Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[C:14]3[NH:21][C:20]([CH3:22])=[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.Cl[CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:20]([CH3:22])=[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc12
Reactant: C[Si](C)(C)CCOCCl
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(F)ccc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-(2-cyclopropylmethoxy-5-fluoro-phenyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example D.a3) and commercially available (2-chloromethoxy-ethyl)-trimethyl-silane the title compound is prepared as pale yellow viscous oil.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:12]=[C:13]1[C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][CH2:15][N:14]1[CH2:30][C:31](O)=[O:32].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[O:32]=[C:31]([N:9]1[CH2:10][CH2:11][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8]1)[CH2:30][N:14]1[CH2:15][CH2:16][C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:13]1=[O:12]
Reactant: c1ccc(C2CCNC2)cc1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCC(c2ccccc2)C1
Reaction time: 8 h

Procedure:
A solution of 3-phenylpyrrolidine (0.029 g, 0.194 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.052 g, 0.176 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.051 g, 0.244 mmol) in dichloromethane (0.5 mL) was stirred at room temperature. After stirring overnight, the reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.14-7.43 (m, 15H), 4.09-4.22 (m, 2H), 3.63-4.11 (m, 2H), 3.26-3.63 (m, 5H), 2.77-2.89 (m, 2H), 2.22-2.42 (m, 1H), 1.91-2.13 (m, 1H); MS (ESI+) m/z 425 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][C:16]([CH2:17][NH:18][C@H:19]([CH:23]3[CH2:25][CH2:24]3)[C:20]([OH:22])=O)=[C:11]2[C:10]([C:26]([O:28][CH3:29])=[O:27])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=N[C:40]2[CH:41]=[CH:42][CH:43]=[N:44][C:39]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CCCC1.CN1CCOCC1>C1COCC1>[CH:39]1([NH:44][C:20](=[O:22])[C@H:19]([NH:18][CH2:17][C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:9]=[C:10]([C:26]([O:28][CH3:29])=[O:27])[C:11]=23)[CH:23]2[CH2:24][CH2:25]2)[CH2:40][CH2:41][CH2:42][CH2:43]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@@H](C(=O)O)C3CC3)c12
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCCC1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@@H](C(=O)NC3CCCC3)C3CC3)c12
Temperature: 43 °C
Reaction time: 36 h

Procedure:
To (R)-2-((1-(tert-butoxycarbonyl)-3-(methoxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methylamino)-2-cyclopropylacetic acid was added THF (2 mL), followed by HATU (94 mg, 0.246 mmol), cyclopentanamine (70.0 mg, 0.822 mmol) and 4-methylmorpholine (83 mg, 0.822 mmol). The suspension was stirred at 43° C. for 36 h to afford the title compound, which was used in the next step without further purification. [M+H] calc'd for C25H34N4O5, 471; found, 471.5.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:22]#[N:23])[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[C:5]([F:24])[CH:4]=1>O1CCOCC1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:22]#[N:23])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[C:5]([F:24])[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(Cl)cc2F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#CC1(c2ccc(Cl)cc2F)CCNCC1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
HCl (4.0 N in dioxane, 10 mL, 40 mmol, 7.1 equiv) was added to a solution of 1,1-dimethylethyl 4-(4-chloro-2-fluorophenyl)-4-cyano-1-piperidinecarboxylate (1.9 g, 5.6 mmol, 1 equiv) in 1,4-dioxane (25 mL) at 23° C. The resulting solution was warmed to 45° C. and stirred for 1 hour (white precipitation formed). The suspension was concentrated to afford 4-(4-chloro-2-fluorophenyl)-4-piperidinecarbonitrile as a pale-yellow solid. EtOH (1.6 mL, 38.1 mmol, 6.8 equiv) was slowly added to a suspension of lithium aluminium hydride (LAH) (1.15 g, 30.3 mmol, 5.4 equiv) in glyme (16 mL) at 0° C. The resulting suspension was heated to reflux and stirred for 5 min. A suspension of the newly prepared 4-(4-chloro-2-fluorophenyl)-4-piperidinecarbonitrile in glyme (10 mL) was added in portions. The resulting brown suspension was refluxed for 1 h, then cooled to 0° C. Water (8 mL) was added slowly at 0° C. and the resulting suspension was warmed to room temperature and stirred for 30 min. The suspension was filtered through Celite pad and the solid was rinsed with CH2Cl2 (200 mL). The filtrate was dried over anhydrous potassium carbonate. The dried solution was concentrated. The residue was purified by reverse phase C18 column to afford 6-chloro-1,2-dihydrospiro[indole-3,4′-piperidine] as a white powder (1.2 g, 5.4 mmol, 96%). MS (ES) m/e 223 [M+H]+.
Reaction SMILES: [C:1]([S:4][C:5]1[S:12]S[CH:10]2[N:7]([C:8](=[O:13])[CH2:9]2)[C:6]=1[C:14]([O:16][CH3:17])=[O:15])(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[2H]C(Cl)(Cl)Cl>[C:1]([S:4][C:5]1[S:12][CH:10]2[N:7]([C:8](=[O:13])[CH2:9]2)[C:6]=1[C:14]([O:16][CH3:17])=[O:15])(=[O:3])[CH3:2]
Reactant: COC(=O)C1=C(SC(C)=O)SSC2CC(=O)N12
Agent: [2H]C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)C1=C(SC(C)=O)SC2CC(=O)N12
Yield: 61.5 %

