Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH3:10].[H-].[Na+].[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14].C1([O-])C=CC=CC=1>C1COCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: COc1cc(O)ccc1Br
Agent: [H-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A solution of 4-bromo-3-methoxyphenol (5.00 g, 24.6 mmol, Chontech) in THF (50 ml) was added dropwise to a suspension of sodium hydride (1.08 g, 60% dispersion in mineral oil, 27 mmol) in THF (100 ml) over 10 min while cooling in ice. The reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 60 min. Triisopropylsilyl chloride was added dropwise to the phenolate solution, and the reaction mixture was stirred at room temperature for 60 min. Water was added to the mixture while cooling in ice, and it was then extracted several times with ethyl acetate. The combined organic phase was washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. Purification by chromatography on silica gel (mobile phase: 2-10% gradient of ethyl acetate in dichloromethane) afforded 8.67 g (98%) of the desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[N:20][NH:21]2)=[CH:17][CH:16]=1>>[NH:21]1[C:22]2[C:18](=[CH:17][CH:16]=[C:15]([NH:14][C:2]3[N:7]=[C:6]([NH:14][C:15]4[CH:23]=[C:22]5[C:18]([CH:19]=[N:20][NH:21]5)=[CH:17][CH:16]=4)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=3)[CH:23]=2)[CH:19]=[N:20]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: CCOC(=O)c1cnc(Cl)nc1Cl
Product: CCOC(=O)c1cnc(Nc2ccc3cn[nH]c3c2)nc1Nc1ccc2cn[nH]c2c1

Procedure:
In like manner to N2,N4-bis(3-hydroxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine, 2,4-dichloro-5-ethoxycarbonylpyrimidine and 6-aminoindazole were reacted to yield N2,N4-bis(6-indazolyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 8.76 (s, 1H), 7.73 (d, 2H J=8.8), 7.54 (m, 4H), 7.36 (d, 2H, J=9.5 Hz), 4.3 (q, 2H, J=7.0 Hz), 1.34 (3H, J=7 Hz); LCMS: ret. time 27.59 min.; purity: 95%; MS (m/e): 415 (MH+).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][Si](C)(C)[N-][Si](C)(C)C.[Li+].CCCCCC.CI>O1CCCC1>[CH3:21][C:12]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:13][CH2:14][CH2:15][N:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])[CH2:11]1
Reactant: CCOC(=O)C1CCCN(S(=O)(=O)c2ccccc2)C1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CCCCCC
Product: CCOC(=O)C1(C)CCCN(S(=O)(=O)c2ccccc2)C1
Yield: 40 %

Procedure:
At r.t., to the solution of ethyl 1-(phenylsulfonyl)piperidine-3-carboxylate (0.50 g, 2.0 mmol) in tetrahydrofuran (5.0 mL), was slowly added 1.0 M of lithium hexamethyldisilazide in hexane (2.5 mL, 2.5 mmol) with stirring. After stirring for 30 min, to the mixture was added methyl iodide (157 ul, 2.5 mmol). The mixture was stirred at r.t. overnight and was quenched with 10% citric acid, then extracted with ethyl acetate. The extract was washed with water, sat'd sodium bicarbonate solution, water, and brine, successively. The extract was then dried over sodium sulfate (anhydrous). After filtration, the filtrate was concentrated to yield 200 mg (40%) of ethyl 3-methyl-1-(phenylsulfonyl)piperidine-3-carboxylate.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]3=[CH:8][C:9]=2[O:11][CH3:12])[NH:4][CH2:3]1.[CH3:18]I>>[CH3:18][N:4]1[C:5]2[C:10](=[C:9]([O:11][CH3:12])[CH:8]=[C:7]3[CH:13]=[CH:14][CH:15]=[CH:16][C:6]3=2)[C:2]([CH3:17])([CH3:1])[CH2:3]1
Reactant: CI
Reactant: COc1cc2ccccc2c2c1C(C)(C)CN2
Product: COc1cc2ccccc2c2c1C(C)(C)CN2C

