Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][N:4]=1.Br[C:21]1[CH:30]=[C:29]([CH3:31])[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([CH3:32])[CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O.O>CS(C)=O.CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:10][O:9][C:8]1[CH:7]=[C:6]([C:21]2[CH:30]=[C:29]([CH3:31])[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([CH3:32])[CH:22]=2)[CH:5]=[N:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cnc1OC
Reactant: COC(=O)c1c(C)cc(Br)cc1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C)cc(-c2cnc(OC)c(OC)c2)cc1C
Temperature: 90 °C
Yield: 29.6 %

Procedure:
As shown in step 6-i of Scheme 6, 2,3-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Compound 2021, 920 mg, 3.47 mmol), methyl 4-bromo-2,6-dimethyl-benzoate (844 mg, 3.47 mmol), and Cs2CO3 (2.26 g, 6.94 mmol) were taken up in DMSO (12 mL) in a sealable tube. Nitrogen gas was bubbled through the solution for 5 minutes, dppfPdCl2 (141 mg, 0.174 mmol) added, and the vessel sealed. The reaction mixture was heated at 90° C. for 60 minutes under an atmosphere of nitrogen. After cooling, the mixture was poured into EtOAc/water. The organics were washed with water, brine, passed through a plug of Florisil®, and concentrated under reduced pressure to give a solid. The solid was suspended in MeOH and collected by filtration to provide methyl 4-(5,6-dimethoxy-3-pyridyl)-2,6-dimethyl-benzoate (Compound 2022, 310 mg). The filtrate was concentrated and purified by silica gel chromatography (0 to 50% EtOAc/hex) to provide an additional 400 mg of Compound 2022 (total yield 710 mg, 2.4 mmol, 68% yield). This compound was used in subsequent reactions as is.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[O:13])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)([OH:16])N.Cl([O-])=O.[Na+]>CC(C)=O.O.O>[C:1]1([C:7]2[CH:8]=[C:9]([C:12]([OH:16])=[O:13])[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cc(-c2ccccc2)cs1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1cc(-c2ccccc2)cs1
Temperature: 0 °C
Yield: 61.2 %

Procedure:
4-phenyl-thiophene-2-carboxaldehyde (150 mg, 0.80 mmol) was dissolved in acetone-water mixture (2:1) (3 mL) and cooled to 0° C. To this reaction mixture was added sulphamic acid (232 mg, 2.38 mmol) and sodium chlorite (288 mg, 3.18 mmol) dissolved in minimum amount of water. The resulting reaction mixture was allowed to stir at room temperature for half an hour. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over sodium sulphate and concentrated to afford 100 mg (62.5% yield) of 4-Phenyl-thiophene-2-carboxylic acid.
Reaction SMILES: Br.[N:2]1([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:18](O)(=[O:27])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.[Cl-].[Na+].O.C(OCC)(=O)C.C(N(CC)CC)C>[C:18]([N:5]1[CH2:4][CH2:3][N:2]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:7][CH2:6]1)(=[O:27])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: O=C(NN1CCNCC1)c1ccc(F)cc1
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NN1CCN(C(=O)C=Cc2ccccc2)CC1)c1ccc(F)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 40.2 %

