Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[B:35](OC(C)C)([O:40]C(C)C)[O:36]C(C)C.Cl>O.C1(C)C=CC=CC=1.C1COCC1>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([B:35]([OH:40])[OH:36])=[CH:3][CH:4]=2)=[CH:13][CH:12]=1
Reactant: Brc1ccc(-c2ccc(-c3ccc4ccccc4c3)cc2)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: OB(O)c1ccc(-c2ccc(-c3ccc4ccccc4c3)cc2)cc1
Temperature: -60 °C
Yield: 68.8 %

Procedure:
Under an argon gas atmosphere, a mixture of 15.3 g (42.6 mmol) of 2-(4′-bromobiphenyl-4-yl)naphthalene and 200 mL of dehydrated THF was cooled down to −60 degrees C., and added with 32.8 mL (51.1 mmol) of hexane solution of 1.56M n-butyllithium in drops while being stirred. Then, the reaction mixture was stirred for one hour at −60 degree C. The reaction mixture was further cooled down to −60 degrees C., and added with 24.0 g (1.06 mol) of triisopropyl borate in drops. Then, the mixture was warmed up to room temperature to be stirred for 16 hours. The reaction mixture was further added with solution of hydrochloric acid to be stirred for one hour at room temperature. After the reaction, the reaction mixture was further added with toluene, so that aqueous phase thereof was eliminated. After organic phase thereof was cleansed with water and dried with magnesium sulfate, the solvent was distilled away under reduced pressure. By recrystallizing the obtained solid by hexane, 9.50 g of 4′-(naphthalene-2-yl)biphenyl-4-yl boronic acid was obtained at an yield of 67%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([Cl:21])[CH:15]=1.O>CN(C)C=O>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:16]([Cl:21])[CH:15]=1
Reactant: Oc1ccc(Br)cc1Cl
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cc(Br)ccc1OC1CCCC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 98 %