Procedure:
A fifth preferred general synthesis method suitable for the synthesis of N-substituted-3,3-dimethyl-4-hydroxy-benzoindoline compounds, e.g N-methyl-3,3-dimethyl-4-hydroxy-benzoindoline 27, is also shown in FIG. 3. In this method, a 1-amino-3-methoxynapthalene 18 is acetylated with an acid chloride, e.g., 2-bromo-2-methylpropionyl chloride, to give compound 23. Compound 23 is cyclized by reaction with AlCl3 to give compound 24. Compound 24 is then reduced with LAH to give the 3,3-dimethyl-4-methoxybenzoindoline 25. Compound 25 is then alkylated with an alkylating agent, e.g., methyl iodide, to give a N-methyl-3,3-dimethyl-4-methoxybenzoindoline, e.g., compound 26. Subsequent methoxy group deprotection by with boron tribromide gives compound 27. An example of this synthesis is provided in Example 5 below.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].O=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1>[Pd].C(O)C.C(O)(=O)C>[OH:2][CH2:1][CH2:3][NH:4][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1
Reactant: NCCO
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(NCCO)CC1

Procedure:
A slurry of 10% palladium on charcoal (catalytic) in dry ethanol (3 mL) and acetic acid (5 drops) was added to a solution of ethanolamine (0.24 mL) and tert-butyl 4-oxopiperidine-1-carboxylate (0.80 g) in dry ethanol (10 mL) and hydrogenated at 2 bar for 26 hours. The solution was filtered through a glass fibre filter and the filtrate concentrated in vacuo to give the sub-titled compound (0.98 g) as a pale yellow oil.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][C:3]#[C:4][CH2:5][CH3:6].[H-].[Na+].Cl[C:11]1[C:12]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:13][O:14][N:15]=1.O>O1CCCC1>[CH2:1]([O:7][C:11]1[C:12]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:13][O:14][N:15]=1)[CH2:2][C:3]#[C:4][CH2:5][CH3:6]
Reactant: CCC#CCCO
Reactant: Clc1nonc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCC#CCCOc1nonc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-hexyn-1-ol (980 mg, 10 mmol) and sodium hydride (240 mg, 10 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-oxadiazol-3-yl )pyridine (450 mg, 2.5 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.C([Mg]Cl)(C)C.[Cl:26][C:27]1[N:28]=[C:29]([N:34]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)[CH3:35])[S:30][C:31]=1[CH:32]=[O:33]>O1CCCC1>[Cl:26][C:27]1[N:28]=[C:29]([N:34]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)[CH3:35])[S:30][C:31]=1[CH:32]([C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1)[OH:33]
Reactant: CN(Cc1ccc(Cl)cc1)c1nc(Cl)c(C=O)s1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cccnc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2sc(N(C)Cc3ccc(Cl)cc3)nc2Cl)c2cccnc21
Temperature: 0 °C
Yield: 62 %

Procedure:
To a solution of 3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (96, 0.82 g, 2.0 mmol) in tetrahydrofuran (5 mL) at −20° C., isopropylmagnesium chloride (2 M in tetrahydrofuran, 1.1 mL, 2.2 mmol) was added dropwise. The reaction mixture was allowed to warm to 0° C. in 10 minutes. The reaction mixture was then cooled to −40° C. To the reaction mixture was added a solution of 4-chloro-2-[(4-chloro-benzyl)-methyl-amino]-thiazole-5-carbaldehyde (551, 0.41 g, 1.4 mmol) in tetrahydrofuran (10 mL). The reaction mixture was allowed to warm to −10° C. in 30 minutes. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexanes to provide the desired compound as a yellow solid (552, 0.5 g, 60%). MS (ESI) [M+H+]+=575.29.