Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.[CH2:13]([O:15][C:16](=[O:44])[C:17]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[F:43])([CH3:35])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH:28]2[CH2:32][NH:31][C:30](=[O:33])[N:29]2[CH3:34])=[CH:21][CH:20]=1)[CH3:14].[H-].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH2:13]([O:15][C:16](=[O:44])[C:17]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[F:43])([CH3:35])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH:28]2[CH2:32][N:31]([CH2:7][C:6]3[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=3)[C:30](=[O:33])[N:29]2[CH3:34])=[CH:21][CH:20]=1)[CH3:14]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccccc1F
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1)Oc1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Trifluoromethylbenzyl bromide (0.03 mL, 0.169 mmol, d=1.546) and tetrabutyl ammonium iodide (catalytic amount) are added to a 0° C. suspension of 2-(2-Fluoro-phenoxy)-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester (0.050 g, 0.113 mmol) and sodium hydride (0.011 g, 0.281 mmol, 60% suspension on mineral oil), and pre-stirred for 1 h at ambient temperature. The reaction mixture is stirred at ambient temperature for 18 h, diluted with ethyl acetate, and washed with 1N HCl, water, and brine. The organic layer is dried, concentrated, and carried into the next step. MS [EI+] 603 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C:13]([CH:18]([CH3:20])[CH3:19])([OH:17])[CH2:14][CH:15]=[CH2:16])[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:14]([C:13]1([CH:18]([CH3:20])[CH3:19])[O:17][C:29](=[O:31])[N:10]([C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH3:9])[CH2:11][CH2:12]1)[CH:15]=[CH2:16]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CCC(O)(CCN[C@@H](C)c1ccc(Br)cc1)C(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCC1(C(C)C)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.1 %

Procedure:
To a solution of 1-((S)-1-(4-bromophenyl)ethylamino)-3-isopropylhex-5-en-3-ol (802 mg, 2.366 mmol) and triethylamine (139 mg, 2.366 mmol) in CH2Cl2 (20 mL) was added triphosgene (348 mg, 1.18 mmol) at 0° C. under N2, and the mixture was stirred at rt overnight. The reaction mixture was quenched with water, and extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by column chromatography to give 6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-1,3-oxazinan-2-one (480 mg, 56% yield),
Reaction SMILES: C([O:8][C:9](=[O:20])[C@H:10]([CH2:12][C:13]1[CH:18]=[CH:17][C:16](O)=[CH:15][CH:14]=1)[NH2:11])C1C=CC=CC=1.N[C@H:22](C(C(CN1C2C=CC=CC=2C(C2C=CC=CC=2)=NC(NC(=O)[C@H](CC2C=CC(OP(O)(O)=O)=CC=2)NC(=O)C)C1=O)=O)=O)[CH2:23]CSC.C(OC(=O)C)(=O)C.N[C@H](C(O)=O)CC1C=CC(O)=CC=1.C1(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)C=CC=CC=1.C([Sn](CCCC)(CCCC)CCCC)=C.[Cl-].[Li+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:22]([C:16]1[CH:15]=[CH:14][C:13]([CH2:12][C@@H:10]([C:9]([OH:8])=[O:20])[NH2:11])=[CH:18][CH:17]=1)=[CH2:23]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)OCc1ccccc1
Reactant: CSCC[C@H](N)C(=O)C(=O)CN1C(=O)C(NC(=O)[C@H](Cc2ccc(OP(=O)(O)O)cc2)NC(C)=O)N=C(c2ccccc2)c2ccccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Solvent: CC(=O)OC(C)=O
Product: C=Cc1ccc(C[C@H](N)C(=O)O)cc1

Procedure:
