Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]1[NH:11][C:12]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[C:13]([C:28]([O:30][CH3:31])=[O:29])[CH:14]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:27])[C:15]=1[C:16]([O:18][CH3:19])=[O:17].[CH3:37][S:38](Cl)(=[O:40])=[O:39].C(N(CC)CC)C>C(Cl)Cl>[Cl:27][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([Cl:26])[C:20]=1[CH:14]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:10]([CH2:9][CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][S:38]([CH3:37])(=[O:40])=[O:39])[NH:11][C:12]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[C:13]1[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)CC1=C(C(=O)OC)C(c2c(Cl)cccc2Cl)C(C(=O)OC)=C(CCc2ccccc2N)N1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC1=C(C(=O)OC)C(c2c(Cl)cccc2Cl)C(C(=O)OC)=C(CCc2ccccc2NS(C)(=O)=O)N1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of dimethyl 2-[2-(2-aminophenyl)ethyl]-4-(2,6-dichlorophenyl)-6-(2-methoxy-2-oxoethyl)-1,4-dihydro-3,5-pyridinedicarboxylate (500 mg/0.94 mmol) and methanesulfonyl chloride (107 mg/0.94 mmol) in anhydrous CH2Cl2(15 ml) was added triethylamine (94.7 mg/0.94 mmol) at 0° C. under nitrogen atmosphere. The resulting solution was stirred at room temperature for 1 day. The reaction was quenched with water and the separated organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated to afford a crude mixture. This crude was purified by column chromatography on silica gel (Hexane:EtOAc=3:2) to afford a yellow solid (262 mg/46%).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[O:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33]>>[CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([N:30]5[CH2:31][CH2:32][O:28][C:29]5=[O:33])=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C(c1ccc(I)cc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: O=C1NCCO1
Product: O=C(c1ccc(N2CCOC2=O)cc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 84.9 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (473 mg) described in Preparation Example 95, oxazolidin-2-one (104 mg), the title compound (367 mg) was obtained.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[CH2:32][OH:33])[CH2:23][CH2:22]3)=[O:20])=[C:15](I)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N:35]1[CH:40]=[C:39](B(O)O)[CH:38]=[N:37][CH:36]=1>>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[CH2:32][OH:33])[CH2:23][CH2:22]3)=[O:20])=[C:15]([C:39]3[CH:40]=[N:35][CH:36]=[N:37][CH:38]=3)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N4CCC[C@@H]4CO)CC3)n2C)c1
Reactant: OB(O)c1cncnc1
Product: CCCCCCc1cccc(-c2nc(-c3cncnc3)c(C(=O)N3CCC(N4CCC[C@@H]4CO)CC3)n2C)c1

Procedure:
In analogy to the procedure described for example 7, [2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-[4-((R)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-methanone (example 45) was reacted with pyrimidine-5-yl-boronic acid to give the title compound as light yellow oil. MS: 531.3 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)[CH3:2].[Li]CCCC.[F:15][C:16]1[C:17]([F:25])=[C:18](F)[C:19]([F:23])=[C:20]([F:22])[CH:21]=1.Cl>O1CCCC1>[F:15][C:16]1[C:17]([F:25])=[CH:18][C:19]([F:23])=[C:20]([F:22])[C:21]=1[NH:7][C:6]1[CH:8]=[CH:9][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1
Reactant: Fc1cc(F)c(F)c(F)c1F
Reactant: CCc1ccc(N)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1ccc(Nc2c(F)c(F)cc(F)c2F)cc1
Reaction time: 1 h

Procedure:
4-Ethylaniline (242.36 g; 2.00 mol) is dissolved in dry tetrahydrofuran (900 ml). A solution of n-BuLi (2.5 M in hexanes, 800 ml; 2.00 mol) is added under N2 with cooling maintaining the reaction temperature below 15°. After stirring for 1 hour at 10°, neat pentafluorobenzene (168.06 g; 1.00 mol) is added with cooling to the mixture, keeping the temperature at 10-20°. The reaction is stirred at ambient temperature for 1.5 hours, then aqueous HCl (6 N; 500 ml) is added slowly with vigorous stirring and cooling, keeping the reaction temperature below 35°. The quenched reaction is stirred at ambient temperature for 0.5-18 hours. The aqueous layer is separated, and the organic phase is concentrated under reduced pressure (30-150 mm) to one-fourth volume. The concentrate is diluted with heptane (300 ml) and extracted with water (300 ml). The separated top organic layer is stirred over 230-400 mesh silica gel (50 g) and filtered. The filter cake is washed with heptane (4×50 ml). The combined filtrate and washings are concentrated under reduced pressure (20-30 mm) to give solid crude product. This material is recrystallized from hot heptane (200 ml) and collected at 0°. This solid is washed with cold heptane (100 ml) and dried under reduced pressure at 40° to give pure N-(2′,3′,5′,6′-tetrafluorophenyl)-4-ethylaniline.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([Cl:11])[C:5]([Cl:12])=[C:4]([Cl:13])[C:3]=1[Cl:14].O.[NH2:16]N>CS(C)=O>[Cl:1][C:2]1[C:7]([NH:8][NH2:16])=[C:6]([Cl:11])[C:5]([Cl:12])=[C:4]([Cl:13])[C:3]=1[Cl:14]
Reactant: NN
Reactant: O=[N+]([O-])c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Solvent: O
Solvent: CS(C)=O
Product: NNc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Pentachloronitrobenzene containing 5-10% hexaxchlorobenzene, (3.0 g, 10.1 mmole) was dissolved in dimethylsulphoxide (35 ml). Hydrazine hydrate (1.25 g, 25 mmole) was added dropwise with stirring at 25° C. A slight 4°-5° C. increase in temperature was recorded and the solution became red-brown. After approximately 20 minutes a white solid began to be precipitated. Stirring was continued for one hour after which time TLC (1:1 ethyl acetate: 60°-80° C. petrol) indicated that the reaction was complete. The mixture was poured into stirred water (200 ml) and the solid filtered off and dried at 50° C. overnight. The TLC and IR was identical to an authentic sample of pentachlorophenylhydrazine. Yield=2.27 g, 80%.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:6]([C:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[N:19]/[S:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])=[CH:14][CH:13]=1)=[N:7]2.[CH3:32][Mg]Br>C(Cl)Cl>[Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:6]([C:12]1[CH:17]=[CH:16][C:15]([C@H:18]([NH:19][S:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])[CH3:32])=[CH:14][CH:13]=1)=[N:7]2
Reactant: CC(C)(C)S(=O)/N=C/c1ccc(-c2nc3ccnc(Cl)c3cc2-c2ccccc2)cc1
Reactant: C[Mg]Br
Solvent: ClCCl
Product: C[C@@H](NS(=O)C(C)(C)C)c1ccc(-c2nc3ccnc(Cl)c3cc2-c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of N-{(1E)-[4-(5-chloro-3-phenyl-1,6-naphthyridin-2-yl)phenyl]methylene}-2-methylpropane-2-sulfinamide (34-1, 4.53 g, 10.1 mmol) in methylene chloride (100 mL) was added methyl magnesium bromide (30 mL, 42.0 mmol, 1.4M in 75:25 toluene:THF) at −10° C. After 30 minutes, the reaction was quenched by addition of saturated ammonium chloride solution (while maintaining the temperature below 0° C.) and extracted with methylene chloride. The combined organics were washed with water, brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as a pale yellow solid. MS (M+H+): calculated=464.03, observed=464.2
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][OH:8])(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.Cl[P:17]1(=[O:22])[O:21][CH2:20][CH2:19][O:18]1>C(OCC)C>[C:1]([O:5][CH2:6][CH2:7][O:8][P:17]1(=[O:22])[O:21][CH2:20][CH2:19][O:18]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: O=P1(Cl)OCCO1
