Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18]([C@H:23]1[CH2:28][CH2:27][C@H:26]([C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)[CH2:19][CH:20]=[CH:21][CH3:22]>C(Cl)Cl>[O:9]1[CH:21]([CH3:22])[CH:20]1[CH2:19][CH2:18][C@H:23]1[CH2:24][CH2:25][C@H:26]([C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[CH2:27][CH2:28]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC=CCC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC1OC1CC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4.49 g of 90% m-chloroperbenzoic acid in 100 ml of methylene chloride was treated with 11.3 g of powdered potassium carbonate. The mixture was treated dropwise at 0° C. within 5 minutes with a solution of 5.93 g of p-[trans-4-(3-pentenyl)cyclohexyl]benzonitrile in 20 ml of methylene chloride and stirred at room temperature for 2 hours. The mixture was subsequently treated with another 4.49 g of 90% m-chloroperbenzoic acid and the resulting mixture was stirred further. After a total of 70 hours, the reaction mixture was partitioned three times in methylene chloride/10% sodium thiosulphate solution. The organic extracts were washed with sodium thiosulphate solution and water, dried over magnesium sulphate, filtered and concentrated. Chromatographic separation of the resulting, light yellowish oil (6.3 g) on silica gel with ethyl acetate/petroleum ether (vol. 10:90) gave 6.27 g (99.5%) of p-[trans-4-(3,4-epoxypentyl)cyclohexyl]benzonitrile as a colourless oil.
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[F:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]([OH:10])[CH3:1])=[CH:7][C:6]=1[O:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1ccc(F)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.3 %

Procedure:
A stirred solution of 34 ml (0.10 mole) of methylmagnesium bromide (3.0 M in diethyl ether) in 100 ml of tetrahydrofuran was cooled to 0° C., and 22.0 grams (0.10 mole) of 4-fluoro-3-phenoxybenzaldehyde was slowly added during a 30 minute period. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature at which it was stirred for two hours. At the end of this time the reaction was quenched with aqueous 10% hydrochloric acid, and the reaction mixture was extracted with two 100 ml portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 24.0 grams of 1-(4-fluoro-3-phenoxyphenyl)ethanol. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(=O)(O[CH2:20][CH2:21][SH:22])OCC>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([CH2:20][CH2:21][SH:22])[CH2:11][CH2:12]2)=[CH:13][CH:14]=1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Reactant: CCOC(=O)OCCS
Solvent: Cc1ccccc1
Product: Fc1ccc(CC2CCN(CCS)CC2)cc1

Procedure:
A mixture of 4-(4-fluorobenzyl)piperidine (5.9 g, 30.5 mmol) and ethyl 2-mercaptoethyl carbonate (4.8 g, 32 mmol) was heated to reflux in toluene (250 mL) for 18 hr under a nitrogen atmosphere. The toluene was removed in vacuo and the resulting oil was used without purification in the next step.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[C:7]1(=[N:11][S:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])[CH2:10][CH2:9][CH2:8]1>C(Cl)Cl.CCOC(C)=O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[C:5]([C:7]1([NH:11][S:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])[CH2:8][CH2:9][CH2:10]1)#[N:6]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)(C)S(=O)N=C1CCC1
Agent: [Ti+4]
Agent: CC[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)S(=O)NC1(C#N)CCC1
Reaction time: 16 h
Yield: 81.5 %