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:14](=[CH2:15])[C:13](=[O:16])[C@@H:12]2[C@H:10]1[C@H:11]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:33]=[C:34]([SH:39])[CH:35]=[CH:36][C:37]=1[F:38]>C(OCC)C.CCCCCC.C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][C@@:9]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:14]([CH2:15][S:39][C:34]2[CH:35]=[CH:36][C:37]([F:38])=[C:32]([F:31])[CH:33]=2)[C:13](=[O:16])[C@@H:12]2[C@H:10]1[C@H:11]2[C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C1C(=O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]2[C@]1(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: Fc1ccc(S)cc1F
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2C(=O)[C@H]1CSc1ccc(F)c(F)c1
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 97.5 %

Procedure:
Di-tert-butyl (1S,2R,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-methylidene-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylate (1.03 g, 2.43 mmol) in diethyl ether (100 mL) is bubbled with nitrogen gas for 10 minutes. Add 3,4-difluorobenzenethiol (0.36 g, 2.43 mmol) and triethylamine (0.01 mL, 0.05 μmol). The mixture is warmed to 40° C. and stirred for 15 minutes. The mixture is then allowed to cool to ambient temperature, transferred to a separatory funnel, diluted with hexane (40 mL), washed with of 2N aqueous KOH (1×30 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure giving di-tert-butyl (1S,2R,3S,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-{[(3,4-difluorophenyl)sulfanyl]methyl}-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylate (1.35 g, 2.37 mmol): MS (m/z): 567.8 (M−H). This material is taken up in 120 mL of diethyl ether and added slowly over 2 hours to a 200 mL ether solution at −10° C. which contains R-(+)-2-methyl-CBS-oxazaborolidine (981.72 mg, 3.54 mmol) and borane-methyl sulfide complex (2M in tetrahydrofuran, 5.02 mL, 10.04 mmol). The mixture is stirred for an additional hour after final addition of di-tert-butyl (1S,2R,3S,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-{[(3,4-difluorophenyl)sulfanyl]methyl}-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylate. Silica gel (30 g) is added over 30 minutes and the reaction mixture is gradually warmed to ambient temperature. The suspension is filtered, and washed with 300 mL of diethyl ether. The solvent is concentrated under reduced pressure giving a residue. The residue is purified by flash chromatography, eluting with (0 to 15% ethyl acetate/hexanes) to give the title compound (0.844 g, 1.48 mmol, 60.7% yield): MS (m/z): 569.8 (M−H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][NH2:24])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH3:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]=[C:35]=[O:36].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[C:28]1([CH3:27])[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][C:35]([NH:24][CH2:23][CH2:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=3)[N:11]=2)=[CH:16][CH:17]=1)=[O:36]
Reactant: NCCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: Cc1ccccc1N=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccccc1NC(=O)NCCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
In a 25 mL flask, to a solution of 3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine (0.160 g, 0.442 mmol) in dichloromethane (2 mL) was added 2-methyl phenylisocyanate (0.06 g, 0.497 mmol) in dichloromethane (5 mL) followed by triethylamine (0.044 g, 0.414 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and adsorbed onto Celite®. Purification by flash column chromatography (reverse phase) 5% acetonitrile/water provided the title compound as a white solid (0.11 g, 53%).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2.[CH2:15]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:16]#[CH:17]>>[CH2:15]([N:18]1[CH2:23][CH2:22][N:21]([CH2:3][C:4]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]3[C:5]=2[CH:6]=[CH:7][CH:8]=[N:9]3)[CH2:20][CH2:19]1)[C:16]#[CH:17]
Reactant: C#CCN1CCNCC1
Reactant: Oc1ccc(CCl)c2cccnc12
Agent: Cl
Product: C#CCN1CCN(Cc2ccc(O)c3ncccc23)CC1

Procedure:
The title compound was prepared by reaction of 5-chloromethyl-8-hydroxyquinolinoline (A2) with N-propargyl piperazine as follows:
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][NH:12][C:13](=[O:34])[C:14]1[CH:19]=[C:18]([CH:20]=[N:21][OH:22])[C:17]([F:23])=[C:16]([F:24])[C:15]=1[NH:25][C:26]1[CH:31]=[CH:30][C:29]([I:32])=[CH:28][C:27]=1[F:33])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[F:24][C:16]1[C:15]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([I:32])=[CH:28][C:27]=2[F:33])=[C:14]([CH:19]=[C:18]([CH:20]=[N:21][OH:22])[C:17]=1[F:23])[C:13]([NH:12][O:11][CH2:10][CH2:9][OH:8])=[O:34]
Reactant: CC(C)(C)[Si](C)(C)OCCONC(=O)c1cc(C=NO)c(F)c(F)c1Nc1ccc(I)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NOCCO)c1cc(C=NO)c(F)c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
N-[2-(t-butyldimethylsilanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-5-(hydroxyiminomethyl)-benzamide (a mixture of two geometric or atropisomers ) (5.0 mg, 46%) prepared in Process C was dissolved in THF (1 ml), tetrabutylammonium fluoride (1 M solution in THF, 30 μl, 30 μmol) was added thereto, and the mixture was stirred at room temperature for five hours. Water (8 ml) was added to the reaction solution, which was extracted with ethyl acetate (8 ml×3). The organic layers were combined, washed with 0.1 N hydrochloric acid (8 ml) and saturated brine (8 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified with preparative thin layer chromatography (Silicagel 60 F254, 0.5 mm thickness, Merck & Co., Inc., CH2Cl2/MeOH (10:1)) to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(hydroxyiminomethyl)-benzamide (Compound 3) (3.9 mg, 96%) as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][CH:23]([NH:26][CH2:27][C@H:28]([OH:41])[C:29]3[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:30]=3)[CH2:22][CH2:21]2)=[CH:16][CH:15]=1)(=[O:12])=[O:11])=[O:4].[OH-].[Na+]>>[OH:41][C@H:28]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([NH:36][S:37]([CH3:40])(=[O:38])=[O:39])[CH:30]=1)[CH2:27][NH:26][CH:23]1[CH2:24][CH2:25][N:20]([C:17]2[CH:16]=[CH:15][C:14]([NH:13][S:10]([C:9]3[CH:8]=[CH:7][S:6][C:5]=3[C:3]([OH:4])=[O:2])(=[O:12])=[O:11])=[CH:19][CH:18]=2)[CH2:21][CH2:22]1
