Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH2:33](O)[CH3:34].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH3:34])=[CH:30][N:31]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CCO
Reactant: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(O)cn3)[nH]2)cc1)C1CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridin-3-ol (0.260 g) in tetrahydrofuran (10 mL) were added ethanol (0.067 tributylphosphine (0.29 mL) and 1,1′-(azodicarbonyl)dipiperidine (290 mg), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in toluene (10 mL), and hexane (10 mL) was added. The obtained suspension was filtered to remove the precipitate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=20:80-70:30, volume ratio) to give the title compound (0.220 g, yield 80%) as a colorless amorphous solid. MS: 481 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Sn](CCCC)(CCCC)CCCC)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Br[C:26]1[N:27]=[C:28]2[C:34]([C:35]([NH:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH:40]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[CH2:39]3)=[O:36])=[CH:33][NH:32][C:29]2=[N:30][CH:31]=1>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:26]3[N:27]=[C:28]4[C:34]([C:35]([NH:37][CH:38]5[CH2:43][CH2:42][CH2:41][CH:40]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:49])([CH3:48])[CH3:50])[CH2:39]5)=[O:36])=[CH:33][NH:32][C:29]4=[N:30][CH:31]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(Cl)ccc12
Reactant: CC(C)(C)OC(=O)NC1CCCC(NC(=O)c2c[nH]c3ncc(Br)nc23)C1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4CCCC(NC(=O)OC(C)(C)C)C4)c3n2)c2ccc(Cl)cc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
A mixture of 6-chloro-1-methyl-3-(tributylstannyl)-1H-indazole (0.47 g, 1.03 mmol), tert-butyl 3-(2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)cyclohexylcarbamate (0.45 g, 1.03 mmol), CuI (0.07 g, 0.37 mmol) and Pd(PPh3)4 (0.07 g, 0.06 mmol) in 100 mL of DMF was stirred at 80° C. under nitrogen atmosphere overnight. The solvent was removed under reduced pressure and the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 50% acetonitrile/50% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 85% acetonitrile/15% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give tert-butyl 3-(2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)cyclohexylcarbamate (0.3 g, 56%) as a yellow solid. MS: (M+H)+=542.2; 1H NMR (300 MHz, DMSO): δ 9.13-9.07 (m, 1H), 8.48-8.39 (m, 2H), 8.13-8.01 (m, 2H), 7.42-7.30 (m, 1H), 5.20 (s, 3H), 3.44-3.35 (m, 1H), 2.30-2.05 (m, 1H), 1.82-1.38 (m, 4H), 1.32-1.17 (m, 13H).
Reaction SMILES: [NH2:1][C:2]1[N:29]([CH2:30][C:31]([OH:34])([CH3:33])[CH3:32])[C:6]2[N:7]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([CH:18]4[CH2:23][CH2:22][N:21]([CH2:24][CH2:25]Cl)[CH2:20][CH2:19]4)=[CH:14][C:13]=3[O:27][CH3:28])[N:9]=[CH:10][C:5]=2[C:4](=[O:35])[C:3]=1[C:36]([NH2:38])=[O:37].[C:39]([O-])([O-])=[O:40].[K+].[K+]>CO>[NH2:1][C:2]1[N:29]([CH2:30][C:31]([OH:34])([CH3:33])[CH3:32])[C:6]2[N:7]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([CH:18]4[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][O:40][CH3:39])[CH2:20][CH2:19]4)=[CH:14][C:13]=3[O:27][CH3:28])[N:9]=[CH:10][C:5]=2[C:4](=[O:35])[C:3]=1[C:36]([NH2:38])=[O:37]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C2CCN(CCCl)CC2)ccc1Nc1ncc2c(=O)c(C(N)=O)c(N)n(CC(C)(C)O)c2n1
Agent: [K+]
Solvent: CO
Product: COCCN1CCC(c2ccc(Nc3ncc4c(=O)c(C(N)=O)c(N)n(CC(C)(C)O)c4n3)c(OC)c2)CC1
Yield: 75.5 %

