Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([F:11])[C:8](F)=[CH:7][C:6]=1[F:13])[CH3:2].C(N(CC)CC)C.[C:22]([O:26][C:27](=[O:34])[NH:28][CH:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)([CH3:25])([CH3:24])[CH3:23]>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:31]2[CH2:32][CH2:33][CH:29]([NH:28][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:34])[CH2:30]2)=[CH:7][C:6]=1[F:13])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: CCOC(=O)c1cc(F)c(F)cc1F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1cc(F)c(N2CCC(NC(=O)OC(C)(C)C)C2)cc1F
Reaction time: 45 h

Procedure:
To a solution of 2,4,5-trifluorobenzoic acid ethyl ester (Example 1e, 14.8 g, 72.4 mmol) in acetonitrile (225 mL) is added triethylamine (65 mL, 466 mmol) and pyrrolidin-3-ylcarbamic acid tert-butyl ester (16.07 g, 86.2 mmol). After 45 hours, the reaction mixture is diluted with ethyl acetate and washed with saturated NaHCO3, water, and brine. The organic layer is dried over MgSO4, filtered, and the filtrate is concentrated to afford an oil. The resulting residue is purified by flash chromatography (1:5 ethyl acetate/hexanes) to afford the title compound. MS (ES, M+1) m/z 371, mp 98–100° C.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C@H:3]1[C@H:7]([OH:8])[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[H-].[Na+].I[CH3:20]>C1COCC1>[C:12]([O:11][C:9]([N:5]1[CH2:6][C@@H:7]([O:8][CH3:20])[C@H:3]([N:2]([CH3:16])[CH3:1])[CH2:4]1)=[O:10])([CH3:13])([CH3:15])[CH3:14]
Reactant: CN(C)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1N(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of racemic (trans)-tert-butyl 3-(dimethylamino)-4-hydroxypyrrolidine-1-carboxylate (0.96 g, 4.17 mmol) in THF (40 mL) at 0° C. was added NaH (0.25 g, 6.25 mmol, 60% dispersion in mineral oil), and the reaction mixture was stirred at 0° C. for 10 min. Then, iodomethane (0.29 mL, 4.6 mmol) was added dropwise and the resulting mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with sat aq NH4Cl and extracted three times with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to provide racemic-(trans)-tert-butyl-3-(dimethylamino)-4-methoxypyrrolidine-1-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.84 (br. s., 1 H), 3.46-3.54 (m, 1 H), 3.25 (s, 3 H), 3.12-3.22 (obs m, 3 H), 2.72 (br. s., 1 H), 2.16 (s, 6 H), 1.39 (s, 9 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])/[C:4](=[CH:9]\[C:10]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:11]1)/[CH2:5][C:6]([OH:8])=[O:7].C[O-].[Na+].N#N>CO>[CH3:1][O:2][C:3](=[O:20])[C@H:4]([CH2:9][C:10]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:12]1)[CH2:5][C:6]([OH:8])=[O:7]
Reactant: COC(=O)/C(=C\C1(Cc2ccccc2)CC1)CC(=O)O
Agent: C[O-]
Agent: N#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H](CC(=O)O)CC1(Cc2ccccc2)CC1
Reaction time: 24 h
Yield: 91.1 %

Procedure:
A solution of 2-[1-(1-Benzyl-cyclopropyl)-meth-(Z)-ylidene]-succinic acid 1-methyl ester (2.686 g, 9.79 mmol) and sodium methoxide (0.1 eq., 0.98 mmol, 52.9 mg) in dry methanol (25 mL) was degassed with N2 for 5 min then (+)-(2S,5S)-2,5-Diethylphospholanobenzene (cyclooctadiene) Rhodium tetrafluoroborate (25 mg) was added. The mixture was hydrogenated at 60 psi for 24 hr, then concentrated in vacuum. The residue was diluted with NaHCO3 (150 mL) and the solution was made basic with NaOH and extracted with ether (80 mL). The aqueous layer was acidified to pH 1 and extracted with ether (2×100 mL). The acidic extracts were dried (MgSO4) and concentrated in vacuum to afford (R)-2-(1-Benzyl-cyclopropylmethyl)-succinic acid 1-methyl ester as a yellow oil (2.465 g, 91% yield).
Reaction SMILES: [O:1]=[C:2]([C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)[CH2:3][CH2:4][C:5]#[C:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].C1CCCCC=1>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C1(C)C=CC=CC=1>[O:1]=[C:2]([C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)[CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)CCC#CCCC(=O)c1ccco1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: Cc1ccccc1
Solvent: C1=CCCCC1
Product: COC(=O)CC/C=C\CCC(=O)c1ccco1
Yield: 90.6 %

