Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)=O.[NH2:18][NH2:19]>CS(C)=O>[I:17][C:14]1[CH:13]=[C:3]2[C:2](=[CH:16][CH:15]=1)[NH:19][N:18]=[C:4]2[CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1
Reactant: CN1CCC(C(=O)c2cc(I)ccc2F)CC1
Reactant: NN
Solvent: CS(C)=O
Product: CN1CCC(c2n[nH]c3ccc(I)cc23)CC1
Temperature: 100 °C
Yield: 99 %

Procedure:
A mixture of 4-(2-fluoro-5-iodobenzoyl)-1-methylpiperidine (4.20 g, 12.1 mmol), anhydrous NH2NH2 (30 mL), and DMSO (15 mL) was heated at 100° C. overnight, diluted with ice water and filtered. The filtercake was washed with water and dried in vacuo to provide the title compound (4.1 g, 99%), characterized by HNMR and mass spectral analyses.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][C:11](=[O:28])[N:12]2[CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([O:26]C)=[O:25])[CH:19]=2)=[C:8]([NH2:29])[N:7]=1)[CH2:2][CH2:3][CH3:4].CO.[OH-].[K+].Cl>O>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][C:11](=[O:28])[N:12]2[CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([OH:26])=[O:25])[CH:19]=2)=[C:8]([NH2:29])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCOc3cccc(C(=O)OC)c3)c2n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCOc3cccc(C(=O)O)c3)c2n1
Temperature: 85 °C
Reaction time: 4.5 h
Yield: 100 %

Procedure:
To 2-butoxy-8-oxo-9-[2-(3-methoxycarbonylphenoxy)ethyl]adenine (50 mg, 0.12 mmol) obtained in Example 1 were added methanol (2.5 ml) and 2.5N potassium hydroxide (5 m), and the mixture was stirred at 85° C. for 4.5 hours. After cooling, water was added and the resultant was made to pH 5 by concentrated hydrochloric acid. The precipitated crystal was collected by filtration to give 49 mg (0.12 mmol) of the titled compound as a white solid. Yield: 100%.
Reaction SMILES: C([O:3][C:4](=[O:44])[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:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:25]=[C:26]([O:28][CH2:29][CH3:30])[CH:27]=2)[C:10]=1[CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])C.[OH-].[Na+]>>[C:39]([CH2:38][CH2:37][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:25]=[C:26]([O:28][CH2:29][CH3:30])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:44])=[O:3])([OH:41])=[O:40]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCC)cc(-c3ccccc3)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCOc1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccccc2)c1
Yield: 95.7 %

Procedure:
A similar procedure as described in Example 43, step 5 was used, starting from 4-[3-[6-(5-ethoxy-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (240 mg, 0.4 mmol) and 1.0 N aqueous sodium hydroxide (4 mL) to afford 4-[2-(2-carboxy-ethyl)-3-[6-(5-ethoxy-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid (210 mg, 96%) as a light brown waxy solid: ES(+)-HRMS m/e calcd for C33H40O7 (M+Na)+ 571.2666. found 571.2665.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([NH:12][CH:13]([CH3:31])[CH2:14][C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][C:23](Cl)=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=3)=[CH:18][CH:19]=2)=[O:11])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[CH3:61][N:62](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([C:5]1[CH:9]=[C:8]([C:10]([NH:12][CH:13]([CH3:31])[CH2:14][C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:61]#[N:62])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=3)=[CH:18][CH:19]=2)=[O:11])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(Cc1ccc(-c2ccc(Cl)c(C(F)(F)F)c2)o1)NC(=O)c1cc(C(C)(C)C)n[nH]1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(Cc1ccc(-c2ccc(C#N)c(C(F)(F)F)c2)o1)NC(=O)c1cc(C(C)(C)C)n[nH]1
Temperature: 150 °C