Reactant: C=CC(=O)OCCO
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=CC(=O)OCCOP1(=O)OCCO1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
2-Hydroxyethyl acrylate (11.5 ml, 0.1M) and triethylamine (14.6 ml) in dry diethyl ether (250 ml) were cooled to -25° C. under nitrogen as a solution of 2-chloro-2-oxo-1,3,2-dioxaphospholane (14.3 g) in dry diethyl ether was added over 20 minutes. The mixture was stirred for a further 1 hour at -20° C. and then allowed to warm to 10° C. over a further hour. The precipitate was filtered, washed with ethyl acetate (100 ml) and the combined filtrate and washings evaporated under reduced pressure to give a pale yellow oil (21 g).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH2:27][NH2:28])[CH:21]=1>>[Cl:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:28][CH2:27][CH2:26][C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NCCc1cccnc1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2Cl)cn1
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3cccnc3)cc2Cl)cn1
Yield: 91.4 %

Procedure:
Using a method similar to Example 405, using 5-(2-chloro-4-formylphenoxy)pyridine-2-carboxamide (0.0388 g, 0.140 mmol) and 2-(pyridin-3-yl)ethylamine (0.017 g, 0.140 mmol) gives the title compound (0.0490 g, 91.2%): TOF MS ES+ 383.1 (M+H)+, HRMS calcd for C20H20N4O2Cl 383.1275 (M+H)+, found 383.1248, time 0.39 min; Anal. Calcd for C20H19ClN4O2.0.1CH2Cl2: C, 61.90; H, 5.06; N, 14.38. Found: C. 61.90; H, 5.06; N, 14.38.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH:5][C:6](=[O:13])[C@H:7]([CH2:9][C:10](=[O:12])[OH:11])[NH2:8].[ClH:22].[CH:23]([NH:25][C@@H:26]1[C:31](=[O:32])[O:30][C:28](=[O:29])[CH2:27]1)=[O:24].[NH2:33][C@H:34]([C:42]([OH:44])=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O.CO>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH:5][C:6](=[O:13])[C@H:7]([CH2:9][C:10](=[O:11])[OH:12])[NH2:8].[ClH:22].[CH:23]([NH:25][C@H:26]([C:31]([NH:33][C@H:34]([C:42]([OH:44])=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:32])[CH2:27][C:28](=[O:29])[OH:30])=[O:24]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=CN[C@H]1CC(=O)OC1=O
Agent: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Agent: Cl
Solvent: CO
Solvent: O
Product: O=CN[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
The present invention relates to a process for preparing α-L-aspartyl-L-phenylalanine methyl ester or its hydrochloride. α-L-aspartyl-L-phenylalanine methyl ester or its hydrochloride is prepared by a process comprising: condensating N-formyl-L-aspartic acid anhydride and L-phenylalanine in water or in water containing methanol at a pH in the range of 7-12 to form N-formyl-α-L-aspartyl-L-phenylalanine; acidifying the reaction mixture successively with hydrochloric acid in the presence of methanol without isolating the N-formyl-α-L-aspartyl-L-phenylalanine so as to bring it into contact with hydrochloric acid in the presence of methanol for reaction and thereby to deposit α-L-aspartyl-L-phenylalanine methyl ester hydrochloride; separating the α-L-aspartyl-L-phenylalanine methyl ester hydrochloride; and neutralizing said hydrochloride as required.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].Br[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[B:23]1[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH:4][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[B:23]1[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]1