Procedure:
A mixture of 1-oxo-1-furyl-7-methoxycarbonyl-4-heptyne [VII-1] (3.0 g) obtained in Example 13, a Lindlar catalyst (5% Pd-CaCO3 -PbO) (30 mg), cyclohexene (5.26 g) and toluene (12 ml) is charged in an atmospheric hydrogenation apparatus and subjected to reduction at room temperature under atmospheric pressure. After completion of the reaction, the catalyst is removed by filtration and the filtrate is concentrated to give 1-oxo-1-furyl-7-methoxycarbony-cis-4-heptene [VII-2] (2.74 g, yield; 90.4%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12])[CH3:2].[N:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C)C(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CC(O)=O>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C:17]2[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=2)[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12])[CH3:2]
Reactant: OB(O)c1ccncc1
Reactant: CCOc1cc(Br)ccc1[N+](=O)[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CC(=O)O
Product: CCOc1cc(-c2ccncc2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 77.5 %

Procedure:
A solution of 5-bromo-2-nitrophenyl ethyl ether (4.64 g, 18.86 mmol), PdCl2(dppf)*DCM (0.69 g, 0.94 mmol) and 4-pyridylboronic acid (4.03 g, 32.8 mmol) in N,N-dimethylacetamide (113 mL) was deoxygenated by bubbling with N2 (g) for ca 15 min. To this solution was added degassed 1.6 N K2CO3 (aq) (56.6 mL, 6.0 equiv.) and the resulting slurry was warmed to 80° C. for 24 h. The mixture was poured into 300 mL of H2O and neutralized with HOAc. The product was extracted with DCM, and dried (MgSO4). The solvent was rotovaped down and the crude product was purified by flash chromatography to give the title compound of step B (3.57 g, 14.62 mmol, 77.5%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.66-8.70 (m, 2H), 7.97 (d, J=8.42 Hz, 1H), 7.77-7.81 (m, 2H), 7.64 (d, J=1.65 Hz, 1H), 7.47 (dd, J=8.42, 1.65 Hz, 1H), 4.33 (q, J=6.96 Hz, 2H), 1.34 (t, J=6.96 Hz, 3H).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])(=O)C.[OH-].[Na+]>C(COC)OC>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([NH2:4])=[C:6]([N+:12]([O-:14])=[O:13])[CH:7]=1
Reactant: CC(=O)Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: Nc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
A mixture of 1d (3.5 g, 13.5 mmol), dimethoxyethane (100 ml) and aqueous sodium hydroxide (50 ml, 1 M) is heated to 80° C. for 1 hour. After cooling the mixture is poured into ice-water. The product is filtered off, washed with water and dried. Yield 2.77 g (94%). Mp 109-1 10° C.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])[C:2]#[CH:3].[OH2:17].[K+].[Br-]>N1C=CC=CC=1CO.CC([O-])=O.CC([O-])=O.[Cu+2]>[N+:14]([C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[NH:4][CH2:1][C:2]#[C:3][C:3]#[C:2][CH2:1][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:12])=[O:17])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])([O-:16])=[O:15]
Reactant: O
Reactant: C#CCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: OCc1ccccn1
Product: O=[N+]([O-])c1ccc(NCC#CC#CCNc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a suspension of Cu(OAc)2.H2 0 (1.5 g) in pyridinemethanol (1:1, 10 ml) was added N-(2-propynyl)-2,4-dinitroaniline (1.00 g, 4.52×10-1 mole). The reaction mixture was stirred at 50° C. for 30 minutes. The mixture was poured into excess water, and filtered. The crude solid was recrystallized from nitromethane to afford pale green crystals. Yield: 0.86 g (86%). The compound failed to melt at 200° C. but changed from green to bronze color at 120° C. It could be recrystallized from dioxane to give a different crystal form, appearing as orange crystals which turn deep orange at 140° C. IR (KBr): 3380 (NH), 1617, 1592, 1333 and 1312 cm-1 (Ar-NO2).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([C:20](OCC)=[O:21])[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+]>O1CCCC1>[CH2:1]([O:8][CH2:9][C:10]1([CH2:20][OH:21])[CH2:19][CH2:18][C:13]2([O:14][CH2:15][CH2:16][O:17]2)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(COCc2ccccc2)CCC2(CC1)OCCO2
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1(COCc2ccccc2)CCC2(CC1)OCCO2
Yield: 74.9 %