Procedure:
To a solution of N-piperazinyl-p-fluorobenzamide hydrobromide (300 mg), cinnamic acid (161 mg), and 1-hydroxybenzotriazole (173 mg) in N,N-dimethylformamide (6 ml) was added N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (246 mg) and triethylamine (0.28 ml) at 5° C. The mixture was stirred at 5° C. for 1 hour, and then poured into ethyl acetate and brine. The organic layer was separated, dried over magnesium sulfate, and concentrated. The residue was crystallized from ethyl acetate-diethyl ether to give N-(4-cinnamoyl-1-piperazinyl)-p-fluorobenzamide (0.14 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.Cl.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([N:13]([CH3:14])[C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=[C:3]([CH2:2][NH:1][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=3)[N:12]=2)=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: COc1ccc(N(C)c2nc(CN)nc3ccccc23)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(N(C)c2nc(CNC(=O)c3cccnc3)nc3ccccc23)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
To (2-aminomethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (100 mg, 0.34 mmol) and nicotinoyl chloride hydrochloride (91 mg, 0.51 mmol) in CH2Cl2 (3 mL) at 0° C. was added triethylamine (167 mg, 1.2 mmol). The reaction was stirred for 2 h at 0° C. The mixture was washed successively with H2O, 0.1 M HCl, H2O and 5% NaHCO3. The reaction was extracted with EtOAc (3×10 mL), washed with brine, dried (MgSO4) and concentrated providing 64 mg of the title compound. 1H NMR (CDCl3) δ 8.76 (s, 1H), 8.29 (d, 1H), 8.11 (s, 1H), 7.78 (d, 1H), 7.58 (t, 1H), 7.45 (t, 1H), 7.14 (d, 2H), 7.05-7.01 (m, 2), 6.93 (d, 2H), 4.85 (s, 2H), 3.85 (s, 3H), 3.61 (s, 3H); LC-MS (ESI+; 400 ([M+H]+)).
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.Cl.[NH2:26][CH:27]([C:46]([N:48]([CH3:50])[CH3:49])=[O:47])[CH2:28][C:29]1[CH:30]=[C:31]([CH:43]=[CH:44][CH:45]=1)[O:32][C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=1.[NH2:51][C:52]1[N:61]=[C:60]([N:62]2[CH2:67][CH2:66][N:65]([CH3:68])[CH2:64][CH2:63]2)[C:59]2[C:54](=[CH:55][C:56]([C:69](O)=[O:70])=[CH:57][CH:58]=2)[N:53]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[NH2:51][C:52]1[N:61]=[C:60]([N:62]2[CH2:63][CH2:64][N:65]([CH3:68])[CH2:66][CH2:67]2)[C:59]2[C:54](=[CH:55][C:56]([C:69]([NH:26][CH:27]([C:46]([N:48]([CH3:50])[CH3:49])=[O:47])[CH2:28][C:29]3[CH:30]=[C:31]([CH:43]=[CH:44][CH:45]=3)[O:32][C:33]3[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=3)=[O:70])=[CH:57][CH:58]=2)[N:53]=1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Reactant: COC(=O)c1ccc(Oc2cccc(CC(N)C(=O)N(C)C)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[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)c1ccc(Oc2cccc(CC(NC(=O)c3ccc4c(N5CCN(C)CC5)nc(N)nc4c3)C(=O)N(C)C)c2)cc1
Reaction time: 1 h

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.030 g, 0.078 mmol) was added to a solution of methyl 4-{3-[2-amino-3-(dimethylamino)-3-oxopropyl]phenoxy}benzoate HCl salt (0.045 g) and 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (0.015 g, 0.052 mmol) in N,N-dimethylformamide (1.0 mL) with N,N-diisopropylethylamine (0.027 mL, 0.16 mmol) at r.t. The reaction was stirred for 1 h. The product was purified with out workup by HPLC (pH=10) to give the desired(0.012 g, 37%) as a white amorphous solid. 1H NMR (400 MHz, DMSO): δ 8.82 (d, 1H), 7.71 (d, 2H), 7.68 (d, 1H), 7.61 (d, 1H), 7.29 (m, 2H), 7.17 (d, 1H), 7.06 (s, 1H), 6.88 (d, 1H), 6.82 (d, 2H), 6.38 (s, 1H), 5.02 (m, 1H), 3.72 (s, 3H), 3.46 (bs, 4H), 3.27 (s, 4H), 2.98 (bs, 5H), 2.77 (s, 3H), 2.17 (s, 3H). Analytical LCMS (M+H)+: m/z=612.0.
Reaction SMILES: [S:1]([O:11][CH2:12]/[CH:13]=[CH:14]/[CH2:15]OS(C1C=CC(C)=CC=1)(=O)=O)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[N+](CCCC)(CCCC)(CCCC)CCCC.[F-:44]>C1COCC1>[F:44][CH2:15]/[CH:14]=[CH:13]/[CH2:12][O:11][S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)OC/C=C/COS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OC/C=C/CF)cc1
Yield: 38.4 %

