Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@:2]1([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:7][O:6][C@@H:5]([C@@H:8]2[CH2:12][CH2:11][CH2:10][O:9]2)[CH2:4][C@H:3]1[CH2:13][OH:14].FC1C=C(F)C=CC=1[C@@]1(N[C:44]([NH:46][C:47](=[O:54])[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[S:45])[C@H](CO)C[C@H]([C@@H]2C[C@H]2C)OC1>>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[C@@:2]1([NH:1][C:44]([NH:46][C:47](=[O:54])[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)=[S:45])[C@H:3]([CH2:13][OH:14])[CH2:4][C@H:5]([C@@H:8]2[CH2:12][CH2:11][CH2:10][O:9]2)[O:6][CH2:7]1
Reactant: C[C@@H]1C[C@H]1[C@H]1C[C@@H](CO)[C@](NC(=S)NC(=O)c2ccccc2)(c2ccc(F)cc2F)CO1
Reactant: N[C@@]1(c2ccc(F)cc2F)CO[C@@H]([C@@H]2CCCO2)C[C@H]1CO
Product: O=C(NC(=S)N[C@@]1(c2ccc(F)cc2F)CO[C@@H]([C@@H]2CCCO2)C[C@H]1CO)c1ccccc1

Procedure:
{(2R,4R,5S)-5-Amino-5-(2,4-difluorophenyl)-2-[(2S)-tetrahydrofuran-2-yl]tetrahydro-2H-pyran-4-yl}methanol (C101) was converted to the product using the method described for the synthesis of N-({(3S,4R,6R)-3-(2,4-difluorophenyl)-4-(hydroxymethyl)-6-[(1R,2R)-2-methylcyclopropyl]tetrahydro-2H-pyran-3-yl}carbamothioyl)benzamide (C90) in Example 20. Yield: 1.3 g, 2.7 mmol, 70% over 2 steps from (C100). LCMS m/z 477.2 [M+H+].
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)O)[C:10]([CH3:21])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[O:30])=[CH:25][CH:24]=1>>[CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[CH:27][CH:28]=2)[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:10]([CH3:21])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nn(Cc2ccccc2)cc1C(O)C1CCCCC1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Product: Cc1nn(Cc2ccccc2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Yield: 2.3 %

Procedure:
Using (1-benzyl-3-methyl-1H-pyrazol-4-yl)(cyclohexyl)methanol (1.0 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.62 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (28.6 mg, 4%) was obtained as a white solid.
Reaction SMILES: [N+]([NH:4][C:5]([NH2:7])=[O:6])([O-])=O.[F:8][C:9]([F:22])([F:21])[C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[O:13][CH:14]1[CH2:17]N[CH2:15]1.C(Cl)Cl>C(O)C>[F:8][C:9]([F:21])([F:22])[C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[O:13][CH:14]1[CH2:17][N:4]([C:5]([NH2:7])=[O:6])[CH2:15]1
Reactant: NC(=O)N[N+](=O)[O-]
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Solvent: ClCCl
Solvent: CCO
Product: NC(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 6 fold molar excess nitrourea and 3-[3-(trifluoromethyl)phenoxy]azetidine in a 50-50 vol. % mixture of methylene chloride and absolute ethyl alcohol is stirred at room temperature for 48 hr. The mixture is filtered. The filtrate is evaporated to dryness and the residue is partitioned between equal volumes of methylene chloride and water. The water layer is extracted 3 times with methylene chloride. The methylene chloride extracts are combined and evaporated to dryness. The residue is washed with a mixture of 1 vol. of methylene chloride to 20 volumes of toluene and filtered. The precipitate is recrystallized from ethanol/water to give pale yellow crystals. The crystals are triturated with a mixture of 2 volumes methylene chloride to 20 volumes of toluene for 2 hr. White crystals of title compound are obtained, m.p. 151°-152° C.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7](O)=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6].C[N:18]1CCOCC1.ClC(OCC(C)C)=O.N.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([NH2:18])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: CCCC[C@H](NC(=O)OC(C)(C)C)C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a stirred solution of N-Boc-L-Nle-OH (0.5 g, 2.2 mmol) in anhydrous THF (15 mL) under Ar at -230° C. was added 4-methylmorpholine followed by iso-butyl chloroformate (0.21 mL, 2.2 mmol). The reaction mixture was then treated with gaseous NH3 for 1 h. Stirring was continued at -23° C. for an additional 2 h. The mixture was warmed to R.T. and then poured onto 10% aqueous citric acid (20 mL). The mixture was extracted with EA (3×50 mL). The combined organics were washed with sat. NaHCO3 (3×25 mL), sat. NaCl (2×25 mL), dried (MgSO4), filtered and concentrated to afford N-Boc-L-Nle-NH2 as a white solid (0.48 g, 91%): 1H NMR (CDCl3, 300 MHz) δ 0.84-0.92 (m, 3H), 1.22-1.31 (m, 4H), 1.41 (s, 9H), 1.49-1.59 (m, 1H), 1.74-2.01 (m, 1H), 4.03-4.1 (m, 1H), 5.06 (d, 1H), 5.75 (s, 1H), 6.25 (s, 1H) ppm.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]2[CH:3]1[S:4][C:5]([CH3:14])([CH3:13])[CH:6]2[C:10]([OH:12])=[O:11].[Na].[C:16]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]O)=[CH:22][CH:21]=1)(=[O:18])[CH3:17].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[NH2:1][CH:2]1[C:8](=[O:9])[N:7]2[CH:3]1[S:4][C:5]([CH3:14])([CH3:13])[CH:6]2[C:10]([O:12][CH2:24][C:23]1[CH:22]=[CH:21][C:20]([O:19][C:16](=[O:18])[CH3:17])=[CH:27][CH:26]=1)=[O:11]
Reactant: CC(=O)Oc1ccc(CO)cc1
Reactant: CC1(C)SC2C(N)C(=O)N2C1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(COC(=O)C2N3C(=O)C(N)C3SC2(C)C)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
6-Amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, sodium salt (5 mmole) in 50 ml of dimethylformamide is stirred at room temperature while 2 equivalents of p-(acetyloxy)benzyl alcohol is added. The mixture is cooled to 0° C. after which 5.5 mmole of dicyclohexylcarbodiimide in 10 ml of dimethylformamide is added. This mixture is stirred at 0° C. for 1 hour and at room temperature for 4 hours. Dicyclohexylurea is removed by filtration. The filtrate is diluted with chloroform, washed with water, dried over magnesium sulfate, filtered and evaporated to give the title compound.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[C:3]([O:5][CH3:6])=[O:4].[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:1][CH:2]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[C:3]([O:5][CH3:6])=[O:4])=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COC(=O)C(N)c1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(NC(=O)c1ccc(F)cc1)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
A mixture of methyl α-amino-2-thiophene acetate (1.48 g), 4-fluorobenzoyl chloride (1.64 g) and sodium hydrogen carbonate (2.89 g) in methylene chloride (20 ml) and water (20 ml) was stirred at room temperature overnight. The organic layer was collected, washed with water and brine, and the solvent was removed under reduced pressure. The resulting residue was triturated with ethyl acetate-hexane to obtain methyl α-(4-fluorobenzoylamino)-2-thiophene acetate (2.40 g) as colorless powder.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[N:10]=[C:9]1[CH:17]([NH:21][CH2:22][C:23](=[O:37])[CH2:24][CH2:25][N:26]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:36])[CH:18]([CH3:20])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:45]1([CH3:54])[CH:50]=[CH:49][C:48]([C:51](Cl)=[O:52])=[CH:47][CH:46]=1>C(Cl)Cl>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[N:10]=[C:9]1[CH:17]([N:21]([CH2:22][C:23](=[O:37])[CH2:24][CH2:25][N:26]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:36])[C:51](=[O:52])[C:48]1[CH:49]=[CH:50][C:45]([CH3:54])=[CH:46][CH:47]=1)[CH:18]([CH3:20])[CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C(NCC(=O)CCN2C(=O)c3ccccc3C2=O)C(C)C)n(Cc2ccccc2)c(=O)c1C
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)N(CC(=O)CCN2C(=O)c3ccccc3C2=O)C(c2nc(C)c(C)c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.9 %

Procedure:
To 2-{4-[1-(1-Benzyl-4,5-dimethyl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-2-methyl-propylamino]-3-oxo-butyl}-isoindole-1,3-dione (1.024 g, 2.046 mmol) in CH2Cl2 (14 mL) was added triethylamine (0.31 g, 3.069 mmol) and p-toluoyl chloride (0.474 g, 3.069 mmol). The reaction was stirred for 16 h at room temperature, washed with water, dried (Na2SO4), and evaporated to dryness. The residue was purified by flash chromatography on silica gel (1:1 hexanes:EtOAc) to give the title compound as a white foam (0.885 g, 70%). MS(ES+) m/e 619 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH2:20][CH2:19]3)[C:5]2=[N:6][CH:7]=1.C1(C([C:46]2[CH:57]=[CH:56][CH:55]=[CH:54][C:47]=2[C:48]([N:50]=[C:51]([O-:53])[O-])=[O:49])C2C=CC=CC=2)C=CC=CC=1>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:19][CH2:20][N:21]([C:24](=[O:32])[CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([C:51](=[N:50][C:48](=[O:49])[C:47]5[CH:46]=[CH:57][CH:56]=[CH:55][CH:54]=5)[O:53][C:9]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:10]=5)[CH2:28][CH2:27]4)[CH2:22][CH2:23]3)[C:5]2=[N:6][CH:7]=1
Reactant: O=C(CC1CCNCC1)N1CCN(C2c3ccc(Cl)cc3CCc3cc(Br)cnc32)CC1
Reactant: O=C(N=C([O-])[O-])c1ccccc1C(c1ccccc1)c1ccccc1
Solvent: CC(C)O
Product: O=C(N=C(Oc1ccccc1)N1CCC(CC(=O)N2CCN(C3c4ccc(Cl)cc4CCc4cc(Br)cnc43)CC2)CC1)c1ccccc1

Procedure:
1-(3-Bromo-8-chloro-6,11-dihydro-5 H-benzo[5,6]cyclo-hepta[1,2-b] pyridin-11-yl)-4-[(4-piperidinyl)acetyl]piperazine (1 equivalent) (Formula 47.0, prepare as described in Preparative Example 11) and diphenylmethylbenzoylcarbonimidate (1.2 equivalents) [prepare as described in: A. Buschauer, Arch. Pharm., 377-378 (1987)] are dissolved in 2-propanol and the mixture is heated as described in Example 1 above to give the title compound (Formula 24.0).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([OH:13])[N:10]([CH3:14])[N:9]=2)=[CH:4][CH:3]=1.[C:15](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([O:13][CH3:15])[N:10]([CH3:14])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cn1nc(-c2ccc(Br)cc2)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(-c2ccc(Br)cc2)nn1C
Yield: 22.4 %

Procedure:
A mixture of 3-(4-bromophenyl)-5-hydroxy-1-methylpyrazole (2.5 g), acetone (200 ml), potassium carbonate (1.6 g) and methyl iodide (1.4 g) was heated at reflux for 2 hours. The mixture was filtered and the filtrate was evaporated. The residue was purified by flash column chromatography on silica gel using 10% ethyl acetate/toluene as eluent to give 3-(4-bromophenyl)-5-methoxy-1-methypyrazole (590 mg) as a solid, m.p. 71°-73° C.; NMR: 3.6(3H,s), 3.9(3H,s), 6.2(1H,s), 7.5-7.6(2H,d) and 7.6-7.7(2H,d).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]2[C:16]([C:17]([F:20])([F:19])[F:18])=[C:15]([C:21](O)=[O:22])[CH:14]=[N:13]2)[CH2:8][C@@H:7]1[CH3:24])=[O:5])[CH3:2].C(Cl)(=O)C([Cl:28])=O>C(Cl)Cl.CN(C=O)C>[Cl:28][C:21]([C:15]1[CH:14]=[N:13][N:12]([C@H:9]2[CH2:10][CH2:11][C@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C@@H:7]([CH3:24])[CH2:8]2)[C:16]=1[C:17]([F:20])([F:19])[F:18])=[O:22]
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)O)c2C(F)(F)F)C[C@@H]1C
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)Cl)c2C(F)(F)F)C[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a light-yellow clear solution of 1-((1S,3S,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid with its (1R,3R,4R)-isomer (0.3128 g, 0.898 mmol) in DCM (8.98 ml) was added oxalyl chloride (0.095 ml, 1.123 mmol) followed by DMF (1 drop) and the light-yellow clear reaction mixture was stirred at room temperature. After 2 h. The mixture was concentrated in vacuo to give (1S,2S,4S)-ethyl 4-(4-(chlorocarbonyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylcyclohexane carboxylate with its (1R,2R,4R)-isomer as brown syrupy solid. To the residue was added a solution of N-(2-(3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)ethyl)-2,2-dimethylpropan-1-amine (0.352 g, 0.898 mmol) in THF (8.98 ml) followed by DIPEA (0.626 ml, 3.59 mmol). The brown heterogeneous mixture was stirred at room temperature. After 3 h, LC-MS (ESI) showed that the intermediate (1S,2S,4S)-ethyl 4-(4-((2-(3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)ethyl)(neopentyl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylcyclohexanecarboxylate with its (1R,2R,4R)-isomer was formed: LCMS (ESI) m/z 721.1 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:12])[CH2:8][C:9]([CH3:11])=[O:10].[C:18](Cl)(=[O:22])[CH:19]([CH3:21])[CH3:20].Cl>C(OCC)C.O>[CH3:20][CH:19]([CH3:21])[C:18](=[O:22])[CH:8]([C:9](=[O:10])[CH3:11])[C:7]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12]
Reactant: CC(C)C(=O)Cl
Reactant: CCCCOC(=O)CC(C)=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCCCOC(=O)C(C(C)=O)C(=O)C(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under nitrogen atmosphere, to a reactor was added 0.22 mol of potassium tert-butoxide. After evacuating for 2 hrs, 80 ml of THF was added to dissolve the solid with stirring. Then 0.1 mol of butyl acetoacetate was slowly dropped to the reactor cooled in an ice-water bath, and the reaction was continued for further 2 hrs. Then under cooled in the ice-water bath, 0.12 mol of isobutyryl chloride was slowly dropped, and the reaction was continued for further 1.5 hrs. Next, under cooled in the ice-water bath, water was added to dissolve resultant solid, and the reaction mixture was neutralized with hydrochloric acid. Diethyl ether was used to extract product, and the collected organic layer was dried over anhydrous sodium sulfate. Removing solvent by using a rotatory evaporator gave the product.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.C[O:18][B:19](OC)[O:20]C>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([B:19]([OH:20])[OH:18])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 29 %

Procedure:
To a stirred solution of 4-tert-butyl-bromobenzene (21.3 g, 0.0999 mol) in THF (30 mL) at −78° C. under nitrogen was added dropwise a 2.1 M solution of n-butyl lithium in hexanes (45 mL, 0.095 mol), and the mixture was stirred for 1.5 hours. To the mixture was added dropwise neat trimethylborate (10.2 mL, 0.090 mol), and the mixture was allowed to slowly warm to room temperature. The mixture was stirred overnight, then quenched by dropwise addition of 1.0 M aqueous hydrochloric acid. Brine was added, and the organic layer was dried (Na2SO4) and rotary evaporated. The residue was crystallized from n-heptane to give 4.65 g of crude 4-tert-butyl-phenyl-boronic acid as white needles. This material was used directly in the next reaction without further characterization. Thus, in a manner similar to Example 12, Step (b), 4-tert-butyl-phenyl-boronic acid (0.4287 g, 0.00241 mol) was allowed to react with 4-(4-bromo-phenyl)-4-oxo-butyric acid, methyl ester (0.5443 g, 0.00200 mol) in the presence of tetrakis(triphenylphosphine)palladium(0) (0.0472 g, 0.0000408 mol) and 2.0 M aqueous sodium carbonate (2.4 mL, 0.0048 mol) in toluene (5 mL) to give, after chromatography on silica gel (270 g, 230-400 mesh), eluting with toluene then chloroform, 0.50 g. The material was dissolved in diethyl ether, washed with 0.10 M aqueous sodium hydroxide, water and brine. The organics were dried (K2CO3), and rotary evaporated to give 0.45 g of 4-(4′-tert-butyl-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester as a white solid; mp 58-62° C.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][C@@:5]1([N:28]=[N+:29]=[N-:30])[C:16]([O:18][CH2:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH:2]=[CH2:3].[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>C(Cl)Cl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[CH2:1]([C@H:4]1[CH2:8][NH:7][CH2:6][C@@:5]1([N:28]=[N+:29]=[N-:30])[C:16]([O:18][CH2:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH:2]=[CH2:3]
Reactant: C=CC[C@H]1CN(C(=O)OC(C)(C)C)C[C@@]1(N=[N+]=[N-])C(=O)OCC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC[C@H]1CNC[C@@]1(N=[N+]=[N-])C(=O)OCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
While under nitrogen, a solution of racemic 1-tert-butyl 3-(2-oxo-2-phenylethyl) (3R,4S)-4-allyl-3-azidopyrrolidine-1,3-dicarboxylate (0.425 g, 1.02 mmol) in methylene chloride (4 mL) was treated with trifluoroacetic acid (1.2 mL, 15 mmol) quickly dropwise, and the resulting homogeneous mixture was stirred at room temperature. After 40 min, the mixture was concentrated under reduced pressure and dried under high vacuum for several hours to give crude racemic 2-oxo-2-phenylethyl (3R,4S)-4-allyl-3-azidopyrrolidine-3-carboxylate trifluoroacetate as a dark amber viscous oil which was used immediately in the next step. LC-MS ESI+MS found for C16H18N4O3 m/z 315.2 (M+H). 1H NMR (CDCl3, 400 MHz) δ 7.92 (m, 2 H), 7.69 (m, 1 H), 7.55 (m, 2 H), 5.75 (m, 1 H), 5.62 (m, 2 H), 5.24 (d, J=17 Hz, 1 H), 5.20 (d, J=10.2 Hz, 1 H), 4.08 (m, 1 H), 3.80 (m, 1 H), 3.55 (m, 2 H), 2.80 (m, 1 H), 2.63 (m, 1 H), 2.27 (m, 1 H).
Reaction SMILES: B.C1COCC1.[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)=O)=[CH:12][CH:11]=1)([O-:9])=[O:8].C1COCC1>CO>[N+:7]([C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][CH2:18][N:20]2[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]2)=[CH:14][CH:15]=1)([O-:9])=[O:8]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CCc2ccc([N+](=O)[O-])cc2)CC1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(CCCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.7 %

Procedure:
A borane-THF complex (1.08 M THF solution) 23 mL was added dropwise to a mixture of 3.02 g of tert-butyl 4-[3-(4-nitrophenyl)propanoyl]piperazine-1-carboxylate and THF 40 mL under ice cooling in an argon atmosphere, followed by stirring for 10 minutes at room temperature, and then heating under reflux was performed for 2 hours. The reaction mixture was cooled with ice, and 30 mL of methanol was added dropwise thereto, followed by stirring for 3 hours at 50° C. The reaction mixture was concentrated under reduced pressure, water and ethyl acetate were added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (5% methanol/chloroform), thereby obtaining 2.78 g of tert-butyl 4-[3-(4-nitrophenyl)propyl]piperazine-1-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:17])[CH2:13][C:14]([OH:16])=O)[CH2:8][CH2:7]1)=[O:5].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[C:43]1([C:49]2[CH:50]=[CH:51][C:52]([NH2:55])=[N:53][CH:54]=2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:17])[CH2:13][C:14]([NH:55][C:52]2[CH:51]=[CH:50][C:49]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:54][N:53]=2)=[O:16])[CH2:10][CH2:11]1)=[O:5]
Reactant: O=C(O)CC(=O)N1CCN(C(=O)c2ccccc2Br)CC1
Reactant: Nc1ccc(-c2ccccc2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CC(=O)N1CCN(C(=O)c2ccccc2Br)CC1)Nc1ccc(-c2ccccc2)cn1
Reaction time: 0.03 h
Yield: 27.1 %

Procedure:
DMAP (137 mg, 1.1 mmol) was added to 3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-3-oxo-propionic acid (200 mg, 0.56 mmol) in DMF (2 mL) followed by EDCI (129 mg, 0.67 mmol) and HOBT (91 mg, 0.67 mmol). After 2 minutes, 5-phenyl-pyridin-2-ylamine (115 mg, 0.67 mmol) was added and stirring was continued at room temperature overnight. Cold water was then added and it was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford 77 mg (27% yield) of 3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-3-oxo-N-(5-phenyl-pyridin-2-yl)-propionamide. LC/MS [M+H]+: 507.1, 97.03%. 1H NMR (300 MHz, DMSO-d6): δ 10.8 (d, 1H), 8.7-8.6 (bs, 1H), 8.2-8.06 (m, 2H), 7.76-7.64 (m, 3H), 7.54-7.34 (m, 6H), 3.8-3.4 (m, 8H), 3.24-3.1 (m, 2H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:57][C:58]1[CH:59]=[CH:60][C:61]([CH3:74])=[C:62]([C:64]2[CH:69]=[CH:68][C:67]([C:70]([O:72][CH3:73])=[O:71])=[CH:66][CH:65]=2)[CH:63]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:57][C:58]2[CH:59]=[CH:60][C:61]([CH3:74])=[C:62]([C:64]3[CH:69]=[CH:68][C:67]([C:70]([O:72][CH3:73])=[O:71])=[CH:66][CH:65]=3)[CH:63]=2)=[O:8])=[CH:2]1
Reactant: O=C(O)c1ccoc1
Reactant: COC(=O)c1ccc(-c2cc(N)ccc2C)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(-c2cc(NC(=O)c3ccoc3)ccc2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.6 %

Procedure:
3-Furoic acid (557 mg, 4.97 mmol), HATU (1.89 g, 4.97 mmol), HBTU (560 mg, 4.14 mmol), methyl 5′-amino-2′-methyl-1,1′-biphenyl-4-carboxylate (1.0 g, 4.14 mmol) and DIPEA (2.17 ml, 12.43 mmol) were mixed in DMF (5 ml) and the reaction stirred at room temperature for 18 h. The DMF was evaporated under vacuum, the residue partitioned between DCM (50 ml) and aqueous sodium carbonate (1M, 50 ml) and the aqueous extracted with DCM (2×30 ml). The combined organics were washed with brine (75 ml), dried (magnesium sulphate) and concentrated under vacuum. The residue was purified on a silica flash column eluting with DCM/ethanol/ammonia (500:8:1), which after evaporation of the solvents under vacuum gave methyl 5′-(3-furoylamino)-2′-methyl-1,1′-biphenyl-4-carboxylate (800 mg, 58%). LCMS: retention time 3.41 min, MH+336.
Reaction SMILES: [C:1]([C:3]1[C:21]([N+:22]([O-])=O)=[CH:20][CH:19]=[CH:18][C:4]=1[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[C:13]([NH:15][CH2:16][CH3:17])=[O:14])#[N:2].C1CCCCC=1>CCO.[Pd]>[NH2:22][C:21]1[C:3]([C:1]#[N:2])=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[C:13]([NH:15][CH2:16][CH3:17])=[O:14]
Reactant: CCNC(=O)N1CCCCC1COc1cccc([N+](=O)[O-])c1C#N
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CCNC(=O)N1CCCCC1COc1cccc(N)c1C#N
Temperature: 100 °C
Yield: 92.2 %

Procedure:
To a solution of 2-((2-cyano-3-nitrophenoxy)methyl)-N-ethylpiperidine-1-carboxamide (Example 26c, 0.458 g, 1.46 mmol) in EtOH (20 mL) was added cyclohexene (0.74 mL, 7.3 mmol) and catalytic amount of 10% Pd/C (0.146 mg). Reaction mixture was heated at 100° C. for 40 minutes, then filtered through Cellite, washed with EtOH (100 mL) and evaporated to give 2-((3-amino-2-cyanophenoxy)methyl)-N-ethylpiperidine-1-carboxamide (0.407 g, 92%) which was used in to next step without further purification. MS 303 (MH+).