Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7](I)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11].C(N(CC)CC)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:1][C:2]1[C:7]([C:14]#[C:13][Si:10]([CH3:12])([CH3:11])[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Fc1ncccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccnc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.9 %

Procedure:
Into a 1-neck round-bottom flask was added 2-fluoro-3-iodopyridine (1.0 g, 0.0045 mol), trimethylsilylacetylene (0.95 mL, 6.7 mmol), bis(triphenylphosphine)palladium(II) chloride (0.2 g, 0.2 mmol), copper(I) iodide (0.07 g, 0.4 mmol), and triethylamine (0.94 mL, 6.7 mmol) in N,N-dimethylformamide (20 mL). The reaction was stirred at 25° C. for 16 hours. The reaction was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated under vacuum. The product was purified by column chromatography on silica gel (10% ethyl acetate 90% hexanes) to give 0.747 g of the desired product. 1H NMR (400 MHz, CDCl3): δ 7.86-7.89 (m, 1H), 7.55-7.61 (m, 1H), 6.86-6.90 (m, 1H). MS [M+H]=194.0
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:27])[C@H:16]([NH:19]C(=O)OC(C)(C)C)[CH2:17][CH3:18])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1>O1CCOCC1>[ClH:2].[NH2:19][C@H:16]([CH2:17][CH3:18])[C:15]([N:12]1[CH2:13][CH2:14][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1)=[O:27]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@@H](N)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A 4M solution of HCl in dioxane (8 mL) was added to (R)-tert-butyl 1-(4-(4-chlorophenyl)piperidin-1-yl)-1-oxobutan-2-ylcarbamate (0.46 g) and the resulting solution was allowed to stir at rt. for 1.5 h. After this time, the solvent was removed by rotary evaporation to provide an oil. The oil was dried overnight in vacuo to provide (R)-2-amino-1-(4-(4-chlorophenyl)piperidin-1-yl)butan-1-one hydrochloride. MS found: (M+H)+=281.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=O)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH:22]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[N:15][C:14]([O:17][CH2:18][C:19](=[O:21])[NH:28][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:13][CH:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: NC1CCCCC1
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)NC1CCCCC1
Yield: 57 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using cyclohexylamine (24 μL, 0.21 mmol) as the coupling partner. Concentration (no chromatography) yielded 36 mg (57%) of the titled compound. ESI-MS m/z 373 (MH+), 371 (M−H−).
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[O:21]C)=[O:11])=[C:8]([CH3:23])[CH:7]=[C:6]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:5]=1)[CH3:2].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO>[CH2:1]([S:3][C:4]1[C:9]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[OH:21])=[O:11])=[C:8]([CH3:23])[CH:7]=[C:6]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:5]=1)[CH3:2]
Reactant: CCSc1nc(N2CCOCC2)cc(C)c1C(=O)NCc1ccc(F)cc1OC
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCSc1nc(N2CCOCC2)cc(C)c1C(=O)NCc1ccc(F)cc1O
Reaction time: 3 h
Yield: 40 %

Procedure:
To a cooled solution of 209 mg (0.5 mmol) 2-Ethylsulfanyl-N-[(4-fluoro-2-methoxy-phenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example 17) in DCM (7 ml) were added dropwise 5 ml (5.0 mmol, 1M in DCM) BBr3 at −50° C. The RM was then allowed to reach 0° C. and stirring was continued at this temperature for 3 h. Then a 1M aq. NaHCO3 sol. (15 ml) was added at 0° C. and the mixture was diluted with MeOH (10 ml) and DCM (10 ml). The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 7:3) provided 81 mg (0.2 mmol, 40%) 2-Ethylsulfanyl-N-[(4-fluoro-2-hydroxy-phenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example 18). [M+H]+ 406.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)[CH:25]=[C:24](I)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:2].[C:42]1(B(O)O)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:25]=[C:26]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)[CH:27]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccccc3)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Yield: 55.2 %

