Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@@H:10]([CH:11]([CH3:13])[CH3:12])[O:9][CH2:8][CH2:7][N:6]1S(C1C=CC(C)=CC=1)(=O)=O)=[O:4].[Mg]>CO>[CH3:1][O:2][C:3]([C@@H:5]1[C@@H:10]([CH:11]([CH3:13])[CH3:12])[O:9][CH2:8][CH2:7][NH:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1[C@@H](C(C)C)OCCN1S(=O)(=O)c1ccc(C)cc1
Agent: [Mg]
Solvent: CO
Product: COC(=O)[C@H]1NCCO[C@@H]1C(C)C
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of (2R,3S)-2-isopropyl-4-(toluene-4-sulfonyl)-morpholine-3-carboxylic acid methyl ester (0.20 g, 0.59 mmol) and magnesium powder (70 mg, 2.9 mmol) in anhydrous methanol (5 mL) was stirred for 3 hours at 60° C. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue as crude product was used in next step without purification. MS: calc'd (MH+) 188, measured (MH+) 188.
Reaction SMILES: [NH2:1][C:2]([NH:4][N:5]([CH2:15][C:16]([O:18]C)=O)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([CH3:14])[CH:7]=1)=[O:3].C[O-].[Na+]>CO.C(OCC)(=O)C>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([N:5]2[CH2:15][C:16](=[O:18])[NH:1][C:2](=[O:3])[NH:4]2)=[CH:7][C:8]=1[CH3:14]
Reactant: COC(=O)CN(NC(N)=O)c1ccc(OC)c(C)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(N2CC(=O)NC(=O)N2)cc1C

Procedure:
To a solution of methyl [2-[aminocarbonyl]-1-[4-methoxy-3-methyl phenyl]hydrazino]acetate (Intermediate 98, 222 mg, 0.8 mmol) in methanol (5 ml) was added sodium methoxide (43 mg, 0.8 mmol) with stirring and under nitrogen. After 30 minutes further sodium methoxide (43 mg, 0.8 mmol) was added and the reaction stirred at room temperature for 14 hours. Three separate portions of sodium methoxide (43 mg, 0.8 mmol) were then added with 30 minutes between each before the reaction was poured into pH 6 buffer (30 ml) and extracted with ethyl acetate (2×25 ml). The organic extract was dried (MgSO4) and evaporated to give a white semi-solid which was triturated with ethylacetate-ether (~1:1) to give an off white solid. This was dissolved in ethyl acetate (10 ml), filtered and evaporated to give the title compound as an off white solid (18 mg, 10%) m.p. 220°-222° C. (decomp).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1)=[CH:5]OC.[F:19][C:20]([F:29])([F:28])[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:18])[C:4]([C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1)=[CH:5][NH:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]([F:19])([F:28])[F:29])=[CH:22][CH:23]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: COC=C(C(=O)OC)C(=O)c1ccc(C)c(C)c1
Product: COC(=O)C(=CNc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(C)c(C)c1
Yield: 16.6 %

Procedure:
Compound 2c was prepared following the procedure described in Step 2 of Example 1 using 598 mg (2.41 mmol) of the crude 2-(3,4-dimethyl-benzoyl)-3-methoxy-acrylic acid methyl ester 1a and 427 mg (2.65 mmol) of 4-trifluoromethyl-phenylamine. The product 2c was purified by flash chromatography (0-40% ethyl acetate in hexane) to yield 151 mg of 2-(3,4-dimethyl-benzoyl)-3-(4-trifluoromethyl-phenylamino)-acrylic acid methyl ester as a yellow crystalline solid: LC-MSD, m/z for C20H18F3NO3 [M+H]+=378.5; HPLC retention time: 3.0 min.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](Cl)[CH:15]=2)[C@@H:11]([CH3:21])[N:10]([CH2:22][C:23]([F:26])([F:25])[F:24])[C:9]1=[O:27])(C)(C)C>CO.[OH-].[OH-].[Pd+2]>[NH2:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH3:21])[N:10]([CH2:22][C:23]([F:24])([F:25])[F:26])[C:9]1=[O:27]
Reactant: C[C@@H]1[C@H](c2cccc(Cl)c2)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC(F)(F)F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[C@@H]1[C@H](c2ccccc2)C[C@H](N)C(=O)N1CC(F)(F)F
Temperature: 23 °C
Reaction time: 16 h