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: CC1(C)OB(c2c(CBr)ccc3ccccc23)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(NCc2ccc3ccccc3c2B2OC(C)(C)C(C)(C)O2)c(C)c1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 29.2 g (216 mmol) of 2,4,6-trimethylaniline, 50.0 g (144 mmol) of 2-[2-(bromomethyl)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and 22.0 g (159 mmol) of K2CO3 in 1100 cm3 of DMF was stirred at 80° C. for 12 h. The resulting mixture was poured into 2000 cm3 of water. The product was extracted with 3×400 ml of ethyl acetate. The combined extract was dried over MgSO4 and then evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 um; eluent: dichloromethane). Yield 45.0 g (78%). Anal. Calc. For C26H32BNO2: C, 77.81; H, 8.04; N, 3.49. Found: C, 77.99; H, 8.24; N, 3.26. 1H NMR (CDCl3): 8.27 (m, 1H, 8-H in naphthyl), 7.84 (m, 1H, 5-H in naphthyl), 7.81 (d, J=8.4 Hz, 1H, 4-H in naphthyl), 7.54 (m, 1H, 7-H in naphthyl), 7.48 (m, 1H, 6-H in naphthyl), 7.37 (d, J=8:4 Hz, 1H, 3-H in naphthyl), 6.87 (s, 2H, 3,5-H in mesityl), 4.39 (s, 2H, CH2N), 3.68 (br.s, 1H, NH), 2.31 (s, 6H, 2,6-Me in mesityl), 2.30 (s, 3H, 4-H in mesityl), 1.49 (s, 12H, CMe2CMe2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:15][C:16]([OH:18])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl.[CH3:20][NH:21][O:22][CH3:23].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl>ClCCl.O>[CH3:23][O:22][N:21]([CH3:20])[C:16](=[O:18])[CH2:15][C:9]1([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: COc1ccc(C2(CC(=O)O)CCCCC2)cc1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C2(CC(=O)N(C)OC)CCCCC2)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 80.2 %

Procedure:
To a solution of [1-(4-methoxy-phenyl)-cyclohexyl]-acetic acid (1.2 g) in dichloromethane (9.7 ml) was added N,O-dimethylhydroxylamine hydrochloride (577 mg). The mixture was cooled in an ice bath. 1,1′-Carbonyldiimidazole (1.01 g) was added. The mixture was stirred for 5 min at 0° C. and for 2 days at room temperature. A mixture of water and 1 M HCl was added and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated to dryness. The product was purified by chromatography (20 g NH3-modified SiO2, cyclohexane/ethyl acetate 1:0 to 3:2) to give the title compound (1.13 g) as a colorless oil, MS (ESI+): m/z=292.2 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][N:3]1[C@@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15].IC.[H-].[Na+].[C:26](O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:26][C@:5]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][C:2](=[O:1])[N:3]([C@@H:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:15])[CH2:4]1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: C[C@H](c1ccccc1)N1CC(C(=O)OC(C)(C)C)CC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: C[C@H](c1ccccc1)N1C[C@@](C)(C(=O)OC(C)(C)C)CC1=O
Temperature: 50 °C

Procedure:
To a solution of tert-butyl 2-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-4-carboxylate (30.05 g, 0.104 mol) in N,N′-dimethylformamide (210 mL), iodomethane 26.0 mL (59.28 g, 0.418 mol), and then sodium hydride (55%, in oil, 11.35 g, 0.260 mol) was added at room temperature in nitrogen atmosphere while stirring the mixture. When inner temperature increased to about 50° C., the reaction mixture was cooled to 30° C. by adding ice water to the outer bath. After changing the bath to a water bath at an outer temperature of 17° C., the mixture was stirred for 23 hours. The reaction mixture was poured into cold aqueous solution of citric acid (1 L of 10% citric acid and 500 g of ice), and after stirring the mixture for 30 minutes, the mixture was extracted with ethyl acetate (800 mL, 500 mL). The organic layers were combined, and washed with saturated aqueous solution of sodium chloride. After drying with anhydrous sodium sulfate, the mixture was subjected to filtration, and the filtrate was concentrated under reduced pressure. The concentrate was purified by flash silica gel column chromatography (elution was started at hexane:ethyl acetate of 5:1, and after elution of the low polarity isomer, hexane:ethyl acetate was changed to 4:1) to obtain 10.63 g (33.7%) of high polarity isomer the title compound as a white solid. 