Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]([CH2:35][C:36]1[CH:41]=[C:40]([O:42][CH2:43][CH:44]=[CH2:45])[C:39]([Br:46])=[C:38]([O:47][CH2:48][CH:49]=[CH2:50])[CH:37]=1)[C@H:8]([CH2:23][O:24][Si](C(C)C)(C(C)C)C(C)C)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:22])[O:18][CH2:19][CH:20]=[CH2:21])=[CH:12][CH:11]=1)=[O:6])[CH:2]=[CH2:3].N1C=CC=CC=1.F.[Cl-].[NH4+]>C1COCC1>[CH2:1]([O:4][C:5]([N:7]([CH2:35][C:36]1[CH:37]=[C:38]([O:47][CH2:48][CH:49]=[CH2:50])[C:39]([Br:46])=[C:40]([O:42][CH2:43][CH:44]=[CH2:45])[CH:41]=1)[C@H:8]([CH2:23][OH:24])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:22])[O:18][CH2:19][CH:20]=[CH2:21])=[CH:12][CH:11]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)Oc1ccc(C[C@@H](CO[Si](C(C)C)(C(C)C)C(C)C)N(Cc2cc(OCC=C)c(Br)c(OCC=C)c2)C(=O)OCC=C)cc1
Agent: F
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=CCOC(=O)Oc1ccc(C[C@@H](CO)N(Cc2cc(OCC=C)c(Br)c(OCC=C)c2)C(=O)OCC=C)cc1
Yield: 93.6 %

Procedure:
To 24 (1.15 g, 1.49 mmol, 1.0 equiv) in THF (20 mL) in a high density polyethylene vial was added hydrogen fluoride-pyridine (1 mL) once an hour for 4 hours (4 mL total), after which time saturated aqueous ammonium chloride was added and the THF was removed under reduced pressure. The remaining solution was extracted with CH2Cl2. The organics were combined, washed with brine, dried over Na2SO4, and concentrated. Purification by flash chromatography (20→60% EtOAc/hexane) afforded 25 (0.86 g, 94%) as a colorless oil. Rf=0.23 (50% EtOAc/hexane); [α]28D=−29.24° (c=1, CH2Cl2); FTIR (neat, cm−1) 3447, 2932, 1761, 1695, 1588, 1435, 1421, 1242; 1H NMR (400 MHz, DMSO, 80° C.) δ7.18-7.12 (m, 2H), 7.10-7.04 (m, 2H), 6.63 (s, 2H), 6.07-5.94 (m, 3H), 5.90-5.78 (m, 1H), 5.42 (dd, J=15.2, 2.0 Hz, 2H), 5.39 (dd, J=14.0, 1.6 Hz, 1H), 5.30 (dd, J=10.4, 1.6 Hz, 1H), 5.25 (dd, J=10.6, 1.8 Hz, 2H) 5.18 (d, J=16.8 Hz, 1H), 5.13 (d, J=10.4 Hz), 4.73-4.71 (m, 2H), 4.55-4.54 (m, 4H), 4.72 (d, J=4.0 Hz, 2H), 4.36 (d, J=16.0 Hz, 1H), 4.24 (d, J=16.4 Hz, 1H), 4.21-4.12 (m, 1H), 3.62-3.57 (m, 1H), 3.53-3.49 (m, 1H), 2.90-2.77 (m, 2H); 13C NMR (100 MHz, DMSO, 80° C.) δ155.3, 155.1, 152.2, 148.8, 140.1, 136.3, 132.9, 132.8, 131.5, 129.3, 120.1, 116.8, 116.6, 116.3, 105.8, 105.6, 99.1, 69.2, 69.0, 68.1, 64.7, 61.3, 60.5, 48.1, 34.3; HRMS (ES+) calculated for C30H34BrNO8 (M+H)+: 616.1468, found: 616.1570.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.Cl[CH2:22][C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][CH:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O
Temperature: 25 °C