Procedure:
Titanium (IV) ethoxide (3.03 g, 13.3 mmol) was added to a stirring solution of trimethylsilyl cyanide (7.12 mL, 53.1 mmol) and N-cyclobutylidene-2-methylpropane-2-sulfinamide (4.6 g, 27 mmol) in DCM (100 mL) at rt. The reaction was allowed to stir for 16 h. An additional 1.7 mL of TMS-CN was added followed by 1.5 g of TiOEt4. The reaction was allowed to stir at rt for an additional 16 h. The mixture was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give N-(1-cyanocyclobutyl)-2-methylpropane-2-sulfinamide (4.5 g, 22 mmol, 85% yield) consistent by NMR. 1H NMR (400 MHz, CHLOROFORM-d) δ 2.82-2.67 (m, 2H), 2.62-2.34 (m, 2H), 2.26-2.02 (m, 2H), 1.26 (s, 9H).
Reaction SMILES: N#N.[O:3]=[C:4]([CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[O:10][CH:11]=[C:12]([C:14](O)=[O:15])[N:13]=1.CN(C=O)C.C(Cl)(=O)C([Cl:26])=O>C1(C)C=CC=CC=1>[O:3]=[C:4]([CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[O:10][CH:11]=[C:12]([C:14]([Cl:26])=[O:15])[N:13]=1
Reactant: CC(=O)CCCCc1nc(C(=O)O)co1
Reactant: O=C(Cl)C(=O)Cl
Agent: N#N
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)CCCCc1nc(C(=O)Cl)co1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 2-(5-oxo-hexyl)-oxazole-4-carboxylic acid (403 mg, 1.91 mmol) in toluene (19 mL) was treated at 0° C. with a drop of DMF followed by oxalyl chloride (0.20 mL, 2.29 mmol) and the resulting yellow solution was stirred at rt for 1 h. The solvent was then removed under reduced pressure (coevaporation with toluene) to give 2-(5-oxo-hexyl)-oxazole-4-carbonyl chloride as a brown oil.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C:3]([S:5][CH2:6][CH3:7])=[NH:4].C(=O)([O-])[O-].[K+].[K+].[P:15](=[O:21])(Cl)([S:18][CH3:19])[O:16][CH3:17]>C(#N)C>[CH3:17][O:16][P:15]([S:18][CH3:19])([N:4]=[C:3]([S:5][CH2:6][CH3:7])[N:2]([CH3:8])[CH3:1])=[O:21]
Reactant: CCSC(=N)N(C)C
Reactant: COP(=O)(Cl)SC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCSC(=NP(=O)(OC)SC)N(C)C
Yield: 64.2 %

Procedure:
To a mixture of 6.6 g of N,N-dimethylcarbamimidothioic acid, ethyl ester, 8.0 g of finely powdered potassium carbonate and 50 ml of acetonitrile was added dropwise 8.0 g of phosphorochloridothioic acid, O,S-dimethyl ester. The mixture was stirred until no starting material could be detected by GLC (Gas Liquid Chromatography). The salts were then removed by filtration, the filtrate concentrated under vacuum, the residue taken up in ether, the ether solution washed once with water, once with 5% aqueous sodium hydroxide, once with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under vacuum and the residue distilled in a Kugelrohr (bath temperature 140° C., pressure 0.3 mm) yielding 8.2 g (64% of theoretical) of N'-(methoxy(methylthio)phosphinyl)-N,N-dimethylcarbamimidothioic acid, ethyl ester as a colorless oil. The IR and NMR spectra are identical to those obtained from the compound prepared by method A.
Reaction SMILES: [Na].[C:2]([C:5]1[N:6]2[CH:9]([S:10][CH2:11][C:12]=1[CH2:13][S:14][C:15]1[N:19]([CH3:20])[N:18]=[N:17][N:16]=1)[CH:8]([NH:21][C:22](=[O:30])[CH2:23][C:24]1[S:25][C:26](=[O:29])[S:27][CH:28]=1)[C:7]2=[O:31])([OH:4])=[O:3].[C:32]([O:35][CH2:36]I)(=[O:34])[CH3:33].O>CN(C)C=O>[C:32]([O:35][CH2:36][O:3][C:2]([C:5]1[N:6]2[CH:9]([S:10][CH2:11][C:12]=1[CH2:13][S:14][C:15]1[N:19]([CH3:20])[N:18]=[N:17][N:16]=1)[CH:8]([NH:21][C:22](=[O:30])[CH2:23][C:24]1[S:25][C:26](=[O:29])[S:27][CH:28]=1)[C:7]2=[O:31])=[O:4])(=[O:34])[CH3:33]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(=O)s3)C2SC1
Reactant: CC(=O)OCI
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCOC(=O)C1=C(CSc2nnnn2C)CSC2C(NC(=O)Cc3csc(=O)s3)C(=O)N12
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 53.7 %