As illustrated by FIG. 5H, tyrosine benzyl ester 111 can be converted to N-acetyltyrosine benzyl ester (2) using acetic anhydride, with the hydroxy group of the tyrosine being transformed into the trifluoromethyl sufonyl derivative 113 by using phenyl bis[(trifluoromethyl)sulfonyl]amine. Compound 113 this can be coupled to vinyltributyltin in the presence of bis(triphenylphosphine)palladium dichloride and lithium chloride to give the 4-ethenylphenylalanine derivative 114. This product, on refluxing with catechol borane and further transesterification with pinanediol, gives p-boronoethyl-2-phenylalanine derivative 116. Catalytic hydrogenation affords 117, which can be further coupled to yield the desired peptide or peptidomimetic.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:14][CH:13]2[C:37]([NH2:39])=[O:38])=[CH:4][CH:3]=1.O>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:40]2[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH:13]2[C:37]([NH2:39])=[O:38])=[CH:4][CH:3]=1
Reactant: NC(=O)C1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCN1CCCC(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)C1CNCCN1CCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 1.5 h

Procedure:
33.1 g (53.8 mmol) of 1-[4,4-bis(4-fluorophenyl)butyl]-4-tritylpiperazine-2-carboxamide were dissolved in 180 ml of glacial acetic acid, 180 ml of water were added dropwise in the course of 15 minutes, the mixture was subsequently stirred for 90 minutes, the oily precipitate was decanted, 720 ml of H2O and a Little Celite®, a product from Johns-Mannville Corporation, New York, were added, the mixture was filtered and the filtrate was brought to pH 10 with concentrated NaOH and extracted with methylene chloride. The organic phase was dried and concentrated in vacuo.
Reaction SMILES: CC([N:5]([C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]3[C:27]([CH:28]([OH:30])[CH3:29])=[CH:26][CH:25]=[CH:24][N:23]3[CH:31]=2)=[CH:16][CH:15]=1)[CH2:10][CH2:11][OH:12])[C:6](=[O:8])[O-])(C)C.Cl.O1CCOCC1.C(N(CC)C(C)C)(C)C.[Cl:48][C:49]1[CH:50]=[C:51]([CH:66]=[CH:67][C:68]=1[O:69][CH:70]([CH3:72])[CH3:71])C(OC1C(F)=C(F)C(F)=C(F)C=1F)=O>O>[Cl:48][C:49]1[CH:50]=[C:51]([CH:66]=[CH:67][C:68]=1[O:69][CH:70]([CH3:72])[CH3:71])[C:6]([NH:5][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]3[C:27]([CH:28]([OH:30])[CH3:29])=[CH:26][CH:25]=[CH:24][N:23]3[CH:31]=2)=[CH:16][CH:15]=1)[CH2:10][CH2:11][OH:12])=[O:8]
Reactant: CC(O)c1cccn2cc(-c3ccc(C[C@@H](CCO)N(C(=O)[O-])C(C)(C)C)cc3)nc12
Reactant: CC(C)Oc1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1Cl
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(C(=O)N[C@H](CCO)Cc2ccc(-c3cn4cccc(C(C)O)c4n3)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
A mixture of 1,1-dimethylethyl[(1S)-3-hydroxy-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)propyl]carbamate (1.08 g, 2.54 mmol) and 4M HCl in 1,4-dioxane (8.0 mL, 32 mmol) was stirred at room temperature for 30 minutes. The reaction was concentrated to dryness, redissolved in DMF (25 mL), and to this solution was added N,N-diisopropylethylamine (1.64 g, 12.7 mmol) and pentafluorophenyl 3-chloro-4[(1-methylethyl)oxy]benzoate (0.963 g, 2.54 mmol). The mixture was stirred for 3.0 h at room temperature, diluted with water, and extracted into ethyl acetate. The extracts were washed with water and saturated sodium chloride, dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (2% MeOH:EtOAc) to give the title compound (0.7 g, 53%) as a pale yellow powder. MS (ES+) m/e 522 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Br[C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=1.CC1C=CC(S([O-])=O)=CC=1.[Na+].[H-].[Na+]>C1COCC1.O>[C:9]([CH:8]([C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=1)[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)#[N:10]