Procedure:
Potassium carbonate (2.0 g) and bromocyclopentane (0.775 mL) were added to a solution of 4-bromo-2-chlorophenol (1.0 g) in N,N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for four days. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated ammonium chloride solution and water, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give 4-bromo-2-chloro-1-(cyclopentyloxy)benzene as a colorless oil (1.31 g, 98%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.CN(C=O)C.[H-].[Na+].[F:15][C:16]1[C:48]([F:49])=[CH:47][C:19]2[NH:20][C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]4[C:36]([C:37]5[CH:42]=[CH:41][N:40]=[C:39](S(C)(=O)=O)[N:38]=5)=[CH:35][CH:34]=[CH:33][N:32]=4)=[CH:26][CH:25]=3)=[N:22][C:18]=2[CH:17]=1>O.C(OCC)(=O)C>[F:15][C:16]1[C:48]([F:49])=[CH:47][C:19]2[NH:20][C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]4[C:36]([C:37]5[CH:42]=[CH:41][N:40]=[C:39]([NH:7][C:3]6[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=6)[N:38]=5)=[CH:35][CH:34]=[CH:33][N:32]=4)=[CH:26][CH:25]=3)=[N:22][C:18]=2[CH:17]=1
Reactant: Nc1cccnc1
Reactant: CS(=O)(=O)c1nccc(-c2cccnc2Oc2ccc(Nc3nc4cc(F)c(F)cc4[nH]3)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cc2nc(Nc3ccc(Oc4ncccc4-c4ccnc(Nc5cccnc5)n4)cc3)[nH]c2cc1F
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
A resealable reaction vial, under nitrogen, was charged with pyridin-3-amine (0.04 g, 42.50 mmol) and DMF (0.80 ml, 0.1 M). This was cooled to 0° C. and 60% wt in oil sodium hydride added (0.01 g, 42.50 mmol). The reaction mixture was stirred at 0° C. under a nitrogen atmosphere for 35 min. 5,6-Difluoro-N-(4-(3-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine (0.04 g, 0.08 mmol) was added slowly to the mixture which was allowed to warm up to RT and stirred for 1 hr. The reaction mixture was heated to 60° C. and stirred for 1 hr. The reaction mixture was cooled to RT, then diluted with water and ethyl acetate. The layers were separated, the organic layer was dried over sodium sulfate and concentrated under reduced pressure to give oily residue, which was purified by silica prep plate (0.5% NH4OH/9.5% MeOH/Dichloromethane) followed by Gilson reverse phase chromatography (10% to 90% CH3CN/H2O/0.1% TFA) to afford 5,6-difluoro-N-(4-(3-(2-(pyridin-3-ylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine as a yellow solid. MS m/z=509.0 [M+H]+. Calc'd for C27H18F2N8O: 508.48.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9](C3C4C(C=C5C=3C=CC=C5)=CC=CC=4)[CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N(Br)C(=O)C1.C1([C:47]2[CH:48]=[C:49]([C:59]3[C:60]4[C:65]([C:66]([Br:73])=C5C=3C=CC=C5)=[CH:64][CH:63]=[CH:62][CH:61]=4)[CH:50]=[CH:51][C:52]=2C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.O>[C:13]1([C:12]2[CH:11]=[C:10]([C:61]3[C:60]4[C:65](=[C:66]([Br:73])[C:48]5[C:49]([CH:59]=4)=[CH:50][CH:51]=[CH:52][CH:47]=5)[CH:64]=[CH:63][CH:62]=3)[CH:9]=[CH:8][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Brc1c2ccccc2c(-c2ccc(-c3ccccc3)c(-c3ccccc3)c2)c2ccccc12
Reactant: c1ccc(-c2ccc(-c3c4ccccc4cc4ccccc34)cc2-c2ccccc2)cc1
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Brc1c2ccccc2cc2c(-c3ccc(-c4ccccc4)c(-c4ccccc4)c3)cccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
9-(3,4-Diphenylphenyl)anthracene (3.7 g, 9.1 mmole) was suspended in anhydrous DMF (50 ml). After an anhydrous DMF solution (10 ml) of NBS (1.8 g, 10 mmole, 1.1 eq) was added, the resultant mixture was heated at 55° C. for 5 minutes so that the reaction mixture became a homogeneous solution. The obtained solution was stirred at the room temperature for 4 hours and then left standing for one night. The reaction mixture was diluted with water (50 ml). The formed solid substance was separated by filtration and washed with methanol, and a light yellow solid substance (4.2 g, the yield: 95%) was obtained. The obtained product was identified to be 9-(3,4-diphenylphenyl)-10-bromoanthracene in accordance with 1H-NMR.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1.[C:17]([O-])([O-])=O.[K+].[K+]>C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]2[N:16]=[CH:17][N:8]([CH2:9][CH2:10][N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:5]2=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1cc(Br)cnc1NCCN1CCCC1
Agent: [K+]
Solvent: O=CO
Product: Brc1cnc2c(c1)ncn2CCN1CCCC1

Procedure:
A solution of 470 mg (1.65 mmol) 5-bromo-N2-(2-pyrrolidin-1-yl-ethyl)-pyridine-2,3-diamine in 10 mL formic acid is refluxed for 1.5 h. The mixture is made alkaline with saturated K2CO3 solution and extracted with 40 mL EtOAc. The organic phase is dried over Na2SO4 and the solvent is eliminated i.vac.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]([C:11](=O)[NH:12][C:13]1[C:14]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:15][CH:16]=[CH:17][CH:18]=1)[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2]>CC(O)=O>[C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]([C:11]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[N:12]=1)[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccnc1Nc1ccccc1
Solvent: CC(=O)O
Product: CC[C@H](NC(=O)OC(C)(C)C)c1nc2cccnc2n1-c1ccccc1
Temperature: 25 °C
Yield: 83.4 %

