Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.[NH2:18][C:19]1[N:24]2[O:25][C:26](=[O:28])[N:27]=[C:23]2[N:22]=[C:21]([N:29]([CH2:33][CH:34]=[CH2:35])[CH2:30][CH:31]=[CH2:32])[N:20]=1>CN(C)C1C=CN=CC=1.C(N(CC)CC)C.C(Cl)Cl>[CH2:33]([N:29]([CH2:30][CH:31]=[CH2:32])[C:21]1[N:20]=[C:19]([NH:18][C:1](=[O:9])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:24]2[O:25][C:26](=[O:28])[N:27]=[C:23]2[N:22]=1)[CH:34]=[CH2:35]
Reactant: O=C(O)c1ccccc1
Reactant: C=CCN(CC=C)c1nc(N)n2oc(=O)nc2n1
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCN(CC=C)c1nc(NC(=O)c2ccccc2)n2oc(=O)nc2n1

Procedure:
3.3 g. of benzoic acid are dissolved in 70 ml. of methylene chloride and 2.7 g. of triethylamine. The solution is stirred and treted at 0° C. with 3.5 g. of isobutyl chloroformate in 25 ml. of methylene chloride. The mixture is then stirred at 0° C. for 30 minutes and subsequently at room temperature for 1 hour. The solution is treated with a suspension of 5 g. of 7-amino-5-diallylamino-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-2-one in 200 ml. of methylene chloride, 12.5 ml. of triethylamine and 0.6 g. of 4-dimethylaminopyridine. The mixture obtained is stirred at room temperature for 18 hours and then washed with 100 ml. of water. The organic phase is dried over magnesium sulfate and evaporated under reduced pressure. The residue obtained is purified by column chromatography, there being obtained N-{5-diallylamino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-7-yl}benzamide having a melting point of 182°-183° C.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].C([O:13][C:14](=[O:35])[C:15]([S:18][C:19]1[S:20][CH:21]=[C:22]([CH2:24][CH2:25][NH:26][C:27]2[N:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][N:28]=2)[N:23]=1)([CH3:17])[CH3:16])(C)(C)C.CC(C)CCCCO.[BrH:44].C(O)(=O)C>C(OCC)C>[BrH:44].[CH2:33]([C:30]1[CH:29]=[N:28][C:27]([N:26]([CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7])[CH2:25][CH2:24][C:22]2[N:23]=[C:19]([S:18][C:15]([CH3:16])([CH3:17])[C:14]([OH:35])=[O:13])[S:20][CH:21]=2)=[N:32][CH:31]=1)[CH3:34]
Reactant: CC(C)CCCCI
Reactant: CCc1cnc(NCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Agent: Br
Agent: CC(C)CCCCO
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCc1cnc(N(CCCCC(C)C)CCc2csc(SC(C)(C)C(=O)O)n2)nc1

Procedure:
A compound obtained using 1-iodo-5-methylhexane, which is synthesized using 2-[(4-{2-[(5-ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 265-1 and 5-methylhexanol as starting materials and in reference to non-patent reference [Tetrahedron, 38, 11461 (1998)], and by an operation similar to that of Example 326, was dissolved in diethyl ether, and reacted with 30% hydrobromic acid-acetic acid to give the title compound.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH:44]=[CH:45][CH:46]=2)[C:15]([NH:17][C:18]2[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][S:34]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:28]=[CH:27][C:19]=2[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=O)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:48].C(=O)(O)[O-].[Na+]>COCCOC>[C:1]([C:5]1[N:6]=[C:7]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH:44]=[CH:45][CH:46]=2)[C:15]([NH:17][C:18]2[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][S:34]([C:37]3[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=3)(=[O:36])=[O:35])[CH:28]=[CH:27][C:19]=2[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[S:48])[S:8][CH:9]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCOC(=O)COc1ccc(CCCS(=O)(=O)c2ccc(Cl)cc2)cc1NC(=O)c1cccc(OCc2nc(C(C)(C)C)cs2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)COc1ccc(CCCS(=O)(=O)c2ccc(Cl)cc2)cc1NC(=S)c1cccc(OCc2nc(C(C)(C)C)cs2)c1
Reaction time: 5 h
Yield: 76.9 %

