Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O:3][P:4]([O:19][CH2:20][CH3:21])([CH:6]([P:11]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:8][CH2:9]I)=[O:5].[OH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:32])[CH:30]=[CH2:31])=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:2]([O:3][P:4]([CH:6]([P:11]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:8][CH2:9][O:22][C:23]1[CH:24]=[CH:25][C:26]([C:29](=[O:32])[CH:30]=[CH2:31])=[CH:27][CH:28]=1)([O:19][CH2:20][CH3:21])=[O:5])[CH3:1]
Reactant: C=CC(=O)c1ccc(O)cc1
Reactant: CCOP(=O)(OCC)C(CCCI)P(=O)(OCC)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CC(=O)c1ccc(OCCCC(P(=O)(OCC)OCC)P(=O)(OCC)OCC)cc1
Yield: 98.8 %

Procedure:
A mixture of iodide 33 (3.1 g, 6.8 mmol), phenol 27 (1.21 g, 8.17 mmol) and K2CO3 (1.033 g, 7.47 mmol) in acetone (75 mL) was refluxed for 6.5 h. The mixture was cooled, filtered and evaporated. The residue was redissolved in CH2Cl2 (170 mL), filtered through Celite and evaporated to give crude 34 (3.2 g, 99%) which was used directly in the next step. 1H NMR (400 MHz, CDCl3) δ 1.28-1.39 (m, 12H), 1.89-2.25 (m, 4H), 2.26-2.48 (m, 1H), 4.05 (t, J=5.7, 2H), 4.12-4.26 (m, 8H), 5.87 (dd, J=10.6, 1.8, 1H), 6.42 (dd, J=16.9, 1.8, 1H), 6.93 (d, J=8.8, 2H), 7.17 (dd, J=17.0, 10.4, 1H), 7.95 (d, J=8.8, 2H).
Reaction SMILES: Br[CH2:2][C:3]1([CH3:16])[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[CH2:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][NH:18]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.O>[CH3:16][C:3]1([CH2:2][N:18]2[CH2:19][CH2:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17]2)[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CBr)O2
Reactant: c1ccc2c(c1)CCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCc3ccccc3C1)O2

Procedure:
A suspension of 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine (1.4 g), 1,2,3,4-tetrahydroisoquinoline (1.3 g), and potassium carbonate (1.4 g) in N,N-dimethylacetamide (10 mL) was refluxed under nitrogen gas for 15 hours. This reaction mixture was diluted with water and extracted with 2 portions of ethyl acetate. The pooled organic layer was washed with water and saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3:1) to provide 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1,2,3,4-tetrahydroisoquinolin-2-yl)methyl]-5-benzofuranamine. This product was dissolved in ethanol, followed by addition of 1 equivalent of oxalic acid solution in ethanol. This mixture was heated and the resulting solution was concentrated under reduced pressure. The crystals that separated out were collected to provide 1.5 g of the title compound. Yield 68%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[O-2].[Mg+2].O.Cl[C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14]>C(OCC)(=O)C>[OH:8][C:4]1[CH:3]=[C:2]([NH:1][C:13](=[O:14])[O:15][CH:16]([CH3:18])[CH3:17])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)OC(=O)Cl
Reactant: Nc1cccc(O)c1
Agent: [Mg+2]
Agent: [O-2]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)Nc1cccc(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
A mixture of 3-aminophenol (109 g), magnesium oxide (25 g), water (350 ml) and ethyl acetate (100 ml) was stirred vigorously at room temperature while isopropyl chloroformate (123 g) was added slowly. An ice bath was employed to ensure that the temperature did not exceed 30° C. After stirring for one hour at room temperature, the mixture was filtered to remove insoluble particles. These were washed thoroughly with ether, then the filtrates were combined, then separated, and the organic layers were dried over magnesium sulphate. Evaporation under reduced pressure gave a viscous, pale yellow oil which was crystallised from toluene to give 162.7 g of desired product, mp 75°-77° C.
Reaction SMILES: Cl[C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[NH:18]([CH2:22][CH2:23][OH:24])[CH2:19][CH2:20][OH:21]>O1CCOCC1>[OH:21][CH2:20][CH2:19][N:18]([C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])[CH2:22][CH2:23][OH:24]
Reactant: OCCNCCO
Reactant: COC(=O)c1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: C1COCCO1
Product: COC(=O)c1cc(N(CCO)CCO)c([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 97 %

