Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].CCOCC.[CH3:8][N:9]([N:16]=O)C(N[N+]([O-])=O)=N.[CH2:18]([O:25][C:26]1[C:27]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[N:28][N:29]2[CH:34]([C:35](Cl)=[O:36])[CH2:33][N:32]([CH3:38])[C:31](=[O:39])[C:30]=12)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[CH2:18]([O:25][C:26]1[C:27]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[N:28][N:29]2[CH:34]([C:35](=[O:36])[CH:8]=[N+:9]=[N-:16])[CH2:33][N:32]([CH3:38])[C:31](=[O:39])[C:30]=12)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2C(=O)Cl
Reactant: CN(N=O)C(=N)N[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2C(=O)C=[N+]=[N-]
Reaction time: 0.25 h

Procedure:
To a stirring biphasic mixture of 40% aqueous KOH (20 mL) and Et2O (10 mL) at 0° C. was slowly added N-methyl-N-nitroso-N′-nitroguanidine (492 mg, 3.34 mmol). The mixture was stirred for 15 minutes, and the Et2O layer was transferred to a solution of ethyl 3-benzyloxy-7-chlorocarbonyl-5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (262 mg, 0.669 mmol) in CH2Cl2 (10 mL). The reaction was stirred at room temperature for 30 minutes, and the solvent was removed in vacuo to afford the title product. ES MS (M+H)=398.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:43][C:44]([F:55])([F:54])[C:45]1[CH:46]=[C:47]([CH:51]=[CH:52][CH:53]=1)[C:48](O)=[O:49]>ClCCl.O>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:48](=[O:49])[C:47]2[CH:51]=[CH:52][CH:53]=[C:45]([C:44]([F:43])([F:54])[F:55])[CH:46]=2)[N:13]=1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: O=C(NCCNc1nc(Cl)nc2c1ncn2C1CCCC1)c1cccc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
280 mg of the product obtained in Stage 1 of Example 7, 203 mg of 1-hydroxybenzotriazole hydrate, 287 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 4 ml of dichloromethane are mixed together, 230 mg of 3-trifluoromethyl benzoic acid is added and agitation is carried out for 6 hours and 30 minutes at ambient temperature. Water is added, followed by separating, washing with ether, drying and 307 mg of expected product is collected.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:4]=[C:5]([C:8]#[N:9])[S:6][CH:7]=1.CO[Na].[NH4+:15].[Cl-]>CO.C(Cl)Cl>[F:11][C:2]([F:1])([F:10])[C:3]1[N:4]=[C:5]([C:8]([NH2:15])=[NH:9])[S:6][CH:7]=1
Reactant: [NH4+]
Reactant: N#Cc1nc(C(F)(F)F)cs1
Agent: CO[Na]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Product: N=C(N)c1nc(C(F)(F)F)cs1
Temperature: 25 °C
Reaction time: 96 h
Yield: 32 %

Procedure:
To a solution of compound 285b (28.12 g, 1.0 eq.) in MeOH (13 mL) in an ice/water bath was added MeONa (853 mg, 0.1 eq.) portionwise. The reaction mixture was stirred in the ice/water bath for 15 min and at room temperature for 1 hr. NH4Cl (16.88 g, 2.0 eq.) was then added and the mixture was stirred at room temperature for 4 days. Solvent was removed in vacuo. The solid obtained was suspended in DCM (60 mL) and recovered by filtration. The solid was suspended in MeOH (50 mL) and filtered. The filtrate was concentrated under reduced pressure to yield compound 285 as a white solid in 32% yield. MS (ESI, EI+): m/z=196 (MH+).
