Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[S:3])=S.C(O)C.[NH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[NH2:14]>O>[NH:7]1[CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[NH:14][C:1]1=[S:3]
Reactant: NC1CCCCC1N
Reactant: S=C=S
Solvent: O
Solvent: CCO
Product: S=C1NC2CCCCC2N1

Procedure:
To a mixture of 67 g. of carbon disulfide in 300 ml. of ethanol is added dropwise with stirring a solution of 100 g. of 1,2-diaminocyclohexane in 100 ml. of ethanol. The resulting solution is stirred one-half hour after addition; liquid eliminated and the residue dissolved in 300 ml. of water and heated at reflux for 18 hours. The precipitate which forms on cooling is filtered off, washed with water and then with ether and dried under reduced pressure to obtain 3a,4,5,6,7,7a-hexahydro-2-benzimidazolin-thione, m.p. 170°C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:14]([CH2:15][CH2:16][CH2:17][C:18](OCC)=[O:19])[C:13]2[C:23]([CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:24][CH:25]=[C:26]([Cl:27])[C:12]=2[N:11]=1.[BH4-].[Li+]>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[C:13]2[C:23]([CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:24][CH:25]=[C:26]([Cl:27])[C:12]=2[N:11]=1
Reactant: CCOC(=O)CCCn1c(Nc2ccc(C)cc2Br)nc2c(Cl)ccc(C(CC)CC)c21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3ccc(C)cc3Br)n(CCCCO)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.8 %

Procedure:
To a solution of ethyl 4-[2-[(2-bromo-4-methylphenyl)amino]-4-chloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (1.42 g, 2.74 mmol) in tetrahydrofuran (15.0 mL) was added lithium borohydride (178.7 mg, 8.20 mmol) at 0° C. The reaction mixture was stirred at room temperature for 24 hr. The reaction mixture was quenched with water at 0° C. and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was suspended n-hexane and stirred at 70° C. for 30 min. After cooling, the solid was collected by filtration to give the title compound as a colorless powder (1.03 g, 2.16 mmol, 79%).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][N:13](C)[C:14]([NH:16][CH:17]2[CH:24]3[CH2:25][CH:20]4[CH2:21][CH:22]([CH2:26][CH:18]2[CH2:19]4)[CH2:23]3)=[O:15])=[CH:6][CH:5]=1.[OH-].[Na+].O.[CH2:32]1COCC1>>[CH:18]12[CH2:26][CH:22]3[CH2:21][CH:20]([CH2:25][CH:24]([CH2:23]3)[CH:17]1[N:16]([CH3:32])[C:14](=[O:15])[NH:13][CH2:12][CH2:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:2])=[O:28])=[CH:9][CH:8]=1)[CH2:19]2
Reactant: COC(=O)c1ccc(OCCN(C)C(=O)NC2C3CC4CC(C3)CC2C4)cc1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C(=O)NCCOc1ccc(C(=O)O)cc1)C1C2CC3CC(C2)CC1C3
Reaction time: 8 h

Procedure:
A solution of 4-[2-(3-Adamantan-2-yl-1-methyl-ureido)-ethoxy]-benzoic acid methyl ester 562 mg (1.45 mmol), NaOH 1 N 3 ml in THF 5 ml was stirred at RT overnight. Then NaOH 1 N 4 ml was added and the reaction mixture stirred overnight. Water was added and the mixture acidified until pH=2.
Reaction SMILES: N#N.[CH3:3][C:4]1([CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[N:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[N:14]2)[O:8][CH2:7][CH2:6][O:5]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][C:4]1([CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: CC1(CCCCn2ncc([N+](=O)[O-])n2)OCCO1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC1(CCCCn2ncc(N)n2)OCCO1
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-4-nitro-2H-[1,2,3]triazole (250 mg, 0.98 mmol), iron powder (165 mg, 2.93 mmol) and NH4Cl (264 mg, 4.88 mmol) in a mixture of EtOH (3.0 mL) and water (1.5 mL) was stirred at 85° C. for 30 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (20 mL) was added followed by water (20 mL). The aq. layer was extracted with CH2Cl2 (2×20 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a pale yellow oil. LC-MS-conditions 02: tR=0.66 min; [M+H]+=227.47.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:10]2[CH2:14][O:13][C:12](=[O:15])[C:11]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].BrCC(C1C=CC(OC)=CC=1)=O>>[CH3:9][O:8][C:7]1[CH:2]=[CH:3][C:4]([C:10]2[CH2:14][O:13][C:12](=[O:15])[C:11]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=2)=[CH:5][CH:6]=1
Reactant: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)OC2)cc1Cl
Agent: COc1ccc(C(=O)CBr)cc1
Product: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)OC2)cc1

Procedure:
Following the procedure for the preparation of 4-(3-chloro-4-methoxyphenyl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one using 2-bromo-1-(4-methoxyphenyl)ethanone provided the title compound. 1H NMR (500 MHz, CDCl3): δ 8.86-8.78 (m, 2H), 8.21 (d, J=7.8 Hz, 1H), 8.08 (d, J=7.6 Hz, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.68-7.64 (m, 1H), 7.58-7.50 (m, 1H), 7.39 (d, J=7.2 Hz, 2H), 7.29-7.21 (m, 1H), 7.02 (d, J=7.4 Hz, 2H), 6.92 (d, J=7.4 Hz, 2H), 5.41 (s, 2H), 5.05 (s, 2H), 3.92 (s, 3H). MS: M+H: m/z=424.2; M+Na: m/z=446.1. HPLC: 90%, (Condition-C).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1[C:9]1([C:12]#[N:13])[CH2:11][CH2:10]1.CC(C[AlH]CC(C)C)C.[BH4-].[Na+].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1[C:9]1([CH2:12][NH2:13])[CH2:10][CH2:11]1
Reactant: N#CC1(c2cnc(Cl)cc2Cl)CC1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [BH4-]
Solvent: Cc1ccccc1
Solvent: CO
Product: NCC1(c2cnc(Cl)cc2Cl)CC1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
1-(4,6-Dichloro-3-pyridyl)cyclopropanecarbonitrile (0.1 g, 0.469 mmol) was dissolved in Toluene (2.3 mL). At −10° C. DIBAL-H 1M in Toluene (0.98564 mL, 0.986 mmol) was added dropwise. The reaction mixture was stirred 30 min at −10° C. At −10° C. NaBH4 (0.10871 g, 2.816 mmol) was added, then carefully 3 mL MeOH. The reaction mixture was stirred 30 min at rt. It was poured into 25 ml of 1N potassium sodium tartrate. The pale yellow solution was extracted 3 times with Ether. The combined organic phases were washed with brine and dried with Na2SO4, filtrated and the filtrate evaporated. The product was obtained as a pale yellow oil (99 mg).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:6][CH2:5][C:4]([CH:11]([CH3:13])[CH3:12])([C:7]([O:9]C)=[O:8])[CH2:3]1.O.[OH-].[Li+].CO>O1CCOCC1.O>[CH2:1]=[C:2]1[CH2:6][CH2:5][C:4]([CH:11]([CH3:13])[CH3:12])([C:7]([OH:9])=[O:8])[CH2:3]1
Reactant: C=C1CCC(C(=O)OC)(C(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: C=C1CCC(C(=O)O)(C(C)C)C1
Temperature: 80 °C
Reaction time: 48 h
Yield: 111.9 %

Procedure:
A solution of the methyl 3-methylene-1-isopropylcyclopentanecarboxylate (Step A, 1.21 g, 6.64 mmol) in a mixture of dioxane (4 mL) and water (4 mL) containing 1.114 g (26.56 mmol) of lithium hydroxide monohydrate was homogenized with methanol, and stirred at 80° C. for 48 hrs. The solvent was removed in vacuo, the residue was dissolved in water and the non-acidic components were extracted with diethyl ether (3×30 mL), combined ethers were back-washed with water (1×30 mL). The combined aqueous phases were acidified with 2N HCl and extracted with chloroform (6×30 mL), dried (anhydrous magnesium sulfate) and evaporated to dryness to leave 1.25 g of crude acid. It was used in the next reaction step without any further purification.
Reaction SMILES: [C:1]([O:4][C@H:5]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[CH2:6][CH2:7][C@H:8]1[C:11](=[O:12])[N:10]([C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=2)[C@@H:9]1[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)(=[O:3])[CH3:2].[C:34](OC(=O)C)(=[O:36])[CH3:35].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:34]([O:26][C:23]1[CH:24]=[CH:25][C:20]([C@@H:9]2[C@@H:8]([CH2:7][CH2:6][C@H:5]([O:4][C:1](=[O:3])[CH3:2])[C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:11](=[O:12])[N:10]2[C:13]2[CH:14]=[CH:15][C:16]([I:19])=[CH:17][CH:18]=2)=[CH:21][CH:22]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O[C@@H](CC[C@H]1C(=O)N(c2ccc(I)cc2)[C@@H]1c1ccc(O)cc1)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc([C@@H]2[C@@H](CC[C@H](OC(C)=O)c3ccc(F)cc3)C(=O)N2c2ccc(I)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (1S)-1-(4-fluorophenyl)-3-[(2S,3R)-2-(4-hydroxyphenyl)-1-(4-iodophenyl)-4-oxoazetidin-3-yl]propyl acetate (1-7a) (2 g, 3.58 mmol) (prepared according to Burnett, D. S.; Caplen, M. A.; Domalski, M. S.; Browne, M. E.; Davis, H. R. Jr.; Clader, J. W. Bioorg. Med. Chem. Lett. (2002), 12, 311) in CH2Cl2 (25 mL) under nitrogen atmosphere was added acetic anhydride (0.4 mL, 4.30 mmol), triethylamine (0.75 mL, 5.38 mmol) and DMAP. The reaction mixture was stirred at RT for 1 hr and the solvent removed under vacuum. The residue was purified by MPLC (silica column) with stepwise gradient elution; (0-100% EtOAc/hexanes as eluent) to afford the title compound (i-8). m/z (ES) (M-OAc)+. 1HNMR (500 MHz, CDCl3) δ: 7.57 (d, J=8.6, 1H) 7.38-7.26 (m, 5H), 7.22 (br d, J=7.1 H, 2H), 7.14 (d, J=8.5 Hz, 1H), 7.08-7.02 (m, 3H), 5.74 (t, J=6.7 Hz, 1H), 4.62 (d, J=2.3 Hz, 1H), 3.10 (dt, J=2.3, 7.8 Hz, 1H), 2.34 (s, 3H), 2.08 (s, 3H), 2.09-2.03 (m, 2H), 1.94-1.86 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([S:11][CH2:12][C:13](=O)[CH3:14])[CH:8]=[C:7]([F:16])[CH:6]=1)[CH3:2].Cl.[Cl:19][C:20]1[C:21]([F:28])=[C:22]([NH:26]N)[CH:23]=[CH:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:6]=[C:7]([F:16])[CH:8]=[C:9]([S:11][C:12]2[C:23]3[C:22](=[C:21]([F:28])[C:20]([Cl:19])=[CH:25][CH:24]=3)[NH:26][C:13]=2[CH3:14])[CH:10]=1)[CH3:2]
Reactant: NNc1cccc(Cl)c1F
Reactant: CCOC(=O)c1cc(F)cc(SCC(C)=O)c1
Agent: Cl
Product: CCOC(=O)c1cc(F)cc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: 3-fluoro-5-(2-oxo-propylsulfanyl)-benzoic acid ethyl ester and (3-chloro-2-fluoro-phenyl) hydrazine hydrochloride
Reaction SMILES: [C:1](OCC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[C:25]=1[OH:34]>CC1C=CC(C)=CC=1>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][C:1]1[O:34][C:25]2[C:26]([C:30]([F:31])([F:32])[F:33])=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)[CH3:7]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Nc1cccc(C(F)(F)F)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccc(C)cc1
Product: CCOC(=O)Cc1nc2cccc(C(F)(F)F)c2o1
Temperature: 25 °C

Procedure:
2-Nitro-6-trifluoromethyl-phenol (1.8 g) (J. Org. Chem. 1962, 27, 4660-4662) was dissolved in MeOH (20 ml) prior to the addition of 10% Pd/C (1.0 g). The reaction was placed on a Parr aparatus under hydrogen at 60 psi for 4 h. The palladium was filtered off and the solution was concentrated to give 2-amino-6-trifluoromethyl-phenol (1.1 g): 1H NMR (CD3OD, δ ppm, 300 mHz) 6.78 (m, 2H), 6.90 (d, 1H). (22b) A portion (200 mg) of the above derivative (22a) was dissolved in p-xylene prior to the addition of diethyl malonate (0.9 ml) and p-toluenesulfonic acid (22 mg). The reaction was heated to reflux with azeotropic removal of the water. After cooling to rt, the solution was concentrated. Flash chromatography of the resulting residue gave (7-trifluoromethyl-benzooxazol-2-yl)-acetic acid ethyl ester (130 mg). 1H NMR (CDCl3, δ ppm, 300 mHz) 1.30 (t, 3H), 4.09 (s, 2H), 4.25 (q, 2H), 7.41 (t, 1H), 7.60 (d, 2H), 7.90 (d, 1H). (22c) The above derivative (22b) (130 mg) was dissolved in THF (1 ml) prior to the addition of a solution of LiOH in water (1 ml). A couple drops of MeOH were added until the solution became clear. After 2 h at rt, the reaction was partially concentrated and 1N HCl was added to neutralize the reaction. This was exacted with EtOAc. The organic layer was dried, filtered and concentrated to provide (7-trifluoromethyl-benzooxazol-2-yl)-acetic acid (85 mg). 1H NMR (CD3OD, δ ppm, 300 mHz) 4.13 (s, 2H), 7.54 (t, 1H), 7.70 (d, 2H), 7.95 (d, 1H). (22d) (±)(1S*,2R*,4R*)—N4-Isopropyl-N4-methyl-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexane-1,4-diamine TFA salt, from example (19g), (65 mg) was dissolved in DMF (2 ml) prior to the addition of 4-methylmorpholine (74 μl) and example (22c) (39 mg). After cooling to 0° C., BOP reagent (77 mg) was added. The resulting mixture was warmed to rt and stirred overnight before being concentrated. Reverse phase HPLC purification (gradient elution, water/acetonitrile/TFA) of the resulting residue provided the title compound (28 mg). MS found: (M+H)+=598.5
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[C:4]1[CH2:20][NH2:21].[C:22]([NH:41][CH2:42][C:43](O)=[O:44])([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:2][N:3]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[C:4]1[CH2:20][NH:21][C:43](=[O:44])[CH2:42][NH:41][C:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(O)CNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1c(CN)c(-c2ccccc2Cl)c2cc(Cl)ccc21
Agent: Cl
Product: Cn1c(CNC(=O)CNC(c2ccccc2)(c2ccccc2)c2ccccc2)c(-c2ccccc2Cl)c2cc(Cl)ccc21

Procedure:
Using 1-methyl-2-aminomethyl-3-o-chlorophenyl-5-chloroindole hydrochloride and N-tritylglycine, the reaction is effected as in Example 12 (1), whereby 1-methyl-2-(N-trityl-glycylaminomethyl)-3-o-chlorophenyl-5-chloroindole is obtained as crystals melting at 198° to 200° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[CH:18]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)(Cl)Cl>[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[CH2:18][NH:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: NC1CCOCC1
Reactant: O=Cc1ccc2ccccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: c1ccc2cc(CNC3CCOCC3)ccc2c1
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
To a solution of tetrahydro-2H-pyran-4-amine (500 mg) in chloroform (5 mL), 2-naphthoaldehyde (772 mg) was added and the resulting mixture was stirred for 30 minutes. Sodium (triacetoxy)borohydride (1.57 g) was added and the resulting mixture was stirred for 4 hours at room temperature. To the reaction mixture, an aqueous solution of 1 M sodium hydroxide was added and after stirring the resulting mixture, the chloroform layer was separated and dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure and the resulting residue was purified by column chromatography (silica gel cartridge; chloroform/methanol=100:0 to 97:3) to give the titled compound (821 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:21]=3[CH:22]=[CH:23][N:24]=[C:25]4[CH2:30][CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])[N:16]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:13][CH2:12][CH:11]([F:14])[CH2:10]1)#[N:2]>Cl.O1CCOCC1>[C:1]([C:3]1[CH:4]=[C:5]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:21]=3[CH:22]=[CH:23][N:24]=[C:25]4[CH2:30][CH2:31][C:32]([OH:34])=[O:33])[N:16]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:13][CH2:12][CH:11]([F:14])[CH2:10]1)#[N:2]
Reactant: CC(C)(C)OC(=O)CCc1nccc2c(-c3noc(-c4ccc(N5CCC(F)C5)c(C#N)c4)n3)cccc12
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1cc(-c2nc(-c3cccc4c(CCC(=O)O)nccc34)no2)ccc1N1CCC(F)C1
Yield: 16.2 %

Procedure:
1,1-Dimethylethyl 3-(5-{5-[3-cyano-4-(3-fluoro-1-pyrrolidinyl)phenyl]-1,2,4-oxadiazol-3-yl}-1-isoquinolinyl)propanoate (D51; 14 mg, 0.027 mmol) was stirred in 4M HCl in dioxane (1 ml) at room temperature for 7 hrs. The mixture was concentrated in a blow down unit and the residue was purified by Mass Directed Preparative HPLC (Supelcosil ABZ+Plus column, eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid)) to give the title compound as a white solid (2 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23]O)[CH2:19][C@H:18]2[NH:25][C:26](=[O:34])[O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:13]1=[O:35])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Mg+].[Br-]>CC(C)=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:2]([CH3:7])([CH3:3])[CH3:1])[CH2:19][C@H:18]2[NH:25][C:26](=[O:34])[O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:13]1=[O:35])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOC(=O)N[C@@H]1C[C@H](NO)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: C[Mg+]
Agent: [Br-]
Solvent: CC(C)=O
Product: CC(C)(C)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](NC(=O)OCC[Si](C)(C)C)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 84.8 %

Procedure:
A solution of 2-(trimethylsilyl)ethyl (1R,2S,5R)-2-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-5-(hydroxyamino)cyclohexylcarbamate (350 mg, 0.69 mmol) in acetone (5 mL) was stirred at room temperature for 16 h. The mixture was concentrated in vacuo. The residue was dissolved in anhydrous THF (7 mL) and cooled to 0° C. A solution of MeMgBr (1.1 mL, 3M in diethyl ether, 5 eq) was added dropwise. The mixture was stirred at room temperature for 1.5 h. The reaction was quenched with water (5 mL) at 0° C. The mixture was diluted with ethyl acetate (100 mL) and filtered through a pad of celite. The filtrate was washed with brine (30 mL). The solution was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was dissolved in 2 ml of acetonitrile and 1 ml of CS2 was added. The mixture was stirred at room temperature for 1 hours. The solvent was removed and the crude product was purified by silica gel column chromatography, using 1.5% of methanol in dichloromethane as the eluant, to provide the desired 2-(trimethylsilyl)ethyl (1R,2S,5R)-2-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)cyclohexylcarbamate (160 mg, 42%). LC/MS found [M+H]+=547.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N:15]1[CH:16]=[CH:17][CH:18]=[N:19][C:14]=1[C:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ncccn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1=C(c2ncccn2)CCNC1
Yield: 87 %

Procedure:
500 mg of the compound of step 2 of Example 25 was dissolved in 10 ml of methylene chloride, 3.5 ml of trifluoroacetic acid (hereinafter referred to as TFA) was added, then the resultant mixture was agitated at room temperature for 30 minutes. This was concentrated, then an aqueous solution of 10% sodium hydroxide was added and extraction was performed with chloroform. The organic layer was washed by saturated saline and was dried with anhydrous magnesium sulfate. This chloroform was concentrated to obtain the above-referenced compound in an amount of 260 mg (yield of 87%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=O)[CH:5]=[CH:6][C:7]=1[C:8](=[O:11])[NH:9][CH3:10].CCN=C=NCCCN(C)C.Cl.[NH2:31][C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[C:34]([C:40]([F:43])([F:42])[F:41])[CH:33]=1.O>C(Cl)Cl>[C:36]([C:35]1[CH:38]=[CH:39][C:32]([NH:31][C:14]([C:13]([NH:12][C:4]2[CH:5]=[CH:6][C:7]([C:8]([NH:9][CH3:10])=[O:11])=[C:2]([F:1])[CH:3]=2)([CH3:18])[CH3:17])=[O:16])=[CH:33][C:34]=1[C:40]([F:41])([F:42])[F:43])#[N:37]
Reactant: CNC(=O)c1ccc(NC(C)(C)C(=O)O)cc1F
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1ccc(NC(C)(C)C(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)cc1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.8 %

Procedure:
The title compound was made in accordance with General Method 1. 2-(3-Fluoro-4-methylcarbamoyl-phenylamino)-2-methyl-propionic acid (1.27 g) was dissolved in DCM. EDCI-HCl (1.91 g) was added to it and the reaction mixture was stirred for 5 min at RT. 4-Amino-2-(trifluoromethyl)benzonitrile (1.00 g) was added portionwise and stirring was continued for 5 h at RT. Water was added to the reaction mixture, and the product was extracted with DCM. The combined organic layer was washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (100-200 mesh silica gel) eluting with 5% MeOH-DCM to obtain 650 mg of 4-[1-(4-Cyano-3-trifluoromethyl-phenylcarbamoyl)-1-methyl-ethylamino]-2-fluoro-N-methyl-benzamide, HPLC, Column: YMC ODS AQ, 4.6×250 mm, 5 μm, Mobile Phase A:0.05% TFA, Mobile Phase B:ACN, Gradient: 10% to 90% B in 10 min, hold for 10 min, 90% to 10% B in 1 min, Flow Rate: 1 mL/min, Retention time: 11.174 min, M+1: 423.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][NH:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CCNCCc1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCNCCC(=O)O)cn(C)c34)no2)cc1Cl
Temperature: 50 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
To a solution of ethyl N-{2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]ethyl}-β-alaninate (D90) (20 mg) in THF (5 mL) was added aqueous NaOH (2 M, 1 mL). The reaction was stirred at 50° C. for 3 h. The mixture was cooled to room temperature and acidified with aqueous HCl (2 M) to pH 4-5, and then partitioned between ethyl acetate (25 mL) and water (20 mL). The organic phase was evaporated to give the crude product, which was purified by Mass Directed Auto Prep to afford N-{2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]ethyl}-β-alanine (E65) (15 mg, TFA salt). δH (DMSO-d6, 400 MHz): 1.36 (6H, d), 2.61 (2H, t), 3.06 (2H, t), 3.20 (4H, m), 3.65 (3H, s), 4.88 (1H, m), 7.22 (1H, t), 7.31 (1H, s), 7.45 (2H, m), 7.83 (1H, dd), 8.12 (1H, dd), 8.19 (1H, d). MS (ES): C25H27ClN4O4 requires 482; found 483.2 (M+H+).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.Br[CH2:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18]>C(OCC)C.CCOC(C)=O>[CH3:18][CH:17]([CH3:19])[C:16](=[O:20])[CH2:15][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C(=O)CBr
Reactant: Sc1ccccc1
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)C(=O)CSc1ccccc1
Reaction time: 72 h

Procedure:
To a solution of thiophenol (4.44 mL; 43.4 mmol) in diethyl ether (29 mL) was added pyridine (17.2 mL; 0.21 mol), followed by the drop-wise addition of a solution of compound 563-B (7.18 g; 43.5 mmol) in diethyl ether (15 mL), at ambient temperature, and the reaction was stirred for 72 h. The reaction was diluted with EtOAc, washed with 2N HCl, H2O, brine, dried over Na2SO4, filtered and the solvent evaporated under reduced pressure. The crude residue was purified by flash column chromatography (SiO2) eluting with a heptane-EtOAc gradient to afford compound 563-C as an oil. 1H-NMR (CDCl3): δ 1.09-1.10 (d, 6H), 2.90-2.97 (m, 1H), 3.75 (s, 2H), 7.18-7.35 (m, 5H).