Procedure:
3-tert-butyl-N-(1-(5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-yl)propan-2-yl)-1H-pyrazole-5-carboxamide (0.615 g, 1.355 mmol) was weighed into a reaction vial (Biotage) and 11.6 ml of DMF was added. Zinc cyanide (0.350 g, 2.981 mmol), S-Phos (0.112 g, 0.271 mmol) and Pd2(dba)3 (0.100 g, 0.108 mmol) were added. The reaction vial was flushed with nitrogen, capped and heated for 30 min at 150° C. in microwave oven. The mixture was allowed to cool to RT and 30 ml of 1 M NaOH was added. The mixture was extracted with EtOAc for three times and the combined organic layers were washed with water, dried with Na2SO4, filtered and evaporated to dryness. CombiFlash purification afforded 0.094 g of the title product. 1H-NMR (400 MHz; CDCl3): δ 1.29 (d, 3H), 1.33 (s, 9H), 3.00 (d, 2H), 4.49-4.56 (m, 1H), 6.31 (d, 1H), 6.58 (s, 1H), 6.84 (d, 1H), 7.11 (m, 1H), 7.78 (m, 1H), 7.85 (m, 1H), 7.95 (m, 1H).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([N:8]([CH3:31])[C@@H:9]2[CH2:13][CH2:12][N:11]([C:14]3[C:15]4[CH:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:16]=4[N:17]=[CH:18][N:19]=3)[CH2:10]2)=[N:6][CH:7]=1.[O-]CC.[Na+].O>CCO>[CH3:31][N:8]([C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[CH:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10]1)[C:5]1[CH:4]=[N:3][CH:2]=[CH:7][N:6]=1
Reactant: CN(c1cnc(Br)cn1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN(c1cnccn1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Yield: 51.7 %

Procedure:
A solution of (R)-5-bromo-N-methyl-N-(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)pyrazin-2-amine (55 mg, 0.10 mmol) and sodium ethoxide (680 mg, 10 mmol) in EtOH (10.5 mL) was stirred at refluxing temperature for 5 days. It was then treated with water and extracted with EtOAc (2×30 mL). The combined extracts were concentrated and the residue was purified by chromatography on silica gel (PE/EtOAc=1/1). The first compound from the column was collected and confirmed to be (R)-5-ethoxy-N-methyl-N-(1-(7-((2-(trimethylsilyl)ethoxy)-methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)pyrazin-2-amine [MS (m/z), 470 (M+1)+, 21 mg, 41.1% yield) and the later compound from the column was isolated and concentrated to give the title compound (22 mg, 47.8% yield). MS (m/z), 426 (M+1)+
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]2[NH:10][C:9](=S)[CH:8]3[CH2:15][CH2:16][CH2:17][CH:7]3[C:6]=2[CH:5]=1)([O-:3])=[O:2].[NH3:18]>>[NH2:18][C:9]1[CH:8]2[CH2:15][CH2:16][CH2:17][CH:7]2[C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: N
Reactant: O=[N+]([O-])c1ccc2c(c1)C1CCCC1C(=S)N2
Product: NC1=Nc2ccc([N+](=O)[O-])cc2C2CCCC12
Yield: 76 %

Procedure:
As described for Example 4, 8-nitro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinoline-4-thione (100 mg, 0.40 mmol) is reacted with 7N methanolic ammonia solution (15 ml) to form 70 mg (76%) of product.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]([CH3:12])([CH3:11])[CH2:8][CH2:9][OH:10].CC=C(C)C.C(N(CC)CC)C.[S:25](Cl)([CH3:28])(=[O:27])=[O:26]>C(Cl)(Cl)Cl.CCOCC>[S:25]([O:10][CH2:9][CH2:8][C:7]([CH3:12])([CH3:11])[CH2:6][CH:2]1[O:3][CH2:4][CH2:5][O:1]1)(=[O:27])(=[O:26])[CH3:28]
Reactant: CC(C)(CCO)CC1OCCO1
Reactant: CS(=O)(=O)Cl
Agent: CC=C(C)C
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CC(C)(CCOS(C)(=O)=O)CC1OCCO1
Temperature: 5 °C
Reaction time: 4 h

Procedure:
81.9 g of 4-(dioxolan-2-yl)-3,3-dimethylbutanol, prepared above, are dissolved in 600 ml of chloroform, stabilized with amylene, in the presence of 62 ml of triethylamine. The mixture is cooled to 5° C. and 81 ml of mesyl chloride are added dropwise. The mixture is subsequently stirred for 4 hours at 5° C. and then left overnight at this temperature, washed with cold water and evaporated at 30° C. under vacuum. The residue obtained is taken up with ether and washed with sodium bicarbonate. The ether phase is dried over magnesium sulfate and then evaporated at 30° C. under vacuum to give 93.5 g of 4-(dioxolan-2-yl)-3,3-dimethylbutanol mesylate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21].C(N(CC)C(C)C)(C)C>COCCOCCOC>[Cl:1][C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([NH:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][P:18]([O:19][CH2:20][CH3:21])([O:22][CH2:23][CH3:24])=[O:25])[N:5]=[CH:4][N:3]=1
Reactant: CCOP(=O)(CCCCON)OCC
Reactant: O=CNc1c(Cl)ncnc1Cl
Solvent: COCCOCCOC
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(CCCCONc1ncnc(Cl)c1NC=O)OCC
Yield: 77.2 %