Procedure:
To a solution of (E)-1,4-ditosyloxy-2-butene (256 mg, 0.64 mmol) in 10 mL of THF was added Bu4NF (0.7 mL, 1M in THF, 0.7 mmol). The mixture was heated to reflux for 30 min. Evaporation and purification of the residue by flash column chromatography with hexane:ether/2:1 afforded the product as a colorless oil (60 mg, 38%). 1 H NMR (CDCl3, 300 MHz) δ 7.80 (d, J=8.4 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 5.99-5.75 (m, 2H, 4.84 (ddd, JFCH=46.5 Hz, J=4.8, 1.2 Hz, 2H), 4.59-4.56 (m, 2H), 2.46 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[NH:10][CH:9]=[N:8][C:7]2[C:3]=1[N:4]=[CH:5][N:6]=2.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C>[Cl:1][C:2]1[NH:10][CH2:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:7]2[C:3]=1[N:4]=[CH:5][N:6]=2
Reactant: Clc1[nH]cnc2ncnc1-2
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1CNC(Cl)=C2N=CN=C21
Reaction time: 9 h
Yield: 13.9 %

Procedure:
A solution of 0.31 g (2.0 mmol) of 6-chloro-1H-purine and 0.83 g (6.0 mmol) of potassium carbonate in 15 mL of DMF was stirred at 25° C. for 20 min. under argon. To it, 0.53 mL (3.0 mmol) of 1-(chloromethoxy)-2-(trimethylsilyl)ethane (SEM-Cl) was added via syringe, the solution was stirred for 9 h, filtered through Celite, and the filtrate was diluted with diethyl ether, washed with water, and brine, dried (MgSO4), concentrated, and column chromatographed on silica gel using a gradient mixture of hexane and ethyl acetate to give 0.35 g (61% yield) of 115 and 0.08 g (14% yield) of 6-chloro-3-[(2-trimethylsilylethoxy) methyl]-1H-purine (117). Compound 115: mp 33-34° C.; NMR δ 8.70 (s, 1H), 8.24 (s, 1H), 5.62 (s, 2H, NCH2O), 3.60 (t, J=8 Hz, 2H, CH2O), 0.94 (t, J=8 Hz, 2H, CH2Si), −0.12 (s, 9H, MeSi); 13C NMR δ 152.4, 152.2, 151.3, 145.4, 131.5, 72.7 (CN), 67.8 (CO), 17.8, 21.4 (CSi).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:14])=[C:7]([C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])[CH:8]=1)#[N:2].C(OCC)C.CO[C:22](OC)([CH3:24])[CH3:23]>S(=O)(=O)(O)O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:14][C:22]([CH3:24])([CH3:23])[O:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:7]=2[CH:8]=1)#[N:2]
Reactant: COC(C)(C)OC
Reactant: CC(C)(CO)c1cc(C#N)ccc1O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CC1(C)OCC(C)(C)c2cc(C#N)ccc2O1
Reaction time: 1 h

Procedure:
A suspension of 2-(5-cyano-2-hydroxyphenyl)-2-methyl-1-propanol (5 g), prepared as in Example 26, in 2,2-dimethoxypropane was treated with 2 drops sulphuric acid at 10° C. After 1 hour at ambient temperature, diethyl ether was added, and the solution was washed with sodium hydroxide solution and water (twice). It was then dried over magnesium sulphate and run down, yielding 2.4 g of an oil which solidified on standing. The solid was dissolved in petroleum ether (bp 40°-60° C.) and the solution was cooled in an ice/salt bath. The resulting crystalline solid was separated off by filtration, yielding 1.9 g of product, mp 55°-56° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:24][CH2:23]2)[C:10](=O)[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:44])=CC=1>CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:24][CH2:23]2)[C:10](=[S:44])[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CCC(=O)N(Cc2ccc(C)cc2)C2CCN(Cc3ccccc3)CC2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CO
Product: COc1ccc(CCC(=S)N(Cc2ccc(C)cc2)C2CCN(Cc3ccccc3)CC2)cc1
Yield: 94 %