Procedure:
0.064 g of methyl 3-acetylthio-8-oxo-4,5-dithia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylate was dissolved in 1 ml of deuterochloroform and 0.063 g of triphenylphosphine added. TLC and NMR analysis indicated complete conversion of starting material to product. The crude product was chromatographed on silica gel using ethyl acetate/hexane as eluant to give 0.035 g (61%) of purified product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CC(C)(C)C([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:30][CH3:31])=[C:19]2[CH:26]3[CH2:27][CH:22]4[CH2:23][C:24]([Cl:29])([CH2:28][CH:20]2[CH2:21]4)[CH2:25]3)[CH:13]=1)=O>CO>[CH3:31][O:30][C:18](=[C:19]1[CH:20]2[CH2:21][CH:22]3[CH2:23][C:24]([Cl:29])([CH2:25][CH:26]1[CH2:27]3)[CH2:28]2)[C:14]1[CH:13]=[C:12]([OH:11])[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=C1C2CC3CC1CC(Cl)(C3)C2)c1cccc(OC(=O)C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=C1C2CC3CC1CC(Cl)(C3)C2)c1cccc(O)c1
Yield: 88 %

Procedure:
The combined pivaloyl ester fractions (5.5 g, 14.1 mmol) were taken up in 40 ml of methanol and refluxed with 5.37 g of anhydrous potassium carbonate for 40 minutes. The residue remaining after the methanol was stripped off was partitioned between water and 30% ethyl acetate-hexanes, and the organic fractions were concentrated and plug filtered on a short silica gel column to give 4.07 g (88% yield based on 5-chloroadamantan-2-one) of 3-(methoxy-5-chlorotricyclo[3.3.1.13,7 ]dec-2-ylidenemethyl) phenol as a crispy white foam which became slightly tacky upon exposure to air.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:11]([CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:10]2[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=O)=O.C[Si]([C:41]#[N:42])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C.O1CCCC1>[C:27]([O:26][C:24](=[O:25])[NH:23][CH2:22][C:11]1[N:12]([CH2:18][CH:19]([CH3:20])[CH3:21])[C:13](=[O:17])[C:14]2[C:9]([C:10]=1[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[CH:8][C:7]([CH2:6][C:41]#[N:42])=[CH:16][CH:15]=2)([CH3:28])([CH3:29])[CH3:30]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(COS(C)(=O)=O)ccc2c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CC#N)ccc2c1=O
Yield: 74.8 %