Procedure:
4,6-Dichloro-5-formamidopyrimidine (0.441 g, 2.3 mmol), diethyl 4-(aminooxy)butylphosphonate (0.4 g, 1.77 mmol) and N,N-diisopropylethylamine (0.8 ml, 4.6 mmol) in diglyme (15 ml) were stirred at 100° C. for 2.5 hr. The reaction mixture was then allowed to cool, the hydrochloride of N,N-diisopropylethylamine was filtered off and the filtrate was diluted with chloroform (150 ml). The resulting solution was washed with 4% aq. NaHCO3 (1×20 ml) and water (1×20 ml). The combined aqueous layers were extracted with chloroform (6×20 ml) and the combined chloroform solutions were concentrated to an oil. The residue was chromatographed on silica gel (eluted with chloroform: ethanol, 96:4) to yield the title compound (0.520 g, 77%). 1H NMR: δH [(CD3)2SO] 1.22 (6H, t, J=7Hz, (OCH2CH3)2), 1.68 (6H, m, CH2CH 2CH2P), 3.9 (2H, m, NOCH2), 3.97 (4H, m, (OCH2CH3)2), 8.14 (1H, s, H-2), 9.5 (1H, br.s, NHOCH2, D2O exchangeable), 11.0 (1H, NHCHO, D2O exchangeable).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:22][CH:23]([CH3:25])[CH3:24])[S:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=O)=[CH:15][CH:14]=1)(=[O:12])=[O:11]>O1CCCC1>[NH2:19][CH2:17][C:16]1[CH:20]=[CH:21][C:13]([S:10]([N:9]([C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[CH2:22][CH:23]([CH3:25])[CH3:24])(=[O:12])=[O:11])=[CH:14][CH:15]=1
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C(N)=O)cc2)c(C)c1
Solvent: C1CCOC1
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(CN)cc2)c(C)c1
Temperature: 75 °C

Procedure:
4-(N-(2,4-dimethylphenyl)-N-isobutylsulfamoyl)benzamide (263.6 mg, 0.731 mmol) was dissolved in tetrahydrofuran (THF) (10 mL) and to this solution was added borane-tetrahydrofuran complex (1 M) (2.194 mL, 2.194 mmol). The reaction was then heated to 75° C. and refluxed overnight under nitrogen. The reaction was cooled and quenched by the addition of 2 M HCl. The reaction mixture was then neutralised by the slow addition of 10 M sodium hydroxide and the product extracted to the organic phase of an aqueous work up between ethyl acetate and water. The organic phase was passed through a hydrophobic frit and concentrated in vacuo. The crude was purified by mass directed autoprep (formic acid modifier), over 3 injections. The relevant fractions were evaporated in vacuo to give the required product, 152 mg. LCMS [LCMS1] Rt 0.87 min, m/z (ES+) 347 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]#[N:26])=[C:4]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[C:5]2[C:10](=[O:11])[N:9]([CH3:12])[C:8](=[O:13])[N:7]([CH3:14])[C:6]=2[N:15]=1.Br[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH:30]=1.NCC1C(NCC2C=CC3C(=CC=CC=3)C=2)=NC2N(C)C(=O)N(C)C(=O)C=2C=1C1C=C(F)C=CC=1OC>>[NH2:26][CH2:25][C:3]1[C:2]([NH:1][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH:30]=2)=[N:15][C:6]2[N:7]([CH3:14])[C:8](=[O:13])[N:9]([CH3:12])[C:10](=[O:11])[C:5]=2[C:4]=1[C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[O:23][CH3:24]
Reactant: COc1ccc(F)cc1-c1c(C#N)c(N)nc2c1c(=O)n(C)c(=O)n2C
Reactant: CC(C)COc1cccc(CBr)c1
Agent: COc1ccc(F)cc1-c1c(CN)c(NCc2ccc3ccccc3c2)nc2c1c(=O)n(C)c(=O)n2C
Product: COc1ccc(F)cc1-c1c(CN)c(NCc2cccc(OCC(C)C)c2)nc2c1c(=O)n(C)c(=O)n2C

