Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:7][CH2:6][C:5]([C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[N:14][CH:15]=2)([C:8]#N)[CH2:4][CH2:3]1.[OH-:18].[Na+].C[OH:21].O>>[F:1][C:2]1([F:17])[CH2:7][CH2:6][C:5]([C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[N:14][CH:15]=2)([C:8]([OH:21])=[O:18])[CH2:4][CH2:3]1
Reactant: CO
Reactant: Cc1ncc(C2(C#N)CCC(F)(F)CC2)cn1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: Cc1ncc(C2(C(=O)O)CCC(F)(F)CC2)cn1
Temperature: 100 °C
Yield: 92 %

Procedure:
To a mixture of 4,4-difluoro-1-(2-methylpyrimidin-5-yl)cyclohexanecarbonitrile (1.2 g, 5.1 mmol) in MeOH/H2O (20 mL, 1:1) was added NaOH (612 mg, 15.3 mmol) and heated to 100° C. overnight. The MeOH was removed in vacuo. The aqueous layer was extracted with EtOAc (3×30 mL) and the organic layers was discarded. The aqueous layer was adjusted pH to 3˜4 with 3N HCl and extracted with EtOAc (3×30 mL). The organic layer was dried over Na2SO4 and concentracted to give 4,4-difluoro-1-(2-methylpyrimidin-5-yl)cyclohexanecarboxylic acid (1.2 g, yield: 92%). 1H NMR (CDCl3 400 MHz): δ8.81 (s, 2H), 2.80-2.60 (m, 5H), 2.20-2.00 (m, 6H).
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6]Br.Br[C:9]1[CH:19]=[CH:18][C:12]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:11][CH:10]=1.[P:20]([O-:27])(OCC)OCC.Cl>O1CCCC1.C(OCC)(=O)C.O>[CH2:14]([N:13]([CH2:5][CH3:6])[C:12]1[CH:18]=[CH:19][C:9]([PH:20](=[O:27])[C:9]2[CH:19]=[CH:18][C:12]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:11][CH:10]=2)=[CH:10][CH:11]=1)[CH3:15]
Reactant: CCN(CC)c1ccc(Br)cc1
Reactant: BrCCBr
Reactant: CCOP([O-])OCC
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(CC)c1ccc([PH](=O)c2ccc(N(CC)CC)cc2)cc1
Temperature: 40 °C
Reaction time: 0.67 h
Yield: 87 %

Procedure:
Under a nitrogen stream, a solution of magnesium (5.3 g, 1.00 equivalent), a small amount of iodine and a small amount of 1,2-dibromoethane in tetrahydrofuran (30 mL) was stirred at room temperature for 30 min. A solution of 4-bromo-N,N-diethylaniline (49.7 g, 0.217 moL) in tetrahydrofuran (100 mL) was added to the mixture at 25° C. to 35° C. over 1 hr, and the mixture was stirred at 40° C. for 40 min. Then, a solution of diethyl phosphite (9.20 g, 0.30 equivalent) in tetrahydrofuran (20 mL) was added to the mixture at 20° C. to 25° C. for 15 min. 6M Hydrochloric acid (30 mL) and water (30 mL) were added to the mixture at 3° C. to 15° C., and then ethyl acetate (100 mL) was added thereto. The mixture was partitioned, and the organic layer was washed successively with water (30 mL), 5%-aqueous sodium hydrogen carbonate solution (30 mL) and saturated brine (30 mL), dried over anhydrous magnesium sulfate and filtered naturally. Then, the organic layer was concentrated under reduced pressure. The residue was recrystallized from n-heptane to give the title compound (19.82 g, white crystals). yield 87%. melting point 129.1° C.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:8]([NH:9][C@@H:10]2[CH2:17][C@H:13]3[CH2:14][NH:15][CH2:16][C@@:12]3([C:18]([N:20]3[CH2:29][CH2:28][C:27]4[N:26]=[CH:25][C:24]([C:30]([F:33])([F:32])[F:31])=[CH:23][C:22]=4[CH2:21]3)=[O:19])[CH2:11]2)[CH2:7][CH2:6][O:5][CH2:4]1.Cl[C:35]([O:37][CH2:38][CH:39]([CH3:41])[CH3:40])=[O:36]>C(Cl)Cl>[NH3:9].[CH3:1][O:2][C@H:3]1[C@@H:8]([NH:9][C@@H:10]2[CH2:17][C@H:13]3[CH2:14][N:15]([C:35]([O:37][CH2:38][CH:39]([CH3:41])[CH3:40])=[O:36])[CH2:16][C@@:12]3([C:18]([N:20]3[CH2:29][CH2:28][C:27]4[N:26]=[CH:25][C:24]([C:30]([F:33])([F:31])[F:32])=[CH:23][C:22]=4[CH2:21]3)=[O:19])[CH2:11]2)[CH2:7][CH2:6][O:5][CH2:4]1
Reactant: CO[C@@H]1COCC[C@@H]1N[C@@H]1C[C@H]2CNC[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Reactant: CC(C)COC(=O)Cl
Solvent: ClCCl
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1C[C@H]2CN(C(=O)OCC(C)C)C[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Product: N
Temperature: 0 °C
Reaction time: 8 h
Yield: 5 %

Procedure:
To a solution of Example 1 (0.1 g, 0.213 mmol) and TEA (0.12 mL, 0.854 mmol) in DCM (2.6 mL) at 0° C. was added isobutyl chloroformate (0.086 mL, 0.64 mmol). The mixture was stirred at 0° C. for 30 min and at rt overnight. The reaction was quenched by addition of saturated aqueous NaHCO3 solution, extracted with DCM, dried over Na2SO4. Purification by CombiFlash (eluent: 5% methanol in DCM, then 5% 7N NH3 in methanol in DCM) gave the title compound as a white solid. 1H-NMR (400 MHz, CDCl3): δ 0.93 (d, J=6.3 Hz, 6H), 1.57-1.99 (m, 7H), 2.32 (br. s., 1H), 2.74 (br. s., 1H), 3.08-3.56 (m, 10H), 3.56-4.00 (m, 9H), 4.01-4.11 (m, 1H), 4.57-5.07 (m, 2H), 7.70 (br. s., 1H), 8.72 (br. s., 1H); LC/MS: C28H39F3N4O5: m/z 569.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])/[C:5](=[N:7]/[OH:8])/[NH2:6].Br[C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=O)=[CH:19][N:18]=1.C1CCC(N=C=NC2CCCCC2)CC1.[CH:41]1[CH:42]=[CH:43][C:44]2[N:49]([OH:50])[N:48]=[N:47][C:45]=2[CH:46]=1.CCN(C(C)C)C(C)C>C(#N)C>[N:49]1([O:50][C:17]2[N:18]=[CH:19][C:20]([C:21]3[O:8][N:7]=[C:5]([C:4]4[CH:9]=[CH:10][C:11]([O:12][CH:13]([CH3:15])[CH3:14])=[C:2]([Cl:1])[CH:3]=4)[N:6]=3)=[CH:24][CH:25]=2)[C:44]2[CH:43]=[CH:42][CH:41]=[CH:46][C:45]=2[N:47]=[N:48]1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: CC(C)Oc1ccc(/C(N)=N/O)cc1Cl
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(On4nnc5ccccc54)nc3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.2 %

Procedure:
A 25 mL microwave reaction vial was charged with (Z)-3-chloro-N′-hydroxy-4-isopropoxybenzimidamide (0.1 g, 0.437 mmol), 6-bromonicotinic acid (0.097 g, 0.481 mmol), and DCC (0.099 g, 0.481 mmol) in acetonitrile (2.403 ml). HOBT (0.074 g, 0.481 mmol) was added in one portion, the resulting suspension was allowed to stir at room temperature for 10 min. DIEA (0.168 ml, 0.962 mmol) was added dropwise, the reaction mixture was heated at 120° C. for 30 min under microwave irradiation (Biotage Optimizer, 300 W). The solution was cooled, the reaction mixture was partitioned between EtOAc (50 mL) and water (50 mL), the organic layer was washed by water (2×50 mL), and concentrated afforded yellow solid, which was purified via silica gel chromatography (12 g, 20% EtOAc:Heptane) to afford 5-(6-(1H-benzo[d][1,2,3]triazol-1-yloxy)pyridin-3-yl)-3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazole (0.128 g, 0.285 mmol, 65.2% yield) as a white solid. LC/MS (Table 1, Method a) Rt=3.74 min.; MS m/z: 449.18 (M+H)+. 1H NMR (400 MHz, Solvent d-DMSO) ppm 8.88 (dd, J=2.25, 0.65 Hz, 1H), 8.62 (dd, J=8.68, 2.27 Hz, 1H), 8.15 (t, J=5.28 Hz, 2H), 7.97 (dd, J=8.62, 2.14 Hz, 1H), 7.55 (d, J=0.96 Hz, 1H), 7.52-7.44 (m, 2H), 7.36 (dd, J=8.68, 0.70 Hz, 1H), 7.03 (d, J=8.87 Hz, 1H), 4.73-4.61 (m, 1H), 1.46-1.40 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:5]=2[S:4][C:3]=1[CH:15]=[CH:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH:26][C:27]([O:29][CH3:30])=[O:28])=[C:21]([CH3:31])[CH:20]=1)=[O:18].C1COCC1>CO.[C].[Pd]>[CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([F:13])([F:14])[F:12])=[CH:10][C:5]=2[S:4][C:3]=1[CH2:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[C:21]([CH3:31])[CH:20]=1)=[O:18]
Reactant: COC(=O)C=Cc1ccc(C(=O)C=Cc2sc3cc(C(F)(F)F)ccc3c2C)cc1C
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(C(=O)CCc2sc3cc(C(F)(F)F)ccc3c2C)cc1C
Yield: 44.6 %

Procedure:
Methyl 3-[4-[3-[3-methyl-6-(trifluoromethyl)benzothiophen-2-yl]propenoyl]-2-methylphenyl]acrylate (85 mg, 0.19 mmol) was hydrogenated in MeOH (1 mL)/THF (1 mL) for 1 hour at room temperature using 10% palladium-carbon (17 mg) as a catalyst. After removal of the catalyst by filtration, the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1), to give the titled compound as a pale yellow crystal (38 mg, yield 44%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH2:28]([N:32]([CH2:40][C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=1)[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:30][CH3:31]>>[CH2:28]([N:32]([CH2:40][C:41]1[CH:42]=[CH:43][C:44]([NH:45]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:46][CH:47]=1)[C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCN(Cc1ccc(N)cc1)C(=O)OC(C)(C)C
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: CCCCN(Cc1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)OC)ccc32)c2ccccc2)cc1)C(=O)OC(C)(C)C

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(N-butyl-N-tert.butoxycarbonyl-aminomethyl)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C33H37N3O5
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH:26]1([NH2:29])[CH2:28][CH2:27]1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:29][CH:26]4[CH2:28][CH2:27]4)=[O:21])=[CH:17][N:16]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nc1
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC1CC1)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of 6-[3-(4-chloro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (100 mg, 0.28 mmol) and cyclopropylamine (16.1 mg, 0.28 mmol) in THF (10 mL) were added at 0° C., 1-hydroxybenzotriazole hydrate (43.3 mg, 0.28 mmol), N-ethyldiisopropylamine (121 μL, 0.69 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (54.2 mg, 0.28 mmol). The mixture was stirred at room temperature overnight. The solvent was removed by distillation. The remaining material was purified by chromatography (silica, dichloromethane:ethyl acetate=4:6 to 1:0) to afford the title compound (95.2 mg, 86%) as a white solid. MS: m/e=398.0 [M−H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9]/[CH2:10][OH:11])=[CH:4][CH:3]=1.O[C:19]1[CH:30]=[CH:29][C:22]([O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:21]([CH3:31])[CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:9]/[CH2:10][O:11][C:19]2[CH:30]=[CH:29][C:22]([O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:21]([CH3:31])[CH:20]=2)=[CH:6][CH:7]=1
Reactant: OC/C=C(\c1ccccc1)c1ccc(Br)cc1
Reactant: COC(=O)COc1ccc(O)cc1C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccccc2)c2ccc(Br)cc2)cc1C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
The above allyl alcohol (0.889 g, 3.0 mmol), methyl (4-hydroxy-2-methylphenoxy)acetate (0.770 g, 3.9 mmol; see below) and triphenylphosphine (1.30 g, 5 mmol) were dissolved in a mixture of anhydrous toluene (12 mL) and tetrahydrofuran (4 mL). The mixture was cooled to 0° C., kept under nitrogen and diisopropyl azodicarboxylate (0.85 g, 4.2 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 3 h and then at 25° C. for 16 h. The solvents were evaporated in vacuo and the residue was submitted to column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 98:2-90:10) affording methyl (E)-[4-[3-(4-bromophenyl)-3-phenylallyloxy]-2-methylphenoxy]acetate.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.CC(O)=O.CCOC(C)=O.[H][H]>CO.[Pd]>[N:8]1([CH2:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][CH:16]=[CH:15]3)[C:6]2=[N:7][CH:2]=[CH:3][N:4]=[C:5]2[N:10]=[N:9]1
Reactant: Brc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: c1cnc2ccc(Cn3nnc4nccnc43)cc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20 %

Procedure:
A solution of 6-(6-bromo-[1,2,3]triazolo[4,5-b]pyrazin-1-ylmethyl)-quinoline (200 mg, 0.586 mmol) in MeOH (10 mL):AcOH (1 mL): EtOAc (1 mL) was degassed 3 times with nitrogen. To this solution was added Pd/C (20 mg). A balloon containing hydrogen was added via syringe and the reaction was allowed to stir for 18 hours at room temperature. The reaction did not complete and more Pd/C was added (20 mg) and stirred for 18 hours at room temperature. The reaction was stopped when LCMS showed a ratio of 1:1 (product:starting material). The reaction was filtered over celite and washed with EtOAc (50 mL). The filtered solution was concentrated and purified by Biotage silica gel column chromatography with EtOAc: Hexanes to give 30 mg of the product 6-[1,2,3]triazolo[4,5-b]pyrazin-1-ylmethyl-quinoline (20% yield).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[C:13]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:29](=[O:30])[N:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:34][C:33]=3[F:46])[C:27]([CH2:47][CH2:48][CH3:49])=[N:26][C:25]=2[CH3:50])=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14]>C(OCC)(=O)C>[C:13]([O:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:29](=[O:30])[N:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[C:44]4[NH:3][C:4](=[O:7])[O:5][N:45]=4)=[CH:34][C:33]=3[F:46])[C:27]([CH2:47][CH2:48][CH3:49])=[N:26][C:25]=2[CH3:50])=[CH:22][CH:23]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: [NH3+]O
Reactant: CCCc1nc(C)c(-c2ccc(OC(C)(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)c(-c2ccc(OC(C)(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1F
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
A mixture of hydroxylammonium chloride (0.6 g), sodium hydrogen carbonate (0.85 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[5-(4-tert-butoxyphenyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (0.51 g) was added, and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-carbonyldiimidazole (0.25 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.44 g, 77%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.Br[CH2:16][CH2:17][O:18][CH3:19]>CN(C)C=O.O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:16][CH2:17][O:18][CH3:19])=[CH:10][CH:9]=1
Reactant: COCCBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc(Br)cc1
Temperature: 60 °C
Reaction time: 17 h
Yield: 97.3 %

Procedure:
Potassium carbonate (2.4 g, 17.3 mmol) was suspended in N,N-dimethyl formamide (15 mL). 4-bromophenol (1.00 g, 5.78 mmol) and 1-bromo-2-methoxyethane (0.964 g, 6.94 mmol) were added into the reaction sequentially and the resulting mixture was stirred at 60° C. for 17 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL) dried over sodium sulfate and evaporated to give the title compound (1.3 g, 99%) as a yellow oil.
Reaction SMILES: C([O:8][C:9]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:10]=1[O:11][CH2:12][C@H:13]1[CH2:15][O:14]1)C1C=CC=CC=1.[C:23](=O)(O)[O-].[Na+].C(O)C>[Pd].CN1C(=O)CCC1>[N+:20]([C:18]1[CH:17]=[CH:16][C:10]2[O:11][CH2:12][C@@H:13]([CH:15]([OH:14])[CH3:23])[O:8][C:9]=2[CH:19]=1)([O-:22])=[O:21]
Reactant: O=C([O-])O
Reactant: O=[N+]([O-])c1ccc(OC[C@H]2CO2)c(OCc2ccccc2)c1
Agent: [Pd]
Agent: [Na+]
Solvent: CCO
Solvent: CN1CCCC1=O
Product: CC(O)[C@@H]1COc2ccc([N+](=O)[O-])cc2O1
Temperature: 51 °C

Procedure:
A 500 mL three necked Morton flask equipped with magnetic stir bar, thermocouple, gas inlet adapter and gas outlet adapter is charged with (2R)-2-{[2-(benzyloxy)-4-nitrophenoxy]methyl}oxirane (20.00 g, 66.4 mmol), sodium bicarbonate (5.58 g, 66.4 mmol), palladium (5% on carbon, 50% water, 3 g), ethanol (136 mL) and NMP (24 mL). The flask is immersed in an oil bath and heated to 50-52° C. (internal) to effect solution. The stirring is stopped and the flask is flushed with hydrogen gas (300 mL). Stirring is resumed and hydrogen gas is titrated into the solution [1550 mL (69.2 mmol) over 5.5 h]. Heating is discontinued, and a flow of nitrogen is used to sweep the head space for 20 min. Once the solution is cooled to 25° C., the mixture is filtered through a pad of celite and the filter cake is washed with ethanol (50 mL). The resulting solution is concentrated by rotary evaporation removing ˜200 mL of ethanol. The solution is transferred to a separatory funnel and i-PrOAc (220 mL) is added followed by water (200 mL). The mixture is thoroughly shaken and the bottom aqueous layer is drained and discarded. The product containing organic layer is washed with water (3×50 mL), and transferred to a 500 mL three necked flask equipped with a magnetic stir bar, thermocouple, heating mantel, and a distillation head. The i-PrOAc is removed by distillation at atmospheric pressure. Once ˜180 mL has been collected, pyridine (80 mL) is added and the distillation is continued until the head temperature is 108° C. The solution is allowed to cool to room temperature and used directly as illustrated in Schemes I and II, and as described in the Examples below.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[CH:20]1([NH2:23])[CH2:22][CH2:21]1.[OH:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1>>[OH:24][CH:25]1[CH2:26][CH2:27][N:28]([C:31]2[CH:39]=[CH:38][C:34]([C:35]([NH:1][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([C:11]3[CH:12]=[CH:13][C:14]([C:15](=[O:17])[NH:23][CH:20]5[CH2:22][CH2:21]5)=[CH:18][CH:19]=3)[N:6]=[CH:5]4)=[O:36])=[CH:33][CH:32]=2)[CH2:29][CH2:30]1
Reactant: Nc1ccc2c(cnn2-c2ccc(C(=O)O)cc2)c1
Reactant: O=C(O)c1ccc(N2CCC(O)CC2)cc1
Reactant: NC1CC1
Product: O=C(Nc1ccc2c(cnn2-c2ccc(C(=O)NC3CC3)cc2)c1)c1ccc(N2CCC(O)CC2)cc1

Procedure:
Compound 985 was prepared according to the procedure described in Scheme IV from 4-(5-amino-1H-indazol-1-yl)benzoic acid, cyclopropaneamine, and 4-(4-hydroxypiperidin-1-yl)benzoic acid. [M+H]+ calcd for C29H29N5O3: 496.23; found 496.09.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7]C(=O)C(F)(F)F)=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[C:24]([O:31][CH3:32])[CH:23]=2)[N:17]=1>[OH-].[K+]>[NH2:7][CH2:6][C:5]1[CH:14]=[CH:15][C:2]([Cl:1])=[C:3]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[C:24]([O:31][CH3:32])[CH:23]=3)[N:17]=2)[CH:4]=1
Reactant: COc1cc(-n2nc(-c3cc(CNC(=O)C(F)(F)F)ccc3Cl)[nH]c2=O)ccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Product: COc1cc(-n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)ccc1[N+](=O)[O-]
Yield: 100.4 %