Procedure:
To a mixture of (3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-6-yl)methyl methanesulfonate (39 g, 0.75 mmol) in acetonitrile (5 mL) and tetrahydrofuran (4 mL) were added trimethylsilyl cyanide (0.15 mL, 1.1 mmol) and a solution of 1.0 M tetrabutylammonium fluoride: in tetrahydrofuran (1.1 mL), and then the mixture was stirred at 80° C. for 30 min. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:2 (v/v)) to give tert-butyl[6-(cyanomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.25 g, 75%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3](=[O:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[K+]>O.CS(C)=O>[C:12]1([CH2:11][C:2]([CH3:18])([CH3:1])[C:3](=[O:10])[CH:4]([N:5]2[CH:9]=[N:8][CH:7]=[N:6]2)[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(Cc1ccccc1)C(=O)Cn1cncn1
Reactant: ClCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(Cc1ccccc1)C(=O)C(Cc1ccccc1)n1cncn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
48.6 g (0.2 mol) of 3,3-dimethyl-4-phenyl-1-(1,2,4-triazol-1-yl)-butan-2-one, 27.9 g (0.22 mol) of benzyl chloride and 12.3 g (0.22 mol) of potassium hydroxide in 15 ml of water are dissolved in 300 ml of dimethylsulphoxide. The reaction mixture is stirred for a further 8 hours at 50° C. and then poured onto water. The mixture is extracted with ethyl acetate. The organic phase is concentrated and the residue is purified by column chromatography (silica gel/ethyl acetate: cyclohexane =3:1). 54.5 g (81.8% of theory) of 1,5-bisphenyl-2,2-dimethyl-4-(1,2,4-triazol-1-yl)-pentan-3-one of melting point 45°-50° C. are obtained.
Reaction SMILES: S(Cl)(C)(=O)=O.[I:6][C:7]1[C:14]([I:15])=[CH:13][C:12]([I:16])=[CH:11][C:8]=1[CH2:9]O.C(N(C(C)C)CC)(C)C.[Cl-:26].[Li+]>ClCCl.O>[I:6][C:7]1[C:14]([I:15])=[CH:13][C:12]([I:16])=[CH:11][C:8]=1[CH2:9][Cl:26]
Reactant: OCc1cc(I)cc(I)c1I
Reactant: [Cl-]
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: ClCc1cc(I)cc(I)c1I
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.7 %

Procedure:
Mesyl chloride (4.24 ml, 56 mmol) was added dropwise into a suspension of 2,3,5-triiodobenzyl alcohol 1 (9.72 g, 20 mmol) in dry dichloromethane (140 ml) containing diisopropylethylamine (11 ml, 64 mmol) and lithium chloride (4.24 g, 100 mmol) at 0° C. under dry nitrogen gas flow. The reaction mixture was stirred 5 h at room temperature, then cold H2O (100 mL) was added. The resulting aqueous phase was extracted with dichloromethane (2×10 ml). The combined organic extracts were washed with NaHCO3aq (20 ml) and H2O (20 ml) then dried (Na2SO4), filtered and concentrated. The pale yellow solid was also washed with cold absolute ethanol (25 mL). 9.05 g of 2,3,5-triiodobenzyl chloride in the form of a white clean solid was obtained in 90% yield.
Reaction SMILES: [CH3:1][Si:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][CH:14]=[C:15]([C:16]#[N:17])[C:10]=2[CH:9]=[CH:8]1.C(O)C.Cl.[NH2:24][OH:25].C(=O)([O-])[O-].[K+].[K+]>>[OH:25][NH:24][C:16]([C:15]1[C:10]2[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:19])([CH3:18])[CH3:1])[C:11]=2[N:12]=[CH:13][CH:14]=1)=[NH:17]
Reactant: NO
Reactant: C[Si](C)(C)CCOCn1ccc2c(C#N)ccnc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C[Si](C)(C)CCOCn1ccc2c(C(=N)NO)ccnc21
Temperature: 25 °C
Yield: 97.9 %

Procedure:
1-[2-(Trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile (0.05 g, 0.0002 mol) was dissolved in ethanol (2.0 mL, 0.034 mol), and then hydroxylamine hydrochloride (0.023 g, 0.00033 mol) and potassium carbonate (0.10 g, 0.00073 mol) were added. The reaction was heated to reflux for 5 h, and the reaction was then allowed to cool to rt and filtered to remove the solids. The filtrate was concentrated to give the product 0.06 g as yellow oily residue, LC/MS (M+H)+ 307.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:24])[CH:18]([CH3:23])[CH:19]([CH3:22])[CH2:20][CH3:21])=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:25]([OH:27])=[O:26].CO.[OH-].[Na+:31].CCOCC>CN(C)C=O>[O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:24])[CH:18]([CH3:23])[CH:19]([CH3:22])[CH2:20][CH3:21])=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:25]([O-:27])=[O:26].[Na+:31]
Reactant: CCC(C)C(C)C(=O)Nc1ccc2ncn3c(=O)c(C(=O)O)cnc3c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CO
Product: CCC(C)C(C)C(=O)Nc1ccc2ncn3c(=O)c(C(=O)[O-])cnc3c2c1
Temperature: 50 °C
Yield: 57.1 %