Procedure:
The sodium salt of 2-carboxy-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl]-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (5.08 g.) is dissolved in dimethylformamide (100 cc.) at 5° C. A solution of iodomethyl acetate (2 g.) in dimethylformamide (10 cc.) is added to this solution and the reaction mixture is stirred for 10 minutes at 5° C. It is then poured into water (500 cc.) and extracted twice with ethyl acetate (200 cc.). The combined organic phases are washed with water (100 cc.), saturated sodium bicarbonate solution (100 cc.), a 5% sodium bisulphite solution (100 cc.) and a saturated sodium chloride solution (100 cc.). The organic phase is dried over magnesium sulphate, filtered in the presence of decolourising charcoal and concentrated to dryness under reduced pressure (15 mm Hg). This gives a white product (5 g.) which is recrystallised from acetonitrile (50 cc.). 2-Acetoxymethoxycarbonyl-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl]-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (3 g.) is thus obtained as white crystals m.p. 154° C.
Reaction SMILES: [Br:1][C:2]1[C:10]([CH2:11][CH3:12])=[C:9]2[C:5]([C:6]3[CH2:16][CH2:15][O:14][C:13]([CH2:19][C:20](O)=[O:21])([CH2:17][CH3:18])[C:7]=3[NH:8]2)=[CH:4][CH:3]=1>C1COCC1>[Br:1][C:2]1[C:10]([CH2:11][CH3:12])=[C:9]2[C:5]([C:6]3[CH2:16][CH2:15][O:14][C:13]([CH2:19][CH2:20][OH:21])([CH2:17][CH3:18])[C:7]=3[NH:8]2)=[CH:4][CH:3]=1
Reactant: CCc1c(Br)ccc2c3c([nH]c12)C(CC)(CC(=O)O)OCC3
Solvent: C1CCOC1
Product: CCc1c(Br)ccc2c3c([nH]c12)C(CC)(CCO)OCC3
Temperature: 90 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To a stirred solution of 2-(7-Bromo-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid (0.87 g, 2.4 mmol) in THF (5 ml), was added dropwise via syringe borane-tetrahydrofuran complex, 1.0 M solution in tetrahydrofuran (3.6 ml, 3.6 mmol) during 30 min. The mixture was stirred at 90° C. for 8 hr, cooled, quenched with distilled water and 5% HCl, extracted with EtOAc. The organic phases collected, washed with brine, dried over MgSO4, and evaporated to give a residue which was chromatographed on silica gel. Elution with hexane-EtOAc (1:1) gave the product which was further recrystallized in hexane/dichloromethane to give the product (0.64 g, 76%). 1H NMR (300 MHz, CDCl3) δ 7.91 (b, NH), 7.28 (d, 1H), 7.20 (d, 1H), 4.02 (m, 2H), 3.71 (m, 2H), 2.95 (qrt, 1H), 2.81 (m, 1H), 2.75 (t, 1H), 2.69 (t, 1H), 2.58 (t, 1H), 2.19 (m, 1H), 2.04 (m, 2H), 1.26(t, 3H), 0.93 (t, 3H).
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:11])[NH:6][CH:7]=[CH:8][C:9]=1[CH3:10])([O-])=O.[CH3:12]I>[Zn].C(O)(=O)C>[CH3:12][O:11][C:5]1[C:4]([NH2:1])=[C:9]([CH3:10])[CH:8]=[CH:7][N:6]=1
Reactant: CI
Reactant: Cc1cc[nH]c(=O)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1nccc(C)c1N

Procedure:
3-Nitro-4-methyl-2-pyridone was methylated with methyl iodide and reduced with zinc and acetic acid to give 2-methoxy-3-amino-4-methylpyridine. This material was coupled with 2-(4-(1-methylpropyl )phenoxynonanoic acid according to the procedure of Example 25 to give the title compound.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([B:18]([OH:20])[OH:19])=[CH:14][C:13]=1[C:21]([F:24])([F:23])[F:22].Cl>>[OH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([B:18]([OH:19])[OH:20])=[CH:14][C:13]=1[C:21]([F:24])([F:22])[F:23]
Reactant: OB(O)c1ccc(OCCCOC2CCCCO2)c(C(F)(F)F)c1
Agent: Cl
Product: OCCCOc1ccc(B(O)O)cc1C(F)(F)F
Temperature: 50 °C

Procedure:
4-(3-(Tetrahydro-2H-pyran-2-yloxy)propoxy)-3-(trifluoromethyl)phenylboronic acid (30.6 g) was added to hydrochloric acid (1M in MeOH) and the mixture was heated at 50° C. for 40 minutes. Solvent and HCl were then removed under reduced pressure and residue (20.3 g) was used for next step without further purification. Proton NMR indicates 2 sets of product peaks assumed to be monomer and dimer or trimer. 1H NMR (CDCl3 (0.7 ml)+CD3OD (0.2 ml)) δ: 7.7-8.0 (2xd and 2xs, 2H), 7.0 (2xd, 1H), 4.22 (t, 2H), 3.86 (t, 2H), 3.48 (tt, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[OH:13])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2].C(N(CC)CC)C.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[C:27]([O:13][N:10]1[C:11]2[C:6](=[CH:5][C:4]([C:16]([F:19])([F:17])[F:18])=[C:3]([C:1]#[N:2])[CH:12]=2)[NH:7][C:8](=[O:15])[C:9]1=[O:14])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2OC(=O)c1ccccc1
Yield: 97.2 %