Procedure:
Methyl 5-chloro-2,4-dinitrobenzoate (IV) (1.24 g, 4.76 mmol) was treated with diethanolarnine (1.00 g, 9.52 mmol) in dioxane (50 mL) at 50 ° C. for 3 h, and the residue after workup was chromatographed on silica gel. Elution with EtOAc gave methyl 5-[N,N-bis(2-hydroxyethyl)amino]-2,4-dinitrobenzoate (V) (1.52 g. 97%). mp (EtOAc/petroleum ether) 104°-106° C. 1H NMR (CDCl3) δ8.48 (s, 1 H, H-3), 7.45 (s, 1H, H-6), 3.95 (s, 3H, OCH3), 3.81 (t, J=5.0 Hz, 4 H, CH2OH), 3.60 (t,J=5.0 Hz, 4H, CH2N), 2.20 (br, 2H, OH). 13C NMR δ165.89 (COOMe), 147.53 (C-5), 138.67, 136.21 (C-2,4), 133.30 (C-1), 124.22. 121.65 (C-3,6), 59.34 (CH2OH), 54.59 (CH2N), 53.74 (OCH3). Anal. (C12H15N3O8) C,H,N.
Reaction SMILES: CS([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:19][CH:18]=1)=[C:11](OS(C(F)(F)F)(=O)=O)[CH:10]=[CH:9]2)(=O)=O.[F-].[Cs+].B1(B2OCC(C)(C)CO2)OCC(C)(C)CO1.Br[C:60]1[CH:65]=[C:64]([F:66])[CH:63]=[C:62]([F:67])[C:61]=1[F:68]>C(#N)C>[OH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([C:16]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)=[CH:19][CH:18]=1)=[O:32])=[C:11]([C:60]1[CH:65]=[C:64]([F:66])[CH:63]=[C:62]([F:67])[C:61]=1[F:68])[CH:10]=[CH:9]2
Reactant: Fc1cc(F)c(F)c(Br)c1
Reactant: CS(=O)(=O)Oc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2cc(F)cc(F)c2F)ccc2cc(O)ccc12
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 100.1 %

