Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[CH2:8][CH2:7]1)=[O:5].[N:29]1([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][C@H:30]1[C:39](O)=[O:40].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][C@@H:3]([NH:2][C:39]([C@@H:30]2[CH2:31][C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:38][N:29]2[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:40])[C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N+:18]([O-:20])=[O:19])[CH2:8][CH2:7]2)=[O:5])=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Reactant: N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2[N+](=O)[O-])CC1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2[N+](=O)[O-])CC1
Yield: 85 %

Procedure:
Using the procedure described for the synthesis of Preparation V, tert-butyl 3-(N-{(1R)-1-[(4-chlorophenyl)methyl]-2-[4-(2-nitrophenyl) piperazinyl]-2-oxoethyl{carbamoyl)(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate was prepared from (2R)-2-amino-3-(4-chlorophenyl)-1-[4-(2-nitrophenyl)piperazinyl]propan-1-one hydrochloride (570 mg, 1.3 mmol) in DMF (10 mL), Boc-L-Tic-OH (Bachem) (410, 1.5 mmol), HOAT (Aldrich) (180 mg, 1.4 mmol), EDC (Aldrich) (520 mg, 2.70 mmol), and DIEA (Aldrich) (240 μL, 1.4 mmol). The crude material was purified by column chromatography (1:1 hexanes-EtOAc) to give the title compound as a white foam (716 mg). MS (ESI, pos. ion) m/z: 648 (M+H). Calc'd for C34H38ClN5O6: 647.25.
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[Br:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:10]([F:19])[C:9]([OH:20])=[C:8]([CH:21]=[O:22])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:10]([F:19])[C:9]([O:20][CH:2]([CH3:4])[CH3:3])=[C:8]([CH:21]=[O:22])[CH:7]=1
Reactant: CC(C)I
Reactant: O=Cc1cc(Br)c(-c2ccc(F)cc2)c(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1c(C=O)cc(Br)c(-c2ccc(F)cc2)c1F
Temperature: 60 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
2-Iodopropane (21.7 g) was added to a mixture of 6-bromo-2,4′-difluoro-3-hydroxybiphenyl-4-carbaldehyde (26.7 g) and potassium carbonate (23.6 g) in DMF (250 mL) at room temperature. The mixture was stirred at 60° C. under nitrogen atmosphere for 3 hours. The mixture was quenched with water at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography (hexane/ethyl acetate) to give the title compound (28.5 g).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1OB(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[C:2]1[C:15]2[C:10]([CH:9]=[C:8]3[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]3)=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: Brc1c2ccccc2cc2ccccc12
Reactant: OB(O)Oc1ccc2ccccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc2cc(-c3c4ccccc4cc4ccccc34)ccc2c1
Temperature: 25 °C

Procedure:
9-Bromoanthracene (2.57 g, 10.00 mmol), 2-naphthyl boric acid (1.80 g, 12.65 mmol) and sodium carbonate (2.34 g, 22.1 mmol) were suspended in a mixture of toluene (20 mL), ethanol (3 mL) and water (10 mL). To the suspension, was added tetrakis(triphenylphosphine)palladium (0.25 g, 0.22 mmol). The mixture was stirred under reflux for about 24 hours, and then the refluxed mixture was cooled to room temperature. The organic layer was separated and washed with water, and the aqueous layer was extracted by chloroform. The organic extract was dried over magnesium sulfate, and concentrated in vacuo to prepare a 9-(2-naphthyl)anthracene compound C-1 (2.55 g, yield 84).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.S(=O)(=O)=O.N1C=CC=CC=1>CS(C)=O>[O:1]=[CH:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=2)=[CH:19][CH:20]=1
Reactant: NC(=O)c1ccc(Oc2ccc(CCCO)cc2)nc1
Agent: O=S(=O)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: NC(=O)c1ccc(Oc2ccc(CCC=O)cc2)nc1
Temperature: 0 °C
Yield: 35.5 %

Procedure:
Add 6-[4-(3-hydroxy-propyl)-phenoxy]-nicotinamide (0.4051 g, 1.488 mmol) to a stirred solution of triethylamine (0.620 mL, 4.45 mmol) and anhydrous dimethylsulfoxide (4.5 mL). Dissolve pyridine sulfur trioxide (0.7023 g, 4.413 mmol) in anhydrous dimethylsulfoxide (4.5 mL) and add this solution via a cannula to the above stirred solution under nitrogen. Stir the reaction at room temperature for 1 h under nitrogen. Pour the reaction into ice water (50 mL), extract with ethyl acetate (3× 50 mL), dry the ethyl acetate extracts over magnesium sulfate, filter, and concentrate on a rotary evaporator to give the crude product. The crude product is purified by flash chromatography on silica gel eluting with 100% ethyl acetate to yield 0.1428 g (36%) of 6-[4-(3-oxo-propyl)-phenoxy]-nicotinamide: mass spectrum (ion spray): m/z=271.2 (M+1); 1H NMR (CDCl3): 9.84 (t, 1H), 8.58 (d, 1H), 8.16 (dd, 1H), 7.26-7.23 (m, 2H), 7.09-7.05 (m, 2H), 6.95 (d, 1H), 6.02 (br s, 2H), 2.98 (t, 2H), 2.82 (t, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[O:13].C([O-])([O-])=O.[K+].[K+].Br[CH2:21][C:22]([O:24][CH3:25])=[O:23]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:7](=[O:12])[C:6]2=[O:13]
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)C(=O)c2cc(OC)ccc21

Procedure:
To a solution of 5-methoxyindoline-2,3-dione (1 g, 5.64 mmol) in DMF (15 ml), K2CO3 (0.936 g, 6.77 mmol) and methyl 2-bromoacetate (0.628 ml, 6.77 mmol) were added, and the mixture was reacted under microwave irradiation for 1 hour at 100° C. Then the insoluble inorganic salts were filtered off, and the resulting crude title compound was obtained (1.6 g) and used in the next step without further purification. MS/ESI+ 250.1 [MH]+.
Reaction SMILES: N[C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:24]#[C:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:6]3[C:11]([C:12]=2[C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.C1C2C=CC3C(=CC=CC=3)C=2C=CC=1>C1COCC1.C(N(CC)CC)C>[CH:29]1[CH:28]=[CH:27][C:26]([C:25]#[C:24][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]([C:16]#[C:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:13]3[C:4]=2[CH:3]=[CH:2][CH:15]=[CH:14]3)=[CH:31][CH:30]=1
Reactant: Nc1ccc2c(C#Cc3ccccc3)c3ccccc3c(C#Cc3ccccc3)c2c1
Agent: c1ccc2c(c1)ccc1ccccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C(#Cc1c2ccccc2c(C#Cc2ccccc2)c2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 39.6 %

Procedure:
To 120 mg of 2-[4-(carboxybutyl)methylaminophenyl]-3-phenyl-5,6-dihydrothioxene prepared as described above (0.5 mmol) in 5.0 mL of THF was cooled in an ice bath for 30 minutes. 5.0 mL of oxalyl chloride was added to the cooled solution. The reaction mixture was stirred at 4° C. for 3 hours. Oxalyl chloride was evaporated on the rotovap under reduced pressure to give the acid chloride of 2-[4-(carboxybutyl)methylaminophenyl]-3-phenyl-5,6-dihydrothioxene. 2-Amino 9,10-bis-phenylethynyl anthracene (1.0 mmol) in 25 mL of dry THF was added to the residue followed by 2 drops of triethyl amine. The heterogeneous reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was worked up as described for thioxene-phenanthrene. The product, 2-amino-9,10-bis(phenylethynyl)anthracene amide of 2-[4-(carboxybutyl)methylaminophenyl]-3-phenyl-5,6-dihydrothioxene (compound 7 in Table 1) was purified on preparative TLC (CH2Cl2: hexane 9:1) to yield 150 mg of yellow glassy solid.
Reaction SMILES: C([O:3][C:4](=[O:25])[C@@H:5]([N:10]1[CH2:14][C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=2[F:23])=[CH:12][C:11]1=[O:24])[CH2:6][CH:7]([CH3:9])[CH3:8])C.O.[OH-].[Li+]>O1CCCC1>[F:23][C:17]1[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][C:13]1[CH2:14][N:10]([C@@H:5]([CH2:6][CH:7]([CH3:8])[CH3:9])[C:4]([OH:25])=[O:3])[C:11](=[O:24])[CH:12]=1
Reactant: CCOC(=O)[C@H](CC(C)C)N1CC(Oc2cccc(C)c2F)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)O)C2)c1F
Temperature: 20 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a solution containing (S)-2-[4-(2-fluoro-3-methyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid ethyl ester (1.50 g, 0.004 mol) in tetrahydrofuran (40 mL) was treated with an aqueous solution of lithium hydroxide monohydrate (0.5N, 20 mL, 0.010 mol). The mixture was stirred at 20° C. for 2 h, and the solvents evaporated. The residue was dissolved in water and washed with diethyl ether, and the diethyl ether layer discarded. The aqueous phase was acidified with dilute hydrochloric acid (pH <2), and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford (S)-2-[4-(2-fluoro-3-methyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (1.2 g, 87%) as a tan solid.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][C:11]=1[N+:18]([O-:20])=[O:19]>C1COCC1>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:15][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:12][C:11]=1[N+:18]([O-:20])=[O:19]
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
TEA (8.00 mL, 57.5 mmol) followed by pivaloyl chloride (2.80 mL, 22.8 mmol) in THF (25 mL) were added to 4-chloro-3-nitrobenzylamine hydrochloride (5.00 g, 22.4 mmol) in THF (100 mL). The reaction mixture was diluted with THF and stirred at rt for 1.5 h. The mixture was filtered and washed. The filtrate was concentrated to give the sub-title compound.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[NH:9][C:8](=[O:10])[C:7]([C:11]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:16]2)=[O:12])=[CH:6][C:5]=1[Cl:25].[H-].[Na+].I[CH3:29].O>CN(C)C=O>[NH2:3][C:4]1[N:9]([CH3:29])[C:8](=[O:10])[C:7]([C:11]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:16]2)=[O:12])=[CH:6][C:5]=1[Cl:25]
Reactant: CCCCN1CCC(CNC(=O)c2cc(Cl)c(N)[nH]c2=O)CC1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCN1CCC(CNC(=O)c2cc(Cl)c(N)n(C)c2=O)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 5.9 %

Procedure:
To a solution of 6-amino-N-[(1-butyl-4-piperidinyl)methyl]-5-chloro-2-oxo-1,2-dihydro-3-pyridinecarboxamide dihydrochloride (step 2 in example 3, 80 mg, 0.19 mmol) in N,N-dimethylformamide (3 ml), sodium hydride (60% dispersion in mineral oil, 39 mg, 0.97 mmol) was added at 0° C. and the mixture was stirred for 15 min at room temperature. The mixture was cooled to 0° C. and iodomethane (1.0 M in N,N-dimethylformamide, 0.19 ml, 0.19 mmol) was added. After stirring for 18 h at room temperature, the mixture was poured into water, extracted with ethyl acetate (50 ml×2), washed with water (50 ml) and brine (50 ml) and dried over magnesium sulfate. Removal of solvent gave pale yellow oil, which was chromatographed on a column of silica gel eluting with 25% ammonium hydroxide/methanol/dichloromethane (0.2:1:12) to give 4 mg (6%) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[C:3]=1[OH:10].[CH2:11]1[O:13][CH2:12]1>[Cl-].C[N+](C)(C)C.C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[C:3]=1[O:10][CH:12]([OH:13])[CH3:11]
Reactant: C1CO1
Reactant: Oc1c(Br)cc(Br)cc1Br
Agent: C[N+](C)(C)C
Agent: [Cl-]
Solvent: c1ccccc1
Product: CC(O)Oc1c(Br)cc(Br)cc1Br

Procedure:
2,4,6-Tribromophenol (94.9 parts), ethylene oxide (14.7 parts) and tetramethylammonium chloride (2.0 parts) were charged into the same type of reactor as described in Example I. Reactants were heated to 95°-100° C. over 21/2 hours and allowed to react at this temperature for an additional 41/2 hours for the completion of reaction. The product was then dissolved in benzene, washed with water three times, dried with anhydrous sodium sulfate, filtered, and benzene stripped off under vacuum at 40° C. The final product was a slightly colored pasty material having a hydroxyl number of 150.
Reaction SMILES: Br[C:2]([CH3:6])([CH3:5])[CH:3]=[O:4].[CH2:7]([O:9][C:10]([CH2:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11])[CH3:8]>C(O)C>[CH3:5][C:2]([N:16]1[CH2:15][CH2:14][N:13]([CH2:12][C:10]([O:9][CH2:7][CH3:8])=[O:11])[CH2:18][CH2:17]1)([CH3:6])[CH:3]=[O:4]
Reactant: CC(C)(Br)C=O
Reactant: CCOC(=O)CN1CCNCC1
Solvent: CCO
Product: CCOC(=O)CN1CCN(C(C)(C)C=O)CC1
Reaction time: 72 h