Procedure:
A solution of 0.4 g (1.48 mmol) 7-cyano-1-hydroxy-6-trifluoromethylquinoxaline-2,3(1H,4H)-dione in 50 ml dry tetrahydrofuran was added 0.2 ml (1.45 mmol) dry triethylamine and 0.175 ml (1.50 mmol) benzoyl chloride. The mixture was refluxed for 30 min., and then evaporated in vacuo. The residue was stirred with water to give 0.54 g (98%) of 1-benzoyloxy-7-cyano-6-trifluoromethylquinoxaline-2,3(1H,4H)-dione. M.p. 186° C. 1H-NMR (DMSO-d6): 8.47 (1H, s), 8.2 (2H, m), 7.8 (4H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C@H:13]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Cl)[CH:27]=1.[H-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]([CH2:32][C:28]2[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=2)[C@H:13]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: ClCc1cccnc1
Reactant: COc1ccc(S(=O)(=O)N[C@H](CC(C)C)C(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@H](CC(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of t-butyl 2(R)-[[4-methoxybenzenesulfonyl]amino]-4-methylpentanoate (10.0 g, 27.92 mmol)in dimethylformamide (250 mL) at room temperature is added 3-picolyl chloride hydrochloride (4.81 g, 29.32 mmol) followed by sodium hydride (2.79 g, 69.80 mmol, 60% in oil). The reaction mixture is stirred at room temperature for 48 hours. The mixture is quenched with water and extracted with ethyl acetate. The combined organic extracts are washed with brine, dried (Na2SO4), and the solvent is evaporated. The crude product is purified by silica gel chromatography (45% ethyl acetate/hexanes) to provide t-butyl 2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-4-methylpentanoate.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:16](OCC)=[O:17].C(O)(=O)C>COCCOC>[CH:16]([CH:10]([CH2:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:17]
Reactant: CCOC=O
Reactant: CCOC(=O)CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CC(=O)O
Product: CCOC(=O)C(C=O)Cc1ccccc1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a suspension of NaH (2.338 g, 58.5 mmol) in DME (20 mL) was added dropwise a solution of ethyl 3-phenylpropanoate (3.2 g, 19.49 mmol) and ethyl formate (6.28 mL, 78 mmol) in DME (20 mL) at room temperature. The reaction mixture was then stirred overnight. It was neutralized with acetic acid (4 mL), then extracted with EtOAc. The organic phase was collected, washed with brine, dried over Na2SO4, filtered, and concentrated affording the crude title compound (4.02 g, 100% yield). LCMS: rt=2.82 and 3.51 min (a mixture of ketone and enol isomer), [M+H+]=207.1
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:10])[CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].CN(C)C=O.C(N(CC)CC)C.[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>Cl>[C:2]([O:6][C:7](=[O:10])[CH2:8][NH:9][S:37]([C:34]1[CH:33]=[CH:32][C:31]([O:30][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:36][CH:35]=1)(=[O:39])=[O:38])([CH3:5])([CH3:4])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc(OCc2ccccc2)cc1
Reaction time: 1 h
Yield: 80.4 %

Procedure:
To a mixture of glycine tert butyl ester hydrochloride salt (compound of formula XIV, 50 g, 300 mmol) and dimethylformamide (400 ml) at about 0° C. was added triethylamine (127 ml, 885 mmol) and 4-benzyloxybenzenesulfonyl chloride (102 g, 357 mmol). After stirring for about 1 hour, the mixture was warmed to a temperature of about 20° C. to about 25° C., and stirred for about an additional 12 hours. The mixture was diluted with 1M hydrochloric acid, extracted twice with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Trituration of the residue with ether-hexane afforded 91 g of [4-Benzyloxybenzenesulfonylamino]-acetic acid tert-butyl ester (compound of formula XV) as a colorless solid.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:10][C:11]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:12]=1[O:13][CH2:14][CH2:15][CH2:16][O:17][NH2:18].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[Cl:10][C:11]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:27])[Cl:28])[CH:20]=[C:19]([Cl:29])[C:12]=1[O:13][CH2:14][CH2:15][CH2:16][O:17][N:18]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: NOCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCON=Cc2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a mixture of 0.15 g of benzaldehyde and 10 ml of pyridine was added 0.56 g of O-(3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)propyl)hydroxylamine hydrochloride. After stirring at room temperature for 1 hour, the reaction mixture was poured into 5% aqueous citric acid solution, and extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.50 g (yield, 79.4%) of benzaldehyde O-(3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)propyl)oxime, nD22.5 1.5797.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.O>N1C=CC=CC=1>[S:24]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:26])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1ccc(N2CCC(CO)CC2)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc1
Reaction time: 4 h