14.91 g (47.3%) of low polarity isomer of tert-butyl (4R)-4-methyl-2-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-4-carboxylate was also obtained.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[CH3:5][CH:6]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH2:7][C:8]([OH:10])=[O:9].S(=O)(=O)(O)O>ClCCl>[CH3:5][CH:6]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:15])[CH3:16])[CH2:7][C:8]([O:10][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:9]
Reactant: C=C(C)C
Reactant: CC(C)=CCCC(C)CC(=O)O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)=CCCC(C)CC(=O)OC(C)(C)C
Reaction time: 24 h

Procedure:
25 ml of isobutylene were condensed at -78° C. and added to a mixture of 19.4 g (114 mmol) of 3(RS),7-dimethyl-6-octenoic acid and 1 ml of concentrated sulphuric acid in 25 ml of dichloromethane. The mixture was stirred for 24 hours under a dry ice condenser. A further 20 ml of isobutylene were added and the mixture was stirred for 24 hours under a dry ice condenser. The mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulphate and evaporated under a vacuum. The resulting oil was purified by chromatography on silica gel using ethyl acetate/hexane (1:9) for the elution. There were obtained 20.8 g of tert-butyl 3(RS),7-dimethyl-6-octenoate as a colourless oil. 1H NMR (250 MHz, CDCl3) d: 0.9 (d, 3H), 1.1-1.3 (m, 3H), 1.4 (s, 9H), 1.6 (s, 3H), 1.65, (s, 3H), 1.8-2.2 (br m, 4H), 5.05, (m, 1H).
Reaction SMILES: [C:1]([CH:8]([NH2:19])[C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[C:11]([Cl:18])[CH:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>>[Cl:18][C:11]1[CH:10]=[C:9]([CH:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[NH2:19])[CH:17]=[CH:16][C:12]=1[C:13]([NH:25][C:24]1[CH:26]=[CH:27][C:21]([Cl:20])=[C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH:23]=1)=[O:15]
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CC(C)(C)OC(=O)C(N)c1ccc(C(=O)O)c(Cl)c1
Product: CC(C)(C)OC(=O)C(N)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
General procedure G was used to couple 4-(BOC-aminomethyl)-2-chloro-benzoic acid and 4-chloro-3-(pyridin-2-yl)aniline to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)-phenyl)-4-(BOC-aminomethyl)-benzamide with. The crude reaction mixture was treated to TFA and trace water for 1 h prior to concentrating to dryness to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)-phenyl)-4-(aminomethyl)-benzamide.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([F:30])=[C:5]([C:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][C:17]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[N:16]3)=[O:12])[C:6]([F:10])=[C:7]([F:9])[CH:8]=1.[CH2:31]([S:34](Cl)(=[O:36])=[O:35])[CH2:32][CH3:33]>C(Cl)Cl>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:17]2[CH:18]=[N:19][C:20]3[C:15]([N:16]=2)=[CH:14][C:13]([C:11]([C:5]2[C:4]([F:30])=[C:3]([N:2]([S:34]([CH2:31][CH2:32][CH3:33])(=[O:36])=[O:35])[S:34]([CH2:31][CH2:32][CH3:33])(=[O:36])=[O:35])[CH:8]=[C:7]([F:9])[C:6]=2[F:10])=[O:12])=[CH:22][CH:21]=3)=[CH:28][CH:27]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: Nc1cc(F)c(F)c(C(=O)c2ccc3ncc(-c4ccc(Cl)cc4)nc3c2)c1F
Agent: Cl
Solvent: ClCCl
Product: CCCS(=O)(=O)N(c1cc(F)c(F)c(C(=O)c2ccc3ncc(-c4ccc(Cl)cc4)nc3c2)c1F)S(=O)(=O)CCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.3 %

Procedure:
To a solution of (3-amino-2,5,6-trifluorophenyl)(3-(4-chlorophenyl)quinoxalin-6-yl)methanone hydrochloride (100 mg, 0.24 mmol, 1.0 eq.) in DCM (10 mL) were added TEA (242 mg, 2.4 mmol, 10.0 eq.) and propane-1-sulfonyl chloride (172 mg, 1.2 mmol, 5.0 eq.). The resulting mixture was stirred at rt for 1 h, then concentrated. The resulting residue was dissolved in EA (10 mL) and washed with saturated NaHCO3 solution, dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified by flash column chromatography (PE/EA=4/1, v/v) to afford N-(3-(3-(4-chlorophenyl)quinoxaline-6-carbonyl)-2,4,5-trifluorophenyl)-N- (propylsulfonyl)propane-1-sulfonamide (50 mg, 40.3%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([NH:16][CH2:17][CH2:18][NH2:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([NH:16][CH2:17][CH2:18][NH:19][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCCNc1ccccc1
Reactant: N#Cc1ccccc1F
Product: N#Cc1ccccc1NCCNc1ccccc1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 2-fluorobenzonitrile and N-phenylethylenediamine.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:6]2[CH2:5][CH2:4]1.C([Li])CCC.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](OC)[N:21]=1.Cl>C1COCC1>[OH:1][CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][N:10]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH3:18])[N:21]=3)[CH2:11][CH:6]2[CH2:5][CH2:4]1
Reactant: COc1cccc(OC)n1
Reactant: OCC1CCC2CNCCN2C1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(N2CCN3CC(CO)CCC3C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.8 %

Procedure:
According to the procedure reported by Wynberg (J. Org. Chem. 1993, 58, 5101), a solution 0.50 g (2.9 mmol) of racemic (7RS ,9aSR)-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine in 10 mL of dry THF at 0° C. was treated with 2.59 mL (6.5 mmol) of n-butyl lithium (2.5M in hexane). The mixture was kept at 0° C. for 30 min and at room temperature for 1 h, and 0.39 mL (2.94 mmol) of 2,6-dimethoxypyridine was added and the solution refluxed for 16 h. After cooling to room temperature, the mixture was poured into 1M HCl and washed with toluene (3×). The aqueous layer was basified with 1M NaOH and extracted with toluene (1×) and ethyl acetate (1×). The combined organic layers were dried (magnesium sulfate), filtered, and evaporated to give a yellow oil. Purification by flash silica gel chromatography with 9:1 chloroform:methanol gave 0.304 g (37%) of (7RS,9aSR)-7-hydroxymethyl-2-(6-methoxypyridin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:28])=[N:12][CH:13]=[C:14]([C:16]2[CH:17]=[N:18][N:19]([CH2:21][CH2:22][O:23]C(C)(C)C)[CH:20]=2)[CH:15]=1.N>C(O)(C(F)(F)F)=O.CO>[NH2:28][C:11]1[N:12]=[CH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]([CH2:21][CH2:22][OH:23])[CH:20]=2)=[CH:15][C:10]=1[C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: CC(C)(C)OCCn1cc(-c2cnc(N)c(-c3nc4ccccc4o3)c2)cn1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Nc1ncc(-c2cnn(CCO)c2)cc1-c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
3-(1,3-benzoxazol-2-yl)-5-[1-(2-tert-butoxyethyl)pyrazol-4-yl]pyridin-2-amine (485 mg) was dissolved in TFA (3 ml). The resulting solution was stirred at 25° C. for 1 hour. A solution 7N of ammonia in methanol (20 ml) was added to the mixture and adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 1 to 5% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness to afford 2-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]ethanol (315 mg). NMR Spectrum: (DMSOd6) 3.75-3.81 (m, 2H), 4.17 (t, 2H), 4.94 (t, 1H), 7.40-7.49 (m, 2H), 7.64 (bs, 2H), 7.79-7.82 (m, 1H), 7.83-7.86 (m, 1H), 7.92 (s, 1H), 8.21 (s, 1H), 8.41 (d, 1H), 8.52 (d, 1H); Mass spectrum: M+H+ 322.