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][C:8](OC)=CC=1C(O)=O.COC(OC)OC.C(O)(=O)C.N[C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][C:37]=1C)[C:28]([NH:30]C1(C)CC1)=[O:29]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:8][C:9]1([C:26]2[CH:25]=[CH:37][CH:36]=[CH:35][C:27]=2[C:28]([NH2:30])=[O:29])[CH2:2][CH2:10]1
Reactant: COc1ccc(N)c(C(=O)O)c1
Reactant: Cc1ccc(C(=O)NC2(C)CC2)cc1N
Solvent: COC(OC)OC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC1(c2ccccc2C(N)=O)CC1
Yield: 114.2 %

Procedure:
A stirred mixture of 2-amino-5-methoxybenzoic acid (4 g), trimethylorthoformate (3.93 ml), and acetic acid (0.137 ml) in toluene (100 ml) was heated under reflux for 2 hours. 3-amino-4-methyl-N-(1-methylcyclopropyl)benzamide (4.39 g) was added to the reaction mixture and stirring continued in refluxing toluene for 16 hours. The reaction mixture was allowed to cool and then was diluted with ethyl acetate. The organic solution was then washed with 1N HCl solution, 2N NaOH solution (×2), brine, dried (magnesium sulfate) and concentrated to a cream coloured solid. The solid was dissolved in ethyl acetate and the insoluble material removed by filtration. Iso-hexane was added to the filtrate and concentrated to give 3-(6-methoxy-4-oxoquinazolin-3(4H)-yl)-4-methyl-N-(1-methylcyclopropylbenzamide (4.3 g); NMR Spectrum: (DMSOd6) 0.59 (m, 2H), 0.72 (m, 2H), 1.35 (s, 3H), 2.12 (s, 3H), 3.89 (s, 3H), 7.50 (m, 2H), 7.56 (m, 1H), 7.72 (d, 1H), 7.83 (s, 1H), 7.88 (d, 1H), 8.17 (s, 1H), 8.63 (s, 1H); Mass Spectrum: M+Na+ 486.
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][C:7]([NH:10]C(=O)C(C)(C)C)=[N:8][CH:9]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>CO.[Cl-].[Na+].O>[NH2:10][C:7]1[N:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[N:5][CH:6]=1
Reactant: CC(=O)c1cnc(NC(=O)C(C)(C)C)cn1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: CC(=O)c1cnc(N)cn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
To a solution of N-(5-acetylpyrazin-2-yl)-2,2-dimethylpropanamide (300 mg) in methanol (10 mL) was added potassium carbonate (750 mg) at room temperature. It was stirred at 60° C. overnight. To the reaction mixture were added saturated aqueous sodium bicarbonate and saturated brine at room temperature, followed by extraction with a solvent (chloroform:isopropyl alcohol=4:1). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The obtained solid was collected by filtration while washing with a solvent (hexane:diisopropyl ether=1:1), to obtain 1-(5-aminopyrazin-2-yl)ethanone (180 mg) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[N:19]=[C:18](Cl)[S:17][N:16]=1.C(N(CC)CC)C>CS(C)=O.[Cl-].[Na+].O>[C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([C:18]1[S:17][N:16]=[C:15]([Cl:14])[N:19]=1)[CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCCCNC(=O)OC(C)(C)C
Reactant: Clc1nsc(Cl)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: CN(CCCNC(=O)OC(C)(C)C)c1nc(Cl)ns1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