Procedure:
A solution of 100 g 2-bromo-2-methyl-propionaldehyde in 20 ml of ethanol is added dropwise to a mixture of 25.0 g N-[(ethoxycarbonyl)methyl]-piperazine in 80 ml of ethanol at room temperature. The resulting mixture is stirred for 72 hours, concentrated in vacuo, and submitted directly to column chromatography on silica gel with methylene chloride/methanol (95:5 to 80:20) to give the title compound as a yellow oil. Yield: 10.0 g (62% of theory), Rf value: 0.60 (silica gel, methylene chloride/methanol=9:1) Mass spectrum (ESI*): m/z=241 [M−H]*
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:11][CH2:12][OH:13])[CH2:8][CH2:9][OH:10])=[O:6].[N:14]([O-])=[O:15].[Na+].C(Cl)(Cl)Cl.CO>C(O)(=O)C>[Cl:1][CH2:2][CH2:3][N:4]([N:14]=[O:15])[C:5]([N:7]([CH2:11][CH2:12][OH:13])[CH2:8][CH2:9][OH:10])=[O:6]
Reactant: O=N[O-]
Reactant: O=C(NCCCl)N(CCO)CCO
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=NN(CCCl)C(=O)N(CCO)CCO
Yield: 65.9 %

Procedure:
4.0 g of 1-(2-chloroethyl)-3,3-bis(2-hydroxyethyl)urea are dissolved in 30 ml of acetic acid, and 2.5 g of sodium nitrite are added thereto under stirring. The mixture is stirred at room temperature for 4 hours. After the reaction, the mixture is treated in the same manner as described in Example 60-(2) (Solvent used for chromatography: chloroform-methanol (10:1)). 3.0 g of 1-(2-chloroethyl)-1-nitroso-3,3-bis(2-hydroxyethyl)urea are thereby obtained as a yellow oil.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([CH2:12][NH2:13])[OH:11]>>[OH:11][CH2:10][CH2:12][NH:13][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: N#Cc1ccc(F)cc1
Product: N#Cc1ccc(NCCO)cc1

Procedure:
According to a similar manner to that in Reference Example 3, the title compound was synthesized from 4-fluorobenzonitrile and ethanolamine.
Reaction SMILES: [C:1]1([C@@H:7]2[NH:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:22][O:23][CH2:24][CH2:25]Br.O>CN(C=O)C.C(OCC)(=O)C>[CH3:22][O:23][CH2:24][CH2:25][N:12]1[CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][C@@H:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COCCBr
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COCCN1CCN(C(=O)OC(C)(C)C)C[C@@H]1c1ccccc1
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, to a solution of 330 mg of tert-butyl (3S)-3-phenylpiperazine-1-carboxylate in 3.5 mL of DMF was added 75.4 mg of sodium hydride (including 40% mineral oil) under ice-cooling, followed by stirring for 30 minutes. To the mixture was added 0.27 mL of 2-bromoethyl methyl ether, followed by stirring at room temperature for 16 hours. To the mixture were added 75.4 mg of sodium hydride (including 40% mineral oil) and 0.6 mL of 2-bromoethyl methyl ether, followed by further stirring for 8 hours. The mixture was poured into a mixture of water and ethyl acetate, and the aqueous layer was separated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 330 mg of tert-butyl (3S)-4-(2-methoxyethyl)-3-phenylpiperazine-1-carboxylate.
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:10]3=[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:24](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1COCC1>[CH3:24][N:15]1[CH2:14][CH2:13][CH2:12][N:11]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:10]2[CH2:16]1
Reactant: CCOC(=O)c1nc(-c2ccccc2)n2c1CNCCC2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(-c2ccccc2)n2c1CN(C)CCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of intermediate 64A (0.91 g, 3.17 mmol) in 20 mL THF was added formaldehyde (37% in water, 2.36 mL) followed by sodium triacetoxyborohydride (1.34 g, 6.34 mmol) and acetic acid (0.27 mL, 4.76 mmol). The resulting mixture was stirred at room temperature overnight and then quenched with NaHCO3 saturated solution and stirred for 10 minutes. The reaction mixture was concentrated under vacuum and extracted with 10% iPrOH/DCM.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[CH:18]=[CH:19][C:20]([N+:32]([O-:34])=[O:33])=[C:21]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:22]=1.[H-].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:17]2[CH:18]=[CH:19][C:20]([N+:32]([O-:34])=[O:33])=[C:21]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[CH:22]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(OCc3ccccc3)cc2)ccc1[N+](=O)[O-]
Yield: 92.5 %