Procedure:
A solution of [(S)-1-(2-phenylaminopyridin-3-ylcarbamoyl)propyl]carbamic acid tert-butyl ester (4.32 mmol) in AcOH (30 mL) was heated at 70° C. for 3 h. After cooling to RT, the volatiles were removed under reduced pressure and the residue partitioned between DCM and a saturated aqueous solution of NaHCO3. The aqueous phase was extracted with DCM (×3) and the combined organic fractions washed with water, dried (Na2SO4) and concentrated in vacuo to afford the title compound as an oil (1.27 g, crude material). LCMS (Method C): RT 3.24 min [M+H]+ 353.4.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Cl:27])[C:5]2[C:10]([C:11]#[C:12][CH2:13][CH2:14][OH:15])=[CH:9][N:8]([CH2:16][C:17]3[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[C:20]([CH3:26])=[CH:19][N:18]=3)[C:6]=2[N:7]=1.C([NH:35][C@H:36]([C:38](O)=[O:39])[CH3:37])(OC(C)(C)C)=O.CCN=C=NCCCN(C)C.C(O)(C(F)(F)F)=O>CN(C1C=CN=CC=1)C.CC(N(C)C)=O.C(Cl)Cl.O.CCOC(C)=O>[NH2:35][C@@H:36]([CH3:37])[C:38]([O:15][CH2:14][CH2:13][C:12]#[C:11][C:10]1[C:5]2[C:4]([Cl:27])=[N:3][C:2]([NH2:1])=[N:7][C:6]=2[N:8]([CH2:16][C:17]2[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[C:20]([CH3:26])=[CH:19][N:18]=2)[CH:9]=1)=[O:39]
Reactant: COc1c(C)cnc(Cn2cc(C#CCCO)c3c(Cl)nc(N)nc32)c1C
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: COc1c(C)cnc(Cn2cc(C#CCCOC(=O)[C@H](C)N)c3c(Cl)nc(N)nc32)c1C

Procedure:
A solution of 4-[2-Amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-but-3-yn-1-ol (see example 2) (51.7 mg), N-Boc alanine (53.3 mg), DMAP (33.7 mg), and EDCI (54.9 mg) in anhyrous DMA (4 mL) was stirred at rt overnight. Work-up (EtOAc; H2O) gave the crude Boc-protected intermediate. A solution of this intermediate (40 mg) in DCM (1.0 mL) was treated with TFA (0.2 mL) at rt for 5 min, and evaporated. The material was dissolved in MeOH (1 ml) and water (10 mL), and washed with Et2O (10 mL). The organic layer was discarded. The aqueous layer was brought to pH >7 with sat. aq. NaHCO3 and back-extracted with DCM. The title compound was isolates as a solid. HPLC Rt=4.37 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:3]1.[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20](=[CH:28]O)[C:21](=[O:27])[NH:22]2>>[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20](=[CH:28][NH:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH:4]3[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]3)=[CH:15][CH:14]=1)[C:21](=[O:27])[NH:22]2
Reactant: CN1CCCC(COc2ccc(N)cc2)C1
Reactant: O=C1Nc2cccc(F)c2C1=CO
Product: CN1CCCC(COc2ccc(NC=C3C(=O)Nc4cccc(F)c43)cc2)C1
Yield: 67.7 %

Procedure:
In a manner similar to that described in Example 231, 4-(1-methyl-piperidin-3-ylmethoxy)-phenylamine (590 mg, 1.2 equiv.) and 4-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (400 mg, 2.23 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (576 mg, 68%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+].I[CH2:30][CH3:31].C1(S)C=CC=CC=1.C(=O)([O-])[O-].C(N(C(C)C)CC)(C)C>CC(C)=O>[Cl:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH2:30][CH3:31])[CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(O)c(Cl)c2)C1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(C[C@@H]2CNCCO2)cc1Cl
Temperature: 55 °C
Reaction time: 16 h

Procedure:
N-BOC-(R)-2-(3-chloro-4-hydroxybenzyl)morpholine, example 7, intermediate (a) (52 mg, 0.16 mmol), was dissolved in acetone (1.5 mL) with potassium carbonate (44 mg, 0.32 mmol) and iodoethane (38 uL, 0.47 mmol) added in one portion. The reaction was then heated to 55° C. and shaken at that temperature for 16 hrs. The reaction mixture was filtered, washing with acetone (1 mL×2) and the liquor evaporated under a high flow of nitrogen. The residue was dissolved in tetrahydrofuran: ethanol (1:1, 4 mL) and polymer supported thiophenol (0.43 g, 0.64 mmol), MP-carbonate (0.24 g, 0.64 mmol) and diisopropylethylamine (119 uL, 0.68 mmol) added. The reaction was shaken for 24 hrs, then filtered and concentrated under a high flow of nitrogen. The crude residue was dissolved in TFA (20% v/v solution in dichloromethane, 2.0 mL) and shaken for 3 hrs at room temperature. The reaction mixture was added directly to an SCX-2 column (2 g) and washed with dichloromethane (2 mL×2) and methanol (2 mL×2). The SCX-2 column was then washed with ammonia (2N in methanol, 3×2 mL). Combined ammonia washes were concentrated in vacuo. The residue was then purified by preparative HPLC to yield the desired morpholine example 28 as a colorless oil (17 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:2]=1.Br[C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][CH:18]=[CH:17]2.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:11][CH2:10][N:9]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][CH:18]=[CH:17]4)[C:8]2=[O:12])[CH:2]=1
Reactant: O=C1NCCN1c1cccnc1
Reactant: Brc1ccc2ncccc2c1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C1N(c2cccnc2)CCN1c1ccc2ncccc2c1
Yield: 59.7 %

Procedure:
Using the same reaction conditions as in Example 1, 1-pyridin-3-yl-imidazolidin-2-one (I-1b: 117 mg, 0.7215 mmol) was reacted with 6-bromo-quinoline (150 mg, 0.7215 mmol), 1,4-dioxane (5 mL), copper iodide (13 mg, 0.07215 mmol), trans-1,2-diamino cyclohexane (24.78 mg, 0.21645 mmol) and potassium carbonate (199.49 mg, 1.1443 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in chloroform), afforded 125 mg of the product (60.09% yield).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([CH2:12]Br)[CH:3]=1.Cl.[CH3:15][O:16][C:17](=[O:23])[C@@H:18]([CH:20]([CH3:22])[CH3:21])[NH2:19].C(N(CC)CC)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:8])[N:19]([C@H:18]([CH:20]([CH3:22])[CH3:21])[C:17]([O:16][CH3:15])=[O:23])[CH2:12]2
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: COC(=O)[C@H](N)C(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](C(C)C)N1Cc2cc(Br)ccc2C1=O

Procedure:
Methyl 4-bromo-2-(bromomethyl)benzoate (650 mg, 2.12 mmol) and D-valine methyl ester hydrochloride (527 mg, 3.15 mmol) was taken in toluene (6.5 mL) and to this reaction mixture, triethyl amine (428 mg, 4.24 mmol) was added and refluxed for about 16 h. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over anhydrous sodium sulfate and concentrated to obtain an oil, which was purified by column chromatography (silica gel, 30% ethyl acetate in petroleum ether) to obtain the title compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][NH:13][C:12](=[O:16])[CH:11]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:23]I>CN(C)C=O.O>[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([CH3:23])[C:12](=[O:16])[CH:11]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: O=C1NCCN(Cc2ccccc2)C1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(Cc2ccccc2)C(c2ccccc2)C1=O
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
15.3 g of sodium hydride (65% dispersion in mineral oil, 0.414 moles) was suspended in 250 ml of N,N-dimethylformamide at 10° C. To this suspension, 100 g of 4-benzyl-2-oxo-3-phenylpiperazine (0.376 moles) was added portionwise over a period of 30 min and stirred for 15 min. A solution of 64 g of methyl iodide (0.45 moles) in 50 ml of N,N-dimethylformamide was added slowly in 45 min maintaining the temperature below 25° C. and maintained for 1 hour. After completion of the reaction, mass was poured slowly in 1000 ml of cold water (15° C.). The product was extracted with toluene (1×500 ml, 1×300 ml) from aqueous phase. Toluene layer was washed with water (2×200 ml) and concentrated. To the residue, 250 ml of cyclohexane was added and cooled to 10° C. with stirring. Filtered the product and washed with precooled cyclohexane to obtain 98.5 g of 4-benzyl-1-methyl-2-oxo-3-phenylpiperazine product (yield: 93.8%, purity: 99.15 by HPLC)
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:26])[C:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@:18]([F:24])([C@@H:19]([OH:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:25])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][CH:5]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:27]([O:23][C@H:19]1[CH2:20][C@@:21]2([CH3:22])[C@@H:7]([CH2:6][CH:5]=[C:4]2[C:3](=[O:26])[CH2:2][Cl:1])[C@H:8]2[C@@:18]1([F:24])[C@:16]1([CH3:17])[C:11]([CH2:10][CH2:9]2)=[CH:12][C:13](=[O:25])[CH:14]=[CH:15]1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3CC=C(C(=O)CCl)[C@@]3(C)C[C@H](O)[C@@]12F
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)O[C@H]1C[C@]2(C)C(C(=O)CCl)=CC[C@H]2[C@@H]2CCC3=CC(=O)C=C[C@]3(C)[C@@]12F
Temperature: 25 °C

Procedure:
A suspension of 21-chloro-9-fluoro-11β-hydroxypregna-1,4,16-triene-3,20-dione (2.1g) in a mixture of glacial acetic acid (30 ml) and acetic anhydride (30 ml) containing p-toluenesulfonic acid hydrate (2.1g) is stirred at room temperature. After 30 hours the solution is mixed with sodium acetate hydrate (5.0g) and evaporated in vacuo. The residue is dissolved in chloroform, washed with water, dried and evaporated to afford the title compound. One crystallization from acetone affords 1.85g of the title compound, melting point 222°-223° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:21])[C:5]([O:8][C:9]2[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15](O)=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.S(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([F:21])[C:5]([O:8][C:9]2[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15]([Cl:24])=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: CC(Oc1ccc(Oc2ncc(Cl)cc2F)cc1)C(=O)O
Solvent: Cc1ccccc1
Product: CC(Oc1ccc(Oc2ncc(Cl)cc2F)cc1)C(=O)Cl
Temperature: 90 °C
Reaction time: 14 h

Procedure:
63.6 g of 2-[4-(5-chloro-3-fluoropyridin-2-yloxy)phenoxy]propionic acid are dissolved in 700 ml of toluene, then 200 ml of toluene are removed from this solution by distillation. After cooling to 90° C., 25 ml (0.34 mole) of thionyl chloride are added dropwise and the solution is stirred for 14 hours at this temperature. The reaction mixture is then concentrated to a volume of 200 ml and the resultant solution of 2-[4-(5-chloro-3-fluoropyridin-2-yloxy)phenoxy]propionyl chloride in toluene is used direct for the following reaction step.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]([C:11]2[N:12](COCC[Si](C)(C)C)[C:13](Br)=[C:14]([Br:16])[N:15]=2)=[O:10])=[CH:3][CH:2]=1.C(OC([N:33]1[C:41]2[C:36](=[CH:37][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:40]=2)[CH:35]=[C:34]1[C:51]1[O:55][N:54]=[C:53]([CH3:56])[N:52]=1)=O)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:1]1[CH:2]=[CH:3][C:4]([CH2:7][NH:8][C:9]([C:11]2[NH:15][C:14]([Br:16])=[C:13]([C:38]3[CH:37]=[C:36]4[C:41](=[CH:40][CH:39]=3)[NH:33][C:34]([C:51]3[O:55][N:54]=[C:53]([CH3:56])[N:52]=3)=[CH:35]4)[N:12]=2)=[O:10])=[CH:5][CH:6]=1
Reactant: Cc1noc(-c2cc3cc(B4OC(C)(C)C(C)(C)O4)ccc3n2C(=O)OC(C)(C)C)n1
Reactant: C[Si](C)(C)CCOCn1c(C(=O)NCc2ccncc2)nc(Br)c1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1noc(-c2cc3cc(-c4nc(C(=O)NCc5ccncc5)[nH]c4Br)ccc3[nH]2)n1
Temperature: 120 °C

Procedure:
To a solution of 4,5-dibromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid(pyridin-4-ylmethyl)-amide (280 mg, 0.57 mmol) and 2-(3-methyl-1,2,4-oxadiazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-indole-1-carboxylic acid tert-butyl ester (243 mg, 0.57 mmol) in toluene (5.0 ml) is added aqueous Na2CO3 solution (2M, 0.63 ml, 1.26 mmol). The mixture is purged with argon for 10 minutes. (Bis(di-t-butyl(4-dimethylaminutesophenyephosphine)dichloropalladium(II) (81 mg, 0.11 mmol) is added and the reaction mixture is sealed in a sealed tube and heated to 120° C. for 14 hours. The reaction mixture is diluted with ethyl acetate (25 ml), washed with water (15 ml), brine (15 ml), dried over MgSO4, filtered, and concentrated in vacuo. The crude material is purified on reversed phase HPLC. The resulting protected analog is dissolved in 50% trifluoroacetic acid in dichloromethane (10 ml). After 2 hours the solvent is evaporated in vacuo, and the product is purified by reverse phase HPLC, 25 mg, 9%, LC/MS ESI m/z (M+H)+=480.33.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([S:22][CH3:23])[C:4]=1[C:5]([NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=O)=[O:6].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([S:22][CH3:23])[C:4]=1[C:5]([NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:6]
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1=O
Reactant: C1CCNC1
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1N1CCCC1

Procedure:
The title compound, brown gum, MS: m/e=403.4 [(M+H, was prepared in accordance with the general method of example 1 and 2 from 2-methoxy-6-methylsulfanyl-N-(2-oxo-cyclopentyl)-4-trifluoromethyl-benzamide (intermediate M) and pyrrolidine. The cis- and trans-isomer could be separated by column chromatography.
Reaction SMILES: C(OC([N:11]1[CH2:15][C@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[CH2:24][CH2:25][CH2:26][C:27]#[N:28])=O)C1C=CC=CC=1>C(O)C.[C].[Pd]>[C:27]([CH2:26][CH2:25][CH2:24][C@@H:12]1[CH2:13][C@@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19])[CH2:15][NH:11]1)#[N:28]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CCCC#N)N(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)O[C@H]1CN[C@H](CCCC#N)C1
Reaction time: 2 h

Procedure:
(2R,4R)-1-Benzyloxycarbonyl-2-(3-cyanopropyl)-4-t-butyldimethylsilyloxypyrrolidine (1.69 g) was dissolved in 34 ml of ethanol, and 338 mg of 5% palladium-carbon was added thereto, followed by hydrogenation at room temparature under 1 atm. for 2 hours. The catalyst was removed by filtration, and the filtrate was distilled to obtain (2R,4R)-2-(3-cyanopropyl)-4-t-butyldimethylsilyloxypyrrolidine.
Reaction SMILES: C([O:8][CH2:9][C:10]1([CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[O:14][C:13](=[O:15])[CH2:12][CH2:11]1)C1C=CC=CC=1.C(O)C.[H][H]>[Pd].O>[OH:8][CH2:9][C:10]1([CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[O:14][C:13](=[O:15])[CH2:12][CH2:11]1
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCCCOCCC1(COCc2ccccc2)CCC(=O)O1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOCCC1(CO)CCC(=O)O1

Procedure:
A mixture containing 10.2 g (21.83 mmol) of the compound prepared in (e) above, 300 ml of a mixture of ethyl alcohol and water in a ratio of 9:1 and 1.5 g of 5% palladium on carbon (50% water content) was placed in a pressure bottle and hydrogenated at 40° C. under a pressure of 50 lbs. of hydrogen until uptake was complete. The catalyst was then filtered off and the filtrate concentrated in vacuo. The residue was crystallized from methanol to yield a solid.