Procedure:
A mixture of tert-butyl[(3S,5S,6R)-5-(3-chlorophenyl)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)piperidin-3-yl]carbamate (2.75 g, 6.53 mmol) and 20 wt. % palladium hydroxide on carbon (˜50 wt. % wet, 700 mg, 0.50 mmol) in methanol (100 mL) was stirred under a hydrogen balloon at 23° C. for 16 h. The catalyst was removed by filtration through a pad of Celite® and washed thoroughly with methanol and ethyl acetate. Following concentration of the filtrate, a solution of the residue in ethyl acetate (100 mL) pre-cooled to 0° C. was sparged with HCl gas for ˜1 min. The ice-bath was removed and the acidic solution was allowed to warm to 23° C. as stirring was continued for 2 h. The mixture was then concentrated to dryness to afford the title compound as a hydrochloride salt. FIRMS: m/z=287.1361, calculated m/z=287.1366 for C14H18F3N2O. 1H NMR (500 MHz, CD3OD) δ 7.39 (t, 2H, J=7.3 Hz), 7.31 (t, 1H, J=7.3 Hz), 7.27 (d, 2H, J=7.3 Hz), 4.81-4.73 (m, 1H), 4.24 (dd, 1H, J=12.0, 6.8 Hz), 3.94 (p, 1H, J=6.0 Hz), 3.76-3.67 (m, 2H), 2.56 (q, 1H, J=12.7 Hz), 2.42 (m, 1H), 1.00 (d, 3H, J=6.3 Hz).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].[CH2:6]([N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[NH2:1][CH2:2][CH2:3][CH2:4][NH:5][CH:16]1[CH2:15][CH2:14][N:13]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:18][CH2:17]1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: NCCCN
Solvent: CCO
Product: NCCCNC1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 9 h

Procedure:
The starting material is prepared as follows: To the ice cooled stirred solution of 62.5 ml of 1,3-diaminopropane in 100 ml of ethanol, 30 g of 1-benzyl-4-piperidone are added dropwise. The mixture is hydrogenated over 2 g of pre-reduced platinum oxide at 50° and 2.7 atm. for 9 hours. After theoretical hydrogen-uptake the catalyst is filtered off, the filtrate evaporated, the residue distilled and the fraction boiling at 145°-160°/0.2 mmHg collected, to yield the 4-(3-aminopropylamino)-1-benzylpiperidine.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]=[O:5].[H][H]>[Ni]>[CH2:4]([OH:5])[CH2:3][CH2:2][OH:1].[OH:5][CH2:4][CH2:3][CH:2]=[O:1]
Reactant: [H][H]
Agent: [Ni]
Agent: O=CCCO
Product: OCCCO

Procedure:
There is produced a solution containing 8.1 percent by weight of 3-hydroxypropanal and 1.3 percent by weight of dimerized 3-hydroxypropanal both obtained as the result of the above hydration reaction. A known raney nickel catalyst is added to the resulting solution to hydrogenate 3-hydroxypropanal and dimerized 3-hydroxypropanal. Reaction conditions are: a hydrogen pressure of 100 kg/cm2, a reaction temperature of 60° C., and reaction time of six hours. When the reaction ends, the resulting solution is analyzed and it is acknowledged that there is produced 1,3-propanediol in an amount equal to a total of 3-hydroxypropanal and dimerized 3-hydroxypropanal. In other words, 1,3-propanediol is quantitatively produced. This indicates that dimerized 3-hydroxypropanal is converted into 1,3-propanediol by a known hydrogenation process.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15]CC)=[O:14])=[CH:7]2)([O-:3])=[O:2].[OH-].[Li+]>CO.C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([OH:15])=[O:14])=[CH:7]2)([O-:3])=[O:2]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 90 °C

