Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:5]1[CH:45]=[CH:44][C:8]([CH2:9][C:10]2[C:15]([C:16]#[N:17])=[C:14]([O:18][CH3:19])[CH:13]=[C:12]([C@:20]3([O:38][C@H:37]([CH2:39][O:40]C(=O)C)[C@@H:32]([O:33]C(=O)C)[C@H:27]([O:28]C(=O)C)[C@H:22]3[O:23]C(=O)C)[OH:21])[CH:11]=2)=[CH:7][CH:6]=1)[CH3:4].Cl>CO.C1COCC1>[CH2:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][C:10]2[C:15]([C:16]#[N:17])=[C:14]([O:18][CH3:19])[CH:13]=[C:12]([C@:20]3([O:38][C@H:37]([CH2:39][OH:40])[C@@H:32]([OH:33])[C@H:27]([OH:28])[C@H:22]3[OH:23])[OH:21])[CH:11]=2)=[CH:44][CH:45]=1)[CH3:4]
Reactant: CCc1ccc(Cc2cc([C@@]3(O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)cc(OC)c2C#N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)cc(OC)c2C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Aqueous sodium hydroxide solution (1.4 mL, 1 mol/L) is added to 6-(4-ethylbenzyl)-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-methoxy-benzonitrile (0.16 g) dissolved in methanol (1 mL) and THF (1 mL). The solution is stirred at room temperature for 1 h and then neutralized with hydrochloric acid (1 mol/L). After removal of the organic solvents, the residue is diluted with aqueous sodium bicarbonate solution and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are dried (sodium sulphate) and the solvent is evaporated. The remainder is purified by chromatography on silica gel (dichloromethane/methanol 1:0->8:1).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([NH:15][C:16]1([CH:20](O)[CH2:21][CH3:22])[CH2:19][CH2:18][CH2:17]1)(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1C[O:27]CC1>O.C(OCC)(=O)C>[CH2:7]([NH:15][C:16]1([CH2:20][CH:21]([OH:27])[CH3:22])[CH2:19][CH2:18][CH2:17]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCC(O)C1(NC(=O)c2ccccc2)CCC1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(O)CC1(NCc2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
LiAlH4 (1.20 g, 31.6 mmol) was added to a solution of 1-[1-(benzoylamino) cyclobutyl]propanol (2.64 g, 11.3 mmol) in THF (40 mL) at room temperature. The mixture was stirred at room temperature for 1 hour and refluxed for 30 minutes. The mixture was cooled in an ice-water bath and a few drops of water were added. The mixture was then diluted with ethyl acetate, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Flash chromatography (AcOEt) of the residue gave the title compound as a colorless oil (2.25 g, 91%). 1H-NMR (400 MHz, CDCl3) δ 1.21 (3H, d, J=6.1 Hz), 1.63 (1H, dd, J=13.7 and 2.4 Hz), 1.73-1.90 (5H, m), 2.04-2.13 (1H, m), 2.18-2.27 (1H, m), 3.59 (1H, d, J=11.6 Hz), 3.81 (1H, d, J=11.6 Hz), 4.07-4.16 (1H, m), 7.22-7.35 (5H, m).
