Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:2]=1.[H-].[Na+]>CN(C=O)C>[C:6]1([CH2:5][CH2:4][CH2:3][N:12]2[C:13]3[CH:1]=[N:2][C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c3ccccc3n(CCCc3ccccc3)c2cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 111.6 %

Procedure:
Compound 10 (1.2 g, 5 mmol) was mixed with DMF (30 ml). After stirring the mixture at room temperature for 15 minutes, NaH (0.6 g, 15 mmol) was added and stirred until the solution became clear. After that, 1-bromine-3-phenylpropane (2 ml) was added. The mixture was refluxed for 4 h. THF was evaporated in reduced pressure. The resulting solution was added 200 ml 2N HCl solution. The mixture was extracted with ethyl ether. The aqueous phase was neutralized by saturated NaHCO3 solution and then extracted with ethyl acetate. The organic phases were combined, washed with water and brine, dried over sodium sulfate, filtered, concentrated in vacuum and purified with silica gel column chromatography with ethyl acetate as the eluent. Upon recrystallization, white needle crystals (1.0 g, 56%) were obtained, mp 140-142° C.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH2:7]([O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[C:8]#[CH:9]>>[CH3:3][CH:2]([CH3:4])[C:1](=[O:5])[C:9]#[C:8][CH2:7][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1
Reactant: CC(C)C(=O)Cl
Reactant: C#CCOC1CCCCO1
Product: CC(C)C(=O)C#CCOC1CCCCO1

Procedure:
The desired compound was prepared from isobutyryl chloride and 3,4,5,6-tetrahydro-2-(2-propynyloxy)-2H-pyran by analogy to the procedure of Tohda, et. al. (Synthesis, 777 (1977)).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:13][NH2:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C(=N)O[CH2:23][CH:24]=[CH2:25].FC(F)(F)S(O)(=O)=O>C(Cl)Cl.C1CCCCC1.C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:13][NH:14][CH2:25][CH:24]=[CH2:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Reactant: COC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCCCC1
Product: C=CCNC[C@H](NC(=O)OCc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dissolve Nα -(benzyloxycarbonyl)-β-(amino)-L-alanine, methyl ester (15.9 g, 63 mmol) in methylene chloride/cyclohexane (1:1, 600 mL). Add allyl trichloroacetimidate (26 g, 128 mmol) and trifluoromethanesulfonic acid (5 mL, 56.6 mmol). Stir at room temperature under a nitrogen atmosphere for 5 hours and dilute with methylene chloride. Wash with saturated aqueous sodium hydrogen carbonate, water, dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography to give Nα -(benzyloxycarbonyl)-β-(allylamino)-L-alanine, methyl ester.
Reaction SMILES: C[O:2][C:3](=[O:32])[C@H:4]([CH:29]([CH3:31])[CH3:30])[NH:5][C:6](=[O:28])[C@H:7]([CH:25]([CH3:27])[CH3:26])[NH:8][C:9](=[O:24])[C@H:10]([CH2:19][O:20][CH2:21][CH:22]=[CH2:23])[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C([O-])(O)=O.[Na+]>C1COCC1.O>[C:15]([O:14][C:12]([NH:11][C@H:10]([C:9]([NH:8][C@H:7]([C:6]([NH:5][C@H:4]([C:3]([OH:32])=[O:2])[CH:29]([CH3:30])[CH3:31])=[O:28])[CH:25]([CH3:27])[CH3:26])=[O:24])[CH2:19][O:20][CH2:21][CH:22]=[CH2:23])=[O:13])([CH3:16])([CH3:18])[CH3:17]
Reactant: C=CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](C(=O)OC)C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](C(=O)O)C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 70.7 %

Procedure:
N-tert-butoxycarbonyl O-allyl L-seryl L-valyl L-valine methyl ester (8) (10.21 g, 22.31 mmol) was dissolved in THF (170 mL). The solution was cooled to 0° C. (icebath). LiOH monohydrate (1.03 g, 24.6 mmol) was dissolved in de-ionized water (85 mL) and the solution cooled to 0° C. The solution was then added dropwise to the solution of 8 over 20 min. The reaction mixture was stirred for an additional 2 h 40 min at 0° C. Solid NaHCO3 (3.75 g, 44.6 mmol) was added and the mixture stirred for 5 min before the THF was evaporated. The solution was diluted with water (170 mL), washed with Et2O (2×170 mL), acidified to pH 2 by addition of 2 M aqueous H2SO4 and extracted with EtOAc (3×250 mL). The combined organic fractions were dried with anhydrous MgSO4 and the solvent evaporated affording the title compound as a white solid (7.00 g, 71%); δH (300 MHz; d6-DMSO) 12.53 (1H, br s, COOH), 8.00 (1H, d, J 8, NH (Valx)), 7.62 (1H, d, J 9, NH(Valy)), 7.02 (1H, d, J 8, NH (Ser(All))), 5.84 (1H, ddt, J 5, 10 and 17, CH═CH2), 5.23 (1H, ddt, J 1, 3 and 17, CH═CHH)), 5.12 (1H, ddt, J 1, 3 and 10, CH═CHH), 4.34 (1H, dd, J 7 and 9, CαH(Valy)), 4.21-4.15 (1H, m, CαH(Ser(All))), 4.10 (1H, dd, J 6 and 8, CαH(Valx)), 3.92 (2H, dt, J 1 and 5, CH2CH═CH2), 3.59-3.45 (2H, m, CH2), 2.06-1.91 (2H, m, CH(CH3)2), 1.38 (9H, s, (CH3)3), 0.90-0.80 (12H, m, CH3); δC (75 MHz; d6-DMSO) 172.6, 170.9, 169.5, 155.1, 134.9, 116.3, 78.2, 71.0, 69.5, 57.2, 56.9, 54.6, 31.1, 29.6, 28.1, 19.0, 19.0, 17.9, 17.7; m/z (ESI) 466.2518 ([M+Na]+; C21H37N3O7Na requires 466.2529)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([OH:11])=O)=[CH:4][N:3]=1.C(Cl)(=O)C([Cl:15])=O>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([Cl:15])=[O:11])=[CH:4][N:3]=1
Reactant: Cc1nc(Cl)ncc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc(Cl)ncc1C(=O)Cl
Yield: 61.3 %

