-up at 40° C. and 40 bar and fitted with a 10% Pd/C cartridge. The so obtained solution is evaporated to give 1-methyl-10-oxa-tricyclo[5.2.1.0*2,6*]decane-3,5-dione (9.2 g).
Reaction SMILES: [C:1]1([C:7]2[C:16]([NH:17][C@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:26]([O:28]C)=[O:27])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:32]I.Cl>C1COCC1>[CH3:32][N:17]([C@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])[C:16]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:26]([OH:28])=[O:27])=[CH:11][CH:10]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N[C@@H](C)c3ccccc3)nc2c1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](c1ccccc1)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of (S)-methyl 2-phenyl-3-(1-phenylethylamino)quinoxaline-6-carboxylate (110 mg, 0.29 mmol, 1.00 equiv) in THF (9 mL), sodium hydride (137.9 mg, 5.74 mmol, 20.00 equiv, 60%). The resulting solution was stirred for 1 h at room temperature in an ice/salt bath. This was followed by the addition of a solution of CH3I (407.8 mg, 2.87 mmol, 10.00 equiv) THF (1 mL) dropwise with stiffing at 0° C. The resulting solution was stirred for overnight at 20° C. in an ice/salt bath. The pH value of the solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1). This resulted in 40 mg (36%) of (S)-3-(methyl(1-phenylethyl)amino)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [C:1](N)(=[O:3])[CH3:2].C=O.O.Cl.[NH:9]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][C:11]([OH:13])=[O:12].C(NCC(O)=O)(=O)C>COCCOC>[C:1]([N:9]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: O=C(O)CNCC(=O)O
Reactant: CC(N)=O
Agent: C=O
Agent: CC(=O)NCC(=O)O
Agent: Cl
Solvent: O
Solvent: COCCOC
Product: CC(=O)N(CC(=O)O)CC(=O)O
Temperature: 110 °C
Yield: 87 %

Procedure:
A 300 mL autoclave was charged with acetamide (VII) (11.8 g, 0.2 mole), 95% paraformaldehyde (13.6 g, 0.43 mole), water (12.9 g, 0.72 mole), 37% HCl (1.8 g, 0.018 mole), DME (90 mL), and Co2(CO)8 (4.1 g, 0.012 mole) and pressurized to 1500 psi (10,345 kPa) CO at 25° C. This mixture was heated to 110° C. for 30 minutes. HPLC analysis of this stream gave an 87% yield of (XVI), 0.5% iminodiacetic acid (XIV), and 4.0% N-acetylglycine (XVIII).
Reaction SMILES: C[O:2][C:3](=[O:14])[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[OH-].[Li+].O1CCCC1.O>CO>[C:8]1([NH:7][C:5](=[O:6])[CH2:4][C:3]([OH:14])=[O:2])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)CC(=O)Nc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CC(=O)Nc1ccccc1

Procedure:
Hydrolysis of the N-Phenyl-malonamic acid methyl ester from step a (6.8 g, 35.2 mmol) with lithium hydroxide (8.9 g, 212 mmol) in a mixture of methanol (160 mL), tetrahydrofuran (160 mL) and water (160 mL) at room temperature for 3 h, afforded the title acid (5.76 g, 91.3%). 1H NMR (400 MHz, DMSO-d6) δ: 12.64 (s, 1H), 10.11 (s, 1H), 7.58 (d, 2H), 7.31 (t, 2H), 7.06 (t, 1H), 3.36 (s, 2H).
Reaction SMILES: CO[C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:31])[CH2:12][O:13][CH:14]2[C:18]([CH3:19])=[C:17]([CH3:20])[C:16](=[O:21])[N:15]2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:6][CH:5]=1.CC1C=CC(N)=NC=1>>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:15]2[C:16](=[O:21])[C:17]([CH3:20])=[C:18]([CH3:19])[CH:14]2[O:13][CH2:12][C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([CH3:3])=[CH:5][N:6]=2)=[O:31])=[CH:28][CH:27]=1
Reactant: COC(=O)c1ccc(NC(=O)COC2C(C)=C(C)C(=O)N2Cc2ccc(OC)cc2)nc1
Agent: Cc1ccc(N)nc1
Product: COc1ccc(CN2C(=O)C(C)=C(C)C2OCC(=O)Nc2ccc(C)cn2)cc1