Procedure:
A mixture of ethyl 2-[3-[(4-tert-butyl-2-thiazolyl)methoxy]benzoylamino]-4-[3-(4-chlorophenylsulfonyl)propyl]phenoxyacetate (176 mg, 0.26 mmol), diphosphorus pentasulfide (69 mg, 0.31 mmol), sodium bicarbonate (28 mg, 0.33 mmol) and 1,2-dimethoxyethane (5 ml) was stirred for 5 hours with heating under reflux, and insoluble matter was removed by filtration. The resulting filtrate was diluted with ethyl acetate, washed with water and brine in that order, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (eluent=hexane:ethyl acetate=3:1-2:1) to give ethyl 2-[3-[(4-tert-butyl-2-thiazolyl)methoxy]thiobenzoylamino]-4-[3-(4-chlorophenylsulfonyl)propyl]phenoxyacetate (143 mg, 0.20 mmol, 78%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[NH:2][NH2:3].C(O)C.[CH3:11][C:12]1[NH:13][CH:14]=[C:15]([CH:17]=O)[N:16]=1>C(O)C.C(O)(=O)C>[CH2:6]([O:5][C:1](=[O:4])[NH:2][N:3]=[CH:17][C:15]1[N:16]=[C:12]([CH3:11])[NH:13][CH:14]=1)[CH3:7]
Reactant: Cc1nc(C=O)c[nH]1
Reactant: CCOC(=O)NN
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)NN=Cc1c[nH]c(C)n1

Procedure:
A solution of 16.68 gm. of ethyl carbazate in 50 ml. of hot ethanol is added to a solution of 16.50 gm. of 2-methyl-4-imidazolecarboxaldehyde in 100 ml. of hot ethanol containing 2 drops of acetic acid. The reaction is carried out as described in Example 32 giving the desired product, m.p. 210.5°-211.5° C.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].O=CC(Cl)(Cl)Cl.[Cl-].[OH:19][NH3+:20].Cl.NC1C=CC=CC=1>>[CH:8]1[CH:7]=[CH:6][C:11]([NH:1][C:2](/[CH:4]=[N:20]/[OH:19])=[O:3])=[CH:10][CH:9]=1
Reactant: [NH3+]O
Reactant: O=C1Nc2ccccc2C1=O
Agent: Cl
Agent: O=CC(Cl)(Cl)Cl
Agent: [Cl-]
Solvent: Nc1ccccc1
Product: O=C(/C=N/O)Nc1ccccc1

Procedure:
The isatin derivative (9) can be synthesized, for example, as shown in the following reaction scheme. That is, an aqueous solution obtained by adding chloral and hydroxylammonium chloride to hydrochloride of an aniline derivative (10) as a starting material is reacted for 0.5 to 2 hours with heating at 70° to 110° C. to give an isonitrosoacetanilide derivative, and this product is cyclized with concentrated sulfuric acid and hydrolyzed to give an isatin derivative (9). ##STR10## wherein R1A to R1D are as defined above.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[NH2:14])[CH:5]=[CH:6][C:7]=1[F:8].C1CCN2C(=NCCC2)CC1.[CH:26]([S:29](Cl)(=[O:31])=[O:30])([CH3:28])[CH3:27]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[NH:14][S:29]([CH:26]([CH3:28])[CH3:27])(=[O:31])=[O:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NC1CCCC1c1ccc(F)c(F)c1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 100 mL round bottom flask equipped with a magnetic stirrer was charged with (+,−) cis-[2-(3,4-difluoro-phenyl)-cyclopentylamine (1.40 g, 7.10 mmol) from preparation 15, methylene chloride (20.0 mL) and the solution cooled to 0° C. DBU (1.27 mL, 8.52 mmol) and isopropylsulfonyl chloride (0.96 mL, 8.52 mmol) were added. The reaction was then stirred at 0° C. for 60.0 minutes and brought to room temperature with stirring overnight. The reaction was diluted with methylene chloride and washed with 1N HCl, brine and the organic layer dried over sodium sulfate. The title compound was purified by radial chromatography eluting with methylene chloride to give 910 mg (42%) of the purified title compound. The nmr was consistent with the assigned structure.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:29]2[CH2:34][CH2:33][C:32]([CH3:36])([CH3:35])[CH2:31][CH2:30]2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([N:26]=[N+:27]=[N-:28])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[CH3:37][Si:38]([C:41]#[CH:42])([CH3:40])[CH3:39]>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:29]2[CH2:30][CH2:31][C:32]([CH3:35])([CH3:36])[CH2:33][CH2:34]2)=[CH:8][C:9]=1[N:10]([C:11]([C@H:13]1[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]1)=[O:12])[C@H:20]1[CH2:25][CH2:24][C@H:23]([N:26]2[CH:42]=[C:41]([Si:38]([CH3:40])([CH3:39])[CH3:37])[N:28]=[N:27]2)[CH2:22][CH2:21]1)=[O:4]
Reactant: COC(=O)c1sc(C2CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](N=[N+]=[N-])CC1
Reactant: C#C[Si](C)(C)C
Product: COC(=O)c1sc(C2CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](n2cc([Si](C)(C)C)nn2)CC1

Procedure:
A solution of 3-[(trans-4-azido-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(4,4-dimethyl-cyclohexyl)-thiophene-2-carboxylic acid methyl ester (0.90 g, 1.7 mmol) in trimethylsilylacetylene (1.2 ml, 6.8 mmol) was treated in microwave at 120° C. for 2 h. The mixture was concentrated under reduce pressure and the residue purified by silica gel column chromatography (1% MeOH/CH2Cl2 to 10% MeOH/CH2Cl2) to obtain 5-(4,4-Dimethyl-cyclohexyl)-3-{(trans-4-methyl-cyclohexanecarbonyl)-[trans-4-(4-trimethylsilanyl-[1,2,3]triazol-1-yl)-cyclohexyl]-amino}-thiophene-2-carboxylic acid methyl ester (1.1 g, 58%)
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[CH2:10]([CH:12]([C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:16]=1[NH2:17])[CH2:13][CH3:14])[CH3:11]>C(O)C>[Br:1][C:2]1[N:7]=[C:6](/[CH:8]=[N:17]/[C:16]2[C:18]([CH:22]([CH2:23][CH3:24])[CH2:25][CH3:26])=[CH:19][CH:20]=[CH:21][C:15]=2[CH:12]([CH2:10][CH3:11])[CH2:13][CH3:14])[CH:5]=[CH:4][CH:3]=1
Reactant: CCC(CC)c1cccc(C(CC)CC)c1N
Reactant: O=Cc1cccc(Br)n1
Solvent: CCO
Product: CCC(CC)c1cccc(C(CC)CC)c1/N=C/c1cccc(Br)n1

Procedure:
A mixture of 8.00 g (43 mmol) of 6-bromopyridine-2-carbaldehyde, 10.0 g (43 mmol) of 2,6-bis(1-ethylpropyl)aniline in 80 ml of ethanol was refluxed for 8 h. The obtained solution was evaporated to dryness and the residue was re-crystallized from 20 ml of methanol. Yield 11.2 g (65%) of yellow crystalline powder. Anal. calc. for C22H29BrN2: C, 65.83; H, 7.28; N, 6.98. Found: C, 66.01; H, 7.23; N, 6.90. 1H NMR (CDCl3): δ 8.21 (m, 1H, 5-H in Py), 8.15 (s, 1H, CH═N), 7.69 (m, 1H, 4-H in Py), 7.59 (m, 1H, 3-H in Py), 7.10 (m, 1H, 4-H in dipentylphenyl), 7.03-7.04 (m, 2H, 3, 5-H in dipentylphenyl), 2.48 (m, 2H, CHEt2), 1.54 (m, 8H, CH2Me), 0.74 (t, J=7.3 Hz, 12H, CH2Me).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[O:19][CH:18]=[CH:17][C:16]=12)=[O:10].[C:20]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:21]([C:26](O)=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=1>>[C:20]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:21]([C:26]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[O:19][CH:18]=[CH:17][C:16]=23)=[O:10])=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(NC[C@H]1NC[C@@H]2C[C@@H]21)c1cccc2occc12
Reactant: O=C(O)c1ccccc1-c1ccccc1
Product: O=C(NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1ccccc1-c1ccccc1)c1cccc2occc12