Procedure:
To a solution of ethyl 8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate (Reference Example 84) (279 mg, 0.834 mmol) in tetrahydrofuran (4.2 mL), lithium borohydride (91.0 mg, 4.17 mmol) was added with stirring under ice-cooling, and the obtained solution was stirred at 70° C. for 4 hours. The reaction was quenched by adding saturated aqueous ammonium chloride solution to the reaction solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (183 mg, 0.625 mmol, 75%) as a colorless oily compound.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:17][CH2:16][C@@H:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[CH2:32]([CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[CH2:32]([CH:39]1[CH2:44][CH2:43][N:42]([CH2:12][C@H:13]2[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:14]2)[CH2:41][CH2:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](CN2CCC(Cc3ccccc3)CC2)C1
Temperature: 0 °C
Yield: 124.5 %

Procedure:
To a stirred solution of ((1R,4S)-4-(tert-butoxycarbonylamino)cyclopent-2-enyl)methyl 4-methylbenzenesulfonate (step 1, about 0.5 g) in DCM (50 ml), potassium carbonate (about 0.3 g) was added at room temperature and cooled to about 0° C. After ten minutes, 4-benzylpiperidine (0.17 g) was added and stirred the reaction at room temperature for about 6 hours. Completion of the reaction was monitored by TLC. The reaction mixture was neutralized and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (0.45 g) as light yellow liquid. 1H NMR (300 MHz, CDCl3: 1.24-1.29 (m, 1H); 1.39-1.40 (s, 9H); 2.29-2.60 (m, 7H); 2.79-2.80 (m, 1H); 3.70-3.73 (m, 4H); 4.63 (S, 1H); 5.37-5.39 (d, J=6 Hz, 1H); 5.72-5.81 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH2:8]Cl.[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]1[N:31]=[C:19]2[N:20]=[C:21]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[N:22]=[C:23]([NH2:24])[N:18]2[N:17]=1.CCN(CC)CC>CC#N>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH2:8][N:28]1[CH2:27][CH2:26][N:25]([C:21]2[N:22]=[C:23]([NH2:24])[N:18]3[N:17]=[C:16]([C:12]4[O:11][CH:15]=[CH:14][CH:13]=4)[N:31]=[C:19]3[N:20]=2)[CH2:30][CH2:29]1
Reactant: Nc1nc(N2CCNCC2)nc2nc(-c3ccco3)nn12
Reactant: ClCc1c(Cl)cncc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1nc(N2CCN(Cc3c(Cl)cncc3Cl)CC2)nc2nc(-c3ccco3)nn12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3,5-Dichloro-4-chloromethyl-pyridine (1.5 eq.) was added to a solution of 2-furan-2-yl-5-piperazin-1-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (0.14 mmol; see Example 1(a) above) and Et3N (0.3 mmol) in 3 mL of CH3CN. The resulting reaction mixture was stirred at room temp for 18 hours. It was then concentrated and purified by preparative HPLC using a mixture of aqueous CH3CN that has been buffered with 0.1% TFA. 1H-NMR (DMSO-d6) δ 8.9 (s, 2H), 7.60 (d, J=1.0 Hz, 1H), 7.28 (br s, 2H), 7.22 (d, J=3.6 Hz, 1H), 6.68 (dd, J=3.6 Hz, 1.0 Hz, 1H), 3.8 (br s, 2H), 2.2-3.2 (m, 8H). MS: m/z: 447 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:26][CH:27]([CH3:31])[CH2:28][O:29][CH3:30])=[C:12]([NH:17][C:18]([CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=O)[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:32][CH3:33])=[C:5]([CH3:34])[O:4][N:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH3:33][O:32][C:8]1[C:7]([C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:34])=[CH:16][C:15]2[N:14]=[CH:13][C:12]3[N:17]=[C:18]([CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[N:26]([CH:27]([CH3:31])[CH2:28][O:29][CH3:30])[C:11]=3[C:10]=2[CH:9]=1
Reactant: COCC(C)Nc1c(NC(=O)C2CCOCC2)cnc2cc(-c3c(C)noc3C)c(OC)cc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COCC(C)n1c(C2CCOCC2)nc2cnc3cc(-c4c(C)noc4C)c(OC)cc3c21