Procedure:
The product from Example 27, Part B (100 mg, 0.3 mmol) and 5-methylpyridin-2-ylamine (71 mg, 0.66 mmol) were reacted as described in Example 5. After evaporation of the reaction solvent the residue was partitioned between water and EtOAc, and the organic phase was washed with EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered, and evaporated. The title compound was obtained as a white solid by silica gel chromatography. 1H NMR (300 MHz, CDCl3) δ 8.68 (br s, 1H), 8.14 (s, 1H), 8.07 (d, J=8 Hz, 1H), 7.53 (m, 1H), 7.22 (d, J=9 Hz, 2H), 6.79 (d, J=9 Hz, 2H), 5.16 (s, 1H), 4.75 (d, J=15 Hz, 1H), 4.21 (d, J=15 Hz, 1H), 3.70 (s, 3H), 3.68 (d, J=15 Hz, 1H), 3.58 (d, J=15 Hz, 1H), 2.32 (s, 3H), 1.86 (s, 6H). MS: m/z (MH+) 396.
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.Br[C:15]([CH3:19])([CH2:17][CH3:18])[CH3:16].[C:20](#[N:23])[CH:21]=[CH2:22]>C1C=CC=CC=1>[CH3:16][C:15]([CH3:19])([CH2:17][CH3:18])[CH2:22][CH2:21][C:20]#[N:23]
Reactant: C=CC#N
Reactant: CCC(C)(C)Br
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: CCC(C)(C)CCC#N