Procedure:
prepared by reaction of benzofuran-4-carboxylic acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with biphenyl-2-carboxylic acid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[C:11]([OH:22])[N:10]([CH3:23])[N:9]=1)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][C:8]1[C:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[C:11]([OH:22])[N:10]([CH3:23])[N:9]=1
Reactant: Cn1nc(NC(=O)OC(C)(C)C)c(Cc2cccc(Cl)c2Cl)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(N)c(Cc2cccc(Cl)c2Cl)c1O
Yield: 64.3 %

Procedure:
To a solution of tert-butyl(4-(2,3-dichlorobenzyl)-5-hydroxy-1-methyl-1H-pyrazol-3-yl)carbamate (15 g, 40 mmol) in DCM (150 mL), TFA (10 mL) was added dropwise at room temperature with stirring. The reaction mixture was stirred at room temperature overnight. Then the pH of the reaction mixture was adjusted to 10 with aq. Na2CO3, and extracted with DCM (100 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated to provide the titled compound (7 g, 63%), as a white solid; LC/MS: MS (ES+) m/e 272 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 2.90 (s, 3H), 3.45 (s, 2H), 6.06 (s, 2H), 7.01 (d, J=7.8 Hz, 1H), 7.25 (t, J=7.8 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 8.95 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[CH:6]=[O:7].C([O-])([O-])=O.[K+].[K+].Cl[CH2:19][CH2:20][O:21][CH3:22].C(OCC)(=O)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:19][CH2:20][O:21][CH3:22])[CH:6]=[O:7]
Reactant: COCCCl
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1ccc(C=O)cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a solution of 3-methoxy-4-hydroxybenzaldehyde (8.0 g) in DMF (60 mL) was added K2CO3 (8.0 g) and 1-chloro-2-methoxyethane (5.1 g). The resulting mixture was stirred at 80° C. overnight. After reaction finished, ethyl acetate (200 mL) was added, and washed with 2 N aqueous HCl solution, brine, dried over Na2SO4, filtered, concentrated. The residue was washed with petrol ether to give 3-methoxy-4-(2-methoxyethoxy)benzaldehyde (10 g) as a yellow solid. 1H-NMR (400 MHz, CDCl3): δ: 9.86 (s, 1H); 7.45-7.41 (m, 2H); 7.01 (d, J=8.0, 1H); 4.27-4.25 (m, 2H); 3.93 (s, 3H); 3.85-3.82 (m, 2H); 3.46 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][C@:9]23[CH2:16][C@H:15]([NH2:17])[CH2:14][N:13]2[C:12](=[O:18])[N:11]([C:19]2[CH:24]=[C:23]([Cl:25])[N:22]=[C:21]([Cl:26])[CH:20]=2)[C:10]3=[O:27])=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.Cl[C:42]([O:44][CH3:45])=[O:43]>C1COCC1>[F:31][C:2]([F:30])([F:1])[O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][C@:9]23[CH2:16][C@H:15]([NH:17][C:42]([O:44][CH3:45])=[O:43])[CH2:14][N:13]2[C:12](=[O:18])[N:11]([C:19]2[CH:24]=[C:23]([Cl:25])[N:22]=[C:21]([Cl:26])[CH:20]=2)[C:10]3=[O:27])=[CH:6][CH:5]=1
Reactant: COC(=O)Cl
Reactant: N[C@@H]1CN2C(=O)N(c3cc(Cl)nc(Cl)c3)C(=O)[C@@]2(Cc2ccc(OC(F)(F)F)cc2)C1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@@H]1CN2C(=O)N(c3cc(Cl)nc(Cl)c3)C(=O)[C@@]2(Cc2ccc(OC(F)(F)F)cc2)C1
Reaction time: 3 h