Procedure:
A similar procedure as described in Example 12, step 8 was used, starting from 4-{3-[6-(3-iodo-5-thiophen-3-yl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (216 mg, 0.31 mmol) and phenylboronic acid (152 mg, 1.25 mmol) to give 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(5-thiophen-3-yl-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid ethyl ester (110 mg, 55%) as a colorless oil: ES(+)-HRMS m/e calculated for C39H46O6S (M+Na)+ 665.2907, found 665.2907.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH2:15]([O:17][C:18]1[CH:28]=[CH:27][C:21]([CH:22]=[CH:23][C:24](O)=O)=[CH:20][CH:19]=1)[CH3:16]>>[CH2:15]([O:17][C:18]1[CH:28]=[CH:27][C:21](/[CH:22]=[CH:23]/[C:24]2[NH:1][C:2]3[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=3[N:8]=2)=[CH:20][CH:19]=1)[CH3:16]
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: CCOc1ccc(C=CC(=O)O)cc1
Product: CCOc1ccc(/C=C/c2nc3c([nH]2)c(=O)n(CC)c(=O)n3CC)cc1
Yield: 55.5 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 3.00 g (15.1 mmol) of 5,6-diamino-1,3-diethyluracil and 3.20 g (16.7 mmol) of 4-ethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane to give 2.97 g (yield 55%) of Compound 98 as pale yellow needles.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Br:11])[CH:9]=2)[N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:26][N:27]([CH3:32])[CH2:28][C:29](Cl)=[O:30]>O1CCCC1>[Br:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:3]=[C:2]2[NH:1][C:29](=[O:30])[CH2:28][N:27]([CH3:32])[CH3:26]
Reactant: CN(C)CC(=O)Cl
Reactant: CC(C)(C)OC(=O)n1nc(N)c2cc(Br)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)CC(=O)Nc1nn(C(=O)OC(C)(C)C)c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of Example 282B (24.43 g, 78 mmol), potassium carbonate (81 g, 587 mmol) and 2-(dimethylamino)acetyl chloride hydrochloride (43.3 g, 274 mmol) was added tetrahydrofuran (200 mL). The reaction mixture was stirred at room temperature for about 2 hours. The reaction mixture was filtered and the filtrate was washed with water (50 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (3×100 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with methanol in dichloromethane (5%) to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.72 (s, 1H), 8.19 (d, 1H, J=1.6), 8.03 (d, 1H, J=9.0), 7.76 (dd, 1H, J=2.0, 9.0), 3.22 (s, 2H), 2.32 (s, 6H), 1.63 (s, 9H).
Reaction SMILES: [CH2:1]1[CH:8]2[N:4]([C:5](=[O:9])[CH2:6][CH2:7]2)[C:3](=[O:10])[CH2:2]1.[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[CH2:15][Mg]Cl>>[F:11][C:12]1[CH:13]=[C:14]([CH2:15][C:5](=[O:9])[CH2:6][CH2:7][CH:8]2[NH:4][C:3](=[O:10])[CH2:2][CH2:1]2)[CH:18]=[CH:19][CH:20]=1
Reactant: O=C1CCC2CCC(=O)N12
Reactant: Fc1cccc(C[Mg]Cl)c1
Product: O=C(CCC1CCC(=O)N1)Cc1cccc(F)c1
Yield: 62.3 %

Procedure:
Following the procedure described for Preparation 8, Step A, tetrahydro-pyrrolizine-3,5-dione (2 g, 14 mmol) was reacted with 3-fluorobenzylmagnesium chloride (0.25M in Et2O, 62 mL, 15.5 mmol) over 2.5 h. Purification by medium pressure chromatography using a solvent gradient (1:1 hexanes:EtOAc to 2:1 EtOAc:hexanes to EtOAc to 2% MeOH in CH2Cl2 to 10% MeOH in CH2Cl2) provided 5-[4-(3-fluoro-phenyl)-3-oxo-butyl]-pyrrolidin-2-one (2.1730 g). 1H NMR (CDCl3) δ7.32-7.27 (m, 1H), 7.00-6.90 (m, 3H), 6.12 (bs, 1H), 3.69 (s, 2H), 3.59 (m, 1H), 2.52 (t, 2H), 2.30 (m, 2H), 2.19 (m, 1H), 1.75 (m, 2H), 1.65 (m, 1H).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([O:10][CH2:11][C:12]2[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[N:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][C:16]=3[CH3:22])=[N:3][CH:2]=1.C1C=C[NH+]=CC=1.Br[Br-]Br.CC(O)=[O:41]>CC(O)(C)C.[Zn]>[CH3:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[N:14]=[C:13]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])[C:12]([CH2:11][O:10][C:4]1[C:5]3[CH2:9][C:8](=[O:41])[NH:7][C:6]=3[N:1]=[CH:2][N:3]=1)=[CH:21]2
Reactant: CC(=O)O
Reactant: Cc1ccccc1-c1nc2c(C)cccc2cc1COc1ncnc2[nH]ccc12
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Product: Cc1ccccc1-c1nc2c(C)cccc2cc1COc1ncnc2c1CC(=O)N2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 3-((7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)methyl)-8-methyl-2-o-tolylquinoline (120 mg, 0.316 mmol) in AcOH (4 mL) and t-BuOH (2.43 mL) under N2 was added pyridinium bromide perbromide (303 mg, 0.947 mmol) in one portion. After stirring at room temperature for 5 h the solvents was removed, and the remaining solids suspended in H2O and extracted with ethyl acetate, after drying with brine and MgSO4 the crude dry solid was dissolved in THF (8 mL) followed by 5 mL of a saturated NH4Cl solution, this was followed in turn by Zn powder (528 mg, 26 mmol) and stirred at room temperature for 24 h. The mixture was then extracted with ethyl acetate and chromatographed {gradient elution DCM/89:9:1 (DCM/MeOH/NH4OH)}. The solid was recrystallized from DCM to provide the pure product [PI3Kδ IC50=349 nM]. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.29 (1H, s), 8.52 (1H, s), 8.30 (1H, s), 7.89 (1H, d, J=7.8 Hz), 7.65 (1H, d, J=7.0 Hz), 7.51-7.57 (1H, m), 7.30-7.35 (3H, m), 7.22-7.29 (1H, m), 3.47 (2H, s), 2.67 (3H, s), 2.09 (3H, s) Mass Spectrum (ESI) m/e=397.1 [M+1].
Reaction SMILES: I[C:2]1[C:3]2[S:11][CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)[C:4]=2[C:5]([NH2:8])=[N:6][CH:7]=1.[C:25]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:28])[CH:26]=[CH2:27].C(N(CC)CC)C>CN(C=O)C>[NH2:8][C:5]1[C:4]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[CH:10][S:11][C:3]=2[C:2](/[CH:27]=[CH:26]/[C:25]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:7][N:6]=1
Reactant: Nc1ncc(I)c2scc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: C=CC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)/C=C/c1cnc(N)c2c(-c3ccc(Oc4ccccc4)cc3)csc12
Temperature: 80 °C
Yield: 59.8 %

Procedure:
A mixture of Example 10B (0.417 g, 0.94 mmol), tert-butyl acrylate (0.26 mL, 1.74 mol) and triethylamine (0.7 mL, 5 mmol) in DMF (3 mL) was degassed with nitrogen for 45 minutes, treated with PdCl2(o-tol3P)2 (0.032 g, 0.046 mmol), and heated to 80° C. overnight. The resulting mixture was cooled to room temperature, then partitioned between water and ethyl acetate. The organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 30% ethyl acetate/hexanes to provide 0.25 g (61% yield) of the desired product. MS (ESI(+)) m/e 445 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[F:9][C:10]1[CH:36]=[CH:35][C:13]([CH2:14][N:15]2[C:24]3[C:19](=[CH:20][C:21]([CH3:25])=[CH:22][CH:23]=3)[C:18]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[C:17]([C:32]#[N:33])[C:16]2=[O:34])=[CH:12][CH:11]=1>N1C=CC=CC=1>[F:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][N:15]2[C:24]3[C:19](=[CH:20][C:21]([CH3:25])=[CH:22][CH:23]=3)[C:18]([N:26]3[CH2:31][CH2:30][N:29]([C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)=[O:7])[CH2:28][CH2:27]3)=[C:17]([C:32]#[N:33])[C:16]2=[O:34])=[CH:35][CH:36]=1
Reactant: O=C(Cl)c1ccco1
Reactant: Cc1ccc2c(c1)c(N1CCNCC1)c(C#N)c(=O)n2Cc1ccc(F)cc1
Solvent: c1ccncc1
Product: Cc1ccc2c(c1)c(N1CCN(C(=O)c3ccco3)CC1)c(C#N)c(=O)n2Cc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
2-Furoyl chloride (118 μL, 1.2 mmol) was added to a stirred solution of Compound 27 (300 mg, 0.8 mmol) in pyridine (5 mL) under argon at 0° C. The solution was allowed to come to room temperature and further stirred overnight. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried, and recrystallized by hexane and ether to yield 320 mg (85%) of white solids. M.P. 276° C. 1H NMR (DMSO-d6): δ 2.37 (s, 3H), 3.69 (m, 4H), 3.97 (m, 4H), 5.45 (s, 2H), 6.67 (dd, J=1.7, 3.7 Hz, 1H), 7.09 (d, J=3.4 Hz, 1H), 7.12 (m, 2H), 7.26 (m, 2H), 7.35 (d, J=8.7 Hz, 1H), 7.45 (d, J=8.8 Hz, 1H), 7.71 (s, 1H), 7.89 (s, 1H). EIMS m/z 493 (M+23). Anal. (C27H23FN4O3) C, H, N.
Reaction SMILES: Cl[CH:2]([C:9]1[CH:10]=[C:11]([C:20]([CH3:24])([CH3:23])[C:21]#[N:22])[CH:12]=[C:13]([C:15]([CH3:19])([CH3:18])[C:16]#[N:17])[CH:14]=1)[C:3]1[CH:4]=[N:5][CH:6]=[N:7][CH:8]=1.C(N(CC)CC)C>[Pd].C(O)C>[N:5]1[CH:4]=[C:3]([CH2:2][C:9]2[CH:10]=[C:11]([C:20]([CH3:24])([CH3:23])[C:21]#[N:22])[CH:12]=[C:13]([C:15]([CH3:18])([CH3:19])[C:16]#[N:17])[CH:14]=2)[CH:8]=[N:7][CH:6]=1
Reactant: CC(C)(C#N)c1cc(C(Cl)c2cncnc2)cc(C(C)(C)C#N)c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C#N)c1cc(Cc2cncnc2)cc(C(C)(C)C#N)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2,2'-[5-(1-chloro-1-(pyrimidin-5-yl)methyl)-1,3-phenylene]di(2-methylpropi ononitrile), (0.55 g), triethylamine (0.25 ml), 5% palladium-on-carbon (0.02 g) and ethanol (10 ml) was stirred under hydrogen at room temperature and atmospheric pressure for 10 minutes and then filtered. The filtrate was diluted with ethyl acetate (25 ml), and the solution washed with aqueous sodium hydrogen carbonate, dried and evaporated to dryness. The residue was purified by flash chromatography using 1% by volume of methanol in dichloromethane as eluant to give 2,2'-[5-(pyrimidin-5-ylmethyl)-1,3-phenylene]di(2-methylpropiononitrile), mp 132°-134°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22]([O:24]C)=[O:23])=[C:18]([O:28][CH3:29])[CH:17]=3)=[O:15])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1>O>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]([C:16]3[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[C:18]([O:28][CH3:29])[CH:17]=3)=[O:15])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: COC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1OC
Solvent: O
Product: COc1cc(C(=O)CN2CCN(c3ccncc3)CC2)ccc1OCC(=O)O
Yield: 47 %

Procedure:
In a similar manner to Example 2, but starting from the product of Example 5, the title compound was prepared in 47% yield: m.p. 218°-224° C.; NMR(d6DMSO) δ8.16(2H,d), 7.65(1H,dd), 7.53(1H,d), 6.92(1H,d), 6.85(2H,d), 4.73(2H,s), 3.86(2H,s), 3.82(3H,s), 3.36(4H,t) 2.63(4H,t); m/e 386(M+H)+ ; calculated for C20H23N3O5. H2O: C, 59.5; H, 6.2; N, 10.4. found: C, 59.5; H, 5.9; N, 10.1%.
Reaction SMILES: [C:1]12([C:9](Cl)=[O:10])[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[NH2:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:14]1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][N:15]2[CH2:16][CH2:17][C@H:13]([NH:12][C:9]([C:1]34[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]3)[CH2:3][CH2:2]4)=[O:10])[CH2:14]2)=[CH:21][CH:22]=1
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Reactant: O=C(Cl)C12CCC(CC1)CC2
Product: O=C(N[C@H]1CCN(CCc2ccc(F)cc2)C1)C12CCC(CC1)CC2

Procedure:
Bicyclo[2.2.2]octane-1-carbonyl chloride and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine were reacted under the same conditions as in Example 53 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-bicyclo[2.2.2]octane-1-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][C:14]2([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[O:19][C:18](=[O:20])[CH2:17][C:16](=[O:21])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[CH2:27]([N:29]1[C:33]([CH3:34])=[C:32]([CH:35]=O)[C:31]([CH3:37])=[N:30]1)[CH3:28]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][C:14]2([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[O:19][C:18](=[O:20])[C:17]([CH2:35][C:32]3[C:31]([CH3:37])=[N:30][N:29]([CH2:27][CH3:28])[C:33]=3[CH3:34])=[C:16]([OH:21])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: CCn1nc(C)c(C=O)c1C
Solvent: CO
Product: CCn1nc(C)c(CC2=C(O)CC(CCc3ccc(OC(C)C)c(Cl)c3)(C3CCCC3)OC2=O)c1C
Temperature: 40 °C
Reaction time: 0.08 h
Yield: 38.1 %

Procedure:
A solution of 6-[2-(3-chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione (379 mg; 1.0 mmol from step 1 below) and 1-ethyl-3,5-dimethyl-1H-pyrazole-4-carbaldehyde (152 mg; 1.1 mmol) in methanol was heated at 40° C. overnight. The reaction mixture was treated with (CH3)2NHBH3 (65 mg, 1.1 equiv), and heated at 40° C. overnight again. The reaction was partitioned between EtOAc and H2O. The EtOAc layer was dried with Na2SO4, concentrated, and purified by reverse phase HPLC using 0.1% HOAc in H2O and CH3CN. (Column: Water's Bondapak, C18, particle size: 37-55 micron column size: 47×300 mm; Flow rate: 70 ml/min; Detector: was set at 254 nm; Buffer A: 0.1% HOAc in H2O; Buffer B: 0.1% HOAc in CH3CN. The column was equilibrated in A for 20 minutes. The sample was dissolved in 5 ml of DMSO, filtered, and injected onto the column. The gradient was held at 75% A/25% for 5 minutes and then increased linearly to 55% A/45% B in 15 minutes and then continued isocratically at 45% B for another 25 minutes. The desired product eluted at 28 minutes.) The product-containing fractions were lyophilized to afford the title compound as a powder (196.2 mg, 40%). 1H NMR (400 MHz, DMSO-d6): δ 1.13 (t, 3H), 1.26 (d, m overlap, 8H), 1.35-1.63 (m, 6H), 1.75 (m, 2H), 2.02 (s, 3H), 2.10 (s, 3H), 2.21 (m, 1H), 2.39 (m, overlap, 3H), 2.61 (d, J=16.4 Hz, 1H), 3.1 (m, 2H, overlap with H2O peak), 3.81 (q, 2H), 4.56 (7 line pattern, 1H), 6.90 (d, J=8.8 Hz, 1H), 7.00 (d, J=8.8 Hz, 1H), 7.11 (s, 1H). LC-MS (APCI) calcd for C29H39ClN2O4: 514.26, found (M+H+): 515.3 m/z.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([Cl:17])=[CH:12][CH:13]=2)[N:8](C(C)(C)C)[CH:7]=1)=[O:5])[CH3:2].S(=O)(=O)(O)O>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([Cl:17])=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc(Cl)ccc2c1=O
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c[nH]c2nc(Cl)ccc2c1=O
Temperature: 70 °C
Yield: 93.1 %

Procedure:
The product from Example 13a (0.282 gm, 0.91 mmol) was combined at room temperature with 2 mL of TFA containing 2 drops of sulfuric acid. The resulting mixture was heated at 70° C. for 16.5 h. The volatiles were removed under vacuum and the residue suspended in water. The product was collected by vacuum filtration, water washed and dried under vacuum to give the title compound as a cream colored solid (0.214 gm, 93%).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:6][C@H:5]([CH2:7][CH2:8][C:9]2[NH:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=2)[CH2:4][O:3]1.C(=O)([O-])[O-].[Br:25]Br>C(Cl)Cl>[Br:25][C:10]1[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:12][NH:13][C:9]=1[CH2:8][CH2:7][C@@H:5]1[CH2:4][O:3][C:2]([CH3:20])([CH3:1])[O:6]1
Reactant: CC1(C)OC[C@@H](CCc2cc(-c3ccccc3)n[nH]2)O1
Reactant: BrBr
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CC1(C)OC[C@@H](CCc2[nH]nc(-c3ccccc3)c2Br)O1
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a solution of (R)-5-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-3-phenyl-1H-pyrazole (2.3 g, 8.45 mmol) and MP-carbonate (26 g, 84.5 mmol) in CH2Cl2 (100 mL), was added bromine (1.350 g, 8.45 mmol) dropwise at 0° C. After stirring for 1 h, MP-carbonate was filtered off and washed with CH2Cl2. The combined organic layer was poured into water, extracted with CH2Cl2, dried over MgSO4, and then concentrated under reduced pressure. The resulting residue was purified by column chromatography to give the title compound (2.81 g) as an oil. LCMS m/z=351.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:11]3[C:12](=[O:17])[C:13](I)=[CH:14][CH:15]=[C:10]3[N:9]2[S:26]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[C:32]#[N:33])(=[O:28])=[O:27])=[CH:4][CH:3]=1.[CH3:37][C:38]([CH3:43])=[CH:39]B(O)O>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:11]3[C:12](=[O:17])[C:13]([CH:37]=[C:38]([CH3:43])[CH3:39])=[CH:14][CH:15]=[C:10]3[N:9]2[S:26]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[C:32]#[N:33])(=[O:28])=[O:27])=[CH:4][CH:3]=1
Reactant: CC(C)=CB(O)O
Reactant: N#Cc1cccc(S(=O)(=O)N2c3ccc(I)c(=O)n3[C@H](c3ccc(Cl)cc3)[C@@H]2c2ccc(Cl)cc2)c1
Solvent: CO
Solvent: ClCCl
Product: CC(C)=Cc1ccc2n(c1=O)[C@H](c1ccc(Cl)cc1)[C@H](c1ccc(Cl)cc1)N2S(=O)(=O)c1cccc(C#N)c1

Procedure:
The titled compound was prepared according to general method D by reaction of rac-3-[cis-2,3-bis-(4-chloro-phenyl)-5-oxo-2,3-dihydro-6-iodo-5H-imidazo[1,2-a]pyridine-1-sulfonyl]-benzonitrile with 2,2-dimethylethenylboronic acid. The compound was isolated by FCC (2.5% MeOH/DCM). The expected product was characterized by 1H NMR
Reaction SMILES: [OH:1][CH2:2][CH:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[CH3:9][C:10]([CH3:12])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:9][C:10]1([CH3:12])[N:7]2[C:6](=[O:8])[CH2:5][CH2:4][C@@H:3]2[CH2:2][O:1]1
Reactant: O=C1CCC(CO)N1
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC1(C)OC[C@H]2CCC(=O)N21

Procedure:
A mixture of 5-hydroxymethyl-2-pyrrolidone (0.4 g), acetone (5 ml) and p-toluenesulfonic acid (ca. 10 mg) was refluxed in 20 ml of benzene for 20 hours with a Dean-Stark water separator. After working up the reaction mixture, distillation (boiling point 70°-75° C. at 0.5 mm of Hg) yielded 0.2 g or (R)-tetrahydro-3,3-dimethyl-3H,5H-pyrrolo[1,2-c]oxazol-5-one as an oil.