Procedure:
Tri n-butyl tin hydride (19.6 ml.) and α-azo-iso-butyronitrile (0.5 g.) were added succesively to a stirred solution of 2-bromo-2-methylbutane (10 g.) and acrylonitrile (43.5 ml.) in dry benzene (200 ml.). The mixture was heated at reflux for 6 hours, cooled and filtered. The residue was washed with diethyl ether (50 ml.) and the combined filtrates evaporated under reduced pressure. 4,4-Dimethylhexanenitrile was obtained as a colourless liquid (2.1 g.), b.p. 85°-94°/20 mm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1.C(N(CC)CC)C.FC(F)(F)S(O[Si:31]([CH3:34])([CH3:33])[CH3:32])(=O)=O.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:12][CH:13]=[C:14]([O:17][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH2:15][CH2:16]1
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)OC1=CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a stirred solution of 1-(2-fluoro-4-nitrophenyl)piperidin-4-one (Step 1, 250 g, 1.05 mol) and triethylamine (223 g, 2.20 mol) in toluene (4.2 liter) at 0° C. is slowly added trimethylsilyl trifluoromethanesulfonate (TMS-OTf, 280 g, 1.26 mol) via addition funnel. The stirring is continued for 30 min and the mixture allowed to warm to ambient temperature. Water (5 liter) is added and the aqueous layer extracted with EtOAc (3×500 ml). The organics are combined, dried over MgSO4 and the solvent removed under reduced pressure. Hexane (4×500 ml) is added and the solvent removed under reduced pressure. At the fourth co-distillation, a slurry forms (˜300 ml). The mixture is cooled to 0° C. and the solids filtered. The filtrate is concentrated to a slurry, cooled and filtered (2nd crop). Solids are combined to give 273.7 g (84%) of the title compound as a yellow solid, 1H NMR (CDCl3) δ 0.21 (s, 9 H), 2.20 (brs, 2 H), 3.52 (brs, 2 H), 3.62 (brs, 2 H), 4.89 (brs, 1 H), 6.65 (t, 1 H), 7.67 (d, 1 H), 7.73 (d, 1 H).
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.Cl[C:32]1[N:40]=[C:39]2[C:35]([N:36]=[CH:37][N:38]2[CH3:41])=[C:34]([C:42]2[CH:43]=[C:44]([C:64]([F:67])([F:66])[F:65])[C:45]([O:48][CH2:49][CH2:50][CH:51]3[CH2:56][CH2:55][N:54]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:53][CH2:52]3)=[N:46][CH:47]=2)[N:33]=1.CCOC(C)=O.C[C:75]([N:77](C)C)=O>[Zn].[C-]#N.[Zn+2].[C-]#N.FC(F)(F)C([O-])=O.[Pd+2].FC(F)(F)C([O-])=O>[C:75]([C:32]1[N:40]=[C:39]2[C:35]([N:36]=[CH:37][N:38]2[CH3:41])=[C:34]([C:42]2[CH:43]=[C:44]([C:64]([F:67])([F:66])[F:65])[C:45]([O:48][CH2:49][CH2:50][CH:51]3[CH2:56][CH2:55][N:54]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:53][CH2:52]3)=[N:46][CH:47]=2)[N:33]=1)#[N:77]
Reactant: CC(=O)N(C)C
Reactant: Cn1cnc2c(-c3cnc(OCCC4CCN(C(=O)OC(C)(C)C)CC4)c(C(F)(F)F)c3)nc(Cl)nc21
Agent: [Pd+2]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C([O-])C(F)(F)F
Solvent: CCOC(C)=O
Product: Cn1cnc2c(-c3cnc(OCCC4CCN(C(=O)OC(C)(C)C)CC4)c(C(F)(F)F)c3)nc(C#N)nc21
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Zinc (498 mg), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (1.3 g), zinc cyanide (1.8 g), and palladium (II) trifluoroacetate (498 mg) were added to a solution of tert-butyl 4-(2-{[5-(2-chloro-9-methyl-9H-purin-6-yl)-3-(trifluoromethyl)pyridin-2-yl]oxy}ethyl)piperidine-1-carboxylate (8.3 g) in DMAc (125 mL) at room temperature in an argon atmosphere, and the mixture was stirred at 50° C. for 3 hours. After the reaction mixture was cooled to room temperature, EtOAc (100 mL) and Celite were added thereto, and the mixture was stirred at room temperature. The insoluble material was separated by filtration, and a saturated aqueous NaHCO3 solution, saturated brine, and water was added to the filtrate. Extraction was performed on the mixture using EtOAc, and the extract was washed with water and saturated brine. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex:EtOAc=70:30 to 30:70), whereby tert-butyl 4-(2-{[5-(2-cyano-9-methyl-9H-purin-6-yl)-3-(trifluoromethyl)pyridin-2-yl]oxy}ethyl)piperidine-1-carboxylate (7.6 g) was obtained as a solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]1[C:13](Cl)=[O:14].Cl.[NH2:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23].N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:19]([CH2:20][CH2:21][CH2:22][NH:23][C:13]([C:6]1[N:5]([CH2:4][CH2:3][CH:2]([CH3:16])[CH3:1])[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=1)=[O:14])#[N:18]
Reactant: N#CCCCN
Reactant: CC(C)CCn1cc([N+](=O)[O-])cc1C(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)CCn1cc([N+](=O)[O-])cc1C(=O)NCCCC#N
Temperature: 50 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a mixture of the acid chloride 45 (0.6 g, 2.45 mmol) and 3-aminopropylcyanide hydrochloride (0.31 g, 2.57 mmol) in anhydrous toluene was added 1.5 ml of anhydrous pyridine. The reaction mixture was stirred at 50° C. overnight and then evaporated to dryness. The product was purified by chromatography using toluene-ethyl acetate (2:1) to yield white crystals (0.623 g, 87%). 1H NMR (DMSO-d6) δ 8.46 (t, 1H), 8.17 (d, 1H), 7.39 (d, 1H), 4.37 (t, 2H), 3.27 (quintet, 2H), 2.53 (d, 2H), 1.77 (quintet, 2H), 1.60–1.42 (q and quintet, 3H), 0.87 (d, 6H).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[C:10]([Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11]>>[Br:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([C:18]#[C:17][Si:14]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:16])[CH3:15])=[N:3][CH:4]=1
Reactant: Fc1cc(Br)cnc1Br
Reactant: C#C[Si](C)(C)C(C)(C)C
Product: CC(C)(C)[Si](C)(C)C#Cc1ncc(Br)cc1F

Procedure:
The product was prepared analogously to Example 48.1c from 23.4 g (92.0 mmol) of 2,5-dibromo-3-fluoropyridine and 17.5 mL (92.0 mmol) of tert-butylethynyldimethylsilane (with triethylamine as base and PdCl2(PPh3)2 as catalyst). Yield: 23.3 g (81% of theoretical); C13H17BrFNSi (M=314.269); calc.: molpeak (M+H)+:314/316 (Br); found: molpeak (M+H)+:314/316 (Br).