Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][C:12]([OH:14])=O)[C:3]1=[O:15].[Br:17][C:18]1[C:19]([C:24]2[NH:28][CH:27]=[N:26][N:25]=2)=[C:20]([NH2:23])[S:21][CH:22]=1>>[Br:17][C:18]1[C:19]([C:24]2[NH:28][CH:27]=[N:26][N:25]=2)=[C:20]([NH:23][C:12](=[O:14])[CH2:11][N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]([F:1])([F:16])[C:3]2=[O:15])[S:21][CH:22]=1
Reactant: O=C(O)CN1C(=O)C(F)(F)c2ccccc21
Reactant: Nc1scc(Br)c1-c1nnc[nH]1
Product: O=C(CN1C(=O)C(F)(F)c2ccccc21)Nc1scc(Br)c1-c1nnc[nH]1
Yield: 14.7 %

Procedure:
The title compound was prepared from 2-(3,3-difluoro-2-oxoindolin-1-yl)acetic acid (50 mg, 0.22 mmol), 4-bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine (45 mg, 0.18 mmol) using protocol A. HPLC purification gave N-(4-bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(3,3-difluoro-2-oxoindolin-1-yl)acetamide (12 mg) as a white solid (m/z 454.0, retention of 5.696 min in [7]). 1H-NMR (300MHz, CDCl3) δ 13.1 (s, 1H), 7.82 (s, 1H), 7.70 (dd, J=7.5, 1.5Hz, 1H), 7.50 (td, J=7.9, 1.2Hz, 1H), 6.99 (s, 1H), 6.92 (d, J=7.9Hz, 1H), 4.71 (s, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]3[C:30]([CH3:31])=[CH:29][N:28]=[C:27]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([N:39]5[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]5)=[CH:35][CH:34]=4)[N:26]=3)[CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:31][C:30]1[C:25]([NH:24][C:20]2[CH:19]=[C:18]([S:15]([NH:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)(=[O:17])=[O:16])[CH:23]=[CH:22][CH:21]=2)=[N:26][C:27]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH2:40][CH2:41][N:42]([CH3:45])[CH2:43][CH2:44]3)=[CH:35][CH:34]=2)=[N:28][CH:29]=1
Reactant: Cc1cnc(Nc2ccc(N3CCN(C)CC3)cc2)nc1Nc1cccc(S(=O)(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cnc(Nc2ccc(N3CCN(C)CC3)cc2)nc1Nc1cccc(S(=O)(=O)NC2CCNCC2)c1
Reaction time: 3 h

Procedure:
Intermediate 47 (0.2 g, 0.32 mmol) was diluted with DCM (10 mL) and treated with TFA (0.3 mL). After 3 h, reaction solvents removed and resulting residue was purified by HPLC (0.01 g, 6%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[C:24]1([S:34](Cl)(=[O:36])=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:23])[CH:10]([NH:22][S:34]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)(=[O:36])=[O:35])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=S(=O)(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
To a solution of (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.43 mmol) in ethyl acetate (5 ml) were added 1-naphthalenesulfonyl chloride (107 mg, 0.47 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1). Recrystallization from ethyl acetate-hexane gave the title compound (109 mg, 50%).
Reaction SMILES: [SH:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:19])[CH:8]=2)[N:3]=1.Cl[CH2:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([CH3:30])=[CH:24][N:23]=1>>[CH3:29][O:28][C:26]1[C:25]([CH3:30])=[CH:24][N:23]=[C:22]([CH2:21][S:1][C:2]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10](=[O:18])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:19])[CH:8]=3)[N:3]=2)[CH:27]=1
Reactant: Cc1ccc2nc(S)n(-c3ccccc3)c(=O)c2c1
Reactant: COc1cc(CCl)ncc1C
Product: COc1cc(CSc2nc3ccc(C)cc3c(=O)n2-c2ccccc2)ncc1C
Yield: 32.9 %