Procedure:
3.04 g (9.9 mmol) of the compound of Example 4A were dissolved in 100 ml of acetonitrile, and 1.07 g (9.9 mmol) of methyl chloroacetate, 2.73 g (19.8 mmol) of potassium carbonate and a small spatula tip of potassium iodide were added. The reaction mixture was heated at reflux for 1 h, allowed to cool to RT and filtered. The filtrate was freed from the volatile components on a rotary evaporator and the residue was dried under high vacuum. This gave 3.70 g of the title compound in a purity of about 90% (89% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH2:37][CH:38]([CH3:40])[CH3:39])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34](O)=[O:35])[CH2:29]4)[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.C(N(CC)C(C)C)(C)C.[C:56]([C:60]1[CH:61]=[C:62]([NH2:67])[C:63]([NH2:66])=[CH:64][CH:65]=1)([CH3:59])([CH3:58])[CH3:57]>CN(C)C=O>[NH2:67][C:62]1[CH:61]=[C:60]([C:56]([CH3:59])([CH3:57])[CH3:58])[CH:65]=[CH:64][C:63]=1[NH:66][C:34](=[O:35])[CH2:33][CH2:32][CH:30]1[CH2:31][CH:28]([N:27]([CH2:26][C@@H:18]2[C@@H:19]3[C@@H:20]([O:21][C:22]([CH3:24])([CH3:25])[O:23]3)[C@H:16]([N:13]3[C:9]4[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]5[CH:41]=[CH:42][C:43]([O:45][CH3:46])=[CH:44][C:3]=5[O:2][CH3:1])[C:8]=4[CH:15]=[CH:14]3)[CH2:17]2)[CH2:37][CH:38]([CH3:39])[CH3:40])[CH2:29]1
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(CC(C)C)C3CC(CCC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(CC(C)C)C3CC(CCC(=O)Nc4ccc(C(C)(C)C)cc4N)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
N,N,N′,N′-Tetramethyl-0-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (1.52 g, 4.01 mmol) added to a solution of 3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(isobutyl)amino)cyclobutyl)propanoic acid (1.7 g, 2.7 mmol) and N,N-Diisopropylethylamine (1.54 ml, 8.82 mmol) and 4-tert-butylbenzene-1,2-diamine (0.527 g, 3.21 mmol) in N,N-Dimethylformamide (16.6 ml). The reaction was stirred overnight at RT, partially concentrated to ca. 2 mls and then NaHCO3 (saturated) added. Them mixture was extracted with EtOAc 3× and the combined organics were dried with MgSO4 filtered, concentrated and purified by flash chromatography (DCM/7N NH3 in MeOH 95:5) to yield the desired amide (1.71 g) as a solid,
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH2:9]1[CH2:15][S:12](=[O:14])(=[O:13])[O:11][CH2:10]1>C1COCC1>[OH:8][CH2:7][C@H:2]([NH:1][CH2:10][CH2:9][CH2:15][S:12]([OH:14])(=[O:13])=[O:11])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@@H](N)CO
Reactant: O=S1(=O)CCCO1
Solvent: C1CCOC1
Product: CC(C)C[C@H](CO)NCCCS(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of D-(−)-leucinol (2.0 g, 17.1 mmol) in THF (30 mL) was slowly added 1,3-propanesultone (1.94 g, 16.3 mmol). The solution was stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration and washed with acetone (2×20 mL). The solid was dissolved in 50% water/EtOH (240 mL). Dowex Marathon C ion exchange resin (strongly acidic) was added to the solution. The suspension was stirred for 15 minutes before the resin was removed by filtration. The filtrate was evaporated under reduced pressure. The solid was suspended in acetone (50 mL), filtered and dried in the vacuum oven (50° C.), affording the title compound (2.55 g, (65%). 1H NMR (D2O, 500 MHz) δ ppm 3.74 (d, 1H, J=12.7 Hz), 3.56 (d, 1H, J=12.7 Hz), 3.20 (m, 1H), 3.10 (t, 2H, J=7.3 Hz), 2.87 (t, 2H, J=7.3 Hz), 2.00 (m, 2H), 1.49 (m, 2H), 1.31 (m, 1H), 0.80 (d, 3H, J=6.3 Hz), 0.76 (d, 3H, J=6.3 Hz). 13C (D2O, 125 MHz) δ ppm 58.74, 58.01, 48.19, 43.56, 35.98, 24.34, 22.54, 21.63, 20.90. [α]D=−16.3° (c=0.0019 in water), ES-MS 238 (M−1).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:19][C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[O:28])[CH:23]=[CH:24][CH:25]=1>>[CH2:12]([N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](=[O:4])[CH2:2][NH:1][C:27]([NH:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([CH3:19])[CH:21]=1)=[O:28])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: NCC(=O)N(Cc1ccccc1)c1ccccc1
Product: Cc1cccc(NC(=O)NCC(=O)N(Cc2ccccc2)c2ccccc2)c1
Yield: 77.9 %

Procedure:
Working in a manner similar to that described in Example 1, but starting with 2-amino-N-benzyl-N-phenylacetamide (1.9 g) and 3-methylphenyl isocyanate (1.1 g), and after recrystallization in acetonitrile, N-benzyl-N-phenyl-2-[3-(3-methylphenyl)ureido]acetamide (2.3 g), m.p. 175° C., is obtained.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([CH:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)[C:14](=[O:20])[C:15]([CH3:19])([CH3:18])[CH2:16][OH:17])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].I[CH3:32]>C1COCC1>[C:1]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([C:14](=[O:20])[C:15]([CH3:19])([CH3:18])[CH2:16][O:17][CH3:32])[CH:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)[CH2:9]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC1(C)CCC(N(C(=O)C(C)(C)CO)[C@H]2CCN(C(=O)OC(C)(C)C)C2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC(C)(C)C(=O)N(C1CCC(C)(C)CC1)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
To a solution of (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]pyrrolidine (800 mg, 2.02 mmol) prepared in Step B of Example A8 in THF was added NaH (73 mg, 3.03 mmol) and iodomethane (430 mg, 3.03 mmol) at 0° C., and the solution was stirred at rt for 2 h. After the reaction finished, the solution was concentrated in vacuo, extracted with 1N-HCl and EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/Hex=1/2) to give the title compound (784 mg, 94.6%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1>>[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])=[O:14])=[CH:11][CH:10]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: O=C1CCCN1
Product: COc1ccc(C(=O)N2CCCC2=O)cc1

Procedure:
10 g. of 2-pyrrolidinone and 10 g. of p-methoxybenzoyl chloride are heated at 80°-90° C. (internal temperature) in the absence of a solvent for 1 hour. The mixture is then left to cool down and is worked-up as described in Example 3. After recrystallization from alcohol, there is obtained 1-(p-methoxybenzoyl)-2-pyrrolidinone having a melting point of 120°-121° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].Br[CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[C:29]([F:31])[C:28]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])=[C:27]([F:37])[CH:26]=2)[N:24]=1)=[O:18].[H-].[Na+]>CN(C=O)C>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH2:16][C:17]([NH:19][C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH:26]=[C:27]([F:37])[C:28]([O:32][CH2:33][CH:34]([CH3:35])[CH3:36])=[C:29]([F:31])[CH:30]=4)[N:24]=3)=[O:18])[C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14]
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Reactant: CC(C)COc1c(F)cc(-c2csc(NC(=O)CBr)n2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)COc1c(F)cc(-c2csc(NC(=O)Cn3ccc4c3c(=O)n(C)c(=O)n4C)n2)cc1F

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (50 mg, 0.279 mmol) with 2-bromo-N-{4-[4-(2-methylpropoxy)-3,5-difluorophenyl]-1,3-thiazol-2-yl}acetamide (135 mg, 0.334 mmol) in the presence of NaH (10 mg, 0.416 mmol) in dry DMF (5.0 mL) to give 45 mg of the product as an off-white solid; 1H NMR (δ ppm, 300 MHz, DMSO-d6) 0.98 (d, J=6.9 Hz, 6H), 1.96-2.04 (m, 1H), 3.17 (s, 3H), 3.33 (s, 3H), 3.91 (d, J=6.3 Hz, 2H), 5.32 (s, 2H), 6.22 (s, 1H), 7.35 (s, 1H), 7.65 (d, J=9.0 Hz, 2H), 7.77 (s, 1H), 12.68 (br s, 1H); APCI-MS (m/z) 504.11 (M+H)+.
Reaction SMILES: Br[CH:2]1[CH2:4][CH2:3]1.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[N:12]>>[CH:2]1([CH:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=2)[NH2:12])[CH2:4][CH2:3]1
Reactant: N#Cc1ccccn1
Reactant: BrC1CC1
Product: NC(c1ccccn1)C1CC1

Procedure:
The title compound was synthesized according to method G, utilizing Mg powder (240 mg, 10 mmol), bromocyclopropane (1.21 g, 10 mmol), picolinonitrile (520 mg, 5 mmol) and
Reaction SMILES: [CH3:1][C@H:2]1[NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][CH2:3]1.[C:13](OC(=O)C)(=[O:15])[CH3:14].CCN(CC)CC>CN(C=O)C>[CH3:1][C@H:2]1[N:8]([C:13](=[O:15])[CH3:14])[CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][CH2:3]1
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H]1CNc2ccccc2CN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N1Cc2ccccc2NC[C@H]1C
Yield: 34.5 %

Procedure:
(3R)-3-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (8.6 mmol) was allowed to react with 8.4 mmol acetic anhydride and 12.9 mmol Et3N in 20 mL DMF to give 2.9 mmol of 1-[(3R)-3-methyl-1,2,3,5-tetrahydro-4H-1,4-benzodiazepin4-yl]-1-ethanone.
Reaction SMILES: [C:1]([C:5]([C:16]1[CH:17]=[CH:18][N:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[C:21]([C:26]([O:28]CC)=[O:27])[C:20]2=[O:31])(C(OC)=O)[CH2:6][C:7]([O:9]CC)=[O:8])([O:3]C)=[O:2].O=C1N2C(C=CC=C2)=CC=C1C(OCC)=O>>[C:1]([CH:5]([C:16]1[CH:17]=[CH:18][N:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[C:21]([C:26]([OH:28])=[O:27])[C:20]2=[O:31])[CH2:6][C:7]([OH:9])=[O:8])([OH:3])=[O:2]
Reactant: CCOC(=O)CC(C(=O)OC)(C(=O)OC)c1ccn2c(=O)c(C(=O)OCC)ccc2c1
Agent: CCOC(=O)c1ccc2ccccn2c1=O
Product: O=C(O)CC(C(=O)O)c1ccn2c(=O)c(C(=O)O)ccc2c1
Yield: 48 %

Procedure:
Saponification of (20) was done as described for (1). After completion of the reaction, the solvent was evaporated in vacuo, and the resulting yellow solid was dissolved in water. The aqueous layer was acidified to pH 1, and extracted three times with ethyl acetate. Evaporation of the organic solvent gave 8-(1,2-dicarboxyethyl)-4-oxo-4H-quinolizine-3-carboxylic acid (20a) as a yellow solid in 48% yield. M.p. 250° C. 1H NMR (δ, DMSO-d6): 2.72-2.76 (m, 2H), 3.02-3.06 (m, 1H), 7.14 (d, J=9 Hz, 1H), 7.60 (dd, J=2 Hz, J=9 Hz, 1H), 7.99 (s, 1H), 8.34 (d, J=9 Hz, 1H), 9.20 (d, J=9 Hz, 1H). MS: m/z 261.0601 (M-CO2); required for C13H11NO5: 261.0637.
Reaction SMILES: [NH2:1][C:2]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16](=[O:31])[C:17]3[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=3)[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Cl[C:42]([O:44][CH2:45][CH3:46])=[O:43]>C(Cl)Cl.C(OCC)(=O)C>[F:30][C:27]([F:28])([F:29])[C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=1)[C:16]([NH:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:2]2([NH:1][C:42](=[O:43])[O:44][CH2:45][CH3:46])[CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:9][CH2:10]1)=[O:31]
Reactant: CCOC(=O)Cl
Reactant: NC1(CN2CCC(CNC(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)CCCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)NC1(CN2CCC(CNC(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-((1-((1-aminocyclopentyl)methyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide (100 mg, 0.28 mmol) and i-Pr2NEt (0.2 mL, 1.1 mmol) in CH2Cl2 (5 mL) was added ethyl chloroformate (0.05 mL, 0.53 mmol). The reaction mixture was allowed to stir at room temperature for 18 hours and then diluted with ethyl acetate. The organic fraction was washed with sat. NaHCO3, and then brine and dried over Na2SO4. The solvent was removed and the crude was purified by HiTOPs to provide ethyl 1-((4-((3,5-bis(trifluoromethyl)benzamido)methyl)piperidin-1-yl)methyl)cyclopentylcarbamate.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:10][C@H:9](N)[CH2:8][CH2:7][C@@H:6]1[N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]1=[O:28])(=[O:3])[CH3:2].C(C1C(=O)C(=[O:43])C=C(C(C)(C)C)C=1)(C)(C)C>CO.CCOC(C)=O>[C:1]([NH:4][C@@H:5]1[CH2:10][C:9](=[O:43])[CH2:8][CH2:7][C@@H:6]1[N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]1=[O:28])(=[O:3])[CH3:2]
Reactant: CC(C)(C)C1=CC(=O)C(=O)C(C(C)(C)C)=C1
Reactant: CC(=O)N[C@@H]1C[C@H](N)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)N[C@@H]1CC(=O)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-aminocyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (13.3 g, 34 mmol) and 3,5-di-tert-butylcyclohexa-3,5-diene-1,2-dione (7.54 g, 34 mmol) in methanol (160 ml) was stirred at room temperature for 2 h. The solution was concentrated and diluted with acetone (132 ml) and water (33 ml), followed by addition of Dowex-50WX8-200 (33 g). The reaction was stirred at room temperature for 2 h. Dowex-50WX8-200 was removed by filtration and washed with dichloromethane (300 ml). The filtrate was concentrated under vacuum to remove most of acetone. The residue was diluted with dichloromethane (200 ml) and washed with aqueous NaHCO3 solution (200 ml) and brine (200 ml). The combined aqueous layers were extracted with dichloromethane (2×100 ml). The combined organic extracts were dried over Na2SO4 and concentrated. The product benzyl (S)-1-((1S,2R)-2-acetamido-4-oxocyclohexyl)-2-oxopyrrolidin-3-ylcarbamate was obtained as a solid (12 g, 90% yield) by crystallization in EtOAc (100 ml) and Hexane (200 ml). 1H-NMR (500 MHz, DMSO-d6) δ ppm 7.99 (d, J=9.35 Hz, 1H), 7.44 (d, J=8.80 Hz, 1H), 7.28-7.39 (m, 5H), 5.03 (s, 2H), 4.50 (s, 1H), 4.31 (d, J=12.10 Hz, 1H), 4.18 (q, J=8.98 Hz, 1H), 3.27 (m, 2H), 2.82 (dd, J=15.12, 5.22 Hz, 1H), 2.52-2.65 (m, 1H), 2.40 (dd, J=12.92, 4.67 Hz, 1H), 2.15-2.31 (m, 2H), 2.09 (d, J=15.40 Hz, 1H), 1.90 (m, 1H), 1.81 (s, 3H), 1.68 (m, 1H). m/z: 388.46 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13]([CH3:20])=[C:14]([NH2:19])[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]=2[CH3:21])=[CH:4][CH:3]=1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>C(OCC)(=O)C.CCCCCC>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:19][C:14]2[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]3[O:10][C:9]([CH3:21])=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[C:12]=3[C:13]=2[CH3:20])=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1oc2c(C)c(C)c(N)c(C)c2c1-c1ccc(F)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1oc2c(C)c(C)c(NC(=O)c3ccc(F)cc3)c(C)c2c1-c1ccc(F)cc1
Yield: 75 %

Procedure:
By using 3-(4-fluorophenyl)-2,4,6,7-tetramethyl-1-benzofuran-5-amine and 4-fluorobenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 75%. Melting point: 232-234° C. (Ethyl acetate-hexane)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([NH:7][NH2:8])=[O:6].[CH:13]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25]([OH:27])=[O:26])=[CH:17][CH:16]=1)=O>CS(C)=O.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([NH:7][N:8]=[CH:13][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25]([OH:27])=[O:26])=[CH:17][CH:16]=1)=[O:6]
Reactant: O=Cc1ccc(C(=O)O)c2ccccc12
Reactant: NNC(=O)c1ccc(O)c(Cl)c1
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NN=Cc1ccc(C(=O)O)c2ccccc12)c1ccc(O)c(Cl)c1
Reaction time: 16 h

Procedure:
To a solution of 3-chloro-4-hydroxybenzoic acid hydrazide (1.53 g, 8.23 mmol) in DMSO (20 mL) was added a solution of 4-formylnaphthoic acid (1.65 g, 8.23 mmol) in DMSO (2 mL). After stirring the solution for 16 hr, the reaction was diluted with ethyl acetate (30 mL) and water (30 mL). A precipitate formed. The precipitate was collected, washed with hexane and dried to give the product as a white solid in quantitative yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](O)=[O:24])=[CH:18][CH:17]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:23](=[O:24])[CH2:22][C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-piperidine 1-carboxylic acid tert-butyl ester (0.44 g, 2.2 mmol) and 4-chlorophenyl acetic acid (0.34 g, 2 mmol) in dichloromethane (10 mL) were added EDCI (0.55 g, 2.8 mmol), HOBT (0.42 g, 2.8 mmol) and N-methylmorpholine (0.6 g, 6 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, diluted with dichloromethane and extracted with saturated aqueous sodium bicarbonate solution. The aqueous layer was back extracted twice with dichloromethane. The combined organics were dried over sodium sulfate and concentrated in vacuo. Crude product was purified using a short plug of silica gel using ethyl acetate to give the desired product
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[C@@H:13]([CH3:15])[OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](Br)(=[O:21])[CH3:20]>C(O)(=O)C>[C:19]([O:14][C@H:13]([CH3:15])[C@@H:12]([C:16]([OH:18])=[O:17])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])(=[O:21])[CH3:20]
Reactant: CC(=O)Br
Reactant: C[C@@H](O)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: CC(=O)O
Product: CC(=O)O[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
To a solution of N-benzyloxycarbonyl-L-threonine (5 g) in acetic acid (50 ml) was added acetyl bromide (1.75 ml) at room temperature. After stirring for an hour at room temperature, the reaction mixture was concentrated and the residue was diluted with ethyl acetate and washed successively with water (2 times) and brine. After drying over sodium sulfate, the ethyl acetate extract was filtered and concentrated to give O-acetyl-N-benzyloxycarbonyl-L-threonine (3.64 g).
Reaction SMILES: C([O:5][C:6](=[O:35])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[NH:29][C:28](=[O:30])[C:27]4[C:22](=[CH:23][C:24]([O:33][CH3:34])=[C:25]([O:31][CH3:32])[CH:26]=4)[N:21]=3)[CH2:16][CH2:15]2)=[CH:9][CH:8]=1)(C)(C)C>FC(F)(F)C(O)=O>[CH3:32][O:31][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:33][CH3:34])[N:21]=[C:20]([N:17]1[CH2:18][CH2:19][CH:14]([NH:13][C:10]3[CH:11]=[CH:12][C:7]([C:6]([OH:35])=[O:5])=[CH:8][CH:9]=3)[CH2:15][CH2:16]1)[NH:29][C:28]2=[O:30]
Reactant: COc1cc2nc(N3CCC(Nc4ccc(C(=O)OC(C)(C)C)cc4)CC3)[nH]c(=O)c2cc1OC
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2nc(N3CCC(Nc4ccc(C(=O)O)cc4)CC3)[nH]c(=O)c2cc1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 187.8 %

Procedure:
A solution of (15) (0.036 g, 0.074 mmol) in trifluoroacetic acid (5 mL) was capped with a drying tube and stirred at 25° C. for 12 h. The reaction mixture was evaporated to a light brown oily residue (0.059 g, quantitative yield); 1H NMR (DMSO) δ 8.00 (br s, 1H), 7.67 (d, 2H, J=8.3), 7.31 (s, 1H), 6.98 (s, 1H), 6.63 (d, 2H, J=8.2), 6.12 (br s, 1H), 4.22 (d, 2H, J=12.8), 3.86 (s, 3H), 3.81 (s, 3H), 3.65 (m, 1H), 3.28 (m, 2H), 2.03 (m, 2H), 1.49 (m, 2H); 13C NMR (DMSO) δ 167.5, 161.8, 160.7, 155.2, 151.4, 149.6, 146.3, 131.2, 124.2, 123.9, 116.9, 111.2, 108.2, 105.8, 55.8, 55.7, 47.9, 44.6, 30.8; HRMS (FAB) m/z 425.1818 (M+H)+ (C22H24N4O5 requires 425.1819); Anal. (C22H24N4O5 ·2CF3COOH·1CH3OH) C, H, N.
Reaction SMILES: [CH2:1]([NH:6][C:7](=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)[CH2:2][CH:3]([CH3:5])[CH3:4].[H][H]>[Pd].CO>[NH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:1][CH2:2][CH:3]([CH3:4])[CH3:5])=[O:17])=[CH:13][CH:12]=1
Reactant: [H][H]
Reactant: CC(C)CCNC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)CCNC(=O)c1ccc(N)cc1

Procedure:
N-Isopentyl-4-nitrobenzamide (1 g, 4.23 mmol) and methanol (40 ml) were added to palladium on carbon (0.200 g, 1.879 mmol) in a 250 mL SS pressure bottle and the mixture was stirred for 6 hours with hydrogen at 30 psi and room temperature. The mixture was filtered through a nylon membrane and concentrated to provide the title compound.