Procedure:
A mixture of N-((4-Methylphenyl)methyl)-N-(1-(phenylmethyl)piperidin-4-yl)-(4-methoxyphenylmethyl)acetamide (20 mg, 0.045 mmol) and Lawesson's reagent (25 mg, 0.062 mmol), was taken in a glass vial and mixed thoroughly with magnetic stirbars. The glass vial was then irradiated in a microwave oven (900 W, Whirlpool M401) for 8 min. Upon completion of the reaction, the yellow-colored material was transferred to an ion-exchange column with the aid of methanol (2 ml). The ion-exchange column was subsequently washed with CH2Cl2 (2 ml) and methanol (2 ml) and the product was thereafter eluted from the ion-exchange column (10% NH3 in methanol, 2 ml) to give N-((4-Methylphenyl)methyl)-N-(1-(phenylmethyl)piperidin-4-yl)-4-methoxyphenylmethyl thioacetamide (20 mg, 97%) as a white solid; LC-MS: (M+H)+ 459, tr 9.60 min; TLC (CH2Cl2/methanol 20:1) Rf=0.38.
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].[O:7]=[C:8]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:9][C:10]([O:12][CH3:13])=[O:11].CI>CC(C)=O>[CH3:1][CH:9]([C:8](=[O:7])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:10]([O:12][CH3:13])=[O:11]
Reactant: CCCCCCC(=O)CC(=O)OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCCCCCC(=O)C(C)C(=O)OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
K2CO3 (2.67 g) was added to a solution of methyl 3-oxononanoate (3.01 g) and methyl iodide (2.77 g) in acetone (100 ml) and the mixture was stirred at room temperature for 24 hours. The reaction solution was celite filtered, and then the mother liquor was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane/AcOEt=13/1) to obtain methyl 2-methyl-3-oxononanoate.
Reaction SMILES: Cl/[CH:2]=[CH:3]\[C:4]#[C:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12]>[Pd]>[CH3:10][Si:11]([CH3:13])([CH3:12])[C:14]#[C:15][CH:2]=[CH:3][C:4]#[C:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: C#C[Si](C)(C)C
Reactant: CCCCC#C/C=C\Cl
Agent: [Pd]
Product: CCCCC#CC=CC#C[Si](C)(C)C
Yield: 53 %

Procedure:
According to Method A of the above-described General Synthesis Procedures I, the coupling reaction of compound (a4) from Example 4 with trimethylsilylacetylene using palladium as a catalyst gave the title compound (a5) as an oil in 53% yield.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([C:7](O)=[O:8])[C:4]([SH:10])=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:17]=[C:16](Cl)[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][C:13]=1[O:22][CH3:23]>>[Cl:11][C:12]1[C:17]2[C:7](=[O:8])[C:5]3[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=3)[S:10][C:16]=2[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][C:13]=1[O:22][CH3:23]
Reactant: COc1cc([N+](=O)[O-])c(Cl)cc1Cl
Reactant: O=C(O)c1ccccc1S
Product: COc1cc([N+](=O)[O-])c2sc3ccccc3c(=O)c2c1Cl