Procedure:
The solution of N-(4-chloro-3-(1-(3-methoxy-4-nitrophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide (0.500 g, 1.06 mmol) in 20% aq. KOH (20 mL) was stirred for 2-3 h at RT. Excess of solvent was removed under vacuum and filtered off remaining reaction mass to afford 0.400 g of desired product. 1H NMR (300 MHz, DMSO d6): δ1.80 (br s, 2H), 3.72 (s, 2H), 3.91 (s, 3H), 7.27-7.39 (m, 2H), 7.78 (d, J=9.9 Hz, 2H), 8.98 (d, J=8.7 Hz, 1H), 8.25 (s, 1H); MS (m/z): 375.91 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:9]([C:10]#[N:11])[CH2:8][O:7][CH2:6]1)=[O:4].O=S(Cl)Cl.O>N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH2:6][O:7][CH2:8][C:9]=1[C:10]#[N:11])=[O:4]
Reactant: COC(=O)C1COCC1C#N
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)C1=C(C#N)COC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
4-Cyano-tetrahydro furane 3-carboxylic acid methyl ester was dissolved in 4.9 ml of pyridine and treated with 4.4 ml (60 mmol) of SOCl2 during 90 min under nitrogen at 4° C. The resulting solution was warmed to room temperature, stirred for 6 hours and poured into 40 ml water at 4° C. and extracted with benzene. Combined extracts were dried and concentrated in vacuo to give 90% yield of 4-cyano-2,5-dihydro furane 3-carboxylic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2(F)[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:5]=[C:6]([F:9])[C:7]=1[OH:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=[O:46].[F:55][C:56]([F:71])([F:70])[C:57]1[N:61]=[C:60]([CH2:62][N:63]2[CH2:68][CH2:67][CH:66](O)[CH2:65][CH2:64]2)[O:59][N:58]=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:10]2([OH:46])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:5]=[C:6]([F:9])[C:7]=1[O:8][CH:66]1[CH2:67][CH2:68][N:63]([CH2:62][C:60]2[O:59][N:58]=[C:57]([C:56]([F:55])([F:70])[F:71])[N:61]=2)[CH2:64][CH2:65]1
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: OC1CCN(Cc2nc(C(F)(F)F)no2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(c2cc(F)c(O)c(F)c2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cc(F)c(OC3CCN(Cc4nc(C(F)(F)F)no4)CC3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 4-(3,5-difluoro-4-hydroxyphenyl)-4-fluoropiperidine-1-carboxylate D1g in dichloromethane (1 mL) is added to a mixture of triphenylphosphine (48 mg, 0.2 mmol) and diethyl azodicarboxylate (30 mg, 0.2 mmol) in dichloromethane (2 mL), followed by 1-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)piperidin-4-ol D1b (40 mg, 0.15 mmol). The mixture is stirred at room temperature overnight. Concentration and flash chromatography purification (hexanes/ethyl acetate gradient) yields tert-butyl 4-(3,5-difluoro-4-((1-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)piperidin-4-yl)oxy)phenyl)-4-hydroxypiperidine-1-carboxylate D1h as an oil. 19F-NMR (376 MHz, CDCl3) δ=−65.96 (3F), −126.00 (2F). LCMS calcd. for C25H32F5N4O5+ ([M+H]+): 563.2, found: 562.7.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=1)(C)C.[OH-].[K+]>C(O)(C)C>[C:13]([C:10]1[CH:9]=[CH:8][C:7]([C:6]#[CH:5])=[CH:12][CH:11]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1ccc(C#C[Si](C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: C#Cc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
To a stirred solution of 1.44 g (6.23 mmol) of trimethylsilyl (4-tert-butyl) phenylethyne (Compound 23) in 5 ml of isopropanol was added 10 ml of 1 N aqueous KOH and the mixture then stirred at room temperature for 6.5 hours. The isopropanol was removed under vacuum and the residue extracted with ether. The ether extract was washed with dilute HCl until the washings were acidic. The ether solution was then successively washed with water, saturated NaCl and NaHCO3 solutions and then dried (MgSO4). Solvent was then removed in-vacuo to give the title compound as a colorless oil. PMR (CDCl3): & 1.34 (9H, s), 3.05 (1H, s), 7.37 (2H, d, J~8.2 Hz), 7.46 (2H, d, J~8.2 Hz).