Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([C:19]2[O:20][C:21]([C:24]3[N:29]=[C:28]([C:30]([O:32]C)=[O:31])[CH:27]=[CH:26][CH:25]=3)=[CH:22][N:23]=2)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C1COCC1.O.CCOC(C)=O>[O:1]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]([C:19]2[O:20][C:21]([C:24]3[N:29]=[C:28]([C:30]([OH:32])=[O:31])[CH:27]=[CH:26][CH:25]=3)=[CH:22][N:23]=2)=[O:18])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(-c2cnc(C(=O)CCc3ccc(COc4ccccc4)cc3)o2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(-c2cnc(C(=O)CCc3ccc(COc4ccccc4)cc3)o2)n1
Yield: 80.6 %

Procedure:
Methyl 6-(2-(3-(4-(phenoxymethyl)phenyl)propanoyl)oxazol-5-yl)pyridine-2-carboxylate (109 mg, 0.246 mmol) was dissolved in THF/H2O (3:2, 15 mL) and LiOH (18 mg, 0.75 mmol) was added. The reaction solution was stirred at room temperature under an atmosphere of Ar for 15 min before the addition of 1 N HCl to adjust the solution to an acidic pH to quench the reaction. The reaction solution was diluted with EtOAc and the organic and aqueous layers were separated. The aqueous layer was extracted with EtOAc (3×). The organic phases were combined and washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by tritration in ether to provide 6-(2-(3-(4-(phenoxymethyl)phenyl)propanoyl)oxazol-5-yl)pyridine-2-carboxylic acid as a pale yellow solid (85 mg, 81%): 1H NMR (THF-d8, 600 MHz) δ 8.11-8.04 (m, 4H), 7.35 (d, 2H, J=7.9 Hz), 7.29 (d, 2H, J=7.9 Hz), 7.22 (dd, 2H, J=8.5, 7.5 Hz), 6.95 (d, 2H, J=7.8 Hz), 6.87 (t, 1H, J=7.3 Hz), 5.02 (s, 2H), 3.43 (t, 2H, J=7.6 Hz), 3.06 (t, 2H, J=7.6 Hz); 13C NMR (THF-d8, 150 MHz) δ 187.1, 165.6, 160.1, 158.7, 153.4, 150.0, 147.0, 141.4, 139.6, 136.4, 130.0, 129.3, 128.6, 128.4, 125.3, 123.5, 121.3, 115.5, 70.2, 41.3, 30.0; HR ESI-TOF m/z 429.1444 (M+H+, C25H20N2O5, requires 429.1445).
Reaction SMILES: [CH3:1]O.S(Cl)([Cl:5])=O.[NH2:7][C@@H:8]([C:13]([OH:15])=[O:14])[CH2:9][C:10]([OH:12])=[O:11]>C(OCC)C>[ClH:5].[CH3:1][CH:9]([C:10]([OH:12])=[O:11])[C@H:8]([C:13]([OH:15])=[O:14])[NH2:7]
Reactant: N[C@H](CC(=O)O)C(=O)O
Reactant: O=S(Cl)Cl
Reactant: CO
Solvent: CCOCC
Product: CC(C(=O)O)[C@@H](N)C(=O)O
Product: Cl
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 62 %

Procedure:
Cool methanol (525 mL) to -20° C. and place under an atmosphere of nitrogen. Add, by dropwise addition, thionyl chloride (80 mL). Add D-aspartic acid (100 g, 0.75 mol) in one portion and allow the reaction to warm to room temperature over approximately 1 hour. Stir for 50 minutes at room temperature and pour into anhydrous ethyl ether (1.5 L). Filter the resulting solid, dissolve partly in warm ethanol (500 mL) and filter again. Add the filtrated to ethyl ether (1.5 L) and filter the resulting solid. Dry to give the title compound (85.3 g, 62%).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[CH3:16][O:17][C:18]1[N:23]=[C:22]([CH3:24])[C:21]([NH:25][CH2:26][CH2:27][NH2:28])=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5]([NH:28][CH2:27][CH2:26][NH:25][C:21]1[C:22]([CH3:24])=[N:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)=[O:6]
Reactant: COc1ccc(NCCN)c(C)n1
Reactant: O=C(O)/C=C/C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NCCNC(=O)/C=C/C(F)(F)F)c(C)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23.3 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (33 mg, 0.23 mmol) was dissolved in DCM (1 ml containing one drop of dimethyl formamide), oxalyl chloride was added (20 μl, 0.23 mmol) and the solution was stirred at room temperature for 15 minutes. This solution was added to a solution of N-(6-methoxy-2-methyl-3-pyridyl)ethane-1,2-diamine (27 mg, 0.15 mmol) and diisopropylethylamine (88 μl, 0.5 mmol) in DCM (2 ml) and the resulting mixture was stirred at room temperature for three hours. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile) to yield 10.5 mg of a solid (0.035 mmol, 23%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH:11]1[C:16]([OH:17])=[CH:15][CH:14]=[C:13]([CH3:18])[CH:12]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH3:18][C:13]1[CH:12]=[CH:11][C:16]([O:17][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)=[CH:15][CH:14]=1
Reactant: Cc1ccc(O)cc1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc3[nH]ccc3c2)cc1
Temperature: 160 °C
Yield: 51.5 %

Procedure:
A mixture of 5-bromo-1H-indole (98.0 mg, 0.500 mmol), p-cresol (108 mg, 1.00 mmol), Cu (32.0 mg, 0.500 mmol), K2CO3 (138 mg, 1.00 mL) and DMF (1.00 mL) was heated at 160° C. for 12 h. The resulting crude mixture was diluted with water (40 mL), the aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC using hexane:EtOAc (4:1) to give the desired product 5-(4-methylphenoxy)-1H-indole (57.5 mg, 51.5%): ESMS m/e: 224.0 (M+H)+.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[C:12]([CH3:20])[CH:11]=2)[CH:2]=1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][C:30]=2[C:36]([F:39])([F:38])[F:37])[CH2:24][CH2:23]1>C(Cl)Cl.CO>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([NH:35][C:32]3[CH:33]=[CH:34][C:29]([CH2:28][N:25]4[CH2:24][CH2:23][N:22]([CH3:21])[CH2:27][CH2:26]4)=[C:30]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)=[O:19])=[C:12]([CH3:20])[CH:11]=2)[CH:2]=1
Reactant: CN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Reactant: Cc1cc(-n2cnc3cccnc32)ccc1CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(-n2cnc3cccnc32)ccc1CC(=O)Nc1ccc(CN2CCN(C)CC2)c(C(F)(F)F)c1

Procedure:
The title compound is prepared as described in Example 7 but using (4-imidazo[4,5-b]pyridin-3-yl-2-methyl-phenyl)-acetic acid (Step 60.1) and 4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (disclosed in WO 03/099771). Title compound: ES-MS: 523.0 [M+H]+; tR=3.11 min (System 1); Rf=0.18 (CH2Cl2/MeOH, 95:5+0.1% NH3aq).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH:9]1[CH2:10][NH:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][CH2:27][CH3:28])=[O:24]>C(Cl)Cl>[CH2:26]([O:25][C:23]([N:11]1[CH2:10][CH:9]2[CH2:14][CH:13]([N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:12]1)=[O:24])[CH2:27][CH3:28]
Reactant: CC(C)(C)OC(=O)N1C2CNCC1C2
Reactant: CCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOC(=O)N1CC2CC(C1)N2C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane (2) (50 mg, 0.25 mmol) in 5 mL of methylene chloride was added triethylamine (67 μL, 0.5 mmol) and the solution was cooled to 0° C. Propyl chloroformate (31 μL, 27.5 mmol) was added and the solution was stirred for 1 h. The solvent was removed in vacuo and the residue was washed with 50 mM sodium acetate in methylene chloride solution. The solution was stirred 10 min and passed through a phase separator. The solvent was removed in vacuo to give crude 3-(propoxycarbonyl)-6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:10]([CH2:19][OH:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:10]([CH2:19][O:20][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.9 %

Procedure:
A solution of 82.0 g (0.31 mol) of 1-benzyl-3-(R)-hydroxymethyl-4(S)-phenyl pyrrolidine (from Step C) and 46.5 g (0.36 mol) of N,N-diisopropylethylamine in 1 L of CH2Cl2 was treated with 54.2 g (0.36 mol) of t-butyldimethylsilyl chloride and the resulting mixture was stirred at rt for 20 h. The reaction was quenched with 750 mL of sat'd NaHCO3 and the layers were separated. The organic layer was combined with 150 g of silica gel and aged for 45 min. The mixture was filtered and the filtrate was concentrated to afford 117 g (100%) of the title compound.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[C:19]([C:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=3)[CH:18]=[CH:17][N:16]=2)[CH2:13][C:12]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[N:11]1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[C:19]([C:21]3[CH2:22][CH2:23][N:24]([S:42]([CH3:41])(=[O:44])=[O:43])[CH2:25][CH:26]=3)[CH:18]=[CH:17][N:16]=2)[CH2:13][C:12]([C:27]([F:32])([F:33])[C:28]([F:30])([F:31])[F:29])=[N:11]1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cc(C3=CCNCC3)ccn2)c(F)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CC=C(c2ccnc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.6 %

Procedure:
1-(2,4-Difluoro-phenyl)-5-[4-(1,2,3,6-tetrahydropyridin-4-yl)-pyridin-2-yl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Example 179, triethylamine (42.0 uL, 0.30 mmol) and methanesulfonyl chloride (7.0 uL, 0.09 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 18 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 15.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[CH:31]=[CH:30][C:10]2[N:11]([CH2:28][CH3:29])[C:12]([CH2:14][C:15]3[N:16]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[F:27])[N:17]=[CH:18][CH:19]=3)=[N:13][C:9]=2[CH:8]=1)=[O:6])[C:2]#[CH:3]>C(O)(=O)C.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[CH2:28]([N:11]1[C:10]2[CH:30]=[CH:31][C:7]([C:5]3[O:6][C:2]([CH3:3])=[CH:1][N:4]=3)=[CH:8][C:9]=2[N:13]=[C:12]1[CH2:14][C:15]1[N:16]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[N:17]=[CH:18][CH:19]=1)[CH3:29]
Reactant: C#CCNC(=O)c1ccc2c(c1)nc(Cc1ccnn1-c1cc(F)ccc1F)n2CC
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: CC(=O)O
Product: CCn1c(Cc2ccnn2-c2cc(F)ccc2F)nc2cc(-c3ncc(C)o3)ccc21

Procedure:
A mixture of crude N-propargyl 1-ethyl-2-{[2-(2,5-difluorophenyl)-pyrazol-3-yl]methyl}-1H-benzimidazole-5-carboxamide (450 mg) and mercury(II) acetate (1 eq) is heated at reflux in acetic acid (15 mL) for 6 h. The mixture is concentrated, saturated aqueous potassium carbonate added and extracted with ethyl acetate (3×). The combined organic layers were washed with water then with saturated aqueous sodium chloride, dried (MgSO4), concentrated, and triturated with ether to give 1-ethyl-2-{[2-(2,5-difluorophenyl)-pyrazol-3-yl]methyl}-5-(5-methyl-oxazol-2-yl)-1H-benzimidazole, which is converted to the hydrochloride salt in ethyl acetate. 1H NMR (d6 DMSO): δ 8.16 (s, 1H), 8.09-9.01 m. (2H), 7.78 (m, 1H), 7.62 (m, 1H), 7.49-7.45 (m, 3H), 7.04 (m, 1H), 6.56 (s, 1H), 4.70 (s, 2H), 4.36 (q, 2H), 2.41 (s, 3H), 1.21 (t, 3H). LCMS MH+ 420.5.
Reaction SMILES: [NH:1]([C:8]1[C:13]([CH2:14]OCC)=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]([OH:32])[CH2:28][N:29]([CH3:31])[CH3:30])=[CH:21][CH:20]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:33]1[CH:37]=[CH:36][N:35]=[CH:34]1>>[NH:1]([C:8]1[C:13]([CH2:14][N:33]2[CH:37]=[CH:36][N:35]=[CH:34]2)=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]([OH:32])[CH2:28][N:29]([CH3:31])[CH3:30])=[CH:21][CH:20]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1c[nH]cn1
Reactant: CCOCc1cnc(Nc2ccc(OCC(O)CN(C)C)cc2)nc1Nc1ccccc1
Product: CN(C)CC(O)COc1ccc(Nc2ncc(Cn3ccnc3)c(Nc3ccccc3)n2)cc1
Yield: 25 %

Procedure:
Using an analogous method to that described in Example 105, but starting from 4-anilino-5-(ethoxymethyl)-2-{4-[2-hydroxy-3-(N,N-dimethylamino)propoxy]anilino}pyrimidine (Example 86) and imidazole, the product was obtained in 25% yield. NMR: 2.18 (s, 6H), 2.2-2.45 (m, 2H), 3.75-3.9 (m, 3H), 4.76 (br s, 1H), 5.20 (s, 2H), 6.75 (d, 2H), 6.89 (d, 1H), 7.08 (t, 1H), 7.20 (d, 1H), 7.32 (dd, 2H), 7.50 (d, 2H), 7.61 (d, 2H), 7.78 (s, 1H), 7.96 (s, 1H), 8.54 (s, 1H), 9.00 (s, 1H); MS (MH+): 460.4.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[N:11]3[CH:12]=[C:13](C)[CH:14]=[CH:15][C:10]3=[N:9][C:8]=2[C:17]2[CH:22]=[CH:21][C:20](C)=[CH:19][CH:18]=2)C=[CH:4][N:3]=[CH:2]1.[ClH:24].ClCC1N2N=CC=CC2=[N:29]C=1C1C=CC(Cl)=CC=1.N1C=CN=N1>>[N:1]1([CH2:6][C:7]2[N:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]3=[N:9][C:8]=2[C:17]2[CH:22]=[CH:21][C:20]([Cl:24])=[CH:19][CH:18]=2)[CH:2]=[N:3][CH:4]=[N:29]1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2cccnn12
Reactant: Cl
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2Cn2ccnc2)cc1
Agent: c1c[nH]nn1
Product: Clc1ccc(-c2nc3ccccn3c2Cn2cncn2)cc1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 1 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-b]pyridazine hydrochloride and 1H-1,2,3-triazole. 1H-NMR (400 MHz, CDCl3, δ) 8.17 (d, J=6.8 Hz, 1H), 8.00 (s, 1H), 7.68 (m, 3H), 7.52 (m, 2H), 7.33 (m, 1H), 7.26 (m, 1H), 6.93 (m, 1H), 5.74 (s, 2H) ppm; m/e 310.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:13])[CH3:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].N1CC[CH2:17][CH2:16][CH2:15]1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:13][CH2:17][CH2:16][CH2:15][CH2:12]2)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CN(C)c1ccc(N)c(C(N)=O)c1
Reactant: C1CCNCC1
Product: NC(=O)c1cc(N2CCCCC2)ccc1N

Procedure:
According to the preparation of 25, piperidine was used to afford 27 (0.8 g) as brown powder; MS m/z 219 (M+).
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[C@H:3]([NH:7][C:8]([N:10]1[C:18]2[CH2:17][CH2:16][N:15]([CH3:19])[CH2:14][C:13]=2[C:12]([C:20]2[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=2[F:28])=[N:11]1)=[O:9])[C:4]([OH:6])=O.CCN(C(C)C)C(C)C.C(OC(Cl)=O)C(C)C.[NH2:48][C@H:49]([C:54]([NH2:56])=[O:55])[CH2:50][CH:51]([CH3:53])[CH3:52]>C(Cl)Cl>[NH2:56][C:54](=[O:55])[C@@H:49]([NH:48][C:4](=[O:6])[C@@H:3]([NH:7][C:8]([N:10]1[C:18]2[CH2:17][CH2:16][N:15]([CH3:19])[CH2:14][C:13]=2[C:12]([C:20]2[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=2[F:28])=[N:11]1)=[O:9])[C:2]([CH3:30])([CH3:1])[CH3:29])[CH2:50][CH:51]([CH3:53])[CH3:52]
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: CN1CCc2c(c(-c3cc(F)c(F)cc3F)nn2C(=O)N[C@H](C(=O)O)C(C)(C)C)C1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound 71 (40 mg) in DCM was added DIEA (45 uL) followed by isobutylchloroformate (26 uL). After stirring at room temperature for 30 min, leucine amide (18 mg) and DIEA (25 uL) was added and stirred for 1 h. The reaction mixture was evaporated and dissolved in MeOH, and purified with a preparative LC-MS to give compound 72. LCMS (+ESI) m/z=537.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].CCN(C(C)C)C(C)C.[CH2:19](Br)[O:20][CH3:21]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:19][O:20][CH3:21]
Reactant: Oc1ccc(F)cc1F
Reactant: COCBr
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc(F)cc1F
Temperature: 25 °C
Yield: 92.6 %

Procedure:
To a solution of 2,4-difluorophenol (11.0 g, 85 mmol) and DIPEA (15.5 mL, 89 mmol) in DCM (150 ml) at 0° C. under nitrogen was added MOM-Br (7.33 mL, 89 mmol) over 1 hr and the reaction mixture then maintained at RT for 16 hr. The resulting mixture was washed successively with water, aq 2M NaOH solution, water and brine, and was then dried (MgSO4) and evaporated in vacuo to afford 2,4-difluoro-1-(methoxymethoxy)benzene as a colourless oil (13.7 g, 88% yield). Rt 3.17 min (Method 1, basic, no ionization observed), which was used directly in the next step (below).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:38]1([CH2:44][C:45]([N:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)=[O:46])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:41]3[CH2:40][CH2:39][N:38]([CH2:44][C:45]([N:47]4[CH2:48][CH2:49][CH2:50][CH2:51]4)=[O:46])[CH2:43][CH2:42]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C(CN1CCNCC1)N1CCCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCCC2)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 2-piperazin-1-yl-1-pyrrolidin-1-yl-ethanone (Oakwood) to give the title compound. HR-MS (ES, m/z) calculated for C39H49Cl2N6O3 [(M+H)+] 719.3238, observed 719.3242.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].Br[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1>>[Cl:19][C:15]1[CH:14]=[C:13]([CH2:12][CH2:11][CH2:10][CH2:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[CH3:1])[CH:18]=[CH:17][CH:16]=1
Reactant: Clc1cccc(CCCBr)c1
Reactant: Cc1ccncc1C
Product: Cc1cnccc1CCCCc1cccc(Cl)c1
Yield: 45.7 %

Procedure:
1.0 g (9.35 mmol) of 3,4-dimethylpyridine and 2.18 g (9.35 mmol) of 1-bromo-3-(3-chlorophenyl)-propane were reacted in the same manner as in Example 26. The reaction product was purified to obtain 1.11 g of the desired compound (yield: 5.9%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39](Cl)=[O:40])=[CH:34][CH:33]=1>C1COCC1>[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39]([NH:1][C:2]2[CH:10]=[C:9]3[C:5](=[CH:4][CH:3]=2)[CH2:6][O:7][C:8]3=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])=[O:40])=[CH:34][CH:33]=1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)Nc2ccc3c(c2)C(=C2C(=O)Nc4ccccc42)OC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of 3-(6-Amino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (50.0 mg, 0.189 mmol) and N,N-diisopropylethylamine (98.8 μL, 0.567 mmol) in 2.0 mL THF was added 4-methoxyphenylacetyl chloride (28.9 μL, 0.189 mmol). After stirring at room temperature for 1 h, the slurry was warmed briefly, stirred 10 min at room temperature, filtered and rinsed with MeOH and EtOAc/hexanes (1:1) to afford the title compound (48.3 mg, 62%) as a yellow solid.
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH:13]=[C:14]3[CH2:19][C@@H:18]([OH:20])[CH2:17][CH2:16][C@:15]3([CH3:21])[C@H:5]1[CH2:4][CH2:3]2.[C:22]([O:26]O)(C)(C)[CH3:23].Cl[O-:29].[Na+]>C(OCC)(=O)C>[C:22]([O:20][C@H:18]1[CH2:17][CH2:16][C@@:15]2([CH3:21])[C:14](=[CH:13][C:12](=[O:29])[C@@H:6]3[C@@H:5]2[CH2:4][CH2:3][C@@:2]2([CH3:1])[C@H:7]3[CH2:8][CH2:9][C:10]2=[O:11])[CH2:19]1)(=[O:26])[CH3:23]
Reactant: CC(C)(C)OO
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: [O-]Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC(=O)[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Temperature: 2.5 °C

Procedure:
The above solution of DHEA-Ac (2) in ethyl acetate (˜1000 ml) was taken in a 5L three necked flask fitted with a thermometer and a pressure equalizing dropping funnel. An aqueous solution of tert-butyl hydroperoxide (70% aqueous solution from Aldrich, 270 ml, 6.0 equivalents) was added and the mixture was cooled to 0-5° C. Aqueous sodium hypochlorite solution (950 ml, 5.25% solution, purchased as house hold bleach) was added dropwise under good stirring to the cooled solution during a period of ten hours at 0-5° C. After completion of addition, the lower aqueous layer was removed and the organic (ethyl acetate) layer was stirred with sodium sulfite solution (100.0 gm in 300 ml of water) for 3 hours at 40-45° C. The aqueous yellow layer was removed and the organic layer was washed twice with 100 ml of half saturated brine, dried over anhydrous magnesium sulfate and concentrated to 50 ml volume. On triturating with hexane, 3β-acetoxyandrost-5-en-7,17-dione (7-oxo-DHEA-Ac, 3) crystallized out as a white solid, yield 79.4 gm (66.5%, based on DHEA), purity (HPLC) 98.86%. The resulting solid was recrystallized from ethanol, providing 3β-acetoxyandrost-5-en-7,17-dione (3) as white crystalline solid (70.0 gm, purity (HPLC) 99.8%, melting point 185-186° C.
Reaction SMILES: Cl.CCOC(C)=O.C(OC([NH:15][NH:16][C:17](=[O:49])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)=[CH:20][C:19]=1[C:36]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:41][CH:40]2[CH2:42][CH:37]1[CH2:38][CH2:39]2)=O)(C)(C)C>C(Cl)Cl>[C:43]1([C:36]2([C:19]3[CH:20]=[C:21]([O:24][CH2:25][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)[CH:22]=[CH:23][C:18]=3[C:17]([NH:16][NH2:15])=[O:49])[CH2:41][CH:40]3[CH2:42][CH:37]2[CH2:38][CH2:39]3)[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1C1(c2ccccc2)CC2CCC1C2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NNC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1C1(c2ccccc2)CC2CCC1C2
Reaction time: 1 h

Procedure:
Cold hydrogen chloride/EtOAc (10 mL; saturated solution) was added to a stirred solution of 4c (0.99 g, 1.76 mmol) in methylene chloride (5 mL) at room temperature. After approximately 1 h, the reaction mixture was concentrated in vacuo and the crude residue partitioned between saturated aqueous sodium bicarbonate and methylene chloride. The organic phase was separated, and the aqueous phase was re-extracted twice with methylene chloride. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo to afford 4d as a white powder (m/z (ES) 464 (MH)+) which was used without further purification in the subsequent reaction.