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].C[O-].[Na+].[CH2:9]([S:11][C:12]1[CH:26]=[CH:25][C:15]([CH2:16][CH:17]([C:22]([CH3:24])=O)[C:18](OC)=[O:19])=[CH:14][CH:13]=1)[CH3:10].O>CO>[CH2:9]([S:11][C:12]1[CH:26]=[CH:25][C:15]([CH2:16][C:17]2[C:18](=[O:19])[NH:4][C:2]([CH3:3])=[N:5][C:22]=2[CH3:24])=[CH:14][CH:13]=1)[CH3:10]
Reactant: CCSc1ccc(CC(C(C)=O)C(=O)OC)cc1
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCSc1ccc(Cc2c(C)nc(C)[nH]c2=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 21.4 %

Procedure:
To a solution of 4-ethylthiobenzyl alcohol (3.7 g) in tetrahydrofuran (80 mL) were added triethylamine (3.0 mL) and methanesulfonyl chloride (1.7 mL) at 0° C., and the mixture was stirred for 30 minutes. After the insoluble material was removed by filtration, the filtrate was added to a suspension of sodium hydride (60%, 0.88 g) and methyl acetoacetate (2.4 mL) in 1,2-dimethoxyethane (100 mL), and the mixture was heated under reflux for 4 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution, and the mixture was extracted with diethyl ether. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed to give methyl 2-(4-ethylthiobenzyl)-acetoacetate (6.1 g). To a suspension of acetoamidine hydrochloride (0.80 g) in methanol (15 mL) was added sodium methoxide (28% solution in methanol, 1.7 mL), and the mixture was stirred for 5 minutes at room temperature. To the reaction mixture was added a solution of methyl 2-(4-ethylthiobenzyl)-acetoacetate (1.5 g) in methanol (5 mL), and the mixture was stirred for 18 hours at room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. To the residue was added ethyl acetate, and the resulting precipitated crystals were collected by filtration and dried to give 5-(4-ethylthiobenzyl)-2,6-dimethyl-3H-pyrimidin-4-one (0.33 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([CH2:22][O:23][CH2:24][C:25]([OH:27])=O)=[O:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([NH:55][C:56]([CH:58]2[CH2:63][CH2:62][C:61]([F:65])([F:64])[CH2:60][CH2:59]2)=[O:57])[CH2:36][CH2:37][N:38]2[CH:43]3[CH2:44][CH2:45][CH:39]2[CH2:40][CH:41]([N:46]2[C:50]([CH3:51])=[N:49][N:48]=[C:47]2[CH:52]([CH3:54])[CH3:53])[CH2:42]3)=[CH:31][CH:30]=1>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:21])[CH2:22][O:23][CH2:24][C:25](=[O:27])[NH:28][C:29]1[CH:30]=[CH:31][C:32]([CH:35]([NH:55][C:56]([CH:58]2[CH2:63][CH2:62][C:61]([F:64])([F:65])[CH2:60][CH2:59]2)=[O:57])[CH2:36][CH2:37][N:38]2[CH:43]3[CH2:44][CH2:45][CH:39]2[CH2:40][CH:41]([N:46]2[C:50]([CH3:51])=[N:49][N:48]=[C:47]2[CH:52]([CH3:54])[CH3:53])[CH2:42]3)=[CH:33][CH:34]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nnc(C(C)C)n1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)c1ccc(N)cc1
Reactant: O=C(O)COCC(=O)NCCCCCCCNC(=O)OCc1ccccc1
Solvent: CN(C)C=O
Product: Cc1nnc(C(C)C)n1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)c1ccc(NC(=O)COCC(=O)NCCCCCCCNC(=O)OCc2ccccc2)cc1
Yield: 72 %

Procedure:
The title compound was prepared according to the general amide coupling procedure by reacting acid 22 with amine 6 in DMF overnight. The crude product was purified with chromatography using CH2Cl2/MeOH (13/1) as eluent to give 260 mg white foaming, in 72% yield. 1H NMR (400 MHz, CDCl3): δ8.96 (s, 1H), 7.57 (d, J=8.48 Hz, 2H), 7.35-7.27 (m, 5H), 7.24 (d, J=8.48 Hz, 2H), 6.75 (m, 1H), 6.70 (m, 1H), 5.12-5.08 (m, 3H), 4.91 (m, 1H), 4.29 (m, 1H), 4.14 (s, 2H), 4.09 (s, 2H), 3.40 (m, 1H), 3.37 (m, 1H), 3.30 (q, J=6.68 Hz, 2H), 3.15 (q, J=6.71 Hz, 2H), 2.99 (m, 1H), 2.48 (s, 3H), 2.43 (t, J=6.48 Hz, 2H), 2.30-4 (m, 6H), 2.01-1 (m, 8H), 1.70-1.46 (m, 9H), 1.376 (d, J=6.80 Hz, 3H), 1.373 (d, J=6.84 Hz, 3H), 1.35-1.31 (m, 6H); 13C NMR (100 MHz, CDCl3): δ 173.50, 168.64, 167.15, 159.17, 156.55, 150.59, 138.31, 136.66, 136.51, 128.54, 128.12, 128.00, 127.12, 120.51, 77.24, 71.66, 71.50, 66.60, 58.90, 58.30, 51.68, 47.77, 47.24, 42.83, 40.98, 39.14, 35.33, 34.59, 32.82 (J13C-19F 25.7 Hz), 29.82, 29.36, 28.71, 26.75 (J13C-19F 10 Hz), 26.48, 25.87, 21.65, 13.15. mp 65-67° C. IR v (Diamond, cm−1): 3273, 1656, 1529, 1515, 1251, 1106, 697. MS (ESI) m/z found 891.9 (M+H)+.
Reaction SMILES: C(OC([NH:8][S:9]([NH:12][CH2:13][C@H:14]1[C@H:20]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[O:19][CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]1)(=[O:11])=[O:10])=O)(C)(C)C.C(OCC)(=O)C.Cl>C(O)C>[ClH:27].[Cl:28][C:23]1[CH:22]=[C:21]([C@@H:20]2[O:19][CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[CH2:13][NH:12][S:9]([NH2:8])(=[O:10])=[O:11])[CH:26]=[CH:25][C:24]=1[Cl:27]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: NS(=O)(=O)NC[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 146.9 %

Procedure:
To a solution of tert-butyl (6S,7R)-6-({[(tert-butoxycarbonyl)sulfamoyl]amino}methyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (172 mg) in ethanol (0.5 mL) was added 4.0 M hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure. The obtained crystals were recrystallized from ethanol-water to give the title compound (89 mg) as colorless crystals.
Reaction SMILES: [Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[N:22]1[CH:27]=[C:26]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH:30]=[CH:31][NH:32]3)[CH:25]=[N:24][CH:23]=1.[OH2:37]>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[N:24]1[CH:25]=[C:26]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH2:30][C:31](=[O:37])[NH:32]3)[CH:27]=[N:22][CH:23]=1
Reactant: O
Reactant: c1cc(-c2cncnc2)c2cc[nH]c2c1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: CCO
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2cncnc2)N1
Reaction time: 1.5 h
Yield: 75 %

Procedure:
Pyridinium tribromide (90% (Aldrich), 4 g, 11.22 mmol) was added portion-wise over 10 minutes to a suspension of 4-pyrimidin-5-yl-1H-indole (730 mg, 3.74 mmol) in 2-methyl-2-propanol (25 mL), ethanol (15 mL) and acetic acid (9 mL). The mixture was stirred at room temperature for 2 hours after which acetic acid (36 mL), water (1 mL) and zinc (3.2 g, 56.1 mmol) were added. Stirring was continued for 1.5 hours. Residual zinc dust was filtered and washed with methanol. The filtrate was concentrated and the syrupy residue was stirred in water (100 mL) overnight. The precipitate which formed was filtered, washed with water to remove zinc and pyridine salts and dried under high vacuum to give 595 mg (75%) of 4-pyrimidin-5-yl-1,3-dihydroindol-2-one as a light brown solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[CH2:4][CH:3]1[CH:9]([CH3:12])[C:10]#N.[H-].C([Al+]CC(C)C)C(C)C.C(O)(=[O:25])C.O>C1(C)C=CC=CC=1>[CH3:1][CH:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[CH2:4][CH:3]1[CH:9]([CH3:12])[CH:10]=[O:25]
Reactant: CC(=O)O
Reactant: CC(C#N)C1CC(C)(C)CC1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C=O)C1CC(C)(C)CC1C
Temperature: 25 °C

Procedure:
2-(2,4,4-Trimethylcyclopentyl)propanenitrile 6 is placed in toluene at 10° C. under an inert atmosphere. 1.2 eq. of Dibal (diisobutylaluminum hydride) are added thereto dropwise. The reaction medium is stirred at ambient temperature for a few hours and is then poured onto a 20:40:40 mixture of acetic acid, water and ice. The aqueous phase is extracted once with toluene. The combined organic phases are washed with a sodium bicarbonate solution and then with an aqueous sodium chloride solution. After drying over magnesium sulfate, filtering through paper and evaporating the solvent, the crude product, obtained in the form of three diastereomers observed by GC in proportions of 73:16:11, is distilled under reduced pressure.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[C:30]([CH3:32])[CH:31]=3)[C:26](O)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:59][C:60]1[CH:61]=[C:62]([CH2:67][NH2:68])[CH:63]=[CH:64][C:65]=1[CH3:66]>ClCCl>[Br:59][C:60]1[CH:61]=[C:62]([CH2:67][NH:68][C:26]([C:25]2[CH:29]=[C:30]([CH3:32])[CH:31]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:14][CH2:15][O:16][CH2:17][CH2:18]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:33][CH3:34])=[O:22])[CH:24]=2)=[O:27])[CH:63]=[CH:64][C:65]=1[CH3:66]
Reactant: Cc1ccc(CN)cc1Br
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(C)c(Br)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
The 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-5-methylbenzoic acid (0.931 g, 2 mmol) was partially dissolved in the dichloromethane (50 mL), and HBTU (0.758 g, 2.000 mmol) was added followed sequentially by [(3-bromo-4-methylphenyl)methyl]amine (0.400 g, 2.000 mmol), and TEA (0.558 mL, 4.00 mmol). The mixture was allowed to stir under argon overnight at room temperature. The solvent was removed on a rotavap and the residue was taken up in EtOAc (100 mL) and washed 3× with water (50 mL) (emulsion formed, a few drops of 1N NaOH helps break emulsion), 1× with brine, dried over anhydrous Na2SO4, filtered and evaporated to give the crude residue. The residue was taken up in methylene chloride and absorbed on Isolute® Sorbent and purified by Combiflash using an 80 g silica column eluted with 0-10% DCM/MeOH. The product fractions were combined and concentrated to give N-[(3-bromo-4-methylphenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-5-methyl-1,3-benzenedicarboxamide (1.073 g, 1.635 mmol, 82% yield) as a white solid. LC-MS m/z 647.4 (M+H)+, 0.98 min (ret time); mp 117-119° C.
Reaction SMILES: [OH:1][C@H:2]([C:22]1[CH:23]=[CH:24][C:25]([O:41]COCC[Si](C)(C)C)=[C:26]([N:28](COCC[Si](C)(C)C)[S:29]([CH3:32])(=[O:31])=[O:30])[CH:27]=1)[CH2:3][NH:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.O.F[B-](F)(F)F.[Li+]>C(#N)C>[OH:41][C:25]1[CH:24]=[CH:23][C:22]([C@@H:2]([OH:1])[CH2:3][NH:4][CH2:5][CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[CH:12][CH:13]=2)=[CH:27][C:26]=1[NH:28][S:29]([CH3:32])(=[O:31])=[O:30]
Reactant: COc1ccc(-c2ccc(OCCNC[C@H](O)c3ccc(OCOCC[Si](C)(C)C)c(N(COCC[Si](C)(C)C)S(C)(=O)=O)c3)cc2)cc1
Agent: F[B-](F)(F)F
Agent: [Li+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(-c2ccc(OCCNC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)cc2)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
N-[5-{(R)-1-hydroxy-2-[2-(4′-methoxybiphenyl-4-yloxy)ethylamino]ethyl}-2-(2-trimethylsilylethoxymethoxy)-phenyl]-N-(2-trimethylsilylethoxymethyl)methanesulfonamide was dissolved in acetonitrile (0.25 mL). Water (0.05 mL) and a 1 mol/L solution of lithium tetrafluoroborate in acetonitrile (0.26 mL) were added to the solution, and the mixture was stirred at 80° C. for 3 hrs. The reaction mixture was purified by reverse phase column chromatography (Shiseido Capcell Pak MG ODS, 5 μm, 120 Å, 20×50 mm, Flow rate 30 mL/minute, linear gradient 0.1% aqueous formic acid/acetonitrile=90/10-10/90 over 5 minutes). The fraction was concentrated in vacuo to afford the title compound (0.009 g).
Reaction SMILES: F[C:2](F)(F)S(OC)(=O)=O.[F:10][C:11]([F:24])([C:13]([F:23])([O:18][C:19]([F:22])([F:21])[F:20])[C:14]([F:17])([F:16])[F:15])[O-:12].CN([S+](N(C)C)N(C)C)C>C(#N)C1C=CC=CC=1>[F:10][C:11]([O:12][CH3:2])([F:24])[C:13]([F:23])([O:18][C:19]([F:20])([F:22])[F:21])[C:14]([F:17])([F:16])[F:15]
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: [O-]C(F)(F)C(F)(OC(F)(F)F)C(F)(F)F
Agent: CN(C)[S+](N(C)C)N(C)C
Solvent: N#Cc1ccccc1
Product: COC(F)(F)C(F)(OC(F)(F)F)C(F)(F)F
Temperature: 25 °C

Procedure:
Methyl trifluoromethanesulfonate, 8.53 g (0.052 mol), was added dropwise to a stirred solution of 23.0 g (0.055 mol) of tris(dimethylamino)sulfonium 1,1,2,3,3,3-hexafluoro-2-(trifluoromethoxy)propoxide (prepared as in Example 10) in 50 mL of benzonitrile at 25°. The reaction mixture warmed spontaneously to 40°. After stirring for one h at ambient temperature the more volatile portion of the reaction mixture was distilled out at reduced pressure, and then redistilled at atmospheric pressure to give 8.96 g (65%) of the ether as a colorless liquid: bp 64.4°; 1H NMR (CDCl3) δ3.71 ppm (s); 19F NMR (CDCl3) δ-54.1 ppm (m, 3F), -80.8 ppm (m, 3F), δ-88.6 ppm (m, 2F) and -146.1 ppm (m, 1F). Anal. Calcd. for C5H3F9O2 : C, 22.57; H, 1.14; F, 64.27. Found: C, 22.63; H, 1.17; F, 63.67.
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH:28]=[CH:29][C:30]#[N:31]>>[C:16]1([C:14]2[N:15]=[C:11]3[CH:10]=[C:28]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=4)[CH:29]=[C:30]([NH2:31])[N:12]3[N:13]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: N#CC=Cc1ccccn1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccccc2)n1)c1ccccc1
Product: Nc1cc(-c2ccccn2)cc2nc(-c3ccccc3)nn12

Procedure:
The title compound, mp. 278-280° C., MS m/e (%): 288 (M+H+, 100), was prepared in accordance with the general method of example 22 from 3-benzenesulfonylmethyl-5-phenyl-1H-[1,2,4]triazole and 3-pyridin-2-yl-acrylonitrile.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[O:34][CH:35]([CH3:37])[CH3:36].C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:27][C:28]1[CH:29]=[C:30]([N:3]2[C:4](=[O:26])[C:5]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=[C:2]2[CH3:1])[CH:31]=[CH:32][C:33]=1[O:34][CH:35]([CH3:37])[CH3:36]
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)Oc1ccc(B(O)O)cc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCc1nc(C)n(-c2ccc(OC(C)C)c(Cl)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), (3-chloro-4-isopropoxyphenyl)boronic acid (1.00 g), triethylamine (2.00 mL), pyridine (1.00 mL) and molecular sieves 4 A (2.0 g) in methylene chloride (15 mL) was added copper(II) acetate (1.00 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.00 g, 67%).
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](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[N:56]1([C:62]2[N:67]=[CH:66][C:65]([NH2:68])=[CH:64][N:63]=2)[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>ClCCl>[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]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:68][C:65]2[CH:66]=[N:67][C:62]([N:56]3[CH2:61][CH2:60][O:59][CH2:58][CH2:57]3)=[N:63][CH:64]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1
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
Reactant: Nc1cnc(N2CCOCC2)nc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2cnc(N3CCOCC3)nc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reaction time: 0.33 h
Yield: 97.3 %

Procedure:
A solution 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 (59.9 mg, 0.128 mmol) in dichloromethane (3 ml) was treated with DIPEA (66.8 mg, 0.514 mmol) and DIPHENYLPHOSPHINIC CHLORIDE (75.8 mg, 0.314 mmol) and stirred for 20 min under argon. 2-MORPHOLIN-4-YLPYRIMIDIN-5-AMINE (23.4 mg, 0.130 mmol, Atlantic Research) was added. After stirred 2.5 hrs, the reaction mixture was diluted with dichloromethane, washed with sat. NaHCO3, water and brine. After dried over Na2SO4, the crude material was purified by silica gel chromatography with ethyl acetate and n-hexanes to give chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-(2-morpholinopyrimidin-5-yl)-5-neopentylpyrrolidine-2-carboxamide (78.4 mg., 97.2%) as a white solid. MS (ES+) m/z Calcd: [(M+H)+]: 629.19. found: 629.2.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[CH:24]([OH:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:29](Cl)(=[O:31])[CH3:30].[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35]>CN(C)C=O.C(C(C)=O)C>[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].[C:29]([O:26][CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24](=[O:25])[N:16]1[CH2:15][CH2:14][CH2:13][N:10]1[CH2:9][CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: O=C1c2ccccc2C(O)N1CCCN1CC=C(c2ccccc2)CC1
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OC1c2ccccc2C(=O)N1CCCN1CC=C(c2ccccc2)CC1
Reaction time: 20 h
Yield: 25.9 %

Procedure:
A solution of 2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-3-hydroxy-1-isoindolinone (6 g) in anhydrous dimethylformamide (70 cc) is added to a suspension of sodium hydride (as a 50% suspension in oil) (0.8 g) in anhydrous dimethylformamide (20 cc) at a temperature close to 20° C. in the course of 10 minutes and agitation is continued for 1 and a half hours. Then, 1.4 g of acetyl chloride is added in the course of 10 minutes, and agitation is continued for a further 20 hours. The suspension obtained is poured into distilled water (70 cc) and extracted with methylene chloride (4×50 cc). The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in methyl ethyl ketone (55 cc). A solution of oxalic acid (1.3 g) in methyl ethyl ketone (20 cc) is added and agitation continued for 1 hour at a temperature close to 20° C. The precipitate formed is separated by filtration. 1.8 g of 3-acetoxy-2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1-isoindolinone oxalate are thus obtained, melting at 166° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[C:18]([O:20][CH3:21])=[O:19])[C:3]1=[O:22].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[CH:15]([N:13]([CH3:14])[C@H:10]1[CH2:9][C@@H:8]([C:18]([O:20][CH3:21])=[O:19])[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=3)[C:3]2=[O:22])[CH2:12][CH2:11]1)([CH3:17])[CH3:16]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](NC(=O)c2cccc(C(F)(F)F)c2)C1=O
Yield: 38.8 %

Procedure:
A solution of (1R,2S,5R)-methyl 2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(isopropyl(methyl)amino)-cyclohexanecarboxylate (50 mg, 0.16 mmol), 3-(trifluoromethyl)benzoic acid (38 mg, 0.20 mol), EDCI (38 mg, 0.20 mmol), HOBT (27 mg, 0.20 mmol), and Et3N (20 mg 0.20 mmol) in CH2Cl2 was stirred overnight at room temperature. The solution was washed with water and brine, concentrated in vacuo and the residue chromatographed on silica gel (3%–5%–10% (NH4OH/MeOH)/CH2Cl2) to give 30 mg of the title product as a white solid. MS found: (M+H)+=484.25