Reactant: N#CCc1ccc(F)cc1
Reactant: Cc1cccnc1Br
Agent: Cc1ccc(S(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccnc1C(C#N)c1ccc(F)cc1
Yield: 78.2 %

Procedure:
Under argon atmosphere, to a mixture of 4-fluorophenylacetonitrile (3.97 g), 2-bromo-3-methylpyridine (5.00 g) and sodium 4-methylphenylsulfinate (10.48 g) in THF (125 ml) was added sodium hydride (2.35 g, 60%) at 0° C. to the mixture, and the mixture was heated to reflux for 3.5 hours. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:3), to give 2-(α-cyano-4-fluorobenzyl)-3-methylpyridine (5.14 g) as brown oil.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([OH:20])=[C:15]([CH3:21])[CH:14]=1)=[C:7]2[CH3:22].Br.[CH2:24]([N:26]([CH2:30][CH3:31])[CH2:27][CH2:28]Br)[CH3:25].O>CN(C)C=O>[CH2:24]([N:26]([CH2:30][CH3:31])[CH2:27][CH2:28][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([OH:20])=[C:15]([CH3:21])[CH:14]=1)=[C:7]2[CH3:22])[CH3:25]
Reactant: CCN(CC)CCBr
Reactant: Cc1cc(-c2[nH]c3ccc(O)cc3c2C)cc(C)c1O
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc2[nH]c(-c3cc(C)c(O)c(C)c3)c(C)c2c1
Reaction time: 0.5 h

Procedure:
1.6 g of 60% sodium hydride was suspended in 50 ml of dimethylformamide, and under ice cooling, 5-hydroxy-2-(4-hydroxy-3,5-dimethylphenyl)-3-methylindole was added. After stirring for 30 minutes, 2.8 g of 2-diethylaminoethylbromide hydrobromide was added. The mixture was stirred for 2 hours. The reaction mixture was poured into cold water, and extracted with ethyl acetate. The extract was purified by silica gel column chromatography, and then subjected to thin-layer chromatography to give 5-(2-diethylaminoethoxy)-2-(4-hydroxy-3,5-dimethylphenyl)-3-methylindole.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[CH3:5][C:6]([CH3:11])=[CH:7][C:8](Cl)=[O:9]>ClCCl.COCCOCCOCCOCCOCCOCCO>[CH3:5][C:6]([CH3:11])=[CH:7][C:8]([N:3]=[C:2]=[S:1])=[O:9]
Reactant: N#C[S-]
Reactant: CC(C)=CC(=O)Cl
Agent: COCCOCCOCCOCCOCCOCCO
Agent: [K+]
Solvent: ClCCl
Product: CC(C)=CC(=O)N=C=S
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a solution of potassium thiocyanate (10 g, 101 mmol, Eq: 1.00) and hexaethylene glycol monomethyl ether (896 mg, 830 μl, 3.02 mmol, Eq: 0.03) in dry dichloromethane (120 ml) was added dropwise at 0° C. a solution of 3-methylbut-2-enoyl chloride (12.0 g, 11.2 ml, 101 mmol, Eq: 1.00) in dry dichloromethane (20.0 ml) over 1 hour under argon atmosphere. After the addition was completed, the mixture (now light brown & turbid) was allowed to warm to 25° C. and was stirred for additional 3 hours. The mixture was filtrated, the filtrate was evaporated the residue was distilled under reduced pressure affording 3-methyl-but-2-enoyl isothiocyanate (9.989 g/70.2%) as a yellow liquid. GC-MS: m/ei=141 (M)/bp: 86° C./2 mbar
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:9]2[S:8][C:7]([NH:10]C(=O)OC(C)(C)C)=[N:6][C:5]=2[C:4](=[O:18])[O:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:10][C:7]1[S:8][C:9]2[C:2]([CH3:1])([CH3:19])[O:3][C:4](=[O:18])[C:5]=2[N:6]=1