Procedure:
16.5 g (66.93 mmol) of ethyl 5-nitroindole-2-carboxylate are dissolved in 200 ml each of methanol and THF, and 67 ml (133.85 mmol) of lithium hydroxide solution are added. The mixture is heated at 90° C. for half an hour. After cooling, the mixture is, for work-up, diluted and extracted with aqueous hydrochloric acid and ethyl acetate. The organic phase is washed with sat. sodium chloride solution, dried with sodium sulphate, filtered and dried under reduced pressure.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][NH:11]3)=[CH:4][C:3]=2[O:2]1.Cl[C:24]1[N:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[CH:26][N:25]=1>CN(C=O)C>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:24]3[N:25]=[CH:26][C:27]([C:30]4[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=4)=[CH:28][N:29]=3)=[CH:4][C:3]=2[O:2]1
Reactant: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)OCO2)NCC3
Reactant: COc1ccc(-c2cnc(Cl)nc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc(-c2cnc(N3CCc4c([nH]c5ccccc45)C3c3ccc4c(c3)OCO4)nc2)cc1

Procedure:
1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (2.72 g, 9.6 mmol) (prepared according to the process as disclosed in WO97/43287, Intermediate 7, page 24) and 2-chloro-5-(4-methoxyphenyl)pyrimidine (1.04 g, 4.78 mmol) were stirred in DMF (20 mL, anhydrous) at 120° C. for 16 h. The resulting mixture was quenched with saturated NH4Cl, extracted with ethyl acetate and dried with MgSO4. The reaction mixture solvent was evaporated and the residue purified by column chromatography (silica gel, ethyl acetate:hexanes=1:2) to yield the product as a white solid.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9](Cl)(=[O:11])=[O:10].[CH2:14]([NH2:17])[CH2:15][CH3:16].CCCCCC.CCOC(C)=O>C(Cl)Cl.[OH-].[Na+]>[CH2:14]([NH:17][S:9]([C:2]1[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=1[CH3:13])(=[O:11])=[O:10])[CH2:15][CH3:16]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: CCCN
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCNS(=O)(=O)c1c(C)cc(C)cc1C
Yield: 69.9 %

Procedure:
Mesitylenesulfonyl chloride (12.0 g, 55 mmol) and propylamine (2.96 g, 50 mmol) in CH2Cl2 (60 mL) and 1 N NaOH (60 mL) were combined and worked up by the method of 31. Column chromatography (3:1 hexane/EtOAc) afforded 8.44 g (85%) of 65 as a crystalline solid: mp 53-54° C.; NMR δ 0.86 (t, 3 H, J=7), 1.44-1.51 (m, 2 H), 2.30 (s, 3 H), 2.64 (s, 6 H), 2.86 (q, 2 H), 4.40 (br t, 1 H), 6.96 (s, 2 H). Anal. (C12H19NO2S) C, H, N.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[Br:15][C:16]1[O:20][C:19]([C:21](O)=[O:22])=[CH:18][CH:17]=1>>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C@H:3]([CH2:2][NH:1][C:21]([C:19]2[O:20][C:16]([Br:15])=[CH:17][CH:18]=2)=[O:22])[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Reactant: O=C(O)c1ccc(Br)o1
Product: CC(C)(C)OC(=O)N1CC[C@H](CNC(=O)c2ccc(Br)o2)C1

Procedure:
59.1 Using general procedure E, (R)-3-aminomethyl-1-N-tert-butoxycarbonyl-pyrrolidine was coupled with 5-bromo-furan-2-carboxylic acid to give (R)-3-{[(5-bromo-furan-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester. Pale yellow solid. MS373.1 ([M−H]−)
Reaction SMILES: [OH:1][CH:2]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:7]([O:8][C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H:5]([OH:6])[C@H:3]1[OH:4]>C([O-])(=O)C>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:20]([CH2:22][OH:23])[OH:21])[OH:8])[OH:6])[OH:4]
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Agent: CC(=O)[O-]
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 0.25 h

Procedure:
In 30 ml of lactose solution having a concentration of 13.3 (W/V) % prepared by dissolving lactose in a 0.05 M acetate buffer solution of pH 4.5 was immersed 0.2-0.25 ml of an immobilized lactase. The reaction was allowed to proceed at 30° C. under reciprocating shaking (more than 100 rpm with an amplitude larger than 3.5 cm) for 15 minutes. Then the amount of glucose produced was determined with a glucose oxidase-peroxidase-dye system. The amount of enzyme which produces 1μ mol of glucose per minute is defined as one unit (1 ILU). The dry weight of an immobilized lactase is determined as mentioned below. That is, after the termination of the reaction, the immobilized lactase was filtered, dried at 50° C. under reduced pressure for 8 hours or more, placed in a desiccator at room temperature (18°-25° C.) for 1.5 hours or more, the weight thereof was then measured and this value is regarded as the dry weight of the immobilized lactase. The activity of an immobilized lactase is represented by the unit per gram of dry weight (1 ILU/g-IML).
Reaction SMILES: [OH:1][CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7](O)[C@H:5]([OH:6])[C@@H:3]1O.[C:13]([O:16][C:17](=[O:19])[CH3:18])(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:16][CH:17]1[O:19][C@H:7]([CH2:5][O:6][C:11](=[O:12])[CH3:9])[C@@H:9]([O:10][C:2](=[O:1])[CH3:3])[C@H:11]([O:12][C:5](=[O:6])[CH3:7])[C@@H:18]1[O:10][C:2](=[O:1])[CH3:3])(=[O:15])[CH3:14]
Reactant: OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1OC(OC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 96.7 %

Procedure:
Analogously, as described in the literature [M. L. Wolfrom and A. Thompson in Methods in Carbohydrate Chemistry (R. L. Whistler, M. L. Wolfrom and J. N. BeMiller, Eds.), Academic Press, New York, Vol. II, 53, pp. 211-215, (1963)], the reaction of 150 g (832.5 mmol) of α,β-D-mannopyranose with a mixture that consists of 1500 ml of absolute pyridine and 1500 ml of acetic acid anhydride after working-up yields 315 g (96.7%) of the above-mentioned title compound as crude product in the form of a viscous and colorless oil. By 1H-NMR-spectroscopic study of the thus obtained title compound, it was possible to determine the α to β ratio of both anomers at 4:1. A separation of the α,β-anomers of the above-mentioned title compound can thus be eliminated in performing the subsequent reaction steps.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][C:21]([F:24])([F:23])[F:22])[N:3]=1.CC[N:27]([CH:31]([CH3:33])[CH3:32])C(C)C>CN(C=O)C.CCOC(C)=O>[NH2:27][C@H:31]1[CH2:32][CH2:8][C@H:7]([CH2:2][NH:3][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][C:21]([F:24])([F:23])[F:22])[N:3]=2)[CH2:6][CH2:33]1
Reactant: CCN(C(C)C)C(C)C
Reactant: FC(F)(F)Oc1ccccc1CNc1ncc(C(F)(F)F)c(Cl)n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2C(F)(F)F)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 109.9 %

Procedure:
To a solution of the above (4-chloro-5-trifluoromethyl-pyrimidin-2-yl)-(2-trifluoromethoxy-benzyl)-amine (80 mg, 0.22 mmol) in DMF (2 mL) was added the Boc-protected cyclohexyl amine (74 mg, 0.33 mmol) followed by DIPEA (37 μL, 0.22 mmol). The reaction mixture was stirred at 70° C. for 3 h. When the reaction was complete, the reaction mixture was diluted with EtOAc and washed with water (×4). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel preparative TLC using 95:5 CH2Cl2:MeOH as an eluent. The resulting residue was then re-dissolved in CH2Cl2 (10 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 2 h and treated with saturated NaHCO3. The product was extracted with CH2Cl2 and dried over anhydrous Na2SO4. Silica gel preparative TLC using CH2Cl2:MeOH:NH4OH 10:1:0.2 as an eluent afforded 56 mg (56%) of the title compound as a white solid, m/z 462.4 [M−1]+.
Reaction SMILES: [CH:1]1[N:5]=[CH:4][NH:3][C:2]=1[CH2:6][C@H:7]([NH:11][C:12]([CH2:14][CH2:15][NH2:16])=[O:13])[C:8]([OH:10])=[O:9].C(N(CC)CC)C.[Br:24][CH2:25][CH2:26][CH2:27][C:28](Cl)=[O:29]>CN(C)C=O.C(OCC)(=O)C>[Br:24][CH2:25][CH2:26][CH2:27][C:28]([NH:16][CH2:15][CH2:14][C:12]([NH:11][C@H:7]([C:8]([OH:10])=[O:9])[CH2:6][C:2]1[N:3]=[CH:4][NH:5][CH:1]=1)=[O:13])=[O:29]
Reactant: NCCC(=O)N[C@@H](Cc1cnc[nH]1)C(=O)O
Reactant: O=C(Cl)CCCBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CCCBr)NCCC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of carnosine (5 g, 22.1 mmoles) in N,N-dimethylformamide (80 ml), triethylamine (4.62 ml, 33.1 mmoles) and 4-bromobutyrylchloride (chloride of 4-bromobutyric acid-83.85 ml, 33.1 mmoles) are added. The solution is left under stirring for 24 hours at room temperature, then it is diluted with ethyl acetate and the organic phase is washed with water. The organic phase is then anhydrified with sodium sulphate and evaporated at reduced pressure. The obtained crude product is purified by chromatography on silica gel eluting with ethyl acetate, obtaining the final product.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:31]1[C:43]2[CH:42]([CH2:44][O:45][C:46]([NH:48][C@H:49]([C:51](O)=[O:52])[CH3:50])=[O:47])[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]=2[CH:34]=[CH:33][CH:32]=1>>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=2)[CH:14]=1)[C:51](=[O:52])[C@H:49]([CH3:50])[NH:48][C:46]([O:45][CH2:44][CH:42]1[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:35]2[C:43]1=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:47])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: COc1cc(-c2cc(CNCCO[Si](C)(C)C(C)(C)C)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN(CCO[Si](C)(C)C(C)(C)C)C(=O)[C@H](C)NC(=O)OCC3c4ccccc4-c4ccccc43)ccn2)cc(OC)c1OC

Procedure:
N-[2-(tert-Butyldimethylsilyloxy)ethyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amine (756 mg) and N-(9-fluorenylmethoxycarbonyl)-L-alanine (544 mg) were treated in the same manner as in Preparation Example 9 to obtain the title compound. Since this compound was unable to be isolated from impurities, it was used in the next reaction without purifying it as it is.
Reaction SMILES: [C:1]([C:5]1[CH:37]=[CH:36][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[N:19]=[C:20]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([CH:33]=O)=[CH:29][CH:28]=4)[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=3)[C:13]=2[CH3:35])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:38][CH2:39][CH2:40][NH:41][CH2:42][CH2:43][OH:44].C(O)(=O)C.[BH4-].[Na+]>CO>[OH:38][CH2:39][CH2:40][N:41]([CH2:33][C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:20]2[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=[C:18]([C:14]3[C:13]([CH3:35])=[C:12]([NH:11][C:9](=[O:10])[C:8]4[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:37][CH:36]=4)[CH:17]=[CH:16][CH:15]=3)[N:19]=2)=[CH:28][CH:29]=1)[CH2:42][CH2:43][OH:44]
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(C=O)cc2)n1
Reactant: OCCNCCO
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(CN(CCO)CCO)cc2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-tert-butyl-N-{3-[6-(4-formyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide (4) (110 mg; 0.22 mmol) was dissolved in methanol (10 mL) and 1 mL 2-(2-hydroxy-ethylamino)-ethanol was added. To the stirring reaction solution was then added 0.25 mL glacial acetic acid, followed by 0.25 g powdered molecular sieves (4 Å; activated) and the resulting slurry allowed to stir at rt for 4 hr under N2, then heated to 50° C. After 3 hr at 50° C., the reaction was cooled to rt and excess NaBH4 powder (0.5 g) was added portionwise to the stirring slurry. After gas evolution ceased, the reaction slurry was then adsorbed directly onto silica gel and was chromatographed using methanol/CH2Cl2 (1:9) as eluent to provide N-{3-[6-(4-{[bis-(2-hydroxy-ethyl)-amino]-methyl}-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide (5) (75 mg) as an off-white solid. MS 584.24 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9](N)=[O:10].[OH:21][S:22]([OH:25])(=[O:24])=[O:23].[C:26](=O)([O-])[O-:27].[Na+].[Na+]>CO>[S:22](=[O:23])(=[O:21])([OH:25])[OH:24].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9]([O:27][CH3:26])=[O:10]
Reactant: O=C([O-])[O-]
Reactant: NC(=O)C(c1ccccc1Cl)N1CCc2sccc2C1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 67.5 °C
Reaction time: 0.5 h

Procedure:
5 g of (+)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetamide was dissolved in 20 ml methanol and the solution warmed to 65 to 70° C. 15 mL (0.28 mol) of chilled conc. H2SO4 (98%, −15° C.) was added slowly in 1 hr maintaining the temperature till −15° C. After the completion of addition the reaction mixture was heated at 70° C. for 16 hrs. The solvent was distilled off under reduced pressure and to the residue 50 mL of water was added and stirred for 30 min followed by cooling to −5° C. The pH of reaction mixture was adjusted between 9 to 10 using aq. sodium carbonate. The residue was extracted with 100 mL ethyl acetate. The organic layer was dried over anhydrous Na2SO4, and evaporated under vacuum. The combined eluent was evaporated at reduced pressure to yield 2.8 g of crude product purified by column chromatography, using hexane:ethyl acetate (9:1) as eluent to give 2 g of titled compound (1) and 1 g of the starting material (S)-(+)-(II).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1[NH2:4].C(O[C:16]([S:18][K])=[S:17])C.O.Cl>CN(C)C=O>[F:10][C:9]([F:12])([F:11])[C:6]1[CH:7]=[CH:8][C:2]2[S:17][C:16]([SH:18])=[N:4][C:3]=2[CH:5]=1
Reactant: CCOC(=S)S[K]
Reactant: Nc1cc(C(F)(F)F)ccc1Br
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc2sc(S)nc2c1
Temperature: 120 °C

Procedure:
Into a solution of 2-bromo-5-(trifluoromethyl)aniline (1.5 g, 6.25 mmol, 1.00 equiv) in N,N-dimethylformamide (10.0 mL) was added ethoxy(potassiosulfanyl)methanethione (2.2 g, 13.72 mmol, 2.20 equiv) under nitrogen. The resulting mixture was heated for 4 h at 120° C. in an oil bath. After cooled down, water (70.0 mL) and hydrogen chloride (15.0 mL, 1 mol/L) were added. The solid was collected by filtration, dissolved in ethyl acetate and dried over anhydrous sodium sulfate. Filtration and evaporation of the solvent afforded the title compound. as a gray white solid. MS m/z [M+H]+ (ESI): 236
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:12](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
A mixture of 3-fluoro-4-nitrophenol (2.56 g), potassium carbonate (4.5 g) and iodomethane (4.63 g) in N,N-dimethyl-formamide (15 mL) was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was washed with diethyl ether. The extract was washed with water twice, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 3-fluoro-4-nitroanisole (2.56 g). This material was dissolved in 1,2-dichloroethane (13 mL). To the solution was added chlorosulfonic acid (1.3 mL), and the mixture was heated for reflux for 4 hours. The reaction mixture was diluted with methylene chloride, and the resulting mixture was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1) to give the title compound (0.51 g).