Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:18](B(O)O)=[C:19]2[CH2:24][CH2:23][CH2:22][N:20]2[N:21]=1.C(=O)(O)[O-].[Na+].C(#N)C>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.O>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:18]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[CH:7]=2)=[C:19]2[CH2:24][CH2:23][CH2:22][N:20]2[N:21]=1
Reactant: OB(O)c1c(-c2ccccn2)nn2c1CCC2
Reactant: Ic1ccc2nccn2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: c1ccc(-c2nn3c(c2-c2ccc4nccn4c2)CCC3)nc1
Yield: 71.9 %

Procedure:
Add tetrakis(triphenylphosphine)palladium(0) (0.58 g, 0.5 mmol) to a 2 L flask containing a solution of 6-iodo-imidazo[1,2-a]pyridine (6.16 g, 25.2 mmol), 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid (Preparation 5; 6.07 g, 26.5 mmol), and sodium bicarbonate (4.24 g, 50.5 mmol) in 2.5:1 acetonitrile:water (700 mL). Reflux the reaction mixture for 3 h, cool, concentrate to about one half of the volume, extract into dichloromethane (4×250 ml), and concentrate. Flash chromatography using a gradient from 100% hexanes to 100% ethyl acetate (10 min, 45 ml/min), followed by isocratic 100% ethyl acetate (2 L), removes most impurities. Elution with ethyl acetate/methanol mixtures followed by tituration in hot ethyl acetate affords the title compound as a white solid 5.46 g, (72%). MS ES+ m/e 301.9 (M+1). 1H-NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.39 (d, J=3.2 Hz, 1H), 7.87 (s, 1H), 7.81-7.76 (m, 2H), 7.51 (d, J=1.2, 1H), 7.42 (d, J=9.2 Hz, 1H), 7.26 (m, 1H), 7.05 (dd, J=9.2, 2 Hz, 1H), 4.2 (t, J=6.6 Hz, 2H, 2.99 (t, J=6.6 Hz, 2H), 2.59 (m, 1H).
Reaction SMILES: [NH2:1][CH:2]1[C:8]([CH3:10])([CH3:9])[S:7][C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[N:4]([CH2:15][C:16]([N:18]([CH:27]([CH3:29])[CH3:28])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:17])[C:3]1=[O:30].[F:31][C:32]1[CH:33]=[C:34]([N:38]=[C:39]=[O:40])[CH:35]=[CH:36][CH:37]=1>C(Cl)Cl>[F:31][C:32]1[CH:33]=[C:34]([NH:38][C:39](=[O:40])[NH:1][CH:2]2[C:8]([CH3:9])([CH3:10])[S:7][C:6]3[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=3[N:4]([CH2:15][C:16]([N:18]([CH:27]([CH3:28])[CH3:29])[C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)=[O:17])[C:3]2=[O:30])[CH:35]=[CH:36][CH:37]=1
Reactant: O=C=Nc1cccc(F)c1
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(N)C(C)(C)Sc3ccccc32)C(C)C)cc1
Solvent: ClCCl
Product: COc1ccc(N(C(=O)CN2C(=O)C(NC(=O)Nc3cccc(F)c3)C(C)(C)Sc3ccccc32)C(C)C)cc1

Procedure:
Similarly to Example 22, to 2-(3-amino-2,2-dimethyl-4-oxo-3,4-dihydro-2H-benzo [b][1,4]thiazepin-5-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, intermediate 34 G (300 mg, 0.70 mmol) in DCM (2 mL) was added m-fluorophenyl isocyanate (0.80 mL, 0.70 mmol) to give the crude titled compound (225 mg, 57%). A sample (75 mg) was purifid by RP-HPLC (40-60%, over 30 min) to give the titled product (47 mg). tR =20.9 min (40-60%, over 30 min); 1HNMR (300 MHz, d6-DMSO) d 0.96 (d, J=6.2 Hz, 3H), 1.21 (s, 6H), 3.59 (d, J=16.2 Hz, 1H), 3.76 (s, 3H), 4.26 (d, J=7.8, 1H), 4.55 (d, J=16.2, 1H), 4.80 (m, 1H), 6.74 (m, 1H), 7.19 (m, 3H), 7.20 (m, 2H), 7.32 (m, 1H), 7.49 (m, 1H), 7.60 (m, 2H), 9.03 (s, 1H); MS(FAB) m/z 565.1 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[CH:12])=[CH:7][CH:6]=1.[CH3:14][O:15][C:16](=[O:27])[CH2:17][CH2:18][C:19]1[C:24]([OH:25])=[CH:23][CH:22]=[C:21](I)[N:20]=1>>[CH3:14][O:15][C:16](=[O:27])[CH2:17][CH2:18][C:19]1[C:24]([OH:25])=[CH:23][CH:22]=[C:21]([C:12]#[C:11][C:8]2[CH:7]=[CH:6][C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:13])=[CH:10][CH:9]=2)[N:20]=1
Reactant: C#Cc1ccc(CC(=O)OC)cc1
Reactant: COC(=O)CCc1nc(I)ccc1O
Product: COC(=O)CCc1nc(C#Cc2ccc(CC(=O)OC)cc2)ccc1O
Yield: 39.6 %

Procedure:
Under the conditions of example 5 A, 5 g of the crude 4-ethinylphenylacetic acid methyl ester is reacted with 7.9 g of 3-(3-hydroxy-6-iodo-2-pyridyl)-propionic acid methyl ester, worked up, and the crude product is chromatographed on silica gel with hexane/0-50% ethyl acetate. 3.6 g of 3-{3-hydroxy-6-[2-(4-methoxycarbonylmethylphenyl)-ethinyl]-2-pyridyl}-propionic acid methyl ester of melting point 122°-125° C. is obtained.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[NH:8][C:7]([C:11]2[CH:12]=[C:13]([CH:22]=[CH:23][C:24]=2[Cl:25])[CH2:14][NH:15]C(=O)C(F)(F)F)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>O>[C:1]([N:5]1[C:9](=[O:10])[NH:8][C:7]([C:11]2[CH:12]=[C:13]([CH2:14][NH2:15])[CH:22]=[CH:23][C:24]=2[Cl:25])=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1nc(-c2cc(CNC(=O)C(F)(F)F)ccc2Cl)[nH]c1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)n1nc(-c2cc(CN)ccc2Cl)[nH]c1=O
Yield: 100.6 %

Procedure:
The title compound was prepared according to the procedure described in Intermediate-66 by using N-(3-(1-tert-butyl-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-4-chlorobenzyl)-2,2,2-trifluoroacetamide (Example-120, 0.400 g, 1.062 mmol), KOH (0.119 g, 2.12 mmol), water (5 mL) and THE (5.0 mL) to afford 0.300 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([N:13]1[CH2:20][CH:19]2[CH:15]([CH2:16][NH:17][CH2:18]2)[CH2:14]1)=[O:12].Cl[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([N:13]1[CH2:20][CH:19]2[CH:15]([CH2:16][N:17]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=3)[CH2:18]2)[CH2:14]1)=[O:12]
Reactant: COc1ccc(C(=O)N2CC3CNCC3C2)c(OC)c1
Reactant: Cc1cccc(Cl)n1
Product: COc1ccc(C(=O)N2CC3CN(c4cccc(C)n4)CC3C2)c(OC)c1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 38 and 2-chloro-6-methyl-pyridine. MS (ESI): mass calculated for C21H25N3O3, 367.45; m/z found 368.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Br)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.C(N(C(C)C)CC)(C)C.[NH2:21][C:22]1[N:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1>CC(O)C>[Br:1][C:2]1[N:3]=[C:4]([NH:21][C:22]2[N:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]3)=[CH:24][CH:23]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: Brc1cn2ccnc2c(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(Br)cn4ccnc34)nc2)CC1
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 48.2 %

Procedure:
A mixture of 6,8-dibromoimidazo[1,2-a]pyrazine (1.2 g, 4.3 mmol), diisopropylethylamine (1.1 g, 8 mmol), and tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (1 g, 3.5 mmol) in IPA (20 mL) was stirred at 130° C. under microwave irradiation for 1.5 h. The resulting suspension was filtered and the solid was washed with water and dried in vacuum to afford the crude product, which was further purified by silica gel chromatography eluting with CH2Cl2/MeOH (50:1) to afford 106a as a white solid (800 mg, 50%). MS: [M+H]+ 474.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].[Cl:8][C:9]1[CH:10]=[C:11]([N+:17]([O-:19])=[O:18])[CH:12]=[C:13]([Cl:16])[C:14]=1F>CN(C=O)C>[Cl:8][C:9]1[CH:10]=[C:11]([N+:17]([O-:19])=[O:18])[CH:12]=[C:13]([Cl:16])[C:14]=1[N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=[N+]([O-])c1cc(Cl)c(F)c(Cl)c1
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)c(-n2cccn2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Pyrazole (1.43 g, 21,0 mmol) in 3 ml of DMF is added dropwise at RT to a suspension of sodium hydride (50%; 1.0 g, 21.0 mmol) in 10 ml of DMF. The mixture is stirred at RT for 30 min., after which it is added dropwise at 5° over a period of 30 min. to a solution of 3,5-dichloro-4-fluoronitrobenzene (3.0 g, 15.0 mmol) in 20 ml of DMF. After reaction is complete, the reaction mixture is quenched with water and extracted with ethyl acetate. The combined organic layers are washed with water and with brine and dried to give a yellow solid, 1-(2,6-dichloro-4-nitrophenyl)-pyrazole.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][NH:13][CH2:14][CH3:15])[CH2:8][CH2:7]1)[CH3:2].F[C:18]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:19]=1[CH:20]=[O:21].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH2:14]([N:13]([CH2:12][C@H:9]1[CH2:10][CH2:11][C@H:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:16])[CH2:7][CH2:8]1)[C:18]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:19]=1[CH:20]=[O:21])[CH3:15]
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Reactant: CCNC[C@H]1CC[C@H](CC(=O)OCC)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2ccc(C(F)(F)F)cc2C=O)CC1

Procedure:
A stirred mixture of ethyl{trans-4-[(ethylamino)methyl]cyclohexyl}acetate (Intermediate 7; 130 mg; 0.57 mmol), 2-fluoro-5-(trifluoromethyl)benzaldehyde (100 mg; 0.52 mmol) and potassium carbonate (215 mg; 1.56 mmol) in toluene (4 mL) was heated at reflux for 14 h. The reaction was washed with H2O and sat. KHSO4 (10 mL each) and the aqueous layers were re-extracted with toluene (10 mL). The combined organic layers were washed with brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo to afford ethyl [trans-4-({ethyl[2-formyl-4-(trifluoromethyl)phenyl]amino}methyl)cyclohexyl]acetate as a yellow oil. LCMS=400.2 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)=O)[CH:7]=1.[Na].[Cl-].[Al+3].[Cl-].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH2:8][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:7]=1
Reactant: CCOc1ccc(C(=O)c2cc(Br)ccc2Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na]
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
To a stirred solution of Example 1A (1.440 kg, 4.26 mol) in anhydrous THF (7.2 L) under nitrogen was added sodium boronhydride (161 g, 4.26 mol) in one portion at 10˜15° C. After stirring for 30 min, the mixture was cooled to −5˜0° C. and aluminum (III) chloride (1136 g, 8.52 mol) was added carefully portionwise to the reaction mixture over 2 h. The reaction mixture was stirred at 0˜5° C. for 3 h after the addition. The reaction mixture was refluxed (65˜70° C.) for 15 h. The reaction was concentrated and water (5 kg) was added dropwise slowly in 3˜4 h under nitrogen atmosphere so that the internal temperature did not exceed 40° C. The reaction mixture was stirred for 3 h at 0˜5° C. The precipitate was filtered and washed with water (1.5 L). The crude product was then dissolved in 7.2 L absolute ethanol at 50˜55° C. The solution was slowly cooled to 25° C. in 3 h and at 10˜15° C. for 10 h, and 0˜5° C. for 2 h. The slurry was filtered and the solid was washed with chilled ethanol (500 mL) and dried under vacuum at 35° C. to afford the crude product. This product was recrystallized from absolute ethanol (5 L) once more and dried under vacuum at 35° C. to give the desired product (1.310 kg, yield 94%; HPLC purity>99%). 1H NMR (CDCl3, 400 MHz): δ 7.21˜7.29 (m, 3H), 7.11 (d, J=8.8 Hz, 2H,), 6.85 (d, J=8.8 Hz, 2H,), 3.99˜4.07 (m, 4H), 1.43 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH:1]([C:3]([C@@H:5]1[CH2:9][C:8](=[N:10][O:11][CH3:12])[CH2:7][N:6]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:4])[NH2:2].C(N(CC)CC)C.[C:27](N1C=CN=C1)(N1C=CN=C1)=[O:28]>C1COCC1>[CH3:12][O:11]/[N:10]=[C:8]1\[CH2:9][C@@H:5]([C:3]2[O:4][C:27](=[O:28])[NH:2][N:1]=2)[N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]\1
Reactant: CON=C1C[C@@H](C(=O)NN)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CO/N=C1\C[C@@H](c2n[nH]c(=O)o2)N(C(=O)OC(C)(C)C)C1
Reaction time: 5 h

Procedure:
To a stirring solution of tert-butyl (2S,4EZ)-2-(hydrazinocarbonyl)-4-(methoxyimino)-1-pyrrolidinecarboxylate (Intermediate 9, 1.84 mmoles; 500 mg) and triethylamine (2.76 mmoles; 27 mg) in THF (25 mL) at 0° C. was added 1,1′-carbonyldiimidazole (2.76 mmoles, 448 mg). The stirring was continued for 5 hours. Another portion of triethylamine and 1,1′-carbonyldiimidazole were added and stirring was continued at room temperature overnight. The solvent was evaporated and the residue was dissolved in EtOAc and washed with NH4Clsat., and 10% NaHCO3, and brine. The organic layer was dried over Na2SO4 and evaporated to dryness to give the desired N-protected intermediate, tert-butyl (2S,4E)-4-(methoxyimino)-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-1-pyrrolidinecarboxylate, as a white foam (460 mg, 84%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([F:25])[CH:17]=2)=[N:4][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([OH:14])[C@@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1.Cl.[NH2:27][C@@H:28]([C:44]1[CH:49]=[C:48]([F:50])[CH:47]=[C:46]([Br:51])[CH:45]=1)[CH2:29][N:30]([CH3:43])[S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N+:40]([O-:42])=[O:41])(=[O:33])=[O:32].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:27][C@@H:28]([C:44]3[CH:49]=[C:48]([F:50])[CH:47]=[C:46]([Br:51])[CH:45]=3)[CH2:29][N:30]([CH3:43])[S:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[N+:40]([O-:42])=[O:41])(=[O:33])=[O:32])=[O:21])=[C:18]([F:25])[CH:17]=2)=[N:4][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([OH:14])[C@@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1
Reactant: CN(C[C@@H](N)c1cc(F)cc(Br)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: Nc1ncc([C@H]2CC[C@H](O)[C@@H](F)C2)nc1-c1ccc(C(=O)O)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN(C[C@@H](NC(=O)c1ccc(-c2nc([C@H]3CC[C@H](O)[C@@H](F)C3)cnc2N)cc1F)c1cc(F)cc(Br)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzoic acid (300 g, 95% assay, 815.8 mmol) and (S)—N-(2-amino-2-(3-bromo-5-fluorophenyl)ethyl)-N-methyl-2-nitrobenzenesulfonamide hydrochloride (397.7 g, 848.5 mmol) in DMF (2.5 kg) was added DIPEA (421.8 g, 3263.4 mmol), followed by EDCl (312.8 g, 1631.7 mmol) and HOAt (222.1 g, 1631.7 mmol). After the reaction mixture was stirred at 25° C. for 18 hours, the reaction temperature was lowered to 10° C. before IPAC (3.5 kg) and water (4.0 kg) was added. The mixture was stirred for 10 minutes and then the layers were separated. The aqueous layer was extracted with IPAC (2.5 kg). The combined organic layers were washed successively with 10% aqueous Na2CO3 (4.5 kg) and water (2×4 kg), and then concentrated under vacuum (<100 mbar) at 40-45° C. to give 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N—((S)-1-(3-bromo-5-fluorophenyl)-2-(N-methyl-2-nitrophenylsulfonamido)ethyl)-2-fluorobenzamide as a foam (670 g, assay purity is 93%), which was used in next step without further purification. ESI-MS (m/z): 763.1216, 765.1161 ([M+H]+, 100). Mp=115-117° C. HPLC (method A), retention time=10.57 min. 1H NMR (400 MHz, CDCl3): 8.11 (t, J=8 Hz, 1H), 7.99 (m, 1H), 7.91 (s, 1H), 7.59-7.72 (m, 5H), 7.35 (s, 1H), 7.19 (d, J=8 Hz, 1H), 7.09 (d, J=8 Hz, 1H), 5.46 (br. s, 1H), 4.77 (br. s, 2H), 4.48-4.55, 4.35-4.42 (m, 1H), 3.93 (q, J1=12 Hz, J1=16 Hz, 1H), 3.73-3.82 (m, 1H), 3.33 (q, J1=4 Hz, J1=12 Hz, 1H), 3.00 (s, 3H), 2.78-2.85 (m, 1H), 2.31-2.37 (m, 1H), 2.12-2.20 (m, 1H), 1.84-1.96 (m, 2H), 1.60-1.71 (m, 1H), 1.47-1.56 (m, 1H).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Br.CC(O)=[O:17]>>[OH:17][C:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)O
Reactant: c1ccc2c(c1)sc1ccccc12
Agent: Br
Product: Oc1cccc2sc3ccccc3c12
Temperature: 130 °C

Procedure:
To a stirred solution of the dibenzothiophene (0.040 g, 0.19 mmoles) isolated from Step D in HOAc (2.5 mL) was added 40% HBr (0.65 mL, 5.6 mmoles) under N2. The reaction was heated to 130° C. for 20 hrs. The resulting green solution was partitioned between EtOAc and ice/brine. The organic layer was washed with sat. NaHCO3 (2X) and brine. The EtOAc extract was dried over Na2SO4 and concentrated in vacuo to give an off-white solid (0.0366 g). Purification by plate layer chromatography with 1:1 hexane/CH2Cl2 afforded the desired phenol as a white solid (0.0294 g).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[O:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[C:36]([C:43](=[O:46])[CH2:44]Br)=[CH:35]1>CN(C=O)C.O>[O:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[C:36]([C:43](=[O:46])[CH2:44][O:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:23]2[N:22]=[CH:21][N:20]([C:1]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:24]=2)=[CH:35]1
Reactant: O=C(CBr)c1coc2ccccc12
Reactant: Oc1ccccc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(COc1ccccc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1coc2ccccc12
Reaction time: 0.17 h
Yield: 60 %

Procedure:
To a stirred solution of 2-(1-trityl-1H-imidazol-4-yl)phenol (0.5 mmol) in anhydrous DMF (3 mL) at 0° C. was added NaH (36.0 mg, 0.75 mmol). The resulting suspension was allowed to stir for 10 min. To the resulting solution was added 1-(benzofuran-3-yl)-2-bromoethanone (0.50 mmol). After stirring overnight, the reaction mixture was carefully diluted, with water and extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with water, brine and dried (Na2SO4). The solvent was removed under reduced pressure and the crude product was purified by column chromatography. Yield 60%. 1H NMR: 5.16 (s, 2H), 6.88 (d, 1H, J=8.10 Hz), 7.06-7.47 (m, 20H), 7.54 (d, 2H, J=7.92 Hz), 8.22 (dd, 2H, J=7.60 Hz, 1.35 Hz), 8.33 (s, 1H).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH2:11][C@@H:12]([CH2:17][CH:18]=[CH2:19])[C:13]([O:15][CH3:16])=[O:14].[CH2:20]([CH:23]([CH2:27][CH2:28][CH3:29])[C:24](O)=[O:25])[CH2:21][CH3:22].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl>CN(C=O)C>[CH2:20]([CH:23]([CH2:27][CH2:28][CH3:29])[C:24]([NH:11][C@@H:12]([CH2:17][CH:18]=[CH2:19])[C:13]([O:15][CH3:16])=[O:14])=[O:25])[CH2:21][CH3:22]
Reactant: C=CC[C@H](N)C(=O)OC
Reactant: CCCC(CCC)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: C=CC[C@H](NC(=O)C(CCC)CCC)C(=O)OC
Reaction time: 18 h
Yield: 115.5 %

Procedure:
Step A (1): DIEA (2.52 mL, 14.5 mmol) was added to a mixture of (S)-methyl 2-aminopent-4-enoate hydrochloride (500 mg, 3.03 mmol) [Del Valle, J. R.; Goodman, M. J. of Org. Chem. 2004, 69, 8946-8948], 2-propylpentanoic acid (417 mg, 2.89 mmol), EDC (581 mg, 3.03 mmol), and HOBt (409 mg, 3.03 mmol) in DMF (15 mL) at rt. The mixture was stirred for 18 h and subsequently poured into 200 mL 1M HCl. The aqueous layer was extracted with EtOAc/hexanes (95:5) (2×200 mL). The combined organic extracts were washed with brine, dried with MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to give (S)-methyl 2-(2-propylpentanamido)pent-4-enoate 852 mg (quantitative yield) as a white solid. LC-MS (M+H)+=256.16. 1H NMR (500 MHz, CDCl3) δ 5.90 (s, 1H) 5.64-5.85 (m, 1H) 4.95-5.14 (m, 2H) 4.04 (dd, J=5.04, 2.29 Hz, 2H) 3.75 (s, 3H) 2.28-2.46 (m, 1H) 2.07-2.29 (m, 2H) 1.62-1.64 (m, 1H) 1.46-1.47 (m, 1H) 1.18-1.36 (m, 4H) 0.87 (t, J=6.87 Hz, 3H).
Reaction SMILES: [F:1][C:2]([CH3:35])([C:23]([NH:25][CH2:26][CH2:27][C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])=[O:24])[C:3]([NH:5][C@@H:6]1[C:12](=[O:13])[N:11]([CH3:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]1=2)=[O:4].CCCCCCC>C(O)(C)C>[F:1][C@:2]([CH3:35])([C:23]([NH:25][CH2:26][CH2:27][C:28]([F:33])([F:34])[C:29]([F:32])([F:31])[F:30])=[O:24])[C:3]([NH:5][C@@H:6]1[C:12](=[O:13])[N:11]([CH3:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]1=2)=[O:4]
Reactant: CN1C(=O)[C@@H](NC(=O)C(C)(F)C(=O)NCCC(F)(F)C(F)(F)F)c2ccccc2-c2ccccc21
Solvent: CCCCCCC
Solvent: CC(C)O
Product: CN1C(=O)[C@@H](NC(=O)[C@](C)(F)C(=O)NCCC(F)(F)C(F)(F)F)c2ccccc2-c2ccccc21
Yield: 11 %

Procedure:
The separation of 0.2 g of the two isomers of (2RS)-2-fluoro-2-methyl-N-[(S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-N′-(3,3,4,4,4-pentafluoro-butyl)-malonamide (Example WG) was performed on a preparative chiral HPLC column (CHIRALPAK® AD, pressure: flow: 35 ml/min) using a 4:1 mixture of n-heptane and isopropanol as the eluent. There were obtained 23 mg [11% of theory, optical integrity >99.5% d.e., MS: m/e=502 (M+H)+] of the first eluting isomer (2R)-2-Fluoro-2-methyl-N-[(S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-N′-(3,3,4,4,4-pentafluoro-butyl)-malonamide and 22 mg [11% of theory, optical integrity >99.5% d.e., MS: m/e=502 (M+H)+] of the later eluting isomer (2S)-2-fluoro-2-methyl-N-[(S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-N′-(3,3,4,4,4-pentafluoro-butyl)-malonamide, each as a yellowish foam.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([O:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[C:29]([CH:31]4[CH2:34][CH2:33][CH2:32]4)[N:28]=[C:27]([C:35]([CH3:38])([CH3:37])[CH3:36])[N:26]=3)[CH2:21][CH2:20]2)[N:10]=1)C1C=CC=CC=1>O1CCCC1.[Pd]>[C:35]([C:27]1[N:26]=[C:25]([N:22]2[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][CH2:16][O:15][C:11]3[N:10]=[C:9]([OH:8])[CH:14]=[CH:13][N:12]=3)[CH2:24][CH2:23]2)[CH:30]=[C:29]([CH:31]2[CH2:32][CH2:33][CH2:34]2)[N:28]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCOc3nccc(OCc4ccccc4)n3)CC2)n1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCOc3nccc(O)n3)CC2)n1
Reaction time: 3 h
Yield: 59.8 %

Procedure:
0.75 g of 4-{4-[3-(4-benzyloxy-pyrimidin-2-yloxy)-propyl]-piperazin-1-yl}-2-tert-butyl-6-cyclobutyl-pyrimidine (1.45 mmol) were dissolved in 20 ml of tetrahydrofuran and, after addition of 0.1 g of 10% Pd/C, the reaction mixture was hydrogenated for 3 h at 40° C. After filtration, additional catalyst (0.2 g of 10% Pd/C) was added and the mixture was again hydrogenated for 1 h at 40° C. Finally, the catalyst was removed by filtration, the solvent evaporated under reduced pressure, and the remaining oil crystallized by addition of acetonitril to yield 0.37 g of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:34])[C@H:4]([CH2:30][CH2:31][S:32][CH3:33])[NH:5][C:6](=[O:29])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:20]=2Cl)=[CH:9][C:8]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28].[H-].[Na+:36].[F:37][C:38]1[CH:39]=[C:40]([CH:43]=[C:44]([F:46])[CH:45]=1)[CH2:41][OH:42]>CN(C=O)C>[Na+:36].[F:37][C:38]1[CH:39]=[C:40]([CH:43]=[C:44]([F:46])[CH:45]=1)[CH2:41][O:42][C:20]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[CH:14]=[CH:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([NH:5][C@H:4]([C:3]([O-:34])=[O:2])[CH2:30][CH2:31][S:32][CH3:33])=[O:29])=[C:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH:9]=1
Reactant: OCc1cc(F)cc(F)c1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C=Cc2cnccc2Cl)cc1-c1ccccc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCC[C@H](NC(=O)c1ccc(C=Cc2cnccc2OCc2cc(F)cc(F)c2)cc1-c1ccccc1C)C(=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-[4-(2-(4-chloropyridin-3-yl)ethenyl)-2-(2-methylphenyl)benzoyl]methionine methyl ester, prepared as in Example 1040, (27 mg, 0.05 mmol) was dissolved in DMF (1 mL) with 3,5-difluorobenzyl alcohol (0.1 mL) and treated with NaH (60% in mineral oil, 6.5 mg, 0.16 mmol). After stirring 18 hours at ambient temperature, the reaction was evaporated and lyophilized from water to provide 29 mg of the title compound. MS m/e 589 (M+H)+.