Procedure:
The 4-hydroxymethyl-N-(4-nitrophenyl)piperidine (47.3 g, 200 mmol) obtained in Example 4(1) was dissolved in pyridine (300 ml), and p-toluenesulfonyl chloride (45.8 g, 240 mmol) was added thereto under ice-cooling, followed by stirring for 4 hours. Water was added to the reaction mixture, and the precipitate was collected by filtration. The obtained solid was dried under reduced pressure, thereby obtaining 4-tosyloxymethyl-N-(4-nitrophenyl)piperidine (72.7 g, 93%) as a yellow solid.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:32]2[CH2:33][CH2:34][N:29]([C:23]3[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=3[CH3:21])[CH2:30][CH2:31]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccc(F)cc1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(CCCc3cc(-c4ccc(F)cc4)n(C(C)(C)C)n3)CC2)c(C)c1

Procedure:
139 mg (79%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propanal (100 mg, 0.365 mmol), 1-(2,4-dimethylphenyl)piperazine (69 mg, 0.365 mmol), DIPEA (0.1 mL, 0.548 mmol) and NaBH(OAc)3 (232 mg, 1.095 mmol).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:7]1[N:8]=[N:9][S:10][CH:11]=1)[C:4]([OH:6])=[O:5].[CH2:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20](Cl)=[O:21])[C:16](=[O:23])[C:15]1=[O:24])[CH3:13]>>[CH2:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([NH:2][CH:3]([C:7]2[N:8]=[N:9][S:10][CH:11]=2)[C:4]([OH:6])=[O:5])=[O:21])[C:16](=[O:23])[C:15]1=[O:24])[CH3:13]
Reactant: NC(C(=O)O)c1csnn1
Reactant: CCN1CCN(C(=O)Cl)C(=O)C1=O
Agent: Cl
Product: CCN1CCN(C(=O)NC(C(=O)O)c2csnn2)C(=O)C1=O
Yield: 81.3 %

Procedure:
The title compound (1.24 g) was prepared from 2-amino-2-(1,2,3-thiadiazol-4-yl)acetic acid hydrochloride [Example 3(a)] (912 mg) and 4-ethyl-2,3-dioxopiperazin-1-ylcarbonyl chloride (953 mg) by the method of Example 1(a).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:31]=[C:30](Cl)[N:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:40]([NH2:43])[CH2:41][CH3:42].O>C1COCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:31]=[C:30]([NH:43][CH2:40][CH2:41][CH3:42])[N:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(Cl)nc(-c3ccccc3)n2)CC1
Reactant: CCCN
Solvent: C1CCOC1
Solvent: O
Product: CCCNc1cc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N2CCN(C(=O)OCC)CC2)nc(-c2ccccc2)n1
Temperature: 40 °C

Procedure:
4-{(S)-4-tert-butoxycarbonyl-2-[(6-chloro-2-phenyl-pyrimidine-4-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester (53 mg) and propylamine (31 μl) were dissolved in THF (0.5 ml). The mixture was stirred at 40° C. until reaction completion. Water was added and it was extracted with EA. The org. layers were dried (Na2SO4) and evaporated off to give 60 mg of the desired pure compound.
Reaction SMILES: Cl.O1CCOCC1.C(OC([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][C:18]=1[F:30])=O)(C)(C)C.C([O-])(O)=O.[Na+]>ClCCl>[CH3:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][NH2:15])=[C:18]([F:30])[CH:19]=1)=[O:29]
Reactant: CC(C)(C)CC(=O)c1ccc(CNC(=O)OC(C)(C)C)c(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)CC(=O)c1ccc(CN)c(F)c1
Reaction time: 6.5 h
Yield: 101.7 %

Procedure:
Add 4N hydrogen chloride in dioxane (5.5 mL, 22 mmol) to a solution of N-(tert-butoxycarbonyl)-4-(3,3-dimethyl-butyryl)-2-fluoro-benzylamine (600 mg, 1.85 mmol) in dichloromethane (22 mL) and stir for 6.5 h. Concentrate in vacuo and wash the solid obtained with diethyl ether. Suspend the solid into saturated aqueous NaHCO3 and stir for 30 min. Extract the aqueous phase twice with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to obtain the title compound as an oil (420 mg, 99%).