Procedure:
The synthesis of title compounds started from Compound 70a and 1-(bromomethyl)-3-isobutoxybenzene, according to procedures described in the synthesis of Compound 70. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.96 (d, J=6.6 Hz, 6H) 1.95-2.04 (m, 1H) 3.19 (s, 3H) 3.53 (s, 1H) 3.65 (d, J=8.6 Hz, 2H) 3.69 (s, 3H) 3.88 (d, J=14.4 Hz, 1H) 4.55 (d, J=14.9 Hz, 1H) 4.68 (d, J=14.9 Hz, 1H) 6.67 (dd, J=8.3, 3.0 Hz, 1H) 6.73 (dd, J=7.9, 2.1 Hz, 1H) 6.85-6.92 (m, 2H) 6.98 (dd, J=9.1, 4.3 Hz 1H) 7.05-7.12 (m, 1H) 7.14 (t, J=8.0 Hz 1H). MS [m+H] calc'd C28H33FN5O4 522. found 522.
Reaction SMILES: [CH:1]1([NH:6][S:7]([C:10]2[C:11]3[CH:12]=[CH:13][C:14](=[O:27])[NH:15][C:16]=3[CH:17]=[C:18]([C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])[CH:19]=2)(=[O:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:35])C(=O)C1>>[Br:35][C:13]1[C:14](=[O:27])[NH:15][C:16]2[CH:17]=[C:18]([C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])[CH:19]=[C:10]([S:7]([NH:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)(=[O:9])=[O:8])[C:11]=2[CH:12]=1
Reactant: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2ccc(=O)[nH]c2c1
Reactant: O=C1CCC(=O)N1Br
Product: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2cc(Br)c(=O)[nH]c2c1

Procedure:
A solution of N-cyclopentyl-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydroquinoline-5-sulfonamide (100 mg, 0.26 mmol) and NBS (150 mg, 3 equiv) was heated at 80° C. for 1 hour. The reaction mixture was partitioned between aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and purified on silica gel (rf=0.75 in ethyl acetate) to give 3-bromo-N-cyclopentyl-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydroquinoline-5-sulfonamide as a white powder.
Reaction SMILES: C([O:5][CH2:6][C@H:7]([CH3:35])[O:8][C:9]1[CH:10]=[C:11]([CH:21]=[C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[CH:23]=1)[C:12]([NH:14][C:15]1[CH:19]=[CH:18][N:17]([CH3:20])[N:16]=1)=[O:13])(C)(C)C.Cl>CO.C(OC(C)=O)(C)C.O>[OH:5][CH2:6][C@H:7]([CH3:35])[O:8][C:9]1[CH:10]=[C:11]([CH:21]=[C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:27][CH:26]=2)[CH:23]=1)[C:12]([NH:14][C:15]1[CH:19]=[CH:18][N:17]([CH3:20])[N:16]=1)=[O:13]
Reactant: C[C@@H](COC(C)(C)C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Agent: Cl
Solvent: CC(=O)OC(C)C
Solvent: CO
Solvent: O
Product: C[C@@H](CO)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 50 °C
Yield: 64 %

Procedure:
To a 25 ml round-bottomed flask was charged 3-[(1S)-2-tert-butoxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[4-(methylsulfonyl)phenoxy]benzamide (498.4 μmol, 250.0 mg). This was dissolved in methanol (4 ml) and HCl (4 ml) was added to the flask in one portion. The reaction was heated to 50° C. for 1.5 hours. Solvent was removed in vacuo to yield a colourless solid that quickly changed to liquid form on standing. The liquid was dissolved in iPrOAc (10 ml) and water (10 ml). The aqueous layer was extracted with further iPrOAc (10 ml). The combined organic layer was dried with MgSO4 and the solvent was removed in vacuo to yield crude title product (142 mg; 63.95% yield) as a white foamy solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2([CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:15][C:14]([OH:16])=[C:13]([CH2:17][C:18]3[N:28]=[C:21]4[N:22]=[C:23](C)[CH:24]=[C:25](C)[N:20]4[N:19]=3)[C:12](=[O:29])[O:11]2)[CH:5]=[CH:4][C:3]=1[C:35]1([C:38]#[N:39])[CH2:37][CH2:36]1.[Cl:40]C1C=C(CCC2(C3CCCC3)OC(=O)CC(=O)C2)C=C(CC)C=1OC.CC1C=NC2N(N=C(C=O)N=2)C=1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2([CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:15][C:14]([OH:16])=[C:13]([CH2:17][C:18]3[N:28]=[C:21]4[N:22]=[CH:23][C:24]([Cl:40])=[CH:25][N:20]4[N:19]=3)[C:12](=[O:29])[O:11]2)[CH:5]=[CH:4][C:3]=1[C:35]1([C:38]#[N:39])[CH2:36][CH2:37]1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(Cl)c1OC
Reactant: Cc1cc(C)n2nc(CC3=C(O)CC(CCc4ccc(C5(C#N)CC5)c(Cl)c4)(C4CCCC4)OC3=O)nc2n1
Agent: Cc1cnc2nc(C=O)nn2c1
Product: N#CC1(c2ccc(CCC3(C4CCCC4)CC(O)=C(Cc4nc5ncc(Cl)cn5n4)C(=O)O3)cc2Cl)CC1

Procedure:
The title compound was prepared analogously to Example B(97), 1-(2-Chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-cyclopropanecarbonitrile was substituted in place of 6-[2-(3-Chloro-5-ethyl-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione in that example and 6-Methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde in place of the 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde in that example. 1H NMR (400 MHz, CDCl3) δ: 1.16–1.18 (m, 2H), 1.19–1.5 (m, 8H), 1.51–1.53 (m, 2H), 1.86–1.89 (m, 2H)), 2.16–2.29 (m, 1H), 2.35–2.47 (m, 3H), 2.59 (d, J=17 Hz, 1H), 3.56 (d, J=16 Hz, 1H), 3.65 (d, J=16 Hz, 1H), 7.08 (d, J=7.8, 1 Hz, 1H), 7.20–7.23 (m, 2H), 8.70 (d, J=2.5 Hz, 1H), 9.41 (d, J=2.5, 1.1 Hz, 1H), 10.7 (s, 1H). C28H27Cl2N5O3.0.25: C, 60.38; H, 4.98; N, 12.57. Found: C, 60.30; H, 4.80; N, 12.53. MS (ESI): 552.2(M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:25]1[CH:26]=[CH:27][C:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[N:29][CH:30]=1>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:1][N:2]1[CH:6]=[C:5]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[N:29][CH:30]=2)[CH:4]=[N:3]1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cn1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc(C(=O)OC(C)(C)C)nc2)cn1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (80.7 mg), bis(tri-tert-butylphosphine)palladium (0) (9.91 mg) and a 1 N potassium phosphate solution (388 μL) were added to a solution of tert-butyl 5-bromopyridine-2-carboxylate (50 mg) in 1,4-dioxane (2 mL). After replacement with nitrogen, the mixture was heated to 100° C. and stirred for eight hours. The reaction solution was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound as a mixture (81 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][CH2:6][C:7]#[C:8][CH2:9][N:10]1[C@@H:15](/[CH:16]=[CH:17]/[C:18](=[O:26])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][CH2:13][CH2:12][C:11]1=[O:27]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu].[Cu].[Cu].[Cu].[Cu].[Cu]>[CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][CH2:6][C:7]#[C:8][CH2:9][N:10]1[C@@H:15]([CH2:16][CH2:17][C:18](=[O:26])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][CH2:13][CH2:12][C:11]1=[O:27]
Reactant: COC(=O)COCC#CCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1ccccc1
Agent: [Cu]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)COCC#CCN1C(=O)CCC[C@@H]1CCC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 77.8 %