Procedure:
A solution of 2-chloro-4-methylpyrimidine-5-carboxylic acid (0.81 g, 4.70 mmol), oxalyl chloride (0.89 g, 7.05 mmol), DMF (2 drops) in CH2Cl2 (23 mL) was stirred at room temperature under N2 for 4 h. The solution was concentrated and distilled to give the title compound (0.55 g, 61%); b.p. 90-100° C., 1.3 mm/Hg; 1H NMR (CDCl3) δ d9.02 (s, 1H), 2.74 (s, 3H).
Reaction SMILES: Cl.[CH3:2][S:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:10][CH:11]=2)[N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:5]=1.C(N(CC)CC)C.[C:32](O)(=[O:39])[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.C(OCC)(=O)C>[CH3:2][S:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([N:13]3[CH2:14][CH2:15][N:16]([C:32]([C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)=[O:39])[CH2:17][CH2:18]3)=[CH:10][CH:11]=2)[N:6]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:5]=1
Reactant: CSc1nn(-c2ccccc2)c2cc(N3CCNCC3)ccc12
Reactant: O=C(O)c1ccncc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1nn(-c2ccccc2)c2cc(N3CCN(C(=O)c4ccncc4)CC3)ccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(methylthio)-1-phenyl-6-(piperazin-1-yl)-1H-indazole hydrochloride (200 mg, 0.55 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL), triethylamine (140.3 mg, 1.39 mmol, 2.51 equiv), isonicotinic acid (82 mg, 0.67 mmol, 1.20 equiv), and the resulting solution was stirred for 10 min at room temperature. HATU (631 mg, 1.66 mmol, 3.00 equiv) was added and resulting solution was stirred for an additional 2 h at room temperature. The resulting solution was diluted with ethyl acetate (20 mL). The resulting mixture was washed with brine (2×15 mL). The resulting mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate:petroleum ether:THF (1:1:1) to yield (4-(3-(methylthio)-1-phenyl-1H-indazol-6-yl)piperazin-1-yl)(pyridin-4-yl)methanone as a light yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[S:43][C:6]2[N:7]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[NH:41][C:40](=[O:42])[O:39][N:38]=4)=[CH:27][CH:26]=3)[C:8](=[O:23])[N:9]([CH2:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=O)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].[NH2:44][O:45][CH2:46][C:47]([OH:49])=[O:48].N1C=CC=CC=1.Cl>O.C(Cl)(Cl)Cl>[CH2:1]([C:3]1[S:43][C:6]2[N:7]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[NH:41][C:40](=[O:42])[O:39][N:38]=4)=[CH:29][CH:30]=3)[C:8](=[O:23])[N:9]([CH2:12][C:13](=[N:44][O:45][CH2:46][C:47]([OH:49])=[O:48])[C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: NOCC(=O)O
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCc1cc2c(=O)n(CC(=NOCC(=O)O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 6-ethyl-3-[2-(4-methoxyphenyl)-2-oxoethyl]-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.2 g), (aminooxy)acetic acid (0.045 g), pyridine (20 mL) was stirred at 80° C. for 16 hr. To the reaction mixture were added chloroform and water, and the mixture was adjusted to pH 4 with 1N hydrochloric acid. The chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a stereoisomer mixture (0.05 g, 22%).
Reaction SMILES: O.N#N.C[Li].[CH3:6]COCC.[C:11]([O:15][C:16]([N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=2)[C:21](=[O:30])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C1COCC1.CCOC(C)=O.CCCCCC.CCOC(C)=O>[C:11]([O:15][C:16]([N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=2)[C:21]([OH:30])([CH3:6])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCOCC
Reactant: COc1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2=O
Agent: N#N
Agent: [Li]C
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2(C)O
Temperature: 140 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a flame dried 250 mL 3-necked rb flask equivuipped with a magnetic stir bar was added Ce(III)Cl.7 H2O (2.74 g, 7.35 mmol., 2 equiv). The flask was heated in a 140° C. oil bath under reduced pressure (~1 ton) for 2.5 h. The flask was cooled to rt and slowly filled with N2 g. The white powder was suspended in dry THF (30 mL), stirred at rt for 1 h and then cooled to -78° C. To the white suspension was added a 1.4M solution of methyl lithium (MeLi) in Et2O (5.25 mL, 7.35 mmol, 2 equiv) by syringe. The dark yellow/brown solution stirred at -78° C. for 1 h and then 1-t-butoxycarbonyl-1,2,3,4-tetrahydro-7-methoxy-4-quinolone dissolved in 3 mL THF was added. The solution stirred at -78° C. for 3 h and was warmed to 0° C. for 2 h. The reaction did not go to completion and staffing material was observed by TLC (silica gel, hexane/EtOAc, 3:1). The reaction was quenched with H2O (1 mL) and allowed to warm to rt. The solution was neutralized with sat NH4Cl solution (5 mL), extracted with EtOAc (3×100 mL), washed with brine (1×100 mL), dried over Na2SO4 and concentrated in vacuo to give a mix of the desired alcohol and starting material. The mixture was taken up in EtOAc and concentrated on Celite™ to give a free flowing powder which was purified via flash column chromatography (silica gel, hexanes/EtOAc, 3:1) to give 796 mg (74%) of the desired product as a vicious clear colorless oil. Data for 1-t-butoxycarbonyl-1,2,3,4-tetrahydro-4-hydroxy-4-methyl-7-methoxy-quinoline: Rf =0.20 (hexanes/EtOAc, 3:1); 1H NMR (400 MHz, CDCl3) 7.42 (d, J=8.7, 1H), 7.33 (d, J=1H), 6.66 (dd, J=2.5, 8.6, 1H), 3.98 (m, 1H), 3.79 (s, 3H, OCH3), 3.61 (m, 1H), 1.98 (m, 2H), 1.58 (s, 3H), 1.53 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([O:7]CC1C=CC=CC=1)=[O:6].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>CN(C=O)C.CCOC(C)=O.[Pd]>[C:29]([O:28][C:26](=[O:27])[CH2:25][O:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(OCc1ccccc1)c1cccc(O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 7-2 (3.6 g, 16 mmol) in DMF (50 mL) was added Cs2CO3 (7.8 g, 238 mmol). After 15 min., tert-butyl bromoacetate (3.2 mL, 35 mmol) was added and the reaction mixture stirred for 20 hrs at ambient temperature. The reaction mixture was diluted with EtOAc and then washed with H2O, and brine, dried (MgSO4), and concentrated to give a yellow oil. The crude yellow oil (5.4 g, 15.8 mmol), 10% Pd/C (500 mg), and EtOAc (100 mL) was stirred under a hydrogen atmosphere (1 atm) for 20 hr. The reaction mixture was then filtered through a celite pad and the filtrate concentrated to give 7-3 as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.I[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH:20]1[CH2:22][CH2:21]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH:20]1([C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[N:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[C:8]2=[O:12])[CH2:22][CH2:21]1
Reactant: Ic1cnccc1C1CC1
Reactant: O=C1NCCc2cc(F)ccc21
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1c2ccc(F)cc2CCN1c1cnccc1C1CC1
Yield: 81.8 %

Procedure:
6-Fluoro-3,4-dihydroisoquinolin-1(2H)-one (I-78d: 500 mg, 3.02938 mmol) was reacted with 3-iodo-4-cyclopropyl-pyridine 816 mg, 3.3323 mmol), 1,4-dioxane (10 mL), copper iodide (57.3 mg, 0.3 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (43 mg, 0.30 mmol) and potassium phosphate (1.92 g, 9.0 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3) afforded 700 mg of the product (81.9% yield).
Reaction SMILES: [H-].[Na+].[CH3:3][OH:4].F[C:6]1[C:13]([F:14])=[C:12]([I:15])[CH:11]=[CH:10][C:7]=1[C:8]#[N:9]>CN(C=O)C>[F:14][C:13]1[C:6]([O:4][CH3:3])=[C:7]([CH:10]=[CH:11][C:12]=1[I:15])[C:8]#[N:9]
Reactant: N#Cc1ccc(I)c(F)c1F
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(C#N)ccc(I)c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.7 %

Procedure:
Sodium hydride (60 mg, 2.5 mmol) was slurried in DMF (15 mL) and treated with dry methanol (120 μl, 96 mg, 3.0 mmol). After stirring for 10 minutes at 25° C., the solution was cooled to −25° C. and treated with 2,3-difluoro-4-iodobenzonitrile (500 mg, 1.9 mmol). After 25 minutes, the mixture was quenched by addition of 10% citric acid solution (5 mL) and warmed to 25° C. The mixture was extracted with ethyl ether (2×15 mL), the combined ether phases washed with water (5 mL), brine, dried (sodium sulfate) and evaporated to give 3-fluoro-4-iodo-2-methoxybenzonitrile (500 mg, 1.8 mmol): LC/MS (m/z=277).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:3]=1.C([O-])(=O)C.[Na+]>[Pd].C(O)C>[F:20][C:17]([F:18])([F:19])[C:13]1[CH:12]=[C:11]([C:4]2[CH:3]=[CH:2][N:7]3[N:8]=[CH:9][N:10]=[C:6]3[N:5]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: FC(F)(F)c1cccc(-c2cc(Cl)n3ncnc3n2)c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: FC(F)(F)c1cccc(-c2ccn3ncnc3n2)c1
Reaction time: 0.5 h

Procedure:
A mixture of 0.30 g. of 7-chloro-5-(m-trifluoromethylphenyl)-1,2,4-triazolo[1,5-a]pyrimidine, 0.10 g. of 10% palladium on charcoal catalyst, and 0.09 g. of anhydrous sodium acetate in 100 ml. of absolute ethanol is hydrogenated at 10 lbs. pressure for 30 minutes. The solution is filtered through a Celite pad and then evaporated to dryness. A methylene chloride solution of this material is washed with an aqueous saturated sodium bicarbonate solution. The organic layer, after drying with anhydrous magnesium sulfate, is passed through a short pad of hydrous magnesium silicate. The eluent is refluxed and the gradual addition of hexane caused the desired compound to crystallize to give product, m.p. 201°-202° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16](C)[CH:15]=[CH:14][C:13]=1C1C=NN(C)C=1)=[O:11].[N:25]1[N:26](C2C=CC=CC=2C(O)=O)[N:27]=[CH:28][CH:29]=1>>[N:25]1[N:26]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH2:1])=[O:11])[N:27]=[CH:28][CH:29]=1
Reactant: O=C(O)c1ccccc1-n1nccn1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: C[C@@H]1CCCN(C(=O)c2ccccc2-n2nccn2)[C@@H]1CN

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) 300 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](O)=[O:21])=[CH:15][CH:14]=1)([O-:12])=[O:11].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:20](=[O:21])[CH2:19][C:16]2[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:18][CH:17]=2)=[CH:5][CH:4]=1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
A mixture of p-anisidine (4.92 g, 40 mmol), 4-nitrophenylacetic acid (7.25 g, 40 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (11.5 g, 60 mmol) in pyridine (40 mL) was stirred at room temperature overnight. The solvent was evaporated, and HCl (1M, 50 mL) was added. The resulting product was filtered and washed with water and ether, and recrystallized from ethanol to give N-(4-Methoxy-phenyl) -2-(4-nitro-phenyl)-acetamide (9.6 g, 84%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][C@H:11]1[O:16][C@H:15]([CH3:17])[CH2:14][NH:13][CH2:12]1.[F:18][C:19]1([F:38])[CH2:22][N:21]([C:23]([C:25]2[C:29]3[CH:30]=[C:31]([CH:36]=[O:37])[C:32](F)=[C:33]([F:34])[C:28]=3[O:27][N:26]=2)=[O:24])[CH2:20]1>C(#N)C.O.[Cl-].[Na+].O>[F:38][C:19]1([F:18])[CH2:20][N:21]([C:23]([C:25]2[C:29]3[CH:30]=[C:31]([CH:36]=[O:37])[C:32]([N:13]4[CH2:14][C@@H:15]([CH3:17])[O:16][C@H:11]([CH3:10])[CH2:12]4)=[C:33]([F:34])[C:28]=3[O:27][N:26]=2)=[O:24])[CH2:22]1
Reactant: C[C@@H]1CNC[C@@H](C)O1
Reactant: O=Cc1cc2c(C(=O)N3CC(F)(F)C3)noc2c(F)c1F
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: C[C@@H]1CN(c2c(C=O)cc3c(C(=O)N4CC(F)(F)C4)noc3c2F)C[C@@H](C)O1
Temperature: 25 °C