Procedure:
Dissolve trifluoromethanesulfonic acid 6-methanesulfonyloxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (10.0 g, 16.6 mmol) in degassed acetonitrile (100 mL). Add cesium fluoride (13.0 g, 83 mmol) and bis(acetato)bis(triphenylphosphine)palladium (1.2 g, 1.7 mmol) followed by bis(neopentyl glycolato)diboron (4.5, 19.9 mmol) and plunge into a 75° C. oil bath under nitrogen. After 15 minutes, add 1-bromo-2,3,5-trifluorobenzene (7.0 g, 33.2 mmol) to the reaction and bis(acetato)bis(triphenylphosphine)palladium (500 mg) and stir at 75° C. for 2.5 hours. Cool the reaction to room temperature and filter through celite. Concentrate the filtrate in vacuo and redissolve the residue in methanol (100 mL). Add KOH (4 g) and stir at room temperature overnight. Pour the reaction into saturated aqueous ammonium chloride and extract with methylene chloride. Dry the organic layer with sodium sulfate, filter and concentrate in vacuo. Purify on 5 SCX columns (loading with methanol and eluting with 2M NH3 in methanol) to obtain 8.4 g (100%) of the title compound. Mass spectrum (ion spray): m/z=506.4 (M+H).
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]2[O:7][CH2:8][C@:3]1([CH2:19][OH:20])[O:4][C@H:5]2[N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH2:18].C[Si](Cl)(C)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.N>N1C=CC=CC=1>[OH:1][C@H:2]1[C@H:6]2[O:7][CH2:8][C@:3]1([CH2:19][OH:20])[O:4][C@H:5]2[N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH:18][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@@]2(CO)CO[C@@H]1[C@@H]2O
Reactant: O=C(Cl)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: N
Solvent: c1ccncc1
Product: O=C(Nc1ncnc2c1ncn2[C@@H]1O[C@@]2(CO)CO[C@@H]1[C@@H]2O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of nucleoside 61A (0.32 g, 1.15 mmol) in anhydrous pyridine (1 cm3) was added trimethylsilyl chloride (0.73 cm3, 5.73 mmol) and the mixture was stirred at room temperature for 20 min. Benzoyl chloride (0.67 cm3, 5.73 mmol) was added at 0° C., and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0° C. and ice-cold water (15.0 cm3) was added. After stirring for 5 min, a 32% (w/w) aqueous solution of ammonia (1.5 cm3) was added and the mixture was stirred for 30 min. The mixture was evaporated to dryness and the residue was dissolved in water (25 cm3). After evaporation of the mixture under reduced pressure, the residue was purified by silica gel chromatography using dichloromethane/methanol (97:3, v/v) as eluent to give nucleoside 61B as a white solid material (0.55 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH2:15][CH3:16])=[CH:12][C:11]([CH2:17][C:18]3[C:19]([NH2:25])=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)=[CH:10][C:9]=2[O:26][CH2:27][C:28]2C=C[CH:31]=[CH:30][CH:29]=2)[CH:5]=[CH:6][CH:7]=1.[C:34](O)(=[O:36])[CH3:35]>C(O)C.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([O:26][CH2:27][CH2:28][CH:29]3[CH2:30][CH2:31][O:36][CH2:34][CH2:35]3)=[CH:10][C:11]([CH2:17][C:18]3[C:19]([NH2:25])=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)=[CH:12][C:13]=2[O:14][CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCc2ccccc2)c1-c1cccc(N)c1
Agent: [Pd]
Solvent: CCO
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCCC2CCOCC2)c1-c1cccc(N)c1

Procedure:
5-(3′-Amino-2-benzyloxy-6-ethoxy-biphenyl-4-ylmethyl)-pyrimidine-2,4-diamine (17.51 g; 39.7 mmol) is hydrogenated in ethanol (66 ml) and acetic acid conc. (198 ml) over Pd/C 10% (8.1 g) for 20 hours. The catalyst is filtered off and the mother liquor is concentrated. The residue is taken up in water and the pH is adjusted to 10 by addition of NH4OH conc. The suspension is filtered with suction and the crystals are washed thoroughly with water and dried under a high vacuum.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[C:17](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1.ClCCl>O1CCOCC1>[CH3:17][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Clc1nccn2c(C3CCOCC3)ncc12
Reactant: O=C([O-])[O-]
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1nccn2c(C3CCOCC3)ncc12
Yield: 77.2 %

Procedure:
Through a suspension of 8-chloro-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazine (2.23 mmol, 531 mg) and potassium carbonate (3.35 mmol, 463 mg) in dioxane (1.5 mL) was bubbled nitrogen for 5 minutes and then trimethylboroxine (4.47 mmol, 1.249 mL, 50 wt % solution in tetrahydrofuran) and 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride complex with dichloromethane (0.223 mmol, 181 mg) were added. After heating the reaction at 100° C. for one hour the reaction mixture was filtered and concentrated in vacuo. Dichloromethane and water were added, the organic layer separated, dried (sodium sulfate) and concentrated in vacuo to yield 374 mg 8-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazine.
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:29]=[CH:28][C:10]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40]Cl>C(OCC)(=O)C>[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([N:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20]3)[CH2:17][CH2:18]2)=[CH:28][CH:29]=1
Reactant: CN(C)CCCl
Reactant: Oc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)CCOc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 42.6 %

Procedure:
N,N-Dimethylformamide (2.5 ml) was added to 1-[1-(4-hydroxyphenethyl)piperidin-4-yl]indoline (0.1 g), potassium carbonate (0.081 g) and 2-dimethylaminoethyl chloride hydrochloride (0.078 g) followed by stirring at 80° C. overnight (12 hr). After allowing to cool, the resultant mixture was mixed with ethyl acetate (200 ml) and the layers were separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (0.052 g) as a brown oil (yield: 27.0%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[C:13]([O:17][C:18]([N:20]1[CH2:24][C@H:23]([CH2:25][OH:26])[C@@H:22]([OH:27])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl>[C:13]([O:17][C:18]([N:20]1[CH2:24][C@H:23]([CH2:25][O:26][S:2]([CH3:1])(=[O:4])=[O:3])[C@@H:22]([OH:27])[CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1C[C@H](CO)[C@@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](COS(C)(=O)=O)[C@@H](O)C1
Temperature: 25 °C
Yield: 33.1 %

Procedure:
Methanesulfonyl chloride (180 μL, 23 mmol) was added dropwise to a CH2Cl2 solution of triethylamine (400 μL, 29 mmol) and (3R,4R)-1-tert-butoxycarbonyl-3-hydroxy-4-(hydroxymethyl)pyrrolidine (1) (2 g, 9.2 mmol) at 0° C. and the resulting solution allowed to warm to room temperature. The reaction was diluted with CH2Cl2, washed with water, brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography to afford (3R,4R)-1-tert-butoxycarbonyl-3-hydroxy-4-(mesyloxymethyl)pyrrolidine (900 mg) as an oil. Without further purification the product was dissolved in DMF (10 mL) and stirred with sodium thiomethoxide (400 mg, 5.7 mmol) at room temp. overnight. The reaction was diluted with toluene washed with water, brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography to afford (3R,4S)-1-tert-butoxycarbonyl-3-hydroxy-4-(methylthiomethyl)pyrrolidine (600 mg, 2.4 mmol) as a syrup, which was not further characterised. (3R,4S)-1-tert-Butoxycarbonyl-3-hydroxy-4-(methylthio)pyrrolidine was dissolved in MeOH (5.0 mL) and cHCl (1.0 mL) and concentrated in vacuo to afford (3R,4S)-3-hydroxy-4-(methylthiomethyl)pyrrolidine hydrochloride (48) as a syrup (442 mg, 26% overall yield for three steps). 13C NMR (D2O) δ 73.5, 51.5, 48.6, 45.2, 34.3, 14.9.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:23])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Cl:20])[CH:19]=2)=[CH:10][CH:9]=1)[NH2:6].[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:26]=1[C:27](O)=[O:28].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:2][O:3][C:4](=[O:23])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Cl:20])[CH:19]=2)=[CH:12][CH:13]=1)[NH:6][C:27]([C:26]1[C:30]([CH3:34])=[CH:31][CH:32]=[CH:33][C:25]=1[Cl:24])=[O:28]
Reactant: Cc1cccc(Cl)c1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2cc(Cl)cn(C)c2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(-c2cc(Cl)cn(C)c2=O)cc1)NC(=O)c1c(C)cccc1Cl
Yield: 45.6 %

Procedure:
A solution of 4-(5-chloro-1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester hydrochloride (89.5 mg, 0.25 mmol), 2-chloro-6-methylbenzoic acid (47 mg, 0.28 mmol), DIEA (175 μL, 1.0 mmol) and HBTU (133 mg, 0.35 mmol) in DMF (3 mL) was stirred at room temperature for 4 hr. The mixture was concentrated, the residue was dissolved in ethyl acetate (15 mL), was washed with 0.5 N HCl (1×5 mL), sat. NaHCO3 (1×5 mL), brine (1×5 mL) and was dried (MgSO4). The residue obtained upon evaporation was chromatographed on 25 g of silica gel, eluting with 3:1 ethyl acetate:hexane to give N-[(2-chloro-6-methylphenyl)carbonyl]-4-(5-chloro-1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester (54 mg). LR(+)LSIMS: m/z 962 (2M+NH4), 945 (2M+H), 490 (M+NH4), 473 (M+H (2 Cl)).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCOC(C)=O>[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:2][CH2:3][CH:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)=[CH:29][CH:30]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Yield: 72.7 %