Procedure:
A solution of {4-[(R)-2-Oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-but-2-ynyloxy}-acetic acid methyl ester (30 mg, 0.078 mmol) in toluene (2 mL) was added via cannula to a round-bottomed flask containing hydrido(triphenylphosphine)copper(I) hexamer (154 mg, 0.078 mmol) at −40° C. under nitrogen. The reaction was allowed to warm to rt and stirred for 2.5 h. The reaction was quenched with NH4OH/NH4Cl (1:1, 8 mL) and extracted with EtOAc (3×10 mL). The combined extracts were dried washed with brine (10 mL) then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (20% →40% EtOAc/CH2Cl2, gradient) afforded 23.4 mg (78%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH2:14][CH:13]2[C:12](=O)[CH2:11][CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:16][NH:17][CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCCl.C([O-])(O)=O.[Na+]>[ClH:1].[CH3:16][N:17]([CH3:18])[CH:12]1[CH2:11][CH2:10][C:9]2([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH:13]1[CH2:14]2
Reactant: O=C1CCC2(c3ccc(Cl)c(Cl)c3)CC12
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCCl
Product: CN(C)C1CCC2(c3ccc(Cl)c(Cl)c3)CC12
Reaction time: 0.5 h

Procedure:
The mixture of 5-(3,4-dichlorophenyl)bicyclo[3.1.0]hexan-2-one (110 mg, 0.45 mmol) in DCE (3 mL) and dimethylamine (2M solution in THF, 5 mL, 4.5 mmol) was treated with sodium triacetoxyborohydride (95 mg, 0.45 mmol) at room temperature. The reaction mixture was stirred for 0.5 h, then the reaction mixture was diluted with saturated NaHCO3, extracted with CH2Cl2(3×), dried over K2CO3, filtered and concentrated in vacuo to afford the target compound. The oily crude residue (96 mg, 79%) was converted to HCl salt. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.11 (t, 1 H) 1.77-1.87 (m, 1 H) 1.96-2.02 (m, 1 H) 2.03-2.22 (m, 3 H) 2.25-2.37 (m, 1 H) 2.81 (d, 3 H) 2.92 (d, 3 H) 3.72-3.90 (m, 1 H) 6.96 (dd, 7 H) 7.21 (d, 7 H) 7.33 (d, 7 H) 12.07-12.30 (broad, 1 H), 13C NMR (126 MHz, CHLOROFORM-d) δ ppm 15.96 (s, 1 C) 24.22 (s, 1 C) 25.84 (s, 1 C) 31.02 (s, 1 C) 33.20 (s, 1 C) 42.65 (s, 1 C) 42.69 (s, 1 C) 69.75 (s, 1 C) 125.96 (s, 1 C) 128.61 (s, 1 C) 130.52 (s, 1 C) 130.57 (s, 1 C) 132.58 (s, 1C) 142.82 (s, 1 C). 13C NMR (400 MHz, CHLOROFORM-d) d ppm 15.96 (s, 1 C) 24.22 (s, 1 C) 25.84 (s, 1 C) 31.02 (s, 1 C) 33.20 (s, 1 C) 42.65 (s, 1 C) 42.69 (s, 1 C) 69.75 (s, 1 C) 125.96 (s, 1 C) 128.61 (s, 1 C) 130.52 (s, 1 C) 130.57 (s, 1 C) 132.58 (s, 1C) 142.82 (s, 1 C). MS (M+1) 270.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1.C([Li])CCC.CN(C)[CH:22]=[O:23]>C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[O:23])[C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])=[N:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)C(=O)Nc1ccc(F)cn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)C(=O)Nc1ncc(F)cc1C=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of N-(5-fluoro-pyridin-2-yl)-2,2-dimethylpropionamide (39.2 g) in dry diethyl ether (1200 ml) under an atmosphere of nitrogen at −78° C. was added dropwise t.-butyl lithium in hexanes (1.7M, 300 ml). The mixture was stirred at −78° C. for 2 hours then dry N,N-dimethylformamide (160 ml) was added and the slurry stirred at −78° C. for 1 hour then allowed to slowly warm to ambient temperature and stirred for an additional 1 hour. The mixture was quenched with aqueous 2M hydrochloric acid until a clear biphasic solution was formed and the organic phase separated. The aqueous phase was further extracted with diethyl ether. The extracts were combined, washed with brine (300 ml), dried over magnesium sulfate, filtered and evaporated under reduced pressure to give the required product as a pale yellow solid, 40 g. 1H NMR (CDCl3) δ: 11.20 (1H, s), 9.94 (1H, s), 8.59 (1H, d), 7.84 (1H, dd), 1.42 (9H, s).