Procedure:
Reaction of a mixture of 4.5 g (0.0343 mol) of 2-(diethylaminoethyl)hydrazine, 7.5 g (0.0233 mol) of 1-chloro-2-methoxy-4-nitro-9H-thioxanthen-9-one in 200 ml of DMF as described in Example 53 gave 7.6 g of product. 1-Chloro-2-methoxy-4-nitro-9H-thioxanthen-9-one is prepared from 2-thiobenzoic acid and 2,4-dichloro-5-nitroanisole [C. Bloomfield, A. K. Manglik, R. B. Mootie, K. Schofield, and G. D. Tokin, J. Chem. Soc. Perkin Trans. II, 75 (1983)] in the manner of Example 58.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:24])([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)[C:8]([O:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:9])[CH2:3]1.[ClH:26].[CH:27](=[NH:31])OCC>C(O)C>[ClH:26].[F:25][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:24])([C:17]2[CH:18]=[CH:19][C:20]([Br:23])=[CH:21][CH:22]=2)[C:8]([O:10][CH:11]2[CH2:12][CH2:13][N:14]([CH:27]=[NH:31])[CH2:15][CH2:16]2)=[O:9])[CH2:3]1
Reactant: O=C(OC1CCNCC1)[C@](O)(c1ccc(Br)cc1)[C@@H]1CCC(F)(F)C1
Reactant: CCOC=N
Agent: Cl
Solvent: CCO
Product: N=CN1CCC(OC(=O)[C@](O)(c2ccc(Br)cc2)[C@@H]2CCC(F)(F)C2)CC1
Temperature: 25 °C
Reaction time: 13 h
Yield: 60.1 %

Procedure:
To a solution of 13 mg of piperidin-4-yl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)ethanoate in 1 ml of anhydrous ethanol, 4 mg of ethyl formimidate hydrochloride was added, followed by 13 hours' stirring at room temperature. The reaction liquid was condensed to dry solid. Purifying the crude product on silica gel column chromatography (eluent: chloroform/methanol=10/1), 9 mg of the title compound was obtained as a colorless solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1O.C(N1C=CN=C1)(N1C=CN=C1)=O>C1COCC1>[O:12]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:10]1[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][OH:1])=[CH:8][CH:7]=1
Reactant: O=C(O)Cc1ccc(CO)cc1
Reactant: Nc1ccccc1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: OCc1ccc(Cc2nc3ccccc3o2)cc1
Temperature: 180 °C
Reaction time: 72 h
Yield: 20.8 %

Procedure:
A mixture of (4-hydroxymethyl-phenyl)-acetic acid (5.0 g, 30.1 mmol) and 2-amino-phenol (6.6 g, 60.2 mmol) was heated at 180° C. for 3 h. The crude residue was cooled and then dissolved in THF (50 mL). The resulting solution was treated with carbonyldiimidazole (3.7 g, 22.5 mmol) and stirred at 80° C. for 72 h. The reaction mixture was then partitioned between EtOAc (200 mL) and water (200 mL). The organic layer was dried (MgSO4), filtered and concentrated. Purification by silica gel flash chromatography (0% to 80% EtOAc in hexanes) followed by a second silica gel flash chromatography (0% to 10% CH3OH in CH2Cl2) afforded a colorless oil. The crude oil was then partitioned between EtOAc (200 mL) and 1 N NaOH (200 mL). The organic layer was dried (MgSO4), filtered and concentrated to afford the title compound as a colorless oil (1.5 g, 20%). MS (ESI): mass calcd. for C15H13NO2, 239.09; m/z found, 240.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.70-7.68 (m, 1H), 7.49-7.46 (m, 1H), 7.40-7.35 (m, 4H), 7.33-7.29 (m, 2H), 4.69 (br d, J=4.5. Hz, 2H), 4.28 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CCOC(=O)C=C1CCC(c2ccc(O)cc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CCC(c2ccc(O)cc2)CC1
Yield: 90.1 %

Procedure:
6.646 g of ethyl [4-(4-hydroxyphenyl)cyclohexylidene]acetate (26.53 mmol, 1 eq.) are placed in 150 mL of ethyl acetate in a Parr bottle under nitrogen. 0.77 g of 10% palladium-on-charcoal (0.72 mmol, 0.03 eq.) is added and the reaction medium is placed under 50 psi of hydrogen for 3 hours at 25° C. The reaction medium is filtered and concentrated to give 6.27 g of ethyl [4-(4-hydroxyphenyl)cyclohexyl]acetate.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.C(N(CC)CC)C>CC(C)=O>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(CN)cc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(CNS(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 69.9 %