Procedure:
To a solution of the compound from Example 63 (0.075 g) in THF (4 mL) was added DIEA (0.10 mL) and methyl chloroformate (0.020 mL). After 3 hours, the reaction was concentrated and purified by chromatography (silica gel; 98:2 CH2Cl2/methanol, Chromatotron) to afford the titled compound (0.0715 g): MS (m/z) 533 [MH+]. mp 119.8° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:34])=[O:26])=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[BH4-].[Na+].O.C(OCC)(=[O:41])C>C1COCC1.[Cu]Cl>[CH3:1][O:2][C:3](=[O:35])[C@H:4]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25]([C:27]2[C:28]([Cl:34])=[CH:29][CH:30]=[CH:31][C:32]=2[Cl:33])=[O:26])=[CH:22][CH:23]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][CH2:15][CH2:16][OH:41])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7]
Reactant: CCOC(C)=O
Reactant: C=CCCC1(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)OC)CCCC1
Agent: Cl[Cu]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)C1(CCCCO)CCCC1
Temperature: 25 °C
Reaction time: 36 h
Yield: 62 %

Procedure:
To a suspension of 4-[[(2,6-dichlorophenyl)carbonyl]arnino]-N-[[1-(3-butenyl)cyclopentyl]-carbonyl]-L-phenylalanine methyl ester (3.13 mmol, 1.62 g) and anhydrous copper (I) chloride (5.0 mmol, 500 mg) in THF (30 mL) was added solid sodium borohydride (5.0 mmol, 200 mg) at −5° C. over 5 min. After the addition, the reaction mixture was allowed to warm to room temperature and the brown reaction mixture was stirred for 36 h at which time TLC analysis of the mixture indicated the absence of starting material. Then, the excess hydride was quenched by the addition of water (5 mL) and the reaction mixture was cooled to 0° C. To this, a solution of sodium acetate (20 mL, 3.0N) was added dropwise maintaining the temperature below 10° C. this was followed by H2O2 (25 mL, 30%). After addition of hydrogen peroxide, the reaction mixture was allowed to warm to room temperature and was stirred for 3 h and followed by 1 h at 40-45° C. to complete the hydrolysis. Then, it was poured into a mixture of water (50 mL) and ethyl acetate (50 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (2×30 mL). The comined extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent gave a crude product which was purified by silica gel column chromatography to afford 1.04 g (62%) of a white amorphous solid. HR MS (C27H32Cl2N2O5): Obs. mass, 535.1758. Calcd. mass, 535.1766, M+H).
Reaction SMILES: Cl([O-])(=O)(=O)=O.[C:6]([O-])(=O)[CH3:7].[C:10]1([CH3:17])[CH:15]=[CH:14][C:13]([Tl+2])=[CH:12][CH:11]=1.O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC=CC=1>[CH3:17][C:10]1[CH:15]=[CH:14][C:13]([C:10]2[CH:15]=[CH:14][C:6]([CH3:7])=[CH:12][CH:11]=2)=[CH:12][CH:11]=1
Reactant: Cc1ccc([Tl+2])cc1
Reactant: CC(=O)[O-]
Agent: [Pd+2]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: c1ccccc1
Product: Cc1ccc(-c2ccc(C)cc2)cc1

Procedure:
A solution of 1000 parts by weight of p-tolyl thallium acetate perchlorate (p-CH3C6H4TlClO4CH3COO) in 6000 parts by weight of water and a solution of 2 parts by weight of palladium (II)-acetate [Pd(OAc)2 ] in 1500 parts by weight of benzene were stirred together vigorously for 2 hours at 60° C. Then the organic phase was separated and the benzene was distilled off under reduced pressure. 310 parts by weight of a residue remained which contained 297 parts by weight of p-tolyl acetate and 11 parts by weight of 4,4-dimethyl biphenyl in addition to palladium compounds. The reaction rate was 99% with a selectivity of 95%. The mixture was rectified over a short column at 10 m bar with the fraction passing over between 79° and 85° C. consisting of pure p-tolyl acetate. The distillation residue was taken up in acetone, and 4,4'-dimethyl biphenyl in pure form was obtained by addition of water.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)=[CH:24][CH:23]=3)[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.ClC1C=CC=C(C(OO)=[O:43])C=1.S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:22]3[CH:23]=[CH:24][C:25]([C:28]4[CH:33]=[CH:32][N+:31]([O-:43])=[CH:30][CH:29]=4)=[CH:26][CH:27]=3)=[O:34])[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: O=C(c1ccc(-c2ccncc2)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccc(-c2cc[n+]([O-])cc2)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Temperature: -20 °C
Reaction time: 21 h