Procedure:
Diisopropylethylamine (1.432 ml, 8.20 mmol) and (2R,6R)-2,6-dimethylmorpholine (1.027 ml, 8.20 mmol) were added to a solution of 3-(3,3-difluoroazetidine-1-carbonyl)-6,7-difluorobenzo[d]isoxazole-5-carbaldehyde (Intermediate 241, 1.906 g, 6.31 mmol) in acetonitrile (50 ml). The reaction was stirred at reflux for 20 hours. The reaction was cooled to room temp, diluted with water and brine and extracted twice with ethyl acetate. The organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography using a gradient of DCM to ethyl acetate. Fractions were combined and concentrated to give the title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH:51]1[CH2:56][CH2:55][CH:54]([O:57][C:58]2[CH:59]=[N:60][CH:61]=[C:62]([C:64]([F:67])([F:66])[F:65])[CH:63]=2)[CH2:53][CH2:52]1>CN(C=O)C.O>[O:27]=[C:25]([N:51]1[CH2:52][CH2:53][CH:54]([O:57][C:58]2[CH:59]=[N:60][CH:61]=[C:62]([C:64]([F:66])([F:65])[F:67])[CH:63]=2)[CH2:55][CH2:56]1)[CH2:24][NH:23][C:21]([C:18]1[CH:17]=[C:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:20][N:19]=1)=[O:22]
Reactant: FC(F)(F)c1cncc(OC2CCNCC2)c1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2cncc(C(F)(F)F)c2)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 45.9 %

Procedure:
DIPEA (140 mg, 1.1 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (87 mg, 0.35 mmol) in DMF (2 mL) followed by HOBt (47 mg, 0.35 mmol) and EDCI.HCl (73 mg, 0.38 mmol). After 2 minutes 3-(piperidin-4-yloxy)-5-trifluoromethyl-pyridine hydrochloride (100 mg, 0.35 mmol) (prepared by method used for the synthesis of Intermediate 15) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, the solid was collected. Purification of the solid by washing with 10% MeOH in CHCl3 afforded 76 mg (47.5% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(5-trifluoromethyl-pyridin-3-yloxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 474, 99%. 1H NMR (300 MHz, DMSO-d6): δ 13.8 (m, 1H), 8.68 (m, 1H), 8.58 (s, 1H), 8.1 (m, 1H), 7.9 (m, 1H), 7.8 (m, 2H), 7.4 (m, 4H), 7.1 (m, 1H), 5.0 (m, 1H), 4.2 (m, 2H), 4.0 (m, 1H), 3.8 (m, 1H), 3.4 (m, 1H), 3.3 (m, 1H), 2.0 (m, 2H), 1.7 (m, 2H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][N:11]=[CH:12][C:13]1[O:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1.[N+](C1OC(C=O)=CC=1)([O-])=O.N(C1SC2C=C([C:42]([F:45])([F:44])[F:43])C=CC=2N=1)N>>[F:43][C:42]([F:45])([F:44])[C:7]1[CH:8]=[CH:9][C:4]2[N:3]=[C:2]([NH:10][N:11]=[CH:12][C:13]3[O:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)[S:1][C:5]=2[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(C=NNc2nc3ccccc3s2)o1
Reactant: NNc1nc2ccc(C(F)(F)F)cc2s1
Agent: O=Cc1ccc([N+](=O)[O-])o1
Product: O=[N+]([O-])c1ccc(C=NNc2nc3ccc(C(F)(F)F)cc3s2)o1

Procedure:
The compound 3g was prepared according procedure described for 3a by employing 5-nitrofuran aldehyde (141 mg, 1 mmol) and 2-hydrazino-6-trifluoromethyl-benzothiazole (233 mg, 1 mmol) at 70° C. for 2 h (yield 302 mg, 85%).