Procedure:
A mixture of N-(7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-4-((1-methoxypropan-2-yl)amino)quinolin-3-yl)tetrahydro-2H-pyran-4-carboxamide (for a preparation see Intermediate 3) (11.95 g, 25.5 mmol) and p-toluenesulfonic acid (1.2 g, 25.5 mmol) in toluene (250 ml) was heated under nitrogen at reflux using a Dean-Stark apparatus for 3 days. Further p-toluenesulfonic acid (0.2 g, 4.3 mmol) was added and heating continued overnight. Water (750 ml) was added, and the mixture basified to pH 8 using saturated aqueous sodium hydrogen carbonate solution. The aqueous was extracted with ethyl acetate (3×750 ml), the organic layers combined, dried (hydrophobic frit) and evaporated under reduced pressure. The residual solid was triturated in ether (˜200 ml), sonicated briefly. The majority of the solid appeared to be a fine powder. The fine powder suspended in the ether was decanted, the solid isolated by filtration, and dried in a vacuum oven to give crude 4-(8-methoxy-1-(1-methoxypropan-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinolin-7-yl)-3,5-dimethylisoxazole (6.3 g). This material was triturated in ether (˜100 ml), sonicated briefly, and stood overnight at room temperature. The solid was isolated by filtration and dried in a vacuum oven 4-(8-methoxy-1-(1-methoxypropan-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinolin-7-yl)-3,5-dimethylisoxazole (4.9 g, 10.88 mmol, 42.6% yield). LCMS (formate): Rt 0.75 min, MH+451.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:18][CH2:12][C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc(OCc2ccccc2)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-benzyloxybenzyl alcohol (2 g, 9.3 mmol) and carbon tetrabromide (4 g, 12.1 mmol) in CH2Cl2 (70 mL), cooled to 0° C., was added a solution of triphenylphosphine (2.9 g, 11.2 mmol) in CH2Cl2 (20 mL). The reaction was stirred at rt for 3 h and concentrated. Purification by flash chromatography (silica gel, 0-8% EtOAc/hexanes) gave 1-((3-(bromomethyl)phenoxy)methyl)benzene. 1H NMR (400 MHz, CDCl3) δ 7.39 (m, 5H), 7.25 (m, 1H), 7.00 (m, 2H), 6.92 (m, 1H), 5.06 (s, 2H), 4.46 (s, 2H).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27](Cl)=[N:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[C:32]([C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)#[CH:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu]I>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([C:33]#[C:32][C:34]4[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=4)=[N:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C#Cc1ccncc1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nccnc2Cl)CC1
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nccnc2C#Cc2ccncc2)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
3′-Chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid (3,5-bis-trifluoromethylphenyl)amide (200 mg, 0.441 mmol, prepared in Example 16b) was dissolved in 1.8 mL of acetonitrile. Another mixture was prepared containing 4-ethynylpyridine hydrochloride (125 mg, 0.896 mmol), palladium(II) acetate (12 mg, 0.053 mmol), copper(I) iodide (5 mg, 0.026 mmol), triphenylphosphine (28 mg, 0.107 mmol) and triethylamine (600 μL) in 600 μL of acetonitrile. The two mixtures were combined and stirred at 80° C. for 1 hr under a nitrogen atmosphere. The reaction mixture was filtered through Celite and concentrated under vacuum. The material was used without further purification.
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([CH:13]([OH:15])[CH3:14])[N:10]=[C:9]1[CH3:16])C1C=CC=CC=1.[H][H]>[Pd].CO>[OH:15][CH:13]([C:11]1[N:10]=[C:9]([CH3:16])[NH:8][CH:12]=1)[CH3:14]
Reactant: Cc1nc(C(C)O)cn1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1nc(C(C)O)c[nH]1
Temperature: 50 °C
Reaction time: 16 h
Yield: 110.4 %

Procedure:
A Parr shaker was charged with 10.0 g (46.23 mmole) of 1-benzyl-4-(1-hydroxyethyl)-2-methylimidazole, 60 ml of methanol and 2.0 g of 5% palladium-on-carbon (50% water). Hydrogen gas was introduced to 30 psi (2.04 atmospheres), the mixture heated to 50° C. and shaken for 16 hours. It was cooled to 30° C., filtered through diatomaceous earth and the filter cake washed with 10 ml of methanol. Evaporation of the combined filtrate and wash under reduced pressure gave 6.44 g (97% yield) of the title product as an oil.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH:15]([C:18]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([CH3:27])[CH3:26])[C:19]=1[NH2:20])([CH3:17])[CH3:16].[CH3:28][C:29]([CH3:31])=O.C(O)(=O)C>ClCCCl>[CH:29]([NH:20][C:19]1[C:18]([CH:15]([CH3:17])[CH3:16])=[CH:24][CH:23]=[CH:22][C:21]=1[CH:25]([CH3:27])[CH3:26])([CH3:31])[CH3:28]
Reactant: CC(C)=O
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)Nc1c(C(C)C)cccc1C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.1 %

Procedure:
NaBH(OAc)3 (3.2 g, 15 mmol) was added into a solution of 2,6-diisopropylaniline (0.940 mL, 4.98 mmol), acetone (1.8 mL, 25 mmol) and acetic acid (0.57 mL, 10 mmol) in 1,2-dichloroethane (30 mL) at room temperature. After stirring at room temperature for 16 h, the reaction was quenched by adding 1M NaOH aq. solution (20 mL). The organic layer was extracted with CH2Cl2 (30 mL), and the volatiles were evaporated under reduced pressure. Column chromatography (silica gel, 20:1 hexane/ethyl acetate) gave the product (0.733 g, 66.8%). 1H NMR (300 MHz, CDCl3) δ 7.24-6.95 (m, 3H), 3.47-3.12 (m, 3H), 2.86 (br. s, 1H), 1.27 (d, J=7.0 Hz, 12H), 1.19 (d, J=6.4 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 142.4, 142.1, 123.6, 123.3, 51.6, 28.0, 24.5, 23.7. HRMS-ESI (m/z): [M+H]+ calcd for C15H26N, 220.2065; found, 220.2064.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)#[N:10].C[Si](C)(C)[N-][Si](C)(C)C.[K+]>>[C:9]([C:11]1([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=2)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)#[N:10]
Reactant: Fc1cccc(F)n1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2cccc(F)n2)CC1

Procedure:
2,6-Difluoropyridine (2 g, 17 mmol) and tert-butyl 4-cyanopiperidine-1-carboxylate (2.4 g, 11 mmol) were reacted in the presence of potassium hexamethyldisilazide (14 mmol) using the method described in example 8-1 to afford the desired product: tert-butyl 4-cyano-4-(6-fluoropyridin-2-yl)piperidine-1-carboxylate: 1H NMR δ (ppm)(CDCl3): 7.86 (1 H, q, J=7.9 Hz), 7.54 (1 H, dd, J=2.3, 7.4 Hz), 6.93-6.91(1 H, m), 4.28 (21H, br s), 3.17 (2 H, br s), 2.25-2.17 (2 H, m), 2.02 (2 H, d, J=14.6 Hz), 1.48 (9H, s).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[C:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:3]1=[O:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:36](O)(=[O:38])[CH3:37].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:36]([O:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[C:9][CH2:10][N:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)[C:3]1=[O:16])(=[O:38])[CH3:37]
Reactant: O=C1[C@@H](O)CCN1CC#CCN1CCCC1
Reactant: CC(=O)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1CCN(CC#CCN2CCCC2)C1=O
Reaction time: 8 h

Procedure:
A solution of 0.5 g of (S)-3-hydroxy-1-[4-(1-pyrrolidinyl)-2-butynyl]-2-pyrrolidinone, 0.75 g of triphenylphosphine and 0.2 ml of acetic acid in 20 ml of tetrahydrofuran was stirred at room temperature in a tap water bath. A 0.6 g portion of diethyl azodicarboxylate was added dropwise, this mixture was stirred overnight, then the solvent was removed in vacuo. The residue was purified by chromatography (silica gel), giving 0.4 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Si]([O:47][CH2:48][C:49]1[S:53][C:52]([C:54](=[N:56]O)[NH2:55])=[C:51]([CH2:58][CH3:59])[CH:50]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:56]=[C:54]([C:52]3[S:53][C:49]([CH2:48][OH:47])=[CH:50][C:51]=3[CH2:58][CH3:59])[N:55]=2)[CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccc(Oc2ccccc2)c(Cl)c1
Reactant: CCc1cc(CO[Si](C)(C)C(C)(C)C)sc1C(N)=NO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCc1cc(CO)sc1-c1noc(-c2ccc(Oc3ccccc3)c(Cl)c2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 12 (12a) using 3-chloro-4-phenoxybenzoic acid (0.12 g, 0.50 mmol) that was obtained in Example 15 (15a), 1-hydroxybenzotriazole (72 mg, 0.53 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.10 g, 0.53 mmol), 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-3-ethyl-N′-hydroxythiophene-2-carboximidamide (0.15 g, 0.48 mmol) that was obtained in Example 10 (10d), and 1.0 M solution of tetrabutylammoniumfluoride in tetrahydrofuran (0.96 mL, 0.96 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:3) as the eluent to afford the title compound (0.17 g) in a yield of 87% as a pale yellow crystalline solid.