Procedure:
A solution/suspension of tert-butyl 4-(2-bromoethyl)piperidine-1-carboxylate (1.22 g, 4.18 mmol), 4-(benzyloxy)phenol (1.01 g, 5.04 mmol, 1.20 equiv.), K2CO3 (830 mg, 6.01 mmol, 1.40 equiv.) and KI (75 mg, 0.45 mmol, 0.11 equiv.) in acetone was heated to reflux under N2 overnight. After cooling to room temperature, the mixture was diluted with 100 mL of EtOAc, and the solids were filtered off. The filtrate was concentrated under vacuum, and the residue was applied onto a silica gel column, which was eluted with ethyl acetate/petroleum ether (1:5) to afford the product (1.25 g, 73%) as a white solid. 1H NMR (CDCl3, 300 MHz) δ 7.43-7.29 (m, 5H), 6.90 (d, 2H, J=6.6 Hz), 5.01 (s, 2H), 4.08 (d, 2H, J=7.2 Hz), 3.95 (t, 1H, J=4.2 Hz), 2.70 (t, 2H, J=9.6 Hz), 1.71-1.69 (m, 5H), 1.45 (s, 9H), 1.20-1.15 (m, 2H). LC-MS (ESI) m/z 434 (M+Na+).
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][CH:5]=C[N:3]=1.ON1C(=O)C2=CC=CC=C2C1=O.O=O.[C:22]([OH:25])(=[O:24])[CH3:23]>>[N:3]1[CH:2]=[CH:7][CH:6]=[CH:5][C:23]=1[C:22]([OH:25])=[O:24]
Reactant: CC(=O)O
Reactant: Cc1ccccn1
Agent: O=C1c2ccccc2C(=O)N1O
Agent: O=O
Product: O=C(O)c1ccccn1
Yield: 77 %

Procedure:
The mixture of 9.3 g (100 mmol) of 2-methylpyridine, 1.6 g (10 mmol) of N-hydroxyphthalimide, 0.15 g (0.5 mmol) of cobalt(II)acetylacetonato, 250 mL of acetic acid was reacted at 100° C. for 6 hours in an atmosphere of oxygen to obtain 2-pyridinecarboxylic acid (picolinic acid: yield 77%) with 2-methylpyridine conversion of 82%. From the reaction mixture, acetic acid was distilled off. 400 mL of benzonitrile and 400 mL of water were added thereto, shaken sufficiently, and allowed to stand to be separated into two liquid phases. To the resultant organic layer was further added 400 mL of water, shaken sufficiently, and allowed to stand to be separated into two liquid phases. The aqueous layer and the organic layer were analyzed by a liquid chromatography, and as a result, the extraction ratio of N-hydroxyphthalimide (on basis of N-hydroxyphthalimide contained in the reaction mixture) into the organic layer was 83%, the extraction ratio of phthalimide into the organic layer was 85%, the extraction ratio of phthalic acid into the organic layer was 66%, and the extraction ratio of cobalt(II)acetylacetonato (on basis of cobalt(II)acetylacetonato contained in the reaction mixture) into the aqueous layer was 97%.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:12]1[CH:19]=[N:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15]>CN(C=O)C>[CH2:3]([O:10][C:12]1[CH:19]=[N:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N#Cc1ccncc1Cl
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccncc1OCc1ccccc1
Yield: 87 %