Procedure:
By using 1.60 g of 4-benzyloxyphenol, 2.29 g of t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate, 0.35 g of sodium hydride (55% by weight) and 20 ml of anhydrous N,N-dimethylformamide, reaction and purification were carried out in a similar manner to that described in Reference Example 6, whereby 3.33 g of the title compound were obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].CN1CCOCC1.[N:22]1[CH:27]=[CH:26][N:25]=[CH:24][C:23]=1[C:28](O)=[O:29].C1(N=C=NC2CCCCC2)CCCCC1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:28]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][N:22]=1)=[O:29]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)c1cnccn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1
Reaction time: 2 h
Yield: 98 %

Procedure:
The product L-phenylalanine methyl ester hydrochloride of Preparation example 1 (1.12 g, 5.2 mmol) was dissolved in 20 ml of THF, and neutralized with N-methyl morpholine (NMM) (0.7 ml, 6.2 mmol), then cooled with an ice bath for later use. Pyrazinecarboxylic acid (0.65 g, 5.2 mmol) was added to another reaction flask, dissolved with 20 ml of THF, cooled with an ice water bath, dicyclohexylcarbodiimide (DCC) (1.07 g, 5.2 mmol) and HOBt (0.84 g, 6.2 mmol) were added at 0° C. and reacted for 40 min at 0° C., to which the solution of L-phenylalanine methyl ester hydrochloride in THF prepared, cooled and neutralized according to the above was added, the reaction was monitored by TLC and completed after 2 h, insoluble N,N′-dicyclohexylurea (DCU) was removed by filtration, to the filtrate was added 150 ml of ethyl acetate, washed with 5% sodium bicarbonate solution, 10% citric acid solution, 5% sodium bicarbonate solution, saturated salt solution (2×20 ml) successively. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and evaporated the solvent under reduced pressure, 1.37 g of white solid was obtained with a yield of 98%, m.p.: 152-155° C. 1H-NMR (CDCl3, 300 MHz): δ 3.26 (—CH2, m, 2H), 3.75 (—CH3, s, 3H), 5.09 (—CH, m, 1H), 7.15˜7.32 (-Ph, m, 5H), 8.23 (—CONH, d, 1H), 8.52 (-Pyz, d, 1H), 8.74 (-Pyz, d, 1H), 9.37 (-Pyz, s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:27][O:28][C:29](=[O:35])[CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32]>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[CH3:27][O:28][C:29](=[O:35])[C:30]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([CH3:16])[CH:11]=1)([CH2:33][CH3:34])[CH2:31][CH3:32]
Reactant: Cc1cc(I)ccc1OCc1ccccc1
Reactant: CCC(CC)C(=O)OC
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCC(CC)(C(=O)OC)c1ccc(OCc2ccccc2)c(C)c1
Temperature: 25 °C
Yield: 44.9 %

Procedure:
To a mixture of 1-benzyloxy-4-iodo-2-methyl-benzene (494 mmoles; 160 g) and lithium bis(trimethylsilyl)amide (1.20 moles; 200 g) in 250 ml of toluene at 0-5° C. is added a solution of 2-ethyl-butyric acid methyl ester (988 mmoles; 129 g, Synthesis, 1985 (3), 320) in 250 ml of toluene over 30 m, causing the reaction to exotherm to 18 C. The cloudy yellow solution is allowed to warm to RT and stir for 20 m. Tri-tert-butylphosphine (4.94 mmoles; 1.30 mL; 1.00 g) in 200 ml of toluene and bis(dibenzylideneacetone)palladium (7.90 mmoles; 4.54 g) are added sequentially, and the dark mixture is stirred at ambient temperature for 62 h. The mixture is diluted with 1 L of EtOAc, filtered through a bed of Hyflo, and rinsed with another 1 L of EtOAc. The filtrate is concentrated. The dark orange oil (˜200 g) is purified by flash chromatography (10% EtOAc/hexanes, 1 kg of silica) to give the title compound as a light orange oil (72.4 g). The mixed fractions are combined and re-subjected to the same chromatography conditions to give the another batch of title compound as a yellow oil (50.6 g). 1H NMR (CDCl3) δ 7.40 (m, 5H), 7.02 (m, 2H), 6.83 (d, J=9.2 Hz, 1H), 5.06 (s, 3H), 3.64 (s, 3H), 2.27 (s, 3H), 2.02 (m, 4H), 0.73 (t, J=7.4 Hz, 6H).