Procedure:
To a suspension of 4-oxo-10-(2,3-dimethylpentanamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylic acid (7.3 g) in N,N-dimethylformamide (120 ml) was added methanol (140 ml) under stirring at 50° C. To this solution was added dropwise sodium hydroxide solution (sodium hydroxide 0.79 g in water 2.37 ml and ethanol 15.8 ml) under stirring for 15 minutes at ambient temperature, and was stirred for 30 minutes at ambient temperature. To this solution ether (250 ml) was added and stirred. The precipitated crystals were collected by filtration and washed two times with water and ether, and dried under reduced pressure to give sodium 4-oxo-10-(2,3-dimethylpentanamido)-4H-pyrimido[1,2-C]-quinazoline-3-carboxylate (1 hydrate) (4.4 g).
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]([C:10](=[O:12])[CH3:11])=[C:8]([CH2:13][CH3:14])[N:7]=[C:6]1[CH2:15][CH2:16][CH3:17].C([N-]C(C)C)(C)C.[Li+].[O:31]([C:38]1[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=1[CH2:40]I)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[F:1][C:2]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]([C:10]([CH2:11][CH2:40][C:39]2[CH:42]=[CH:43][CH:44]=[CH:45][C:38]=2[O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:12])=[C:8]([CH2:13][CH3:14])[N:7]=[C:6]1[CH2:15][CH2:16][CH3:17]
Reactant: CCCc1nc(CC)c(C(C)=O)n1Cc1ccc(I)cc1F
Reactant: ICc1ccccc1Oc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCc1nc(CC)c(C(=O)CCc2ccccc2Oc2ccccc2)n1Cc1ccc(I)cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 29.6 %

Procedure:
1-(2-fluoro-4-iodobenzyl)-5-acetyl-4-ethyl-2-propyl- 1H-imidazole (5.52 g, 13.3 mmol) was dissolved in 50 mL of THF. The mixture was cooled at 0° C. under N2 and lithium diisopropylamide (7.3 mL of 2M in THF, 14.6 mmol) was added. After stirred at 0° C. for 15 minutes, a solution of o-phenoxybenzyl iodide (5.22 g, 16.8 mmol) in THF (15 mL) was added. The reaction mixture was warmed up to room temperature and stirred for 2 h. The mixture was partitioned between EtOAc and H2O. The two layers were separated. The aqueous layer was extracted with EtOAc. The combined organic solution was washed with brine, dried over MgSO4. It was concentrated and chromatographed on silica gel with 10-50% EtOAc/hexane to yield 2.35 g of the desired product. MS m/e 597.2, [M+H]+ ; IR (KBr): 1646 cm-1 for CO; 1H NMR (300 MHz, CDCl3): δ 0.95 (t, 3H, CH3), 1.22 (t, 3H, CH3), 1.65 (m, 2H, CH2), 2.57 (m, 2H, CH2), 2.82 (q, 2H, CH2), 2.98 (m, 2H, CH2), 3.10 (m, 2H, CH2) 5.42 (s, 2H, CH2Ar), 6.22 (t, 1H, ArH), 6.82 (d, 1H, ArH), 6.90 (d, 2H, ArH), 7.02 (m, 2H, ArH), 7.18 (d, 1H, ArH), 7.22 (m, 2H, ArH), 7.30 (m, 2H, ArH), 7.40 (d, 1H, ArH). ##STR66##
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4](=[O:7])[CH2:5]Cl.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4](=[O:7])[CH2:5][N:17]1[C:13](=[O:23])[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16]1=[O:18]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)cc1Cl