Procedure:
A mixture of 0.59 g of 60% sodium hydride (in oil) and 5 ml of DMF was stirred while ice-cooling. To the reaction mixture, 1.59 g of benzyl alcohol was added. The reaction mixture was stirred at the same temperature for 10 minutes. To the reaction mixture, 2.0 g of 3-chloroisonicotinonitrile was added, and the reaction mixture was stirred at the same temperature for 30 minutes and at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and then to ethyl acetate was added to the reaction mixture, followed by filtration of insoluble matters. The filtrate was concentrated under reduced pressure and the resultant residue was subjected to silica gel column chromatography to give 2.64 g of 3-benzyloxy isonicotinonitrile.
Reaction SMILES: N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C=CC1C=CC=CC=1.O[C@@H:34]([C@H:37]1[O:42][C:41]([CH3:44])([CH3:43])[O:40][C@H:39]2[C@@H:45]([O:49][CH2:50][CH3:51])[C:46](=[O:48])[O:47][C@@H:38]12)[CH2:35]O.II>C1(C)C=CC=CC=1>[CH2:50]([O:49][C@@H:45]1[C@@H:39]2[O:40][C:41]([CH3:44])([CH3:43])[O:42][C@H:37]([CH:34]=[CH2:35])[C@@H:38]2[O:47][C:46]1=[O:48])[CH3:51]
Reactant: CCO[C@H]1C(=O)O[C@@H]2[C@H]1OC(C)(C)O[C@@H]2[C@H](O)CO
Agent: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C=Cc1ccccc1
Solvent: Cc1ccccc1
Product: C=C[C@H]1OC(C)(C)O[C@@H]2[C@H]1OC(=O)[C@@H]2OCC
Reaction time: 2 h

Procedure:
2.12 g of imidazole (31.13 mmol) and 10.37 g of triphenylphosphine supported by a styrene copolymer (Fluka, cas: 39319-11-4, 31.13 mmol) are added to a 250 mL three-necked flask containing 2.15 g of 49 (7.78 mmol) and 100 mL of toluene, with stirring and under an argon atmosphere. The medium is heated to the reflux temperature, and 5.93 g of iodine (23.35 mmol) are added in small portions. The heating is continued for 2 h, and then the mixture is cooled, the resin is filtered and washed with 20 mL of toluene and 50 mL of AcOEt. The filtrate is washed twice with 150 mL of a solution of water saturated with NaHCO3. The organic phase is dried over anhydrous magnesium sulphate, filtered and then evaporated to dryness. The crude product is chromatographed on a silica cartridge (250 g, eluent CH2Cl2/MeOH— in a 0 to 10% MeOH gradient). 800 mg of expected product 50 are recovered.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:37]=[CH:36][C:13]([CH2:14][N:15]2[CH:19]=[C:18]([C:20]3[CH:21]=[C:22]4[N:27]([C:28]5[CH:29]=[C:30]([CH:32]=[CH:33][C:34]=5[CH3:35])[NH2:31])[CH:26]=[CH:25][N:23]4[N:24]=3)[CH:17]=[N:16]2)=[CH:12][CH:11]=1.FC(F)(F)C(O)=O.[C:45]([C:49]1[CH:50]=[C:51]([CH:55]=[C:56]([CH2:58][N:59]2[CH2:63][CH2:62][CH2:61][CH2:60]2)[CH:57]=1)[C:52](O)=[O:53])([CH3:48])([CH3:47])[CH3:46]>>[C:45]([C:49]1[CH:50]=[C:51]([CH:55]=[C:56]([CH2:58][N:59]2[CH2:60][CH2:61][CH2:62][CH2:63]2)[CH:57]=1)[C:52]([NH:31][C:30]1[CH:32]=[CH:33][C:34]([CH3:35])=[C:28]([N:27]2[C:22]3[N:23]([N:24]=[C:20]([C:18]4[CH:17]=[N:16][N:15]([CH2:14][C:13]5[CH:12]=[CH:11][C:10]([O:9][CH3:8])=[CH:37][CH:36]=5)[CH:19]=4)[CH:21]=3)[CH:25]=[CH:26]2)[CH:29]=1)=[O:53])([CH3:48])([CH3:46])[CH3:47]
Reactant: COc1ccc(Cn2cc(-c3cc4n(-c5cc(N)ccc5C)ccn4n3)cn2)cc1
Reactant: CC(C)(C)c1cc(CN2CCCC2)cc(C(=O)O)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cn2cc(-c3cc4n(-c5cc(NC(=O)c6cc(CN7CCCC7)cc(C(C)(C)C)c6)ccc5C)ccn4n3)cn2)cc1

Procedure:
70 mg (0.14 mmol) of the compound of Example 8A and 51 mg (0.14 mmol) of the compound of Example 22A were reacted analogously to the procedure of Example 48A. This gave 83 mg (88% pure, 83% of theory) of the title compound.