Procedure:
4-(Chlorosulfonyl)benzoic acid (5 g, 22.7 mmol) was added, in three portions as a solid, to a stirring solution of 4-methoxy benzylamine (6.1 g, 45 mmol) and triethylamine (2.3 g, 22.7 mmol) in acetone (100 mL) cooled to 0° C. via an ice water bath over a 10 minute period. The ice bath was removed and the reaction was stirred for an additional 4 hours. The reaction mixture was diluted with a solution of 5% acetic acid in H2O (150 mL) and extracted with ethyl acetate (3×, 100 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated on the rotovap. The resulting white solid was triturated with hexanes/ethyl acetate (9/1) to afford 4-(N-(4-methoxybenzyl)sulfamoyl)benzoic acid (5.1 g, 70%) as a white solid. 1H NMR (400 MHz, DMSO d6) δ 3.68 (s, 3H), 3.91 (s, 2H), 6.79 (d, J=8.4 Hz, 2H), 7.10 (d, J=8.8 Hz, 2H), 7.80 (d, J=8.8 Hz, 2H), 8.02 (d, J=8.4 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:16]([CH2:22][OH:23])[CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]([NH:28][C@@H:29]([CH:33]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:30](O)=[O:31])=[O:27].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>>[CH3:24][O:25][C:26](=[O:27])[NH:28][C@H:29]([C:30](=[O:31])[NH:21][CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]([N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:22][OH:23])[CH:33]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)CN([C@H](CO)CCCCN)S(=O)(=O)c1ccc(N)cc1
Reactant: COC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Product: COC(=O)N[C@H](C(=O)NCCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1)C(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared from (1S)-4-amino-N-(5-amino-1-hydroxymethyl-pentyl)-N-isobutyl-benzenesulfonamide (VII-deprotected) (step D) and (2S)-2-methoxycarbonylamino-3,3-diphenyl-propionic acid (step E) using the coupling procedure with HOBt and EDAC described in example 3 (step D). The final product was obtained in 67% yield (121 mg).
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].[CH:6]([NH2:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1C=CC=CC=1>O>[CH:1](=[N:19][CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C=O
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)C=NC(c1ccccc1)c1ccccc1

Procedure:
14.4 parts of isobutyraldehyde was added to 36.6 parts of benzhydrylamine in 100 parts of dry benzene at room temperature with stirring. The cloudy mixture was heated to reflux with water-separation for 4 hours. On cooling the solution was filtered to remove a small amount of solid and evaporated to give isobutylidenebenzhydrylamine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:19]([CH3:22])([O-:21])=[O:20].Cl.O>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C@@H:10]([OH:11])[CH2:22][N+:19]([O-:21])=[O:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](C=O)Cc1ccccc1
Reactant: C[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)C[N+](=O)[O-]
Yield: 60.6 %

Procedure:
To a stirred solution of 62.3 mg (0.25 mmol) of (R)-2-t-butoxycarbonylamino-3-phenylpropanal [synthesized by the method described in Journal of Medicinal Chemistry, 130, 1162 (1987)] in 1.0 ml of THF was added at 0° C., 0.27 ml (5 mmol) of nitromethane, followed by dropwise addition of 0.5 ml (0.025 mmol) of the lanthanum/(R)-1,1'-bi-2-naphthol complex solution (Reference Example 1, 0.05 mol/l). The resultant mixture was stirred at 0° C. for 2 hours. To this solution were added 0.5 ml of 1N hydrochloric acid and 3 ml of water. The mixture was extracted with diethylether, the extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silicagel column chromatography (eluent; n-hexane-ethyl acetate 8:2) to give 47 mg of (2S,3R)-3-t-butoxycarbonylamino-1-nitro-4-phenyl-2-butanol. Yield 60%. (2S,3R)-3-t-Butoxycarbonylamino-1-nitro-4-phenyl-2-butanol: