Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:9])(C)[C:4]([O:6][CH3:7])=[O:5].S([O-])([O-])(=O)=O.[Mg+2].[CH3:16][O:17][C:18]1[CH:27]=[C:26]2[C:21]([C:22]([CH:28]=O)=[CH:23][CH:24]=[N:25]2)=[CH:20][CH:19]=1.[BH4-].[Na+]>ClCCl.CCOC(C)=O.C(N(CC)CC)C>[CH3:16][O:17][C:18]1[CH:27]=[C:26]2[C:21]([C:22]([CH2:28][NH:2][CH:3]([CH3:9])[C:4]([O:6][CH3:7])=[O:5])=[CH:23][CH:24]=[N:25]2)=[CH:20][CH:19]=1
Reactant: COc1ccc2c(C=O)ccnc2c1
Reactant: COC(=O)C(C)(C)N
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)NCc1ccnc2cc(OC)ccc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 43.2 %

Procedure:
A mixture of 1.23 g of methyl α-aminoisobutyrate hydrochloride and 1.12 ml of triethylamine in 30 ml of dichloromethane is stirred at 0° C. for 20 minutes. Next, 1 g of magnesium sulfate and 1.5 g of 7-methoxyquinoline-4-carbaldehyde are added. Stirring is continued for 15 hours at room temperature and the mixture is then concentrated under reduced pressure. The residue is taken up in 35 ml of methanol, the solution obtained is cooled to 0° C. and 0.31 g of sodium borohydride is then added portionwise. The reaction medium is stirred at a temperature in the region of 20° C. for 15 hours. The reaction medium is concentrated under reduced pressure. The residue obtained is taken up in 100 ml of EtOAc. The precipitate formed is filtered off and the filtrate is concentrated under reduced pressure and then purified by flash chromatography on a column (SiO2, EtOAc as eluent, Ar), and 0.95 g of the expected product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8](O)=[O:9].C(Cl)(=O)C([Cl:19])=O>CN(C=O)C.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([Cl:19])=[O:9]
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(C=CC(=O)Cl)cc1OC
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a mixture of 3,4-dimethoxycinnamic acid (540 mg), DMF (2 drops) and tetrahydrofuran (10 ml) was added oxalyl chloride (0.27 ml) dropwise. The mixture was stirred at room temperature for 40 minutes, at the end of which time the solvent was distilled off to give 3,4-dimethoxycinnamoyl chloride. The chloride was dissolved in dichloromethane (10 ml) followed by addition of 3-amino-4-(2-methylphenyl)-7,8-dihydrocyclopenta[g][1]benzopyran-2(6H)-one (582 mg) and N,N-dimethylaniline (0.25 ml). The mixture was then stirred at room temperature for 20 hours, after which it was washed with water, dried (MgSO<) and distilled to remove the solvent. The residue was chromatographed on silica gel and eluted with benzeneacetone (9:1) to give 3-(3,4-dimethoxycinnamoylamino)-4-(2-methylphenyl)-7,8-dihydrocyclopenta[g][1]benzopyran-2(6H)-one as oil. The oil was crystallized from ethanol-isopropyl ether (648 mg, 67.4%). Recrystallization from acetone gave colorless needles, m.p. 159°-160° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[NH:9][C:8]([SH:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br.Br[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[CH2:21]Br>CC(O)(C)C.Cl>[CH3:1][C:2]1[C:10]2[N:9]3[CH2:21][CH:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[S:11][C:8]3=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: BrCC(Br)c1ccccn1
Reactant: Cc1cccc2nc(S)[nH]c12
Agent: Br
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: CC(C)(C)O
Product: Cc1cccc2nc3n(c12)CC(c1ccccn1)S3
Reaction time: 2 h
Yield: 7.2 %

Procedure:
4-Methyl-2-mercaptobenzimidazole (13.32 g) was suspended in 2-methylpropan-2-ol (150 ml) and potassium tertbutoxide (9.04 g) added. The mixture was stirred for 2 hours and 2-(1,2-dibromoethyl)pyridine hydrobromide (27.68 g) added. The mixture was stirred at ambient temperature for 1 hour and then at reflux for 2 hours. The reaction mixture was filtered and the solid washed with ether. The filtrate was evaporated to dryness under reduced pressure and the residue combined with the first solid obtained. The combined material was dissolved in 2N HCl (100 ml). The aqueous solution was extracted with ethyl acetate, basified (Na2CO3) and extracted with dichloromethane. The organic layer was dried (MgSO4) and the solvent removed under reduced pressure. The residue was purified on Florisil using chloroform as eluent and on silica using ethyl acetate as eluent to give the title compound (1.55 g) mp 128°-130° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:10]([C:11]([CH3:18])([CH3:17])[CH2:12][O:13][CH2:14][O:15][CH3:16])=[CH:9][C:8](Br)=[CH:7][C:6]=1[C:20]([CH3:23])([CH3:22])[CH3:21].[Li]C(C)(C)C.CN([CH:32]=[O:33])C.[Cl-].[NH4+]>C1COCC1>[C:20]([C:6]1[CH:7]=[C:8]([CH:9]=[C:10]([C:11]([CH3:18])([CH3:17])[CH2:12][O:13][CH2:14][O:15][CH3:16])[C:5]=1[O:4][CH2:3][O:2][CH3:1])[CH:32]=[O:33])([CH3:23])([CH3:22])[CH3:21]
Reactant: CN(C)C=O
Reactant: COCOCC(C)(C)c1cc(Br)cc(C(C)(C)C)c1OCOC
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCOCC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1OCOC
Temperature: 25 °C
Yield: 83.1 %

Procedure:
A solution of 48 (925 mg, 2.38 mmol) in THF (20 ml) was cooled to −50° C., and t-BuLi (1.7 M in pentane, 3.08 ml, 5.24 mmol) was dropwise added to the solution while maintaining the temperature below −40° C. After completion of the addition, the mixture was stirred at this temperature, and DMF (0.12 ml) in THF (5 ml) was added. The mixture was warmed slowly to room temperature. Aqueous solution of saturated ammonium chloride (50 ml) was added, and the mixture was extracted with ethyl acetate (50 ml). The organic layer was washed with saturated brine (50 ml), and after dryness, the solvent was removed in vacuo. The residue was purified by column chromatography to yield 669 mg (83.1%) of 49 as colorless oil. 1H NMR (CDCl3) δ: 1.47 (9H, s, tBu), 1.48 (6H, s, 2×CH3), 3.29, 3.66 (each 3H, s, CH3), 3.84 (2H, s, CH2), 4.60, 4.95 (each 2H, s, CH2), 7.81 (1H, d, J=2.2 Hz, Ar—H), 7.84 (1H, d, J=2.2 Hz, Ar—H), 9.92 (1H, s, CHO).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O>[C:22]1([CH2:21][CH2:20][O:12][C:10]2[CH:9]=[CH:8][C:6]3[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]=3[CH:11]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N#Cc1nc2ccc(O)cc2s1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1nc2ccc(OCCc3ccccc3)cc2s1
Temperature: 25 °C
Yield: 50.2 %

Procedure:
A suspension of 2-cyano-6-hydroxybenzothiazole (1.00 g, 5.68 mmol) in acetone (5 mL) was prepared in a 100-mL 2-necked round-bottomed flask fitted with a reflux condenser. Anhydrous potassium carbonate (1.18 g, 8.52 mmol) was added to the reaction mixture and the suspension turned to a yellow solution. Then (2-bromoethyl)benzene (1.37 g, 0.88 mL, 7.38 mmol) was added and the reaction mixture was heated at reflux for using a heated stir plate and oil bath. Progress of the reaction was monitored by HPLC analysis of reaction aliquots. After 15 h of reflux the reaction was about 40% complete. Additional (2-bromoethyl)benzene (0.5 equivalents, 2.84 mmol) and potassium carbonate (0.5 equivalents, 2.84 mmol) were added periodically during the course of two days until the starting material was consumed. The reaction mixture was allowed to cool to ambient temperature and then filtered to remove inorganic salts. The filtrate was concentrated by rotoevaporation to provide 2.2 g of a crude oil. The crude product was purified by flash chromatography on silica gel using an initial mobile phase consisting of a mixture of 9:1 heptane-ethyl acetate. The mobile phase was adjusted to a mixture of 5:1 heptane-ethyl acetate, and then adjusted to a mixture of 7:3 heptane-ethyl acetate to provide 800 mg (50% yield) of the desired product as an off-white foam. The structure was confirmed by 1H NMR analysis in DMSO-d6.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][C:6](=O)[CH:5]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=O)[CH2:4]1.[NH2:19][C:20]1[CH:28]=[C:24]([C:25]([OH:27])=[O:26])[C:23]([OH:29])=[CH:22][CH:21]=1>C(O)(=O)C>[C:25]([C:24]1[CH:28]=[C:20]([N:19]2[C:6]3[CH2:7][CH2:8][CH:3]([O:2][CH3:1])[CH2:4][C:5]=3[CH:10]=[C:11]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:21]=[CH:22][C:23]=1[OH:29])([OH:27])=[O:26]
Reactant: COC1CCC(=O)C(CC(=O)c2ccccc2)C1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Solvent: CC(=O)O
Product: COC1CCc2c(cc(-c3ccccc3)n2-c2ccc(O)c(C(=O)O)c2)C1

Procedure:
A mixture of 24.6 g. (0.1 mole) of 4-methoxy-2-phenacylcyclohexanone, 15.3 g. (0.1 mole) of 5-aminosalicylic acid, and 80 ml. of glacial acetic acid was heated under reflux for 1.5 hours, filtered, cooled and again filtered. The collected solid was washed with acetic acid and petroleum ether and recrystallized from acetonitrile to provide 22.5 g. (62%) of crystals, m.p. 207°-210°.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[C:6]([C@@H:12]([NH2:14])[CH3:13])=[N:7]2.Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[NH:25][CH:26]=[N:27]2.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[C:6]([C@@H:12]([NH:14][C:23]1[N:31]=[CH:30][N:29]=[C:28]3[C:24]=1[N:25]=[CH:26][NH:27]3)[CH3:13])=[N:7]2
Reactant: C[C@H](N)c1nc2cccc(Cl)c2cc1-c1cccc(F)c1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2cccc(Cl)c2cc1-c1cccc(F)c1

Procedure:
Prepared according to Procedure H using (1S)-1-(5-chloro-3-(3-fluorophenyl)-quinolin-2-yl)ethanamine (0.050 g, 0.166 mmol), 6-chloropurine (0.031 g, 0.20 mmol, 1.2 eq) and DIEA (0.33 mmol, 2.0 eq) in n-butanol (3 mL). N-((S)-1-(5-chloro-3-(3-fluorophenyl)quinolin-2-yl)ethyl)-9H-purin-6-amine [PI3Kδ IC50=5 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 9.22 (s, 1H), 8.63 (s, 1H), 8.44-8.47 (m, 3H), 8.42 (s, 1H), 8.34 (s, 1H), 7.87-7.94 (m, 2H), 7.56 (t, 1H), 1.79 (d, 3H), Mass Spectrum (ESI) m/e=419 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:23](OCCC(C)C)=O.Cl>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:7][C:8]=1[Cl:9])[NH:6][N:23]=[CH:10]2
Reactant: CC(C)CCON=O
Reactant: Cc1cc(Cl)c(Cl)cc1N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Clc1cc2cn[nH]c2cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
To a solution of 4,5-dichloro-2-methylaniline (1.69 g, 9.6 mmol) in CHCl3 (25 ml) at 0° C. was slowly added acetic anhydride (2.09 ml, 22.1 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h. A thick white precipitate had gradually formed. Potassium acetate (283 mg, 2.88 mmol) was added followed by slow addition of isoamyl nitrite (2.78 ml, 20.6 mmol). The reaction mixture was heated at reflux overnight. The homogeneous deep orange reaction mixture was cooled to room temperature and concentrated. Water (10 mL) was added and the mixture was reconcentrated to an orange solid. This solid was suspended in conc. HCl (15 mL) and heated at 60° C. for 2 h then cooled to 0° C. and neutralized with 50% NaOH. Extracted with EtOAc, dried over MgSO4 and concentrated to an orange solid. This solid was dissolved in THF/MeOH (1:1, 25 mL) and 10% NaOH (3 mL) was added. The deep maroon reaction mixture was stirred at room temperature for 5 min then neutralized with 1.0 M HCl and diluted with water. The mixture was extracted with EtOAc (2×) then dried over MgSO4 and concentrated. The residue was absorbed onto silica gel and purified by chromatography with 30% to 50% EtOAc/hexanes to afford 1.50 g (84%) of 5,6-dichloro-1H-indazole as a light orange solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.04 (s, 1H), 7.89 (s, 1H), 7.68 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:7]=2[O:6][CH:5]=1.CC(C)([O-])C.[K+].[C:21]1([C:27]2[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(=O)C>CN(C=O)C.O>[C:21]1([C:27]2[CH:28]=[CH:29][C:30]([CH2:31][O:1][CH2:2][CH2:3][C:4]3[C:8]4[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:7]=4[O:6][CH:5]=3)=[CH:33][CH:34]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: ClCc1ccc(-c2ccccc2)cc1
Reactant: COc1cccc2c(CCO)coc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2c(CCOCc3ccc(-c4ccccc4)cc3)coc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.1 %

Procedure:
3-(2-hydroxyethyl)-7-methoxybenzofuran (373 mg) was dissolved in DMF (7 ml) and potassium t-butoxide (261 mg) was added to the obtained solution, followed by stirring the resulting solution at room temperature for 20 minutes. To this reaction solution, 4-phenylbenzyl chloride (511 mg) was added and the solution was stirred at room temperature for 1 hour. Acetic acid was added to the reaction solution and the resultant was poured into water layer (50 ml), followed by extraction twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=5/1) using silica gel to obtain the desired compound (613 mg, yield: 88%).
Reaction SMILES: COC(=O)CC.C[O:8][C:9](=[O:40])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH2:20][CH:21]=[CH:22][C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=2)[CH:13]=1>O=[Pt]=O.CO>[C:34]1([S:31]([N:19]([CH2:18][C:14]2[CH:13]=[C:12]([CH2:11][CH2:10][C:9]([OH:40])=[O:8])[CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=2)(=[O:33])=[O:32])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: COC(=O)CCc1cccc(CN(CC=Cc2cc(Cl)cc(Cl)c2)S(=O)(=O)c2ccccc2)c1
Agent: O=[Pt]=O
Solvent: CO
Solvent: CCC(=O)OC
Product: O=C(O)CCc1cccc(CN(CCCc2cc(Cl)cc(Cl)c2)S(=O)(=O)c2ccccc2)c1
Yield: 103.7 %

Procedure:
3-[3-Benzenesulfonyl-[3-(3,5-dichloro-phenyl)-propyl]-amino}-methyl)-phenyl]-propionic acid methyl ester. A mixture 3-[3-({benzenesulfonyl-[3-(3,5-dichloro-phenyl)-allyl]-amino}-methyl)-phenyl]-propionic acid methyl ester of Step A (237 mg), PtO2 (30 mg), and MeOH was hydrogenated on a Parr shaker at 50 psi for 2 h. The catalyst was removed by filtration through Celite and the volatiles were removed in vacuo to provide the title compound (240 mg). 1H NMR (400 MHz, CDCl3) δ 7.82 (d, 2H), 7.76-7.50 (m, 3H), 7.23 (m, 1H), 7.07 (m, 4H), 6.74 (s, 2H), 4.26 (s, 2H), 3.64 (s, 3H), 3.09 (t, 2H), 2.90 (t, 2H), 2.56 (t, 2H), 2.37 (t, 2H), 1.56 (m, 2H).
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]2[N:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH3:19])[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[C:28]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=4)=[CH:23][CH:22]=3)[C:12]=2[CH:40]=1)=[O:6])[CH:2]=[CH2:3]>C(Cl)Cl.C(O)C>[CH2:16]([C:14]1[N:13]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[C:28]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:25][CH:26]=2)[C:12]2[CH:40]=[C:8]([NH:7][C:5]([NH:4][CH2:1][C:2]3[CH:12]=[CH:40][CH:8]=[CH:9][CH:3]=3)=[O:6])[CH:9]=[CH:10][C:11]=2[N:15]=1)[CH2:17][CH2:18][CH3:19]
Reactant: C=CCNC(=O)Nc1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2c1
Solvent: CCO
Solvent: ClCCl
Product: CCCCc1nc2ccc(NC(=O)NCc3ccccc3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
tert.butyl 4'-[(6-allylaminocarbonylamino-2-n-butyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.10 (Silica gel: methylene chloride/ethanol=19:1)
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[N:8]([N:12]=[CH:13][CH:14]=2)[C:9](=[O:11])[N:10]=1)[CH2:2][CH2:3][CH3:4].[Br:15]Br>C(Cl)(Cl)Cl.C(O)(=O)C>[Br:15][C:14]1[CH:13]=[N:12][N:8]2[C:9](=[O:11])[N:10]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[NH:6][C:7]=12
Reactant: BrBr
Reactant: CCCCc1nc(=O)n2nccc2[nH]1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCCCc1nc(=O)n2ncc(Br)c2[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4.0 g of the product of Example 15 in 25 ml of 3:1 chloroform-acetic acid is added 1.5 ml of bromine. The reaction mixture is stirred at room temperature for 4 hours. The chloroform is removed in vacuo and the residue diluted with ice water. The resulting solid is collected, washed with water and dried to give 3.5 g of the desired product as a brown solid, m.p. 188° C.
Reaction SMILES: CN1CCCCC1.[O:8]([C:15]([NH:17][C@H:18]([C:22]([OH:24])=O)[CH:19]([CH3:21])[CH3:20])=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClC(OCC(C)C)=O.[C:33]1([O:39][C:40](=[O:44])[CH:41]([CH3:43])[NH2:42])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl.O>[C:33]1([O:39][C:40](=[O:44])[CH:41]([CH3:43])[NH:42][C:22](=[O:24])[C@H:18]([CH:19]([CH3:20])[CH3:21])[NH:17][C:15]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:16])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)[C@H](NC(=O)Oc1ccccc1)C(=O)O
Reactant: CC(N)C(=O)Oc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CN1CCCCC1
Product: CC(NC(=O)[C@@H](NC(=O)Oc1ccccc1)C(C)C)C(=O)Oc1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 21.7 %

Procedure:
0.24 g of N-methylpiperidine was added to a solution containing 0.57 g of N-phenoxycarbonyl-L-valine dissolved in 40 ml of methylene chloride, at -20° C. After the mixture was stirred for 10 minutes at the same temperature, 0.33 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20° C. 0.5 g of DL-alanine phenyl ester was added to this mixture at -60° C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.2 g of the desired product in the form of white powder (yield: 20%).
Reaction SMILES: N#N.[CH3:3][CH2:4][Mg+].[Br-].B(F)(F)F.CCOCC.[C:16]([O:20][C:21]([N:23]1[CH:28]=[CH:27][C:26](=[O:29])[CH2:25][CH:24]1[CH2:30][CH3:31])=[O:22])([CH3:19])([CH3:18])[CH3:17]>[Cu]I.O1CCCC1>[C:16]([O:20][C:21]([N:23]1[CH:24]([CH2:30][CH3:31])[CH2:25][C:26](=[O:29])[CH2:27][CH:28]1[CH2:4][CH3:3])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC[Mg+]
Reactant: CCC1CC(=O)C=CN1C(=O)OC(C)(C)C
Agent: [Cu]I
Agent: FB(F)F
Agent: N#N
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC1CC(=O)CC(CC)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To CuI (0.82 mmol, 156 mg) in a flask purged with N2 is added 1.00 M tetrahydrofuran solution of EtMgBr (0.82 mmol, 0.82 ml) at −78° C. After stirring the suspension for 30 min, BF3.Et2O (0.41 mmol, 57.9 mg) is added and stirred for 10 min at the same temperature. To the suspension is added tetrahydrofuran solution (3.3 mL) of 2-ethyl-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.41 mmol, 92.7 mg) at −78° C., then the mixture is allowed to stir for 1.5 hours and then allow to stir at −40° C. for 2 hours. The mixture is warmed to room temperature and quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers are washed with brine, dried over MgSO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: hexane/EtOAc=10/1) and separated the cis and trans isomers of racemic 2,6-diethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (50 mg, 50%); ESI-MS m/z: 200 [M-tBu+2]+, Retention time 3.51 min. (condition A).
Reaction SMILES: [C:1]([C:3]1[C:7]([C:8]#[C:9][Si](C)(C)C)=[CH:6][N:5]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:16][C:15]=2[Cl:26])[N:4]=1)#[N:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.O1CCCC1>[C:1]([C:3]1[C:7]([C:8]#[CH:9])=[CH:6][N:5]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([O:21][C:22]([F:24])([F:23])[F:25])=[CH:16][C:15]=2[Cl:26])[N:4]=1)#[N:2]
Reactant: C[Si](C)(C)C#Cc1cn(-c2c(Cl)cc(OC(F)(F)F)cc2Cl)nc1C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C#Cc1cn(-c2c(Cl)cc(OC(F)(F)F)cc2Cl)nc1C#N
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-cyano-1-(2,6-dichloro-4-trifiuoromethoxyphenyl)4-trimethylsilylethynylpyrazole (2.691 g) in dichloromethane (25 ml) was added tetra-n-butylammonium fluoride (6.45 ml of a 1M solution in tetrahydrofuran). Stirring was continued for 30 minutes then the reaction mixture was partitioned between water and dichioromethane. The aqueous layer was separated and extracted twice with di-chloromethane. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel eluting with dichloromethane: hexane (1:1). Combination and evaporation of suitable fractions provided the title compound as a white solid m.p. 95.2-96.0° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:38][CH:39]1[CH2:44][CH2:43][N:42]([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:41][CH2:40]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:48]3[CH2:47][CH2:46][CH:45]([N:42]4[CH2:43][CH2:44][CH:39]([OH:38])[CH2:40][CH2:41]4)[CH2:50][CH2:49]3)=[O:36])[C:16]([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)([CH3:27])[C:17]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: OC1CCN(C2CCNCC2)CC1
Product: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCC(O)CC2)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 4-hydroxy-[1,4′]bipiperidine (ChemBridge) to give the title compound as a racemic mixture. HR-MS (ES, m/z) calculated for C38H49N6O3Cl2 [(M+H)+] 707.3238, observed 707.3232.
Reaction SMILES: Cl[C:2]([CH3:26])([CH3:25])[C:3]([C:5]1[CH:24]=[CH:23][C:8]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:22])[C:18]([CH3:21])(Cl)[CH3:19])=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1)=[O:4].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[O:30]1[CH2:31][CH2:32][N:27]([C:2]([CH3:26])([CH3:25])[C:3]([C:5]2[CH:24]=[CH:23][C:8]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17](=[O:22])[C:18]([CH3:21])([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH3:19])=[CH:13][CH:12]=3)=[O:10])=[CH:7][CH:6]=2)=[O:4])[CH2:28][CH2:29]1
Reactant: C1COCCN1
Reactant: CC(C)(Cl)C(=O)c1ccc(C(=O)c2ccc(C(=O)C(C)(C)Cl)cc2)cc1
Product: CC(C)(C(=O)c1ccc(C(=O)c2ccc(C(=O)C(C)(C)N3CCOCC3)cc2)cc1)N1CCOCC1

Procedure:
78 g of 4,4'-bis-(2-chloro-2-methyl-propanoyl)benzophenone is boiled with 250 ml of morpholine for 15 hours. The excess morpholine is then distilled off under reduced pressure and the residue is crystallized from ethanol. 4,4'-bis-(2-Morpholino-2-methyl-propanoyl)-benzophenone is obtained; m.p. 145°-147°.