Procedure:
The title compound was prepared in a yield of 32.9%, using 2-mercapto-6-methyl-3-phenyl-4(3H)-quinazolinone in place of 2-mercapto-3-phenyl-4(3H)-quinazolinone and 2-chloromethyl-4-methoxy-5-methylpyridine in place of 2chloromethyl-4-methylpyridine hydrochloride.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].Cl[CH2:18][CH2:19][CH2:20][C:21](=[O:23])[CH3:22].C(N(CC)CC)C>C(OCC)C>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH2:18][CH2:19][CH2:20][C:21](=[O:23])[CH3:22])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CC(=O)CCCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)CCCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The thio of Example 2 (5.0 g, 0.021 M) was reacted with 5-chloro-2-pentanone (2.87 ml) and triethylamine (3.0 ml) in ethyl ether (50 ml) by the method of Example 8 to give the title compound, m.p. ca. 65-67° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].C(N(CC)CC)C.[C:17](Cl)(Cl)=[O:18]>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[C:17]=[O:18])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(N)ccc1Cl
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(N=C=O)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
To the stirred mixture of 4-chloro-3-methylaniline (F1, 1.01 g, 7.13 mmol) and triethylamine (866 mg, 8.56 mmol) in methylene chloride (20 mL) at −20° C. under nitrogen was added phosgene solution (0.15 weight/weight in toluene, 6.15 g, 9.13 mmol) dropwise over 5 min. After addition, the reaction mixture was warmed up to room temperature over 2 h, and then stirred at room temperature for another 2 h. After this time, the reaction mixture was cooled to 0° C., and slowly quenched with saturated aqueous sodium bicarbonate (30 mL). The mixture was extracted with ethyl acetate (100 mL). The organic extract was washed with 2 M hydrochloric acid (50 mL), brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was triturated with methylene chloride (40 mL) and filtered. The filtrate was concentrated under reduced pressure to provide compound F2 as a light brown liquid (1.08 g, 90%): 1H NMR (300 MHz, CDCl3) δ 7.27 (d, J=8.4 Hz, 1H), 6.97 (d, J=2.4 Hz, 1H), 6.88-6.84 (m, 1H), 2.34 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:23])[N:15]([CH3:22])[C:16](=[O:21])[N:17]([CH3:20])[C:18]=2[CH3:19])=[C:9]([CH3:24])[CH:8]=1)[NH2:5].[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:28]=1[C:29](Cl)=[O:30].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:23])[N:15]([CH3:22])[C:16](=[O:21])[N:17]([CH3:20])[C:18]=2[CH3:19])=[C:9]([CH3:24])[CH:8]=1)[NH:5][C:29]([C:28]1[C:27]([Cl:26])=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:36])=[O:30]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)c(C)c1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)c(C)c1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47.7 %

Procedure:
To a suspension of 4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-3-methyl-L-phenylalanine methyl ester (0.089 mmol, 34 mg) and 2,6-dichlorobenzoyl chloride (0.1 mmol, 21 mg) in dichloromethane (2 mL) was added diisopropylethylamine (0.4 mmol, 70 uL) at room temperature. After 5 min, everything went into solution and the clear yellow solution was stirred for 15 h at room temperature. The resulting brown solution was diluted with dichloromethane (25 mL). The dichloromethane layer was washed successively with 1N hydrochloric acid (2×25 mL), saturated sodium bicarbonate solution (25 mL), and brine solution (25 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent gave the crude product which was purified by silica gel chromatography using a Biotage (40m) column to afford 22 mg (48% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-3-methyl-L-phenylalanine methyl ester as a viscous oil. ES-HRMS m/e calcd for C25H25Cl2N3O5 (M+Na) 541.1065, found 541.1063.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:61][CH:62]=[CH2:63].FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:63][CH:62]=[CH2:61])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Product: C=CCOC1CCC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CC1OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (200 mg in 3.0 ml 33% methylene chloride in cyclohexane), allyl trichloroacetimidate (88 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (4.5 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 18 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×5 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (156 mg).
Reaction SMILES: [C:1]([C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])#[N:2].Cl.[NH2:17][OH:18].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[NH2:2]/[C:1](=[N:17]\[OH:18])/[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1/C(N)=N/O
Yield: 93 %

Procedure:
A solution of tert-butyl (2S)-2-cyano-1-piperidinecarboxylate (13.10 g) [see Preparation 3] in methanol (500 ml) was added to a solution of hydroxylamine hydrochloride (21.6 g) and sodium carbonate (33.0 g) in water (600 ml). The reaction mixture was warmed to the reflux temperature and stirred for 8 hours after which time the methanol was removed under reduced pressure and the product extracted from the aqueous layer with ethyl acetate (3×500 ml). The combined organic layers were washed with water (500 ml), dried over magnesium sulphate and the solvent removed under reduced pressure to afford tert-butyl (Z)-(2S)-2-[amino(hydroxyimino)methyl]-1-piperidinecarboxylate (14.1 g) as a white solid.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[NH2:18][C:19]1[CH:31]=[C:30]([C:32]2[CH:40]=[CH:39][C:35]3[O:36][CH2:37][O:38][C:34]=3[CH:33]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])O.[Na+]>C(Cl)Cl>[O:36]1[C:35]2[CH:39]=[CH:40][C:32]([C:30]3[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])=[C:19]([NH:18][C:13](=[O:14])[C:12]4[CH:16]=[CH:17][C:9]([F:8])=[CH:10][CH:11]=4)[CH:31]=3)=[CH:33][C:34]=2[O:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc3c(c2)OCO3)cc1N
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(-c2ccc3c(c2)OCO3)cc1NC(=O)c1ccc(F)cc1
Reaction time: 5 h

Procedure:
0.054 mL of triethylamine and 0.034 mL of 4-fluorobenzoyl chloride were added to 3.5 mL of methylene chloride solution containing 60 mg of tert-butyl 2-amino-4-(benzo[1,3]dioxol-5-yl)benzoate at room temperature sequentially and stirred at the same temperature for 5 hours. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1]to obtain tert-butyl 4-(benzo[1,3]dioxol-5-yl)-2-(4-fluorobenzamido)benzoate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[CH2:11]1[O:33][C:32]2[CH:31]=[CH:30][C:15]([CH2:16][C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[C:18]=3[S:26](Cl)(=[O:28])=[O:27])=[CH:14][C:13]=2[O:12]1>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:26]([C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:17]=1[CH2:16][C:15]1[CH:30]=[CH:31][C:32]2[O:33][CH2:11][O:12][C:13]=2[CH:14]=1)(=[O:28])=[O:27]
Reactant: O=S(=O)(Cl)c1c(Cc2ccc3c(c2)OCO3)sc2ccccc12
Reactant: Cc1noc(N)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2c(Cc3ccc4c(c3)OCO4)sc3ccccc23)c1Cl

Procedure:
N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]-benzo[b]thiophene-3-sulfonamide was prepared in the same manner as described in Example 41. Reaction of 4-chloro-3-methyl-5-aminoisoxazole (0.61 mmoles, 81 mg), NaH (1.5 mmoles), 61 mg), and 2-[3,4-(methylenedioxy)benzyl]benzo[b]thiophene-3-sulfonyl chloride (0.74 mmoles, 0.27 g) in THF (4 ml) yielded, after flash chromatography using 50% ethyl acetate/hexanes followed by recrystallization from ethyl acetate and hexanes, 0.23 g (81%) of a light brown solid, m.p. 178-181° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:21])[C:12](=[O:13])[CH:11]=[C:10](/[CH:14]=[CH:15]/[C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)[O:9]2)=[CH:4][CH:3]=1.[CH2:22]([SH:29])[C@@H:23]([OH:28])[C@H:24]([OH:27])[CH2:25][SH:26]>>[OH:27][C@@H:24]([C@H:23]([OH:28])[CH2:22][SH:29])[CH2:25][S:26][CH:15]([C:16]1[CH:20]=[CH:19][S:18][CH:17]=1)[CH2:14][C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)([CH3:21])[C:12](=[O:13])[CH:11]=1
Reactant: CC1(c2ccc(F)cc2)OC(/C=C/c2ccsc2)=CC1=O
Reactant: O[C@H](CS)[C@H](O)CS
Product: CC1(c2ccc(F)cc2)OC(CC(SC[C@@H](O)[C@H](O)CS)c2ccsc2)=CC1=O

Procedure:
Following the procedure of Method C, Example 1, (E)-2-(4-fluorophenyl)-2-methyl-5-[2-(3-thienyl)ethenyl]-3(2H)-furanone was reacted with 1,4-dithio-DL-threitol to give 5-(2-{[(2S*,3S*)-2,3-dihydroxy-4-mercaptobutyl]thio}-2-thien-3-ylethyl)-2-(4-fluorophenyl)-2methylfuran-3(2H)-one: 1H NMR (DMSO-d6) δ1.53, 1.57 and 1.60 (overlapped singlets, 3H), 4.60 (m, 1H), 5.56 and 5.57 (overlapped singlets, 1H), 7.12-7.60 (m, 7H); MS (LR-ESI) m/z 455 (M+H calcd. for C21H24FO4S3 455).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:9][C:8]([N:10]([CH3:13])[CH:11]=[O:12])=[N:7][C:6]=1[CH3:14])=O.[C:15]([NH:18][C:19]([NH2:21])=[S:20])(=[NH:17])[NH2:16]>CO>[NH:18]([C:19]1[S:20][CH:2]=[C:3]([C:5]2[S:9][C:8]([N:10]([CH3:13])[CH:11]=[O:12])=[N:7][C:6]=2[CH3:14])[N:21]=1)[C:15]([NH2:17])=[NH:16]
Reactant: N=C(N)NC(N)=S
Reactant: Cc1nc(N(C)C=O)sc1C(=O)CBr
Solvent: CO
Product: Cc1nc(N(C)C=O)sc1-c1csc(NC(=N)N)n1
Temperature: 5 °C
Yield: 93.2 %

Procedure:
A solution of 5-(2-bromoacetyl)-2-(N-methylformamido)-4-methylthiazole (2.77 g) and N-amidinothiourea (2.37 g) in methanol (30 ml) was stirred for 4 hours at ambient temperature and for 60 minutes under refluxing. The reaction mixture was cooled to 5° C. The resulting precipitate was collected by filtration, washed with cold methanol (5 ml×2) and dried under reduced pressure to give 5-(2-guanidinothiazol-4-yl)-2-(N-methylformamido)-4-methylthiazole (2.76 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([C:24]([O:26]CC)=[O:25])([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]2=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(C1(N2CCCCC2=O)CCNCC1)=O)C.C(OC(ON1C(=O)CCC1=O)=O)C1C=CC=CC=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([C:24]([OH:26])=[O:25])([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]2=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(N2CCCCC2=O)CCN(C(=O)OCc2ccccc2)CC1
Agent: CCOC(=O)C1(N2CCCCC2=O)CCNCC1
Agent: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(C(=O)O)(N2CCCCC2=O)CC1
Reaction time: 1.5 h

Procedure:
1-Benzyloxycarbonyl-4-(ethoxycarbonyl)-4-(2-oxopiperidino)-piperidine. 4-(Ethoxycarbonyl)-4-(2-oxopiperidino)piperidine (9.0 g) in dichloromethane (25 mL) was added to a solution of N-(benzyloxycarbonyloxy)succinimide (8.8 g) and triethylamine (5.4 mL) in dichloromethane (150 mL). After 1.5 hours, the reaction mixture was washed successively with 1.0N hydrochloric acid and saturated aqueous sodium bicarbonate. The separated organic layer was dried and evaporated to give the title compound (11.6 g) as a light yellow solid; MS: m/z=389(M+1); NMR (CDCl3 /CF3COOH): 7.37 (m,5), 5.16 (s,2), 4.28 (q,2, J=7.1), 4.09 (m,2), 3.40 (m,2), 3.28 (m,2), 2.53 (m,2), 2.34 (m,2), 1.83 (m,6), 1.30 (t,3, J=7.1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[O:11]1[CH2:15][CH2:14][O:13][CH:12]1[CH2:16][CH2:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([C@H:24]2[CH2:29][CH2:28][C@H:27]([OH:30])[CH2:26][CH2:25]2)[CH2:20][CH2:19]1>N1C=CC=CC=1>[O:11]1[CH2:15][CH2:14][O:13][CH:12]1[CH2:16][CH2:17][C@H:18]1[CH2:19][CH2:20][C@H:21]([C@H:24]2[CH2:29][CH2:28][C@H:27]([O:30][C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:26][CH2:25]2)[CH2:22][CH2:23]1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: O[C@H]1CC[C@H]([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1
Solvent: c1ccncc1
Product: O=C(O[C@H]1CC[C@H]([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 1.7 g of 4-fluorobenzoyl chloride in 5 ml of pyridine is treated with 2.8 g of trans-4-[trans-4-(2-(1,3-dioxolan-2-yl)ethyl)cyclohexyl]-cyclohexanol (prepared according to Example 3) and stirred at room temperature for 12 hours. Thereafter, the reaction mixture is poured on to ice-water and extracted three times with diethyl ether. The organic phases are washed in succession with saturated sodium hydrogen carbonate solution, with 10 percent hydrochloric acid, with saturated sodium hydrogen carbonate solution and with water, then dried over magnesium sulfate, filtered and concentrated. Chromatographic purification of the resulting crude product-on silica gel with ethyl acetate/petroleum ether (vol. 3:97) gives 4-fluorobenzoic acid trans-4-[trans-4-[2-(1,3-dioxolan-2-yl)ethyl]cyclohexyl]-cyclohexyl ester.
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1CCCCBr.[C:13]1([NH2:24])[C:18](F)=[C:17](F)[C:16](F)=[C:15](N)[C:14]=1F.[ClH:25].Cl>>[ClH:25].[ClH:25].[N:2]1[CH:7]=[CH:6][C:5]([CH2:3][CH2:4][CH2:5][CH2:6][N:2]2[CH2:3][CH2:4][C:5]3[C:14]4[C:13](=[CH:18][CH:17]=[CH:16][CH:15]=4)[NH:24][C:6]=3[CH2:7]2)=[CH:4][CH:3]=1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Reactant: BrCCCCc1ccccn1
Agent: Br
Agent: Cl
Product: c1ccc2c3c([nH]c2c1)CN(CCCCc1ccncc1)CC3

Procedure:
The title compound was prepared following the procedure of Example 1 and using 4-pyridinylbutyl bromide hydrobromide instead of 4-picolyl chloride hydrochloride, and was converted to the dihydrochloride, mp 259°-261° C.
Reaction SMILES: [NH:1]([CH3:9])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].[CH3:10][N:11]([C:13]1[CH:18]=[CH:17][C:16]([N:19]=[N:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[S:29])=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[CH3:12].N[C@H](C(O)=O)C(C)C.CC1OC(C)CN(C(CN2C(=O)SC3C2=CC=CC=3)=O)C1.N(C)[C@H](C(O)=O)C(C)C>O1CCOCC1.O>[CH3:10][N:11]([CH3:12])[C:13]1[CH:14]=[CH:15][C:16]([N:19]=[N:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[C:6](=[O:8])[CH:2]([CH:3]([CH3:4])[CH3:5])[N:1]([CH3:9])[C:28]3=[S:29])=[CH:23][CH:22]=2)=[CH:17][CH:18]=1
Reactant: CN(C)c1ccc(N=Nc2ccc(N=C=S)cc2)cc1
Reactant: CN[C@H](C(=O)O)C(C)C
Agent: CC(C)[C@H](N)C(=O)O
Agent: CC1CN(C(=O)Cn2c(=O)sc3ccccc32)CC(C)O1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)C1C(=O)N(c2ccc(N=Nc3ccc(N(C)C)cc3)cc2)C(=S)N1C
Yield: 95.6 %

Procedure:
From a stock solution of 0.500 M N-(Me)-D,L-valine (20 mmol in 40 mL 0.25 M KOH), a 5.0-mL aliquot (2.5 mmol MeVal) was heated to 60° C. and mixed with 0.100M DABITC (5.0 mL, 0.5 mmol) in dioxane. In order to obtain a homogeneous solution another 3.5 mL dioxane and 2.5 mL water were added. This reaction mixture became inhomogeneous in contrast to the mixture containing Val, indicating that the DABTH-MeVal formed precipitated. The reaction was monitored by TLC (SiO2 Tol/EtOAc, 2:1; spots developed with both UV and long wavelength light) and after 30 min all the DABITC had been consumed. The subsequent extraction was performed as described above. The product crystallized from DCM:hexane (1:4, v/v) to yield 189.0 mg (99.5%) of the desired product. Analysis: m.p. 164.5-169° C., Rf-TLC 0.73 (SiO2; EtOAc:MeOH, 4:1). UV (acetonitrile:water 1:1) λmax=265 nm, ε265=26000 (see also FIG. 12). Fluorescence measurements: see FIGS. 9 and 10. 1H NMR(CDCl3, 25° C.) δ1.05, 1.25[d+d, 3+3H, J=6.9, 7.1 Hz, CH3(γ,γ′)], 2.47 [m, 1H, J=3.3, 6.9, 7.1 Hz, CH(β)], 3.09 [s, 6H, N(CH3)2] 3.4[s, 3H, N—CH3], 4.4 [d, 1H, J=3.3 Hz, CH(α)], 6.74, 6.77 [d+d, 2H, azobenzene C6—H, C7—H] 7.37, 7.40 [d+d, 2H, azobenzene C5—H, C8—H] 7.87, 7.90, 7.92, 7.95 [4d, 4H, azobenzene C1—H—C4—H].