Reactant: CC(C)(C)OC(=O)Nc1nc2c(s1)C(C)(C)OC2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OC(=O)c2nc(N)sc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Example 249A (7.4 g, 26.0 mmol) in CH2Cl2 (20 mL) was added trifluoroacetic acid (20.0 mL, 260 mmol) slowly at 0° C. The reaction mixture was stirred at room temperature for 3 hours, and then concentrated under vacuum. The residue was diluted with ethyl acetate (100 mL) and neutralized with saturated aqueous NaHCO3 solution. The layers were separated and the aqueous phase was extracted with ethyl acetate (5×100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated to afford the title compound. MS (ESI+) m/z 185 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][CH2:6][N:7]1[C:13](=[O:14])[CH2:12][CH2:11][N:10]([C:15](=[O:26])/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[CH2:9][CH2:8]1)C.[OH-].[Li+].OS([O-])(=O)=O.[K+]>O1CCCC1.C(O)C>[Cl:25][C:20]1[CH:19]=[C:18](/[CH:17]=[CH:16]/[C:15]([N:10]2[CH2:11][CH2:12][C:13](=[O:14])[N:7]([CH2:6][CH2:5][C:4]([OH:27])=[O:3])[CH2:8][CH2:9]2)=[O:26])[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: CCOC(=O)CCN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Reaction time: 3 h
Yield: 98.1 %

Procedure:
A solution of 3.50 g (8.47 mmol) of 3-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-propionic acid ethyl ester in 80 ml of tetrahydrofuran/ethanol (1:1) was treated at 0° C. with 16.94 ml (16.94 mmol) of 1 M aq. lithium hydroxide solution, and kept 3 h at this temperature. The reaction was neutralized with cold aqueous 10% KHSO4 and extracted with EtOAc (3×). The organic phases were washed with aqueous 10% NaCl, dried over Na2SO4 and evaporated to yield 3.20 g (98%) of the titled compound as white solid. MS: 385.0 (MH+, 2Cl).
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1[C:17]2[CH:16]([CH2:18][O:19][C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33](O)=[O:34])=[O:21])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1.[C:36]([O:40][C:41](=[O:69])[NH:42][C:43]([C:45]1[S:46][C:47]([S:67][CH3:68])=[C:48]([S:50]([C:53]2[CH:54]=[C:55]([C:59]3[C:64]([CH3:65])=[CH:63][CH:62]=[CH:61][C:60]=3[NH2:66])[CH:56]=[CH:57][CH:58]=2)(=[O:52])=[O:51])[CH:49]=1)=[NH:44])([CH3:39])([CH3:38])[CH3:37].C(N(CC)CC)C>ClCCl.CN(C=O)C.ClCCl>[CH:14]1[C:15]2[CH:16]([CH2:18][O:19][C:20](=[O:21])[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33](=[O:34])[NH:66][C:60]3[CH:61]=[CH:62][CH:63]=[C:64]([CH3:65])[C:59]=3[C:55]3[CH:56]=[CH:57][CH:58]=[C:53]([S:50]([C:48]4[CH:49]=[C:45]([C:43]([NH:42][C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:69])=[NH:44])[S:46][C:47]=4[S:67][CH3:68])(=[O:52])=[O:51])[CH:54]=3)[C:17]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]=2[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)CCCCCCCCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2N)c1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)CCCCCCCCCCNC(=O)OCC2c3ccccc3-c3ccccc32)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.9 %

Procedure:
Thionyl chloride (0.86 mL, 2.36 mmol) was added to a solution of 11-(9H-fluoren-9-ylmethoxycarbonylamino)-undecanoic acid (0.086 g, 0.194 mmol) in dichloromethane/DMF [1 mL/1 drop] and stirred at room temperature for 3 hours. The reaction mixture was evaporated, dissolved in dichloromethane [5 mL] was added dropwise to a solution of {[4-(2′-amino-6′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.050 g, 0.097 mmol) [example 25, step c] and triethylamine (0.03 mL, 0.19 mmol) in dichloromethane [3 mL] at room temperature and stirred for several hours. The crude reaction was evaporated and column chromatography (25% EtOAc in hexanes) of the residue yielded the title compound (0.042 g, 47%) as a solid. ESI-MS (m/z): Calcd. for C50H58N4O7S3: 922.35; found: 923.0.