(3-Methylamino-propyl)-carbamic acid tert-butyl ester (7.00 g, 36.8 mmol) and 3,5-dichloro-[1,2,4]thiadiazole (4.75 g, 30.7 mmol) were dissolved in DMSO (150 mL). Finally, triethylamine (3 mL) was added and the reaction mixture was stirred at room temperature for 24 h. After this period, brine (100 mL) was poured into the reaction vessel and the mixture was transferred to a separatory funnel. The resulting layer was extracted with DCM (3×300 mL). The DCM layer was then dried over anhydrous Na2SO4. The crude product was purified using flash silica chromatography (DCM to 9:1 DCM/MeOH) to afford 6.5 g (69%) of {3-[(3-chloro-[1,2,4]thiadiazol-5-yl)-methyl-amino]-propyl}-carbamic acid tert-butyl ester as a clear oil. [M+H]+ 307.40.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[OH:19][CH2:20][CH:21]1[O:26][C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[O:23][CH2:22]1>C(Cl)Cl>[S:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=1)([O:19][CH2:20][CH:21]1[O:26][C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[O:23][CH2:22]1)(=[O:16])=[O:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1COc2ccccc2O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccccc3O2)cc1
Reaction time: 8 h
Yield: 66 %

Procedure:
Triethylamine (4.2 ml, 30 mmol was added, in one portion, and then, in portions, para-toluenesulfonyl chloride (5.7 g, 30 mmol was added, to a solution of 2-hydroxymethyl-1,4-benzodioxane (Maybridge, 5 g, 30 mmol) in methylene chloride (50 ml). A mild exothermic reaction ensued. The reaction mixture was stirred overnight. Precipitated triethylamine hydrochloride was separated by filtration and washed with methylene chloride (50 ml). The organic medium was washed with 10% aqueous hydrochloric acid (50 ml , water 50 ml , brine (30 ml), and dried over sodium sulfate. Purification of the crude product by column chromatography (400 g fine silica, hexane-ethyl acetatetriethylamine; 100:100:1) yielded pure (1,4-benzodioxan-2-yl)methyl tosylate (66%).
Reaction SMILES: [Br:1][C:2]1[C:24]([CH3:25])=[CH:23][C:5]([O:6][CH:7]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:4][C:3]=1[CH3:26].C(N(CC)CC)C.[CH3:34][O:35][C:36](=[O:40])[CH2:37][CH2:38][NH2:39].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:34][O:35][C:36](=[O:40])[CH2:37][CH2:38][NH:39][C:18](=[O:19])[C:17]1[CH:16]=[CH:15][C:14]([CH:7]([O:6][C:5]2[CH:23]=[C:24]([CH3:25])[C:2]([Br:1])=[C:3]([CH3:26])[CH:4]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:22][CH:21]=1
Reactant: COC(=O)CCN
Reactant: CCCCCCC(Oc1cc(C)c(Br)c(C)c1)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCC(Oc1cc(C)c(Br)c(C)c1)c1ccc(C(=O)NCCC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.9 %

Procedure:
To a mixture of 4-[1-(4-bromo-3,5-dimethyl-phenoxyl)-heptyl]-benzoic acid (1790 mg, 4.27 mmol) in methylene chloride (43 mL) are added triethyl amine (1.79 mL, 12.82 mmol), DMAP (5.0 mg), 3-amino-propionic acid methyl ester (895 mg, 6.4 mmol) and EDCI (2463 mg, 12.8 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a gradient from 0% of ethyl acetate to 100% of ethyl acetate giving racemic 3-{4-[1-(4-bromo-3,5-dimethyl-phenoxyl)-heptyl]-benzoylamino}-propionic acid methyl ester (945 mg).
Reaction SMILES: [C:1](OCC)(OCC)(OCC)C.ClC1C(Cl)=CC(N)=C(N)C=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:33][C:34]1[C:43]([Cl:44])=[CH:42][C:37]2[N:38]=[C:39]([CH3:41])[NH:40][C:36]=2[CH:35]=1.[OH-].[K+].IC>C1(C)C=CC=CC=1.CC(C)=O>[Cl:44][C:43]1[C:34]([Cl:33])=[CH:35][C:36]2[N:40]([CH3:1])[C:39]([CH3:41])=[N:38][C:37]=2[CH:42]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Nc1cc(Cl)c(Cl)cc1N
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Solvent: Cc1ccccc1
Product: Cc1nc2cc(Cl)c(Cl)cc2n1C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
Triethyl orthoacetate (4.6 g, 1 eq) was added drop wise to a refluxing mixture of 4,5-dichloro-1,2-phenylenediamine (5 g, 1 eq) and a catalytic amount of p-toluenesulfonic acid in toluene (40 mL). The mixture was refluxed for 3 hrs and 5.7 g black solid was collected after evaporation of the solvents under reduced pressure and used directly in the following step without further purification. ESI-MS (m/z) calcd (found): 200.0 (201.1) for [M+H]+. To the crude 5,6-dichloro-2-methyl-benzoimidazole (5.7 g, 1 eq) (see FIG. 9) and grinded potassium hydroxide (4.8 g, 3 eq) in acetone (50 mL) was added iodomethane (5.2 g, 1.4 eq) drop wise and the mixture was stirred overnight. The solvent was evaporated under reduced pressure and the residue was partitioned between dichloromethane (200 mL) and water (200 mL). The aqueous phase was washed two times with dichloromethane (200 mL) and the combined organic phase was dried over Na2SO4 and evaporated to dryness. The crude product was recrystallized from ethyl acetate. 5.5 g product was collected as pale flakes with 90.6% yield for two steps. 1H NMR: (CDCl3) 2.55 (s, 3H), 3.63 (s, 3H), 7.28 (s, 1H), 7.68 (s, 1H). 13C NMR: (CDCl3): 13.82, 30.05, 110.20, 120.00, 125.58, 125.75, 134.97, 141.83, 153.93. ESI-MS (m/z) calcd (found): 214.0 (215.1) for [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]([CH:15]=[C:16]2[S:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])=[CH:13][CH:12]=1.[H][H]>[Pd].CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][CH:16]2[S:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])=[CH:13][CH:12]=1
Reactant: [H][H]
Reactant: O=C1NC(=O)C(=Cc2ccc(OCCNc3ncccn3)cc2)S1
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=C1NC(=O)C(Cc2ccc(OCCNc3ncccn3)cc2)S1

Procedure:
A mixture of 5-[4-(2-(2-pyrimidinylamino)ethoxy) benzylidene]-2,4-thiazolidinedione (3 g) and 10% palladium on charcoal (9 g) in DMF (70 ml) was stirred under a pressure of 200 psi of hydrogen until hydrogen uptake ceased. The mixture was filtered through diatomaceous earth, and the filter pad washed exhaustively with DMF. The combined filtrates were evaporated to dryness and the title compound (m.p. 173° C.) obtained following recrystallization from methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1.C(N(CC)CC)C.[C:29](OC(=O)C)(=[O:31])[CH3:30].C(=O)(O)[O-].[Na+]>CN(C)C1C=CN=CC=1.O1CCOCC1.C(OCC)(=O)C>[C:29]([NH:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(N)cc(Nc2ncccc2[N+](=O)[O-])c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)c1cc(NC(C)=O)cc(Nc2ncccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 2-[3-amino-5-methoxycarbonylphenylamino]-3-nitropyridine (1.10 g), triethylamine (0.6 ml) and 4-dimethylaminopyridine (14 mg) in 1,4-dioxane (15 ml) was added acetic anhydride (0.40 ml). The mixture was stirred at room temperature for 20 hours, then poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 2-(3-acetylamino-5-methoxycarbonylphenylamino)-3-nitropyridine (1.21 g).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:48])[C:36]([OH:38])=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.Cl.[NH2:50][C:51]1[S:52][C:53]([Cl:56])=[CH:54][N:55]=1.C1(C[C@H](N2CC3C(=CC=CC=3)C2=O)C(NC2SC=CN=2)=O)CCCCC1>>[Cl:56][C:53]1[S:52][C:51]([NH:50][C:36](=[O:38])[CH:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:48])[CH2:34][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)=[N:55][CH:54]=1
Reactant: Nc1ncc(Cl)s1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(Nc1ncc(Cl)s1)C(CC1CCCCC1)N1Cc2ccccc2C1=O
Yield: 59 %

Procedure:
This compound was prepared via BOP coupling of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared in Step A of Example 1; 120 mg; 0.42 mmol) and 2-amino-5-chlorothiazole hydrochloride (90 mg; 0.51 mmol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide as outlined in Example 1, Step B) to provide N-(5-Chloro-thiazol-2-yl)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl) propionamide as a white solid in 59% yield: EI-HRMS m/e calcd for C20H22ClN3O2S (M+) 403.1121, found 403.1124.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9]([S:11]([C:14]2[S:18][C:17]3[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:16]=3[CH:15]=2)(=[O:13])=[O:12])[CH2:8][C:7](=[O:24])[N:6]1[CH2:25][C:26]1[CH:31]=C[C:29](C#N)=[C:28](N)[CH:27]=1)=[O:4].[N:35]1[CH:40]=[N:39][CH:38]=[N:37][CH:36]=1.CC(O)=O>CCO>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9]([S:11]([C:14]2[S:18][C:17]3[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:16]=3[CH:15]=2)(=[O:12])=[O:13])[CH2:8][C:7](=[O:24])[N:6]1[CH2:25][C:26]1[CH:31]=[C:36]2[C:29]([C:40]([NH2:35])=[N:39][CH:38]=[N:37]2)=[CH:28][CH:27]=1)=[O:4]
Reactant: COC(=O)C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC(=O)N1Cc1ccc(C#N)c(N)c1
Reactant: c1ncncn1
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC(=O)N1Cc1ccc2c(N)ncnc2c1
Yield: 38.9 %

Procedure:
A solution containing (±)-1-(3-amino-4-cyano-benzyl)-4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-6-oxo-piperazine-2-carboxylic acid methyl ester (42 mg, 0.08 mmol), EXAMPLE 99, 1,3,5-triazine (40 mg, 0.48 mmol), and glacial HOAc (30 mg, 0.48 mmol) in absolute EtOH (1 mL) is maintained at reflux for 16 hours. The reaction mixture is concentrated and then dissolved in water/CH3CN and purified by reverse-phase HPLC [Buffer A: water w/0.1% TFA; Buffer B: CH3CN w/0.1% TFA; Gradient: 0% B to 60% B over 30 min] to provide 17 mg (32%) of the title compound as a white solid.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:21]([OH:23])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]=[CH2:20])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:49][O:50][C:51](=[O:58])[C@H:52]([CH2:54][CH:55]([CH3:57])[CH3:56])[NH2:53].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:49][O:50][C:51](=[O:58])[C@@H:52]([NH:53][C:21](=[O:23])[C@@H:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH:19]=[CH2:20])=[CH:15][CH:16]=1)[CH2:54][CH:55]([CH3:57])[CH3:56]
Reactant: C=CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N—BOC—O-allyl-tyrosine (obtained from NeoMPS, San Diego, Calif. 92126, USA) (10.0 g, 32.5 mmol), HATU (12.4 g, 35.8 mmol) and leucine methyl ester hydrochloride (5.90 g, 65.0 mmol) were dissolved in anhydrous DMF (50 mL). DIPEA (22.7 mL, 130 mmol) was added and the reaction mixture was stirred at rt for 18 h before being partitioned between EtOAc and 1M hydrochloric acid. The organic phase was then washed sequentially with 1M hydrochloric acid and brine before being dried (MgSO4), filtered and concentrated in vacuo. Purification was achieved using flash chromatography, eluting with a gradient of 1/5 EtOAc/(50/70) petroleum ether to 100% EtOAc to yield a white solid, 8.45 g, 58%. Rf=0.33 (1/3 EtOAc/(50/70) petroleum ether).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH3:10][N:11]1[C@@H:28]2[CH2:29][C:16]3[CH:17]=[CH:18][C:19]([O:31][CH3:32])=[C:20]4[O:21][C@H:22]5[C:23]([CH2:25][CH2:26][C@:27]2([OH:30])[C@:14]5([C:15]=34)[CH2:13][CH2:12]1)=[O:24].CN(C)C=O.CN1CCOCC1.[N:45]1(C(OC(C)(C)C)=O)[CH2:66][CH2:65][CH2:64][C@H:46]1[C:47]([N:49]1[CH2:63][CH2:62][CH2:61][C@H:50]1[C:51](ON1C(=O)CCC1=O)=[O:52])=[O:48]>>[NH:45]1[CH2:66][CH2:65][CH2:64][C@H:46]1[C:47]([N:49]1[CH2:63][CH2:62][CH2:61][C@H:50]1[C:51]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:52])=[O:48].[CH3:10][N:11]1[C@@H:28]2[CH2:29][C:16]3[CH:17]=[CH:18][C:19]([O:31][CH3:32])=[C:20]4[O:21][C@H:22]5[C:23]([CH2:25][CH2:26][C@:27]2([OH:30])[C@:14]5([C:15]=34)[CH2:13][CH2:12]1)=[O:24]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)ON1C(=O)CCC1=O
Agent: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1)C(=O)O
Reaction time: 18 h

Procedure:
To a solution of Leu-Oxycodone (1.0 eq) in dimethylformamide (10 ml/0.1 mmol) was added 4-methylmorpholine (10 eq) and Boc-Pro-Pro-OSu (2 eq). The reaction was stirred at ambient temperatures for 18 hours, quenched with water, and solvents removed. Crude protected product was purified using reverse phase HPLC. Deprotection occurred using 4N HCl in dioxane (20 ml/mmol) to obtain Pro-Pro-Leu-Oxycodone.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)=[O:11]>>[O:18]([C:15]1[CH:16]=[CH:17][C:12]([C:10](=[O:11])[CH:9]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)c1ccc(Oc2ccccc2)cc1
Reactant: O=Cc1ccccc1
Product: O=C(C=Cc1ccccc1)c1ccc(Oc2ccccc2)cc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from benzaldehyde and 4-phenoxyacetophenone, 1-(4-phenoxyphenyl)-3-phenylprop-2-en-1-one was obtained as yellowish solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][N:4]=[C:3]1[S:7]([CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:8].CN1C=NN=C1S(CC1C=CC(C(O)=O)=CC=1)(=O)=O.[Cl:38][C:39]1[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][C:40]=1[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1>>[Cl:38][C:39]1[CH:45]=[CH:44][C:42]([NH:43][C:14](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([CH2:9][S:7]([C:3]3[N:2]([CH3:1])[CH:6]=[N:5][N:4]=3)=[O:8])=[CH:18][CH:17]=2)=[CH:41][C:40]=1[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: Cn1cnnc1S(=O)Cc1ccc(C(=O)O)cc1
Agent: Cn1cnnc1S(=O)(=O)Cc1ccc(C(=O)O)cc1
Product: Cn1cnnc1S(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
500 mg of methyl 4-(bromomethyl)benzoate was reacted with 4-methyl-4H-1,2,4-triazole-3-thiol via Procedure Q. 804 mg of methyl 4-((4-methyl-4H-1,2,4-triazol-3-ylthio)methyl)benzoate was subsequently reacted via Procedure R to give an approximate 1:9 mixture of methyl 4-((4-methyl-4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzoate and methyl 4-((4-methyl-4H-1,2,4-triazol-3-ylsulfonyl)methyl)benzoate. The mixture of 740 mg was hydrolyzed via Procedure M to give 4-((4-methyl-4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzoic acid and 4-((4-methyl-4H-1,2,4-triazol-3-ylsulfonyl)methyl)benzoic acid. 114 mg of the mixture of 4-((4-methyl-4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzoic acid and 4-((4-methyl-4H-1,2,4-triazol-3-ylsulfonyl)methyl)benzoic acid was coupled to 75 mg of 4-chloro-3-(pyridin-2-yl)aniline via Procedure G. The mixture was seperated on reverse phase HPLC to give N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((4-methyl-4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzamide. MS (Q1) 452.3 (M)+.