Procedure:
In dichloromethane (10 ml), 1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine (300 mg) obtained in Example 1 was dissolved, followed by the addition of 3-chloroperbenzoic acid (382 g) at −20° C. The resulting mixture was stirred at −20° C. for 21 hours. An aqueous solution of sodium sulfite was added to decompose an excess peroxide. Dichloromethane and a saturated aqueous solution of sodium bicarbonate were added to separate an organic layer. After drying the organic layer over anhydrous magnesium sulfate, the residue obtained by distilling off the solvent was purified by chromatography on a silica gel column (2-5% methanol-dichloromethane). After the solvent was distilled off, ether was added to the residue to solidify it, followed by collection through filtration, whereby the title compound (200 mg, 63%) was obtained as a colorless solid.
Reaction SMILES: [Cl:1]Cl.[NH2:3][C:4]1[N:9]=[C:8](SC)[N:7]=[C:6]([C:12]([F:15])([CH3:14])[CH3:13])[N:5]=1>C(O)(=O)C>[NH2:3][C:4]1[N:9]=[C:8]([Cl:1])[N:7]=[C:6]([C:12]([F:15])([CH3:14])[CH3:13])[N:5]=1
Reactant: CSc1nc(N)nc(C(C)(C)F)n1
Reactant: ClCl
Solvent: CC(=O)O
Product: CC(C)(F)c1nc(N)nc(Cl)n1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Chlorine gas was passed at 20 to 25° C. into a suspension of 150 g of 2-amino-4-methylthio-6-(1-fluoroisopropyl)-1,3,5-triazine in 1 liter of glacial acetic acid (15 min). The reaction mixture was stirred for 30 min at approx. 20° C., flushed with nitrogen gas for 1 h at room temperature, poured into 5 liters of ice-cold aqueous solution of 350 g of sodium hydroxide and stirred for 5 min. After filtration with suction and drying, 110 g (80%) of 2-amino-4-chloro-6-(1-fluoroisopropyl)-1,3,5-triazine were obtained as a white powder (m.p. 185° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([NH2:11])[CH2:8][N:7]1[C:12]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])=[O:5])[CH3:2].[OH:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[C:31](O)=[O:32]>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([NH:11][C:31]([C:22]2[CH:23]=[CH:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:21]=2[OH:20])=[O:32])[CH2:8][N:7]1[C:12]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C[C@H](N)CN1C(=O)C1CCCCC1
Reactant: O=C(O)c1ccc2ccccc2c1O
Product: CCOC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1C(=O)C1CCCCC1

Procedure:
(2S,4S)-1-Cyclohexanecarbonyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]pyrrolidine-2-carboxylic acid ethyl ester was prepared (2S,4S)-4-amino-1-cyclohexanecarbonyl-pyrrolidine-2-carboxylic acid ethyl ester and 1-hydroxy-naphthalene-2-carboxylic acid in an analogous manner to example 1. MS calcd. for C25H31N2O5 [(M+H)+] 439.0, obsd. 439.4.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[C:12]1(=[O:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.Cl>O>[F:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:12]2=[O:19])=[CH:6][CH:5]=1
Reactant: O=C1CCCCCC1
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C1CCCCCC1=Cc1ccc(F)cc1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A solution of KOH (0.25 g, 4.46 mmol) in water (4.4 mL) was added to 4-fluoro-benzaldehyde Compound 3a (1.07 mL, 10 mmol) and the suspension was heated to 65° C. Cycloheptanone Compound 1a (1.18 mL, 10 mmol) was added dropwise over a period of 15 mins. The mixture was refluxed for 5 hrs, then stirred overnight at room temperature. The reaction mixture was acidified with 1N HCl (26 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine and dried over Na2SO4, then filtered and concentrated. The resulting yellow residue was purified on a silica gel column (using with 6% EtOAc/Hexane) to give 2-(4-fluoro-benzylidene)-cycloheptanone Compound 3b (1.1 g, 50.4%).