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[CH:10]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][C:15]([N:18](S(C)(=O)=O)[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:6]=1[NH:27][C:28](=[O:36])[C:29]([O:32]C(=O)C)([CH3:31])[CH3:30].Cl.C(Cl)Cl>O.CO>[Cl:4][C:5]1[CH:10]=[C:9]([S:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:16][CH:17]=2)[CH:8]=[CH:7][C:6]=1[NH:27][C:28](=[O:36])[C:29]([OH:32])([CH3:31])[CH3:30]
Reactant: CC(=O)OC(C)(C)C(=O)Nc1ccc(Sc2ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc2)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(C)(O)C(=O)Nc1ccc(Sc2ccc(NS(C)(=O)=O)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
A solution of lithium hydroxide monohydrate (0.177 g) in water (1.8 ml) was added to a stirred solution of N-{2-chloro-4-[4-(N,N-dimesylamino)phenylsulphanyl]phenyl}-2-acetoxy-2-methylpropanamide (Method 26) (0.45 g) in methanol (3.5 ml) and the mixture was stirred at ambient temperature for 4 hours. Water (3 ml) was added and the solution was acidified to pH 2-3 with 1M hydrochloric acid. DCM (20 ml) was added and the organic layer was washed with water (20 ml) and brine, then dried. Volatile material was removed by evaporation and the residue was purified by flash chromatography eluting with 30-70% ethyl acetate/hexane to give the title compound (0.30 g) as a solid. Mp 138-140° C.; NMR (CDCl3): 1.5 (s, 6H), 3.0 (s, 3H), 7.1-7.4 (m, 7H), 8.4 (d, 1H), 9.3 (s, 1H); MS (ESP−):413; EA: found: C, 48.9; H, 4.4; N, 6.5%; C17H19ClN2O4S2 requires C, 49.2; H, 4.6; N, 6.8%.
Reaction SMILES: [CH2:1]([C:8](=[CH2:16])[C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([NH2:19])[CH3:18]>N1C=CC=CC=1>[CH2:1]([O:14][C:13](=[O:15])[CH2:12][NH:11][C:9](=[O:10])[CH:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:16][NH:19][CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(Cc1ccccc1)C(=O)NCC(=O)O
Reactant: CCN
Solvent: c1ccncc1
Product: CCNCC(Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Temperature: 120 °C

Procedure:
4 g (13 mmoles) of N-(2-benzyl propenoyl)-glycine p.fluorobenzyl ester, 14, are dissolved in 15 ml of pyridine. 1.02 g (13 mmoles) of ethylamine in solution in the pyridine are added. The solution is heated to 120° C. for 2 hours. At the end of the reaction, the solution is concentrated to 5 ml, and 50 ml of ether are added. A white product precipitates. It is filtered, washed with water, and then with ether. It is recrystallized in a 50/50 CH3OH/H2O mixture. White crystals are obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][CH2:8][C:9]([N:11]([CH3:32])[CH2:12][CH2:13][N:14]([CH2:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][N:31]=1)[C:24]([O:26]CC)=[O:25])[CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:10])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CO.Cl>O.C1COCC1>[C:1]([O:5][C:6](=[O:33])[CH2:7][CH2:8][C:9]([N:11]([CH3:32])[CH2:12][CH2:13][N:14]([CH2:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][N:31]=1)[C:24]([OH:26])=[O:25])[CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1ccnc(CN(CCN(C)C(=O)CCC(=O)OC(C)(C)C)C(CC)CC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)N(CCN(C)C(=O)CCC(=O)OC(C)(C)C)Cc1cc(C(=O)O)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A mixture of 1.9 g of ethyl 2-{[{2-[(4-tert-butoxy-4-oxobutanoyl)(methyl)amino]ethyl}(pentan-3-yl)amino]methyl}isonicotinate, 8.2 mL of a 1.0 M aqueous sodium hydroxide solution, 8.0 mL of methanol, and 16 mL of THF was stirred overnight at room temperature. The mixture was neutralized using 1.0 M hydrochloric acid, water was added thereto, followed by extraction with chloroform-methanol. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure, thereby obtaining 1.5 g of 2-{[{2-[(4-tert-butoxy-4-oxobutanoyl)(methyl)amino]ethyl}(pentan-3-yl)amino]methyl}isonicotinic acid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[S:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.[CH:14]1[C:23]2[C:18](=[C:19]([CH:24]([CH3:28])[C:25](O)=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[CH:14]1[C:23]2[C:18](=[C:19]([CH:24]([CH3:28])[C:25]([NH:9][CH2:8][C:7]3[CH:10]=[CH:11][C:4]([S:3][C:2]([F:12])([F:1])[F:13])=[CH:5][CH:6]=3)=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1
Reactant: CC(C(=O)O)c1cccc2cnccc12
Reactant: NCc1ccc(SC(F)(F)F)cc1
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1ccc(SC(F)(F)F)cc1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 4-[(trifluoromethyl)thio]benzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 391 (M+H)+; MS (ESI−) m/z 389 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.57 (d, J 7.1, 3H), 4.33 (d, J 6.1, 2H), 4.65 (q, J 7.1, 1H), 7.33 (d, J 8.1, 1H), 7.65 (m, 2H), 7.76 (m, 1H), 7.98 (m, 2H), 8.19 (d, J 7.1, 1H), 8.42 (d, J 7.8, 1H), 8.61 (br s, 1H), 8.62 (d, J 6.8, 1H), 8.73 (d, J 6.8, 1H), 8.96 (t, J 5.8, 1H), 9.86 (s, 1H); Anal. Calcd for C20H17F3N2OS+2.1 HCl: C, 51.44; H, 4.12. Found: C, 51.35; H, 3.91.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH2:14])=[CH:9][CH:8]=2)([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([C:26](O)=[O:27])[CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH:14][C:26]([C:23]1([C:20]3[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=3)[CH2:25][CH2:24]1)=[O:27])=[CH:9][CH:8]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C2(C(=O)O)CC2)cc1
Reactant: CC(C)(C)c1cc2cc(N)ccc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C(=O)Nc3ccc4[nH]c(C(C)(C)C)cc4c3)CC2)cc1
Reaction time: 3 h

Procedure:
2-tert-Butyl-1H-indol-5-amine (19 mg, 0.10 mmol) and 1-(4-methoxyphenyl)-cyclopropanecarboxylic acid (19 mg, 0.10 mmol) were dissolved in N,N-dimethylformamide (1.00 mL) containing triethylamine (28 μL, 0.20 mmol). O-(7-Azabenzotriazol-1-yl) N,N,N′,N′-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) was added to the mixture and the resulting solution was allowed to stir for 3 hours. The crude reaction mixture was filtered and purified by reverse phase HPLC. ESI-MS m/z calc. 362.2, found 363.3 (M+1)+; Retention time 3.48 minutes.
Reaction SMILES: [OH:1][C:2]1[N:3]=[N:4][C:5]([C:9]([OH:11])=O)=[C:6]([OH:8])[N:7]=1.[NH3:12]>CN(C)C=O>[O:1]=[C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]([NH2:12])=[O:11])=[N:4][NH:3]1
Reactant: N
Reactant: O=C(O)c1nnc(O)nc1O
Solvent: CN(C)C=O
Product: NC(=O)c1n[nH]c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In 10 mL of dimethylformamide is suspended 0.5 g of 3,5-dihydroxy-1,2,4-triazine-6-carboxylic acid obtained according to the method described in literature (JP-A-54-79292). Then, 2.06 g of N,N′-carbonyldiimidazole is added thereto, and the resulting solution in stirred at ambient temperature for 6 hours. The reaction mixture is cooled with ice, saturated with gaseous ammonia, and then stirred for 15 minutes at the same temperature as above. The deposited crystals are collected by filtration to obtain 0.37 g of 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide.