Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:27]([OH:29])=O)[CH2:6][S:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2].Cl.C(SCCN)(=O)C.Cl.[C:39]([S:47][CH2:48][CH2:49][NH2:50])(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl.CCOCC>[C:1]([NH:4][C@H:5]([C:27]([NH:50][CH2:49][CH2:48][S:47][C:39](=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:29])[CH2:6][S:7][C:8]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: NCCSC(=O)c1ccccc1
Reactant: CC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: CC(=O)SCCN
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCCSC(=O)c1ccccc1
Yield: 62 %

Procedure:
The coupling reaction of 7 (7.41 mmol) is carried out according to Method B described in the first synthetic route (example 1): S-acetylcysteamine hydrochloride was replaced by S-benzoylcysteamine hydrochloride (T. Wieland and E. Bokelman, Ann. Chem., 1952, 576, 20-34. After the various treatments, the expected compound is isolated by flash chromatography on a silica gel column (eluent: CH2Cl2/ether 15%). 12 is collected in the form of a colorless foam with a yield of 62%. Rf (AcOEt/petroleum ether, 7/3): 0.42. [α]D20=+10.8° (c 1.11, CHCl3).
Reaction SMILES: [CH:1]([C@@H:4]1[N:9]2[C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=[C:12]([NH2:20])[C:11]=3[N:21]=[C:8]2[CH2:7][O:6][CH2:5]1)([CH3:3])[CH3:2]>FC(F)(F)C(O)=O.[Pt]=O>[CH:1]([C@@H:4]1[N:9]2[C:10]3[C:19]4[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=4[N:13]=[C:12]([NH2:20])[C:11]=3[N:21]=[C:8]2[CH2:7][O:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H]1COCc2nc3c(N)nc4c(c3n21)CCCC4
Reaction time: 20 h
Yield: 66.4 %

Procedure:
(11S)-11-Isopropyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (320 mg, 1.13 mmol) was dissolved in 3 mL of trifluoroacetic acid and the solution was placed in a pressure bottle. Platinum oxide (250 mg) was then added and the reaction mixture was shaken under H2 at 50 PSI (3.4×105 Pa). After 20 hours, the reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with a mixture of iso-propanol and CH2Cl2 and the combined filtrates were concentrated under reduced pressure to give a syrup. The syrup was partitioned between H2O and CHCl3. The aqueous portion was made basic by addition of 10% NaOH solution until pH>12. The layers were separated and the organic portion was washed successively with 10% NaOH (2×), H2O and brine. The organic portion was then dried over Na2SO4, filtered and concentrated under reduced pressure to give a tan foam. Crystallization from ethyl acetate gave the title compound (215 mg) as light amber crystals, mp 158.0-160.0° C.
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:11]([OH:13])=O)[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].[NH2:24][C@H:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:26]([CH3:28])[CH3:27]>CCCCCC>[NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:11]([NH:24][C@H:25]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH:26]([CH3:28])[CH3:27])=[O:13])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: CCCCCC
Product: CC(C)[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Yield: 93 %

Procedure:
By condensing Z-Asp(OtBu)-OH and H-Val-OtBu there is obtained Z-Asp(OtBu)-Val-OtBu, m.p. 75° C. (n-hexane), yield: 93%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:12][C:11](=[O:19])[C:10]=2F)[CH:5]=[C:6]([F:8])[CH:7]=1.[F:21][C:22]([F:34])([F:33])[C:23]([C:27]1[S:31][C:30]([SH:32])=[N:29][CH:28]=1)([OH:26])[CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([S:32][C:30]4[S:31][C:27]([C:23]([OH:26])([C:22]([F:21])([F:33])[F:34])[CH2:24][CH3:25])=[CH:28][N:29]=4)=[CH:16][CH:17]=3)[O:12][C:11](=[O:19])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCC(O)(c1cnc(S)s1)C(F)(F)F
Reactant: O=c1oc2ccccc2c(-c2cc(F)cc(F)c2)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCC(O)(c1cnc(Sc2ccc3c(-c4cc(F)cc(F)c4)cc(=O)oc3c2)s1)C(F)(F)F
Temperature: 25 °C

Procedure:
A solution of 4-(3,5-difluorophenyl)-fluoro-2H-chromen-2-one (0.258 g, 0.93 mmol), 1,1,1-trifluoro-2-(2-mercapto-1,3-thiazol-5-yl)butan-2-ol, (0.250 g, 1.03 mmol) and potassium carbonate (0.387 g, 2.8 mmol) in NMP was heated at 120° C. overnight. The mixture was cooled to room temperature and partitioned between aqueous NH4Cl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. The solvent was evaporated and the residue chromatographed on silica gel (toluene/acetone; 95:5) to give the title compound. 1H NMR (400 MHz, CDCl3): δ 7.78 (s, 1H), 7.56 (d, 1H), 7.43 (d, 1H), 7.37 (dd, 1H), 7.00-7.04 (m, 3H), 6.41 (s, 1H), 2.66 (br s, 1H), 2.12 (q, 2H), 0.98 (t, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Na].Br[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22]>CN(C)C=O>[N:1]1([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[C:16](=[O:17])[C:15]3[C:14](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]2=[O:22])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCn1ccnc1

Procedure:
A mixture of 6.3 g. of sodium imidazole, 100 ml. of dimethylformamide and 19.7 g. of N-(4-bromobutyl)-phthalimide was heated on a steam bath for 6 hours and then concentrated to remove volatile material. The residue was boiled with 150 ml. of toluene and the toluene layer was decanted and concentrated. The residue was triturated with diethyl ether and cooled, giving N-[4-(1H-imidazol-1-yl)butyl]-isoindole-1,3(2H)-dione (m.p. 75°-77° C.) which was recovered by filtration.
Reaction SMILES: [F:1][C:2]([F:9])([C:5]([F:8])([F:7])[F:6])[CH2:3][OH:4].N1C=CC=CC=1.[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17].C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl>[S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)([O:4][CH2:3][C:2]([F:9])([F:1])[C:5]([F:8])([F:7])[F:6])(=[O:18])=[O:17]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OCC(F)(F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a solution of 2,2,3,3,3-pentafluoropropanol (5.0 mL, 50 mmol) and pyridine (8.1 mL, 100 mmol) in chloroform (100 mL), cooled at 0° C. and under argon, tosyl chloride (14.29 g, 75 mmol) was slowly added. The resulting mixture was allowed to warm up to room temperature and was stirred at this temperature overnight. Then, 10% aqueous K2CO3 solution was added and the mixture was vigorously stirred for 30 min. The layers were separated, and the organic layer was treated again with K2CO3. After that, it was washed with 2 N HCl, dried over Na2SO4 and the solvent was removed, yielding 12.72 g of the desired compound (84% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+].Br[CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN1C(=O)CCC1.O>[Br:10][C:3]1[CH:4]=[C:5]([Cl:9])[C:6]([O:8][CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])=[CH:7][C:2]=1[NH2:1]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Nc1cc(O)c(Cl)cc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)[Si](C)(C)OCCOc1cc(N)c(Br)cc1Cl
Temperature: 100 °C
Yield: 87.3 %

Procedure:
To a solution of 5-amino-4-bromo-2-chloro-phenol (0.338 g, 1.52 mmol) in NMP (5 ml) was added cesium carbonate (0.644 g, 1.97 mmol), sodium iodide (0.228 g, 1.52 mmol) and 2-bromoethoxy tertbutyldimethylsilane (0.424 g, 1.97 mmol). The mixture was heated to 100° C. for two hours, then cooled to room temperature. Water was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hex:EtOAc/8:2) gave 2-bromo-5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-chloro-phenylamine (0.505 g, 78%) as a white solid.
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=O.[C:7]([C:10]1[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:12][N:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=12)(=[O:9])[CH3:8]>C(Cl)Cl>[O:9]=[C:7]([C:10]1[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:12][N:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=12)/[CH:8]=[CH:3]/[C:2]([OH:6])=[O:5]
Reactant: O=CC(=O)O
Reactant: CC(=O)c1c(-c2ccccc2)nn2ccccc12
Solvent: ClCCl
Solvent: O
Product: O=C(O)/C=C/C(=O)c1c(-c2ccccc2)nn2ccccc12
Temperature: 100 °C
Yield: 7.4 %

Procedure:
A mixture of glyoxylic acid monohydrate (3.50 g) and 3-acetyl-2-phenylpyrazolo[1,5-a]pyridine (5.00 g) was stirred and heated at 100° C. for 4 hours. The warm reaction mixture was dissolved in methylene chloride (50 ml), and then extracted with 1N aqueous solution of sodium hydroxide (50 ml). The aqueous layer was washed with methylene chloride (total 200 ml) and then with ethyl acetate (total 200 ml). The aqueous solution was adjusted to pH 4~5 with 10% hydrochloric acid. The isolated oil was extracted with chloroform. The extract was evaporated in vacuo and crystallized from methylene chloride to give 4-oxo-4-(2phenylpyrazolo[1,5-a]pyridin-3-yl)crotonic acid (0.46 g).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1.CC(C[AlH]CC(C)C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1COCC1>[S:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[C:7]1[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(-c2nc3ccccc3s2)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: OCc1ccc(-c2nc3ccccc3s2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a 0° C. solution of methyl-4-(benzothiazol-2-yl)-benzoate (prepared as described by A. Brembilla, D. Roizard and P. Lochon Synth. Commun. 1990, 20, 3379) (1.08 g, 4 mmol) in THF (20 mL) was added DIBAL-H (20 mL of a 1.0M solution in THF, 20 mmol) over 10 minutes. The resulting solution was stirred at 0° C. for 2 hours, then an aqueous saturated solution of sodium potassium tartrate was added and the biphasic mixture stirred rapidly for 60 min. The phases were separated and the aqueous layer extracted with ether (3×20 mL). The combined organic fractions were dried (Na2SO4), concentrated and purified by column chromatography on silica gel (10:1 CH2Cl2/MeOH) to afford the title compound (0.69 g, 75%). 1H NMR (CD3OD) δ 4.69 (s, 2H), 7.43 (t, 1H, J=7.8 Hz), 7.53 (m, 3H), 7.99 (m, 1H), 8.06 (m, 3H).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:24](=[O:25])[CH:23]=[CH:22][O:21][C:20]=3[CH3:26])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][C:28]1([CH3:40])[O:32][C@H:31]([CH2:33][N:34]2[CH:38]=[CH:37][C:36]([NH2:39])=[N:35]2)[CH2:30][O:29]1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:24](=[O:25])[CH:23]=[CH:22][O:21][C:20]=3[CH3:26])[CH:13]=[N:12]2)[C:8]([NH:39][C:36]2[CH:37]=[CH:38][N:34]([CH2:33][C@@H:31]3[CH2:30][O:29][C:28]([CH3:40])([CH3:27])[O:32]3)[N:35]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1occc(=O)c1Oc1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Product: Cc1occc(=O)c1Oc1cnn(C(CC2CCCC2)C(=O)Nc2ccn(C[C@@H]3COC(C)(C)O3)n2)c(=O)c1

Procedure:
Using the method described in Example 49, 3-cyclopentyl-2-[4-(2-methyl-4-oxo-4H-pyran-3-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 75) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 3-cyclopentyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-2-[4-(2-methyl-4-oxo-4H-pyran-3-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionamide as a white solid as a mixture of diastereomers (1.37 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:5].CN(P(N(C)C)(N(C)C)=O)C.C([Li])CCC.CON(C)[C:38](=O)[C@@H:39]([NH:41]C(=O)OC(C)(C)C)[CH3:40]>C1COCC1>[NH2:41][C@H:39]([C:40]1[N:6]([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[C:4](=[O:5])[C:3]2[C:14]([CH:18]=1)=[CH:15][CH:16]=[CH:17][C:2]=2[Cl:1])[CH3:38]
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: Cc1cccc(Cl)c1C(=O)NCCN1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C[C@H](N)c1cc2cccc(Cl)c2c(=O)n1CCN1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-chloro-6-methyl-N-(2-(pyrrolidin-1-yl)ethyl)benzamide II-26 (1.33 g, 5.0 mmol, 1.0 eq) and HMPA (0.87 mL, 5.0 mmol, 1.0 eq) in THF (12.5 mL) at −60° C. under argon, n-butyllithium solution (2.5 M in hexanes, 5.0 mL, 12.5 mmol, 2.5 eq) was added dropwise while keeping the temperature below −60° C. The resulting mixture was stirred between −70° C. and −60° C. for 30 min. To this mixture, (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (1.39 g, 6.0 mmol, 1.2 eq) was added quickly. The resulting mixture was allowed to slowly warm to RT (over 1 h) and then stirred at RT for an additional 2 h. The reaction mixture was cooled to 0° C., quenched with water (5.0 mL), and then acidified with aqueous HCl (5 M) to adjust the pH to 5-6. The mixture was concentrated in vacuo. The residue was suspended in a mixture of MeOH (20 mL) and H2O (5.0 mL), concentrated HCl (10.0 mL) was added and the resulting mixture was stirred at reflux for 2 h. The mixture was cooled to −5° C. and basified with saturated aqueous NH4OH to adjust the pH to 8-9. The precipitate was filtered off and the filtrate was extracted with DCM (20 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-10% MeOH-DCM) to afford the product, (S)-3-(1-aminoethyl)-8-chloro-2-(2-(pyrrolidin-1-yl)ethyl)isoquinolin-1(2H)-one II-27)as a yellow solid.
Reaction SMILES: O1CCOCC1.O.[C:8]1(=[O:14])[CH2:13][CH2:12][CH2:11][CH:10]=[CH:9]1.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)(=O)C>[C:15]1([C@H:10]2[CH2:11][CH2:12][CH2:13][C:8](=[O:14])[CH2:9]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1C=CCCC1
Reactant: OB(O)c1ccccc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CCC[C@H](c2ccccc2)C1
Temperature: 100 °C

Procedure:
1 ml of dioxane, 0.1 ml of distilled water and 0.4 mmol of cyclohexenone are added to 3.1 mg of Rh(acac)(C2H4)2, 0.012 mmol of compound I.1 and 2 mmol of phenylboronic acid under argon. The reaction mixture is heated at 100° C. for 5 hours. After it has returned to room temperature, the solvents are evaporated off under reduced pressure. The residue obtained is dissolved in 20 ml of ethyl acetate, washed with 5 ml of saturated aqueous sodium hydrogencarbonate solution and then dried over sodium sulfate. The solvents are then evaporated off under reduced pressure. The product is purified by filtration on silica to isolate (S)-3-phenylcyclohexanone, which is characterized by the 1H NMR spectrum below.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:12][S@](C(C)(C)C)=O)[CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[CH3:19]>CO.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:12])[CH:9]([CH3:10])[CH3:11])=[CH:4][C:3]=1[CH3:19]
Reactant: Cc1cc([C@H](N[S@@](=O)C(C)(C)C)C(C)C)ccc1Cl
Agent: Cl
Solvent: CO
Product: Cc1cc([C@H](N)C(C)C)ccc1Cl
Reaction time: 8 h

Procedure:
A solution of intermediate INT 59 (330 mg, 1.09 mmol) in MeOH (8 mL) was treated with HCl (4 M in dioxane, 0.55 mL, 2.2 mmol) and stirred overnight. After evaporation of the solvents, a solid was obtained. The solid was then dissolved in 2 M HCl (30 mL) and washed with EtOAc. The aqueous layer was separated and the pH adjusted to about 11 using 2 M NaOH followed by extraction with CH2Cl2 (3×). The organic extracts were combined, dried over sodium sulfate, filtered and concentrated.
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:15])[CH:12]([Cl:14])[CH3:13].[Li+].[OH-].O.Cl>C1COCC1.CCOC(C)=O>[Cl:14][CH:12]([CH3:13])[C:11]([NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:16])=[O:2])=[O:15]
Reactant: COC(=O)c1ccccc1NC(=O)C(C)Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(Cl)C(=O)Nc1ccccc1C(=O)O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To the 2-(2-chloro-propionylamino)-benzoic acid methyl ester (7.75 g, 32.1 mmol) stirring in THF (40 mL) was added 1M LiOH/H2O (40 mL). The reaction was allowed to stir at 50° C. for 3 h. After this period the reaction was concentrated under vacuum to afford a crude residue that was acidified with 1N HCl. The resulting suspension was then diluted with EtOAc and washed with water (3×50 mL). The organic layer was then washed with brine (25 mL), dried over MgSO4, and concentrated under vacuum to afford crude acid. The crude material was purified by flash chromatography (silica gel, 80% EtOAc/Hex) to afford the desired product as an off white solid (7.1 g, 97% yield). 1H-NMR (CDCl3): δ 8.6 (d, 1H), 8.12 (d, 1H), 7.61 (t, 1H), 7.57 (t, 1H), 4.89 (br, 1H), 4.65 (t, 1H), 1.78 (d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>N1C=CC=CC=1>[CH3:11][O:10][C:8]1[CH:7]=[C:5]([NH:6][S:13]([CH3:12])(=[O:15])=[O:14])[CH:4]=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(N)cc(OC)c1
Solvent: c1ccncc1
Product: COc1cc(NS(C)(=O)=O)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
3,5-Dimethoxyaniline (1 g mg, 6.53 mmol) was dissolved in pyridine (48 ml) and was treated with methanesulfonyl chloride (0.56 ml, 7.18 mmol). The reaction mixture was stirred at room temperature overnight. Methanesulfonyl chloride (0.28 ml, 3.59 mmol) was added and the mixture was stirred at room temperature overnight. The solvent was removed to give 1.7 mg (100% yield) of the title compound as a dark oil. Purity 89%.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:19]=[C:12]2[C:13]([Br:18])=[CH:14][CH:15]=[C:16](Cl)[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O-:21].[Na+].CO>C(O)(=O)C>[CH2:1]([S:8][C:9]1[N:19]=[C:12]2[C:13]([Br:18])=[CH:14][CH:15]=[C:16]([O:21][CH3:20])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(Br)c2nc(SCc3ccccc3)nn12
Reactant: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(Br)c2nc(SCc3ccccc3)nn12

Procedure:
2-Benzylthio-8-bromo-5-chloro[1,2,4]triazolo[1,5-a]pyridine (7.7 g, 0.0217 mol) and 25 percent sodium methoxide in methanol (19.9 mL, 4.7 g, 0.0868 mol) were mixed with 400 mL of methanol and the mixture was heated to reflux for 1.5 hours. It was then cooled and acidified with acetic acid. The volatiles were removed by evaporation under reduced pressure and the residue was dissolved in dichloromethane. The resulting solution was washed with water and concentrated by evaporation under reduced pressure. The resulting residue was triturated with hexane and the solids obtained were recovered by filtration and dried to obtain 7.3 g (96 percent of theory) of the title compound as a light tan powder melting at 78°-79° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][O:26][CH2:27][C@H:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[NH2:33]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:33][C@@H:29]4[CH2:30][CH2:31][CH2:32][C@@H:28]4[CH2:27][O:26][CH3:25])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: COC[C@H]1CCC[C@H]1N
Product: COC[C@H]1CCC[C@H]1NC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3C)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 74 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (1R,2S)-2-(methoxymethyl)cyclopentanamine 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42-1.60 (m, 2H) 1.60-1.83 (m, 3 H) 1.84-2.01 (m, 1 H) 2.20-2.37 (m, 1 H) 2.44 (s, 3 H) 3.19 (s, 3 H) 3.20-3.27 (m, 1 H) 3.40 (dd, J=9.35, 6.06 Hz, 2 H) 4.43 (t, J=7.45 Hz, 1 H) 7.67 (d, J=7.58 Hz, 1 H) 7.74 (br. s., 1 H) 7.81 (d, J=18.69 Hz, 1 H) 8.24-8.70 (m, 3 H) 8.88 (d, J=1.77 Hz, 1 H) 13.24 (br. s., 1 H). MS m/z [M+H]+ 432.2.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:21]=[CH:20][C:10]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:9]([Cl:22])[CH:8]=1.[CH3:23][C:24]([CH3:29])([CH3:28])[CH2:25][CH:26]=[O:27]>C(OCC)C>[C:16]([O:15][C:13]([NH:12][CH2:11][C:10]1[CH:20]=[CH:21][C:7]([CH:26]([OH:27])[CH2:25][C:24]([CH3:29])([CH3:28])[CH3:23])=[CH:8][C:9]=1[Cl:22])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)CC=O
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)cc1Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)CC(O)c1ccc(CNC(=O)OC(C)(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
Add butyllithium (11.7 mL, 18.65 mmol) to a solution of 4-bromo-N-(tert-butoxycarbonyl)-2-chloro-benzylamine (2.601 g, 8.11 mmol) in diethyl ether (86 mL) at −78° C. under nitrogen and stir for 2 h. Add 3,3-dimethylbutyraldehyde (1.868 g, 2.3 mL, 18.65 mmol), stir for 30 min at −78° C. and then warm to room temperature. Add water and extract twice the aqueous phase with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting hexane/EtOAc (85:15) to obtain the desired intermediate as a yellow oil (1.825 mg, 66%).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:19])[N:4]([CH2:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]#[N:14])[C:5](SC)=[N:6][N:7]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1>>[C:13]([C:12]1[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=1[CH2:10][N:4]1[C:3](=[O:19])[C:2]([CH3:1])=[N:7][N:6]=[C:5]1[N:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:21]1)#[N:14]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: CSc1nnc(C)c(=O)n1Cc1ccccc1C#N
Product: Cc1nnc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2ccccc2C#N)c1=O
Temperature: 130 °C
Reaction time: 0.08 h

Procedure:
The mixture of 2-((6-methyl-3-(methylthio)-5-oxo-1,2,4-triazin-4(5H)-yl)methyl)benzonitrile (6, 68 mg, 0.25 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (60 mg, 0.30 mmol) was ground for 5 min and then heated in a tube under nitrogen atmosphere at 130° C. for 13 h. The mixture was separated by silica gel column, and eluted with 2:1 to 1:1 petroleum ether-ethyl acetate and then with 1:1:2 petroleum ether-dichloromethane-ethyl acetate to give (R)-tert-butyl 1-(4-(2-cyanobenzyl)-6-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)piperidin-3-ylcarbamate (7). MS: m/z, 425 (100%, M+1), 447(40%, M+23).