Procedure:
To a suspension of 0.29 g (0.54 mmol) of the product prepared in step 22.1 in 9 mL of anhydrous methanol is added 0.37 g (2.68 mmol) of K2CO3, and the mixture is refluxed for 1 hour. It is evaporated to dryness and the residue is taken up in water and CH2Cl2. The organic phase is dried over MgSO4, filtered and concentrated under vacuum. The crude product is purified by chromatography on a column of silica, eluting with a dichloromethane/methanol gradient (90/10). After triturating in methanol, 0.22 g of the expected product is finally obtained in the form of a yellow solid. Yield=78%.
Reaction SMILES: [C:1]([C:3]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]Br)#[N:2].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.CN(C)C=O>O>[C:1]([C:3]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)#[N:2]
Reactant: c1c[nH]cn1
Reactant: CCCCC(C#N)(CCCCCBr)c1ccc(Cl)cc1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(C#N)(CCCCCn1ccnc1)c1ccc(Cl)cc1Cl
Yield: 47.8 %

Procedure:
A mixture of 6-cyano-6-(2,4-dichlorophenyl)decyl bromide (14.2g., 0.036 mole) imidazole (10g., 0.15 mole) and 5 ml. N,N-dimethylformamide is heated at 120° C. for 24 hours. The reaction mixture is poured into water and extracted with ether. The combined ether extracts are dried over magnesium sulfate and filtered. Into the ethereal solution is bubbled dry hydrogen chloride gas until no more oily precipitate forms. The solvent is then decanted and the oily residue is taken up in acetone and neutralized with dilute ammonium hydroxide solution. The purified free base is extracted into ether and dried over magnesium sulfate. When the solvent is evaporated, a total of 6.5g. (47.8%) of product is obtained, which is identified by nmr.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)=[N:10][O:11][CH:12]=1)(C)(C)C.Cl.O1CCOCC1.C(OCC)C>O1CCOCC1>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][O:19][C:16]2[CH:15]=[CH:14][C:13]([C:9]3[C:8]([NH2:7])=[CH:12][O:11][N:10]=3)=[CH:18][CH:17]=2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)Nc1conc1-c1ccc(OCc2ccc(F)cc2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Nc1conc1-c1ccc(OCc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.5 %

Procedure:
{3-[4-(4-Fluoro-benzyloxy)-phenyl]-isoxazol-4-yl}-carbamic acid tert-butyl ester (1.97 g, 5.13 mmol) was dissolved in 30 mL of dioxane and 30 mL of 4 N HCl/dioxane was added. The reaction was stirred at rt for 4 h and allowed to stand overnight. The resulting crystalline mass was mixed with diethyl ether (20 mL) and stirred for 10 min. The suspension was filtered off and washed with a total of 20 mL of diethyl ether. The filter cake was partitioned between ethyl acetate and 5% NaHCO3 solution and the organic phase separated. The aqueous phase was extracted with once more with ethyl acetate. The combined organic phases were washed twice with brine and dried over Na2SO4. Filtration followed by removal of volatiles under reduced pressure gave 3-[4-(4-fluoro-benzyloxy)-phenyl]-isoxazol-4-ylamine (1.32 g, 91%) as an off-white solid. M+1=285.2
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14](Cl)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][C@@H:24]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25]1.CC(C)([O-])C.[Na+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH:23][C@@H:24]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25]3)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc2c(cc(Cl)c3nnc(C)n32)n1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: Cc1cc2c(cc(N[C@@H]3CCN(C(=O)OC(C)(C)C)C3)c3nnc(C)n32)n1Cc1ccccc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A degassed mixture of 6-benzyl-4-chloro-1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (200.0 mg, 0.6435 mmol, Example 228, Step 7), tert-butyl (3R)-3-aminopyrrolidine-1-carboxylate (0.40 mL, 2.3 mmol, Aldrich), sodium tert-butoxide (190 mg, 1.98 mmol, Aldrich), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (93 mg, 0.16 mmol, Aldrich) and tris(dibenzylideneacetone)dipalladium(0) (74 mg, 0.080 mmol, Aldrich) in toluene (12 mL) was heated at 100° C. for 3.5 hours, then at 125° C. for 2 hours. The reaction mixture was partitioned between water and ethyl acetate, and the aqueous layer was extracted further with two portions of EtOAc. The combined organic extracts were washed with brine, dried over sodium sulfate, decanted and concentrated. The product was purified by flash chromatography, eluting first with a gradient from 0-100% EtOAc in hexanes, then eluting with 5% MeOH in DCM. Yield: (190 mg, 64%). A portion of this material was then purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) to provide a pure title compound.
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([C:17]2[N:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[CH3:34])=[C:24]([CH2:35][O:36][CH3:37])[CH:23]=3)[O:19][N:18]=2)[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]([O:11]C)=[O:10])=[O:5].[OH-].[Na+].CCOC(C)=O>CO.O>[F:1][C:2]1[CH:16]=[C:15]([C:17]2[N:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[CH3:34])=[C:24]([CH2:35][O:36][CH3:37])[CH:23]=3)[O:19][N:18]=2)[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:5]
Reactant: COCc1cc(-c2nc(-c3ccc(C(=O)NCCC(=O)OC)c(F)c3)no2)ccc1-c1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COCc1cc(-c2nc(-c3ccc(C(=O)NCCC(=O)O)c(F)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a solution of example 117 (1 860 mg; 3.69 mmol) in MeOH (40 mL), sodium hydroxide (3.69 mL; 5 M; 18.5 mmol) in H2O was added. The reaction was stirred at RT for 1 h. EtOAc was added and the organic phase washed 3 times with HCl 1M. The organic phase was dried over MgSO4, filtered off and concentrated to afford the title compound as a white powder (1490.0 mg, 82%). 1H NMR: (DMSO-d6, 300 MHz) δ 8.58 (m, 1H), 8.33 (brs, 1H), 8.18 (dd, J=1.7 Hz, 8 Hz, 1H), 8.03 (dd, J=1.7 Hz, 8 Hz, 1H), 7.95 (d, J=10.6 Hz, 1H), 7.84 (t, J=7.6 Hz, 1H), 7.44 (d, J=7.9 Hz, 1H), 7.40-7.22 (m, 3H), 7.15 (m, 1H), 4.23 (d, J=12.9 Hz, 1H), 4.17 (d, J=12.9 Hz, 1H), 3.49 (m, 2H), 3.25 (s, 3H), 2.53 (m, 2H), 2.04 (s, 3H). LC/MS (Method B): 490.3 (M+H)+ 488.4 (M−H)−. HPLC (Method A) Rt: 4.83 min (purity: 99.7%).
Reaction SMILES: C(OC(=O)[CH2:5][O:6][C@H:7]1[CH2:10][C@H:9]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]#[N:32])=[CH:21][C:20]=3[F:33])=[C:14]([CH2:34][CH2:35][CH3:36])[N:13]3[N:37]=[CH:38][N:39]=[C:12]23)[CH2:8]1)C.C[Mg]Br.Cl>O1CCCC1>[F:33][C:20]1[CH:21]=[C:22]([C:25]2[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:23]=[CH:24][C:19]=1[CH2:18][C:15]1[C:16](=[O:17])[N:11]([C@H:9]2[CH2:10][C@H:7]([O:6][CH2:5][C:7]([OH:6])([CH3:10])[CH3:8])[CH2:8]2)[C:12]2[N:13]([N:37]=[CH:38][N:39]=2)[C:14]=1[CH2:34][CH2:35][CH3:36]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@H](OCC(=O)OCC)C2)c2ncnn12
Agent: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@H](OCC(C)(C)O)C2)c2ncnn12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl[(trans-3-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutyl)oxy]acetate (0.13 g) was dissolved in tetrahydrofuran (2 mL), methylmagnesium bromide (0.62 mL, 1.0 M tetrahydrofuran solution) was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 hr. Methylmagnesium bromide (0.62 mL, 1.0 M tetrahydrofuran solution) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed 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 a colorless solid (0.059 g, 45%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH:25]=[CH:26][C:27](=[O:31])[NH:28]5)=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.C(N(CC)CC)C.[CH2:39]([N:41]([CH2:45][CH3:46])[C:42](Cl)=[O:43])[CH3:40].O>ClCCl>[CH2:39]([N:41]([CH2:45][CH3:46])[C:42](=[O:43])[O:31][C:27]1[CH:26]=[CH:25][C:24]2[C:29](=[CH:30][C:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][N:13]3[CH2:12][CH2:11][N:10]([C:6]4[C:3]5[CH:4]=[CH:5][S:1][C:2]=5[CH:9]=[CH:8][CH:7]=4)[CH2:15][CH2:14]3)=[CH:22][CH:23]=2)[N:28]=1)[CH3:40]
Reactant: O=c1ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2[nH]1
Reactant: CCN(CC)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCN(CC)C(=O)Oc1ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2n1
Yield: 12.2 %

Procedure:
To a solution of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one (800 mg) synthesized in the same manner as in WO2006/112464 (Example 1) in dichloromethane (20 ml) was added triethylamine (0.65 ml), with stirring under ice-cooling, diethylcarbamoylchloride (0.5 g) was added and the mixture was stirred at room temperature overnight. Water, was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=20:1) to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yl diethylcarbamate (120 mg).
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[C:20]([CH2:21][CH2:22][CH3:23])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:18][N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[OH:4].[NH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([OH:38])=[O:37])[CH2:31]1.C1CCN2C(=NCCC2)CC1>CS(C)=O>[OH:4][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[C:20]([CH2:21][CH2:22][CH3:23])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:18][N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[CH2:2][N:30]1[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([OH:38])=[O:37])[CH2:31]1
Reactant: O=C(O)C1CCCNC1
Reactant: CCCc1c(-c2nc(-c3ccc(C(O)CBr)cc3)no2)noc1-c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Product: CCCc1c(-c2nc(-c3ccc(C(O)CN4CCCC(C(=O)O)C4)cc3)no2)noc1-c1ccccc1
Temperature: 80 °C

Procedure:
To a mixture of 2-bromo-1-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol, Preparation 1C (30 mg, 0.066 mmol) and piperidine-3-carboxylic acid (25.6 mg, 0.198 mmol) in DMSO (2 mL) was added DBU (0.030 mL, 0.198 mmol). The reaction mixture was heated at 80° C. for 2 hours. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 18 mg 1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.16 (2H, dd, J=8.35, 1.98 Hz), 7.83 (2H, dd, J=7.91, 1.54 Hz), 7.56-7.75 (5H, m), 5.13-5.39 (1H, m), 4.11-4.31 (2H, m), 3.21-3.41 (3H, m), 2.96-3.05 (2H, m), 2.70-2.85 (1H, m), 1.75-2.14 (4H, m), 1.62-1.77 (2H, m), 1.36-1.56 (1H, m), 0.98 (3H, t, J=7.36 Hz). MS (m+1)=503. HPLC Peak RT=3.35 minutes (Analytical Method A). Purity=90%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]([C:16]2[N:17]=[CH:18][S:19][CH:20]=2)C(=O)OC(C)(C)C)=[CH:5][CH:4]=1.[Al](Cl)(C)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:16]2[N:17]=[CH:18][S:19][CH:20]=2)=[CH:21][CH:22]=1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2cscn2)cc1
Agent: C[Al](C)Cl
Solvent: C1CCOC1
Product: COc1ccc(CNc2cscn2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.3 %

Procedure:
To a solution of tert-butyl 4-methoxybenzyl(thiazol-4-yl)carbamate (20.0 g, 62.4 mmol) in THF (100 mL) was added Me2AlCl (1M in THF, Aldrich) (93.6 mL, 93.6 mmol) at 0° C. The reaction was allowed to stir at room temperature for 5 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate (2×500 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude material which was further purified by column chromatography (silica gel 100-200 mesh and 0-50% ethyl acetate in hexanes) to obtain N-(4-methoxybenzyl)thiazol-4-amine (9.8 g, 73%) as an off-white solid. MS (ESI, positive ion) m/z=220.9 (M+1)+. 1H NMR (400 MHz, DMSO) δ 8.73 (d, J=2.2 Hz, 1H), 7.28 (d, J=8.5 Hz, 2H), 6.96-6.76 (m, 2H), 6.54 (t, J=6.3 Hz, 1H), 5.76 (d, J=2.2 Hz, 1H), 4.18 (d, J=6.2 Hz, 2H), 3.71 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[C:6]([O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])=O.[NH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([NH:18][CH2:1][C:3]2[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=2)[C:6]([O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])[CH:20]=1
Reactant: Nc1cccnc1
Reactant: C[Si](C)(C)CCOC(=O)c1cccc(C=O)c1
Product: C[Si](C)(C)CCOC(=O)c1cccc(CNc2cccnc2)c1
Yield: 77 %

Procedure:
By using 500 mg of 2-(trimethylsilyl)ethyl 3-formylbenzoate and 188 mg of 3-aminopyridine, the reaction similar to Preparation Example 14 was performed, thereby obtaining 505 mg of 2-(trimethylsilyl)ethyl 3-[(pyridin-3-ylamino)methyl]benzoate.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.Cl.[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][C:44](O)=[O:45].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>O.CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:21][CH2:22][N:23]([C:44](=[O:45])[CH2:43][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][N:37]=4)[CH2:24][CH2:25]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Reactant: O=C(O)Cc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(C(=O)Cc4ccccn4)CC3)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 10 h
Yield: 72.3 %

Procedure:
A flask was charged with 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (25 mg, 0.05 mmol) (as prepared in Example 14, step (b)), pyridin-2-yl-acetic acid hydrochloride (10 mg, 0.06 mmol), EDCI (12 mg, 0.06 mmol), HOBt (8.0 mg, 0.06 mmol), DIEA (36 μL, 0.20 mmol) and 0.2 mL DMF and stirred at 25° C. for 10 h. The reaction was diluted with 2 mL of H2O and the title compound was purified by RP-HPLC (C18), eluting with 30-50% CH3CN in 0.1% TFA/H2O over 9 min to give 22 mg (70%) of a white solid. 1H-NMR (400 MHz, CD3OD): δ 8.82 (d, 1H), 8.52 (t, 1H), 8.14 (d, 1H), 8.04 (s, 1H), 7.96 (m, 3H), 7.20 (dd, 1H), 7.10 (d, 1H), 5.82 (m, 1H), 4.68 (m, 1H), 4.32 (m, 2H), 4.18 (m, 1H), 3.40 (m, 1H), 2.88 (m, 2H), 2.30 (m, 4H), 2.06-1.60 (m, 8H). Mass spectrum (ESI, m/z): Calcd. for C29H30N6O2, 495.2.2 (M+H). found 495.2.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH:3]([NH:7][C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:11][N:12]=1)[C:4]([OH:6])=O.CCN=C=NCCCN(C)C.Cl.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.CO>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:40][CH2:41][N:42]([C:4](=[O:6])[CH:3]([NH:7][C:8]3[O:9][C:10]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[N:11][N:12]=3)[CH:2]([CH3:1])[CH3:19])[CH2:43][CH2:44]2)=[CH:35][CH:34]=1
Reactant: CC(C)C(Nc1nnc(-c2ccccc2)o1)C(=O)O
Reactant: Clc1ccc(C2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)C(Nc1nnc(-c2ccccc2)o1)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 45.6 %

Procedure:
3-Methyl-2-(5-phenyl-1,3,4-oxadiazol-2-ylamino)butanoic acid (80 mg, 0.3 mmol), EDCI (65 mg, 0.33 mmol), 4-(4-chlorophenyl)-piperidine hydrochloride (78 mg, 0.33 mmol) and HOBt (40 mg, 0.3 mmol) were combined and suspended in DMF (2 mL). Diisopropylethylamine (210 μL, 1.2 mmol) was added and the reaction was stirred at rt. overnight. After this time, methanol (2 mL) was added to the reaction and the mixture was purified directly by preparative HPLC to give 1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methyl-2-(5-phenyl-1,3,4-oxadiazol-2-ylamino)butan-1-one (60 mg, 30%). MS found: 439 (M+H).
Reaction SMILES: [C:1](=[O:18])(ON1C(=O)CCC1=O)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:19]([C:22]1[CH:23]=[C:24]([C@H:28]([NH2:30])[CH3:29])[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20]>C(Cl)Cl.CN(C=O)C>[N+:19]([C:22]1[CH:23]=[C:24]([C@H:28]([NH:30][C:1](=[O:18])[O:2][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:29])[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20]
Reactant: C[C@@H](N)c1cccc([N+](=O)[O-])c1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H](NC(=O)OCc1ccccc1)c1cccc([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 92.5 %

Procedure:
To a solution of benzyl 2,5-dioxopyrrolidin-1-yl carbonate (4.95 g, 19.9 mmol) and TEA (10 mL) in DCM (50 mL) was added a solution of (R)-1-(3-nitrophenyl)ethanamine (3 g, 18 mmol) in DMF (10 mL). The mixture was stirred 2 h and quenched with water (50 mL). The organic layer was separated and dried (MgSO4) before concentrating in vacuo. The residue was purified by flash chromatography (0-35% EtoAc/Hexane) to afford 64A (5 g, 93%) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.50 (d, J=6.59 Hz, 3 H) 4.87-4.98 (m, 1 H) 5.00-5.15 (m, 2 H) 7.34 (s, 5 H) 7.49 (t, J=7.69 Hz, 1 H) 7.64 (d, J=7.03 Hz, 1 H) 8.11 (d, J=7.91 Hz, 1 H) 8.17 (s, 1 H).