Procedure:
1 mmol of 2,4-dichlorophenacyl chloride in DMF was added drop wise to 2 mmol of phthalimide and 2 mmol of Cs2CO3 in DMF at room temperature for fourteen hours and the purified by trituration with diethyl ether to obtain 2-[2-(2,4-dichlorophenyl)-2-oxoethyl]isoindoline-1,3-dione.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].B1C2CCCC1CCC2.C[O-].[Na+].Br[C:30]1[CH:31]=[N:32][C:33]2[C:38]([CH:39]=1)=[CH:37][CH:36]=[CH:35][CH:34]=2.C(Cl)Cl>C1COCC1>[C:13]([O:12][C:10]([N:7]1[CH2:8][CH2:9][CH:4]([CH2:1][CH2:2][CH2:3][C:30]2[CH:31]=[N:32][C:33]3[C:38]([CH:39]=2)=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:5][CH2:6]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: C=CCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Brc1cnc2ccccc2c1
Agent: B1C2CCCC1CCC2
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCCc2cnc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
A solution of 1-(t-butoxycarbonyl)-4-(prop-2-en-1-yl)piperidine (from Procedure 5, Step B) (260 mg, 1.15 mmol) in THF (3 mL) under argon was treated with 0.5M 9-BBN solution in THF (2.30 mL, 1.15 mmol). The resulting mixture was stirred at rt for 2 h, then treated with sodium methoxide (68 mg, 1.25 mmol). The resulting mixture was stirred until it was homogeneous (˜15 min) and then was treated with 3-(bromo) quinoline (0.155 mL, 1.15 mmol) and [1,1′-bis(triphenylphosphino)ferrocene)dichloropalladium.methylene chloride (41 mg, 0.05 mmol). The resulting mixture was heated at reflux for 30 min, cooled and quenched with 1N NaOH (20 mL). The quenched reaction was extracted with 2×50 mL of ether; the extracts were dried over magnesium sulfate, combined and concentrated. FC (15 g of silica gel, 4:1 v/v hexanes/ethyl acetate) afforded the title compound (240 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40]([O:42][CH3:43])=[O:41])=[CH:35][CH:34]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:43][O:42][C:40](=[O:41])[CH2:39][C:36]1[CH:37]=[CH:38][C:33]([NH:32][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10]2)=[O:30])=[CH:34][CH:35]=1
Reactant: COC(=O)Cc1ccc(N)cc1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
A mixture of chiral-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (228 mg, 0.488 mmol), methyl 2-(4-aminophenyl)acetate (200 mg, 1.21 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 241 mg, 0.634 mmol) and iPr2NEt (0.4 mL, 2.29 mmol) in CH2Cl2 (10 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, then concentrated and purified by column chromatography (1-100% of EtOAc/heptane, 12 g Analogix column) to afford chiral (4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-acetic acid methyl ester (209 mg, 69.7%) as an white powder. LCMS (ES+) m/z Calcd for C32H31Cl2F2N3O3+H [M+H)+]: 613.17. found: 614.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11](O)[CH2:10][CH:9]=[CH:8]2.P(Cl)(Cl)([Cl:19])=O>>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([Cl:19])[CH:9]=[CH:8]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)Cc1ccc2c(c1)C=CCN2O
Product: COC(=O)Cc1ccc2nc(Cl)ccc2c1
Yield: 20 %

Procedure:
(1-Hydroxy-quinolin-6-yl)-acetic acid methyl ester (1.0 g, 4.61 mmol) was refluxed for 25 minutes in phosphorous oxychloride (30 mL). The excess phosphorous oxychloride was evaporated, saturated sodium bicarbonate was added and the crude mixture was extracted several times with ethyl acetate. The product was purified via silica gel column chromatography in hexane:ethyl acetate (1:1) to give 0.219 g (20%) of (2-chloro-quinolin-6-yl)-acetic acid methyl ester. 1H NMR (400 MHz, CDCl3) δ 7.99 (d, 1H, J=8.4 Hz), 7.93 (d, 1H, J=8.8 Hz), 7.63 (m, 1H), 7.60 (dd, 1H, J=2.0, 8.4 Hz), 7.30 (d, 1H, J=8.8 Hz), 3.73 (s, 2H), 3.64 (s, 3H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)=[O:11].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCCCCC.CCOC(C)=O>[O:7]([CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)=[O:11])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1ccc(C(=O)CBr)cc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CSc1ccc(C(=O)COc2ccccc2)cc1

Procedure:
To a solution of phenol (9.4 g) and 2-bromo-1-(4-(methylthio)phenyl)ethanone (12.5 g) in 500 mL of acetone was added K2CO3 (13.8 g). The mixture was refluxed for 12 h, then diluted with 500 mL of 1:1 hexane/EtOAc. The solid was removed by filtration and the filtrate was concentrated. The residue was dissolved in Et2O (500 mL), washed with 1N NaOH (100 ml) and dried over MgSO4. After filtration and concentration, the title compound (9 g) was collected by filtration and air dried.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH2:12][CH2:13][C:14]#[N:15])=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[H][H]>[Pd].C(O)C>[CH3:1][C:2]1[C:11]([CH2:12][CH2:13][C:14]#[N:15])=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[N:3]=1
Reactant: Cc1nc2ncccc2cc1CCC#N
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1nc2c(cc1CCC#N)CCCN2

Procedure:
A mixture of the product of STEP 1 (2 g), 10% Pd/C (250 mg) and ethanol (15 mL) was stirred under a balloon of hydrogen gas for 2 hr. Filtration and evaporation prodiuced the title product. 1H (CDCl3) δ 1.83 (2H, p); 2.24 (3H, s); 2.43 (2H, t); 2.62 (2H, t); 2.73 (2H, t); 3.31 (2H, m); 4.81 (1H, broad s); 6.88 (1H, s).