Reactant: COC(=O)c1sccc1S(=O)(=O)Nc1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(NS(=O)(=O)c4ccsc4C(=O)O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from methyl 3-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}anilino)sulfonyl]-2-thiophenecarboxylate (which was obtained in Example 320) by NaOH hydrolysis as a pale grey solid; 1H NMR (300 MHz, DMSO-d6) δ 1.50-1.70 (m, 2H), 1.95-2.10 (m, 2H), 2.50-2.70 (m, 2H), 2.95 (s, 3H), 3.00-3.30 (m, 3H), 3.60-3.70 (m, 2H), 4.75-4.85 (m, 1H), 6.10 (brs, 1H), 6.80 (d, J=9.0 Hz, 2H), 6.85-6.95 (m, 3H), 7.04 (d, J=5.4 Hz, 1H), 7.08 (dd, J=8.4,1.8 Hz, 1H), 7.26 (d, J=1.8 Hz, 1H), 7.39 (d, J=5.4 Hz, 1H), 8.73 (brs, 1H), 9.96 (brs, 1H); MS (ES) m/z: 610.7 (MH+); HRMS Calcd. for C25H31N4O8S3 (MH+): 611.1299. Found: 611.1284.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]([N:21]=[N+]=[N-])=[O:20])[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(N[C@H](C(NN)=O)CC1N=CNC=1)=O)C1C=CC=CC=1.[CH2:46]([NH:50][C:51]([C@@H:53]1[CH2:57][CH2:56][CH2:55]N1)=[O:52])[CH2:47][CH2:48][CH3:49]>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]([N:21]1[CH2:55][CH2:56][CH2:57][C@H:53]1[C:51]([NH:50][CH2:46][CH2:47][CH2:48][CH3:49])=[O:52])=[O:20])[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCNC(=O)[C@@H]1CCCN1
Reactant: [N-]=[N+]=NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Agent: NNC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCNC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
To 75 ml of an ethyl acetate solution of Nα -benzyloxycarbonyl-L-histidine azide (4) prepared from 4.85 g of Nα -benzyloxycarbonyl-L-histidine hydrazide (3) by the method of Reference example 2 was added 2.23 g of compound (31) under ice-cooling and the mixture was placed overnight in a refrigerator to complete the reaction. The reaction mixture was concentrated and the residue was subjected to silica gel column chromatography. By eluting the product with chloroform-methanol-aqueous ammonia (95:5:0.5), 4.13 g of Nα -benzyloxycarbonyl-L-histidyl-N-butyl-L-prolinamide was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=O)=[CH:5][CH:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>ClC1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[S:30])=[CH:5][CH:4]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(C(=O)Nc2ccc([N+](=O)[O-])cc2)cc1
Solvent: Clc1ccccc1
Product: COc1ccc(C(=S)Nc2ccc([N+](=O)[O-])cc2)cc1
Yield: 129.3 %

Procedure:
A mixture of 4-methoxy-4′-nitrothiobenzaniline 3 (1.0 g, 3.7 mmol) and Lawesson's reagent (0.89 g, 2.2 mmol, 0.6 equiv.) in chlorobenzene (15 mL) was heated to reflux for 4 hrs. The solvent was evaporated and the residue was purified with flush column (hexane:ethyl acetate=4:1) to give 820 mg (77.4%) of the product 4 as orange color solid. 1HNMR(300 MHz, DMSO-d6) δ: 8.29(d, 2H, H-3′,5′), 8.00(d, J=8.5 Hz, 2H, H-2′,6′), 7.76(d, 2H), 7.03(d, J=8.4 Hz, 2H), 3.808.37(d, J=5.5 Hz, 2H, H-3′,5′), 8.17(d, J=6.3 Hz, 2H, H-2′,6′), 7.48(d, J=6.6 Hz, 2H), 6.97(d, J=6.5 Hz, 2H), 3.75(s, 3H, MeO). (s, 3H, MeO).
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:18][CH2:19][CH2:20][CH2:21]Br.[I-].[K+]>CC(O)C>[C:5]1([C@@H:2]([N:1]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:3][OH:4])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Product: OC[C@@H](c1ccccc1)N1CCCC1

Procedure:
To a solution of (R)-2-amino-2-phenyl-ethanol (0.5 g, 3.64 mmol) in 2-propanol (40 mL) were added sodium carbonate (1 g, 9.48 mmol), 1,4-dibromobutane (0.57 mL, 4.74 mmol) and potassium iodide (catalytic) in succession, and the mixture was refluxed overnight. After filtration, the sovent was removed under reduced pressure and the crude was used without further purification (0.53 g, 76%). LCMS method: 2, RT: 2.27 min; MI: 191-193 [M+1].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[C:4]=1[C:13]1[CH:18]=[C:17]([C:19](OCC)=[O:20])[N:16]=[C:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:14]=1.[BH4-].[Na+].Cl>C(O)C>[CH2:27]([O:26][C:24]([C:15]1[CH:14]=[C:13]([C:4]2[C:3]([O:2][CH3:1])=[CH:8][C:7]([O:9][CH3:10])=[CH:6][C:5]=2[O:11][CH3:12])[CH:18]=[C:17]([CH2:19][OH:20])[N:16]=1)=[O:25])[CH3:28]
Reactant: CCOC(=O)c1cc(-c2c(OC)cc(OC)cc2OC)cc(C(=O)OCC)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(-c2c(OC)cc(OC)cc2OC)cc(CO)n1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
Compound 12 (2.83 g, 7.27 mmol) was suspended in ethanol (140 mL), and the mixture was heated to 45° C. Sodium borohydride (0.29 g) was added, and the mixture was stirred for 1 h and allowed to cool to room temperature. pH of the solution was adjusted to 3 with 6 M HCl and concentrated. The residue was suspended in dichloromethane and washed with sat. NaHCO3. The organic layer was dried over Na2SO4 and purified on silica gel (eluent petroleum ether bp 40-60° C.:ethyl acetate:triethylamine, 2:5:1; v/v/v). ESI-MS: [M+H]+ 348.14 calc. for C18H22NO6+ 348.14.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[S:24](=[O:26])(=[O:25])[N:23]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:22](=[O:31])[CH2:21]2)=[CH:16][CH:15]=1)[C:10]([NH2:12])=[O:11].C(N(CC)C(C)C)(C)C.Cl[C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43]>O1CCCC1.O>[CH2:45]([O:44][C:42](=[O:43])[NH:8][C@H:9]([C:10](=[O:11])[NH2:12])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]2[S:24](=[O:26])(=[O:25])[N:23]([C:27]([CH3:28])([CH3:30])[CH3:29])[C:22](=[O:31])[CH2:21]2)=[CH:18][CH:19]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CC(C)(C)N1C(=O)CC(c2ccc(C[C@H](N)C(N)=O)cc2)S1(=O)=O
Reactant: O=C(Cl)OCc1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)N1C(=O)CC(c2ccc(C[C@H](NC(=O)OCc3ccccc3)C(N)=O)cc2)S1(=O)=O
Reaction time: 2 h
Yield: 98.4 %

Procedure:
A solution of (S)-2-amino-3-[4-(2-tert-butyl-1,1,3-trioxo-1λ6-isothiazolidin-5-yl)-phenyl]-propionamide trifluoroacetate (600 mg, 1.5 mmol) and N,N-diisopropylethylamine (540 μL, 3.1 mmol) in tetrahydrofuran (7.6 mL) was cooled to 0° C. and treated with benzyl chloroformate (250 μL, 1.7 mmol). The reaction mixture was stirred for 2 h, diluted with water (20 mL), and extracted with ethyl acetate (60 mL). The organic layer was dried with Na2SO4, filtered, and concentrated to give a solid which was purified using flash column chromatography (10% methanol/dichloromethane) to yield the desired product (720 mg, 96%). LCMS found for C24H30N3O6S (M+H)+: m/z=488.
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][CH2:7]N)[C:3]([OH:5])=[O:4].[CH2:9]([O:16][C:17]([NH:19][C:20]([N:32]1C=CC=N1)=[N:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:17]([N:19]([CH2:7][CH2:6][C@H:2]([OH:1])[C:3]([OH:5])=[O:4])[C:20]([NH2:32])=[N:21][C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])([O:16][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:18]
Reactant: NCC[C@H](O)C(=O)O
Reactant: O=C(N=C(NC(=O)OCc1ccccc1)n1cccn1)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=NC(=O)OCc1ccccc1)N(CC[C@H](O)C(=O)O)C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 2(S)-hydroxy-4-amino-butyric acid (0.059 g, 0.50 mmol) in DMF (2 ml) was added N,N′-bis(benzyloxycarbonyl)-1H-pyrazole-1-carboxamidine (0.26 g, 0.70 mmol) followed by DIPEA (0.87 mL, 4.99 mmol) and the reaction was heated to 80° C. and stirred overnight. The crude mixture was purified on a 2-inch reverse-phase HPLC column to yield N,N′-bis-Cbz-2(S)-hydroxy-4-guanidino-butyric acid: MS: m/z (M+H)+ calcd. 430.15, found 430.1.