Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:6][C:7]=1[CH3:8].C(N(CC)CC)C.[F:26][C:27](=[CH2:31])[C:28](Cl)=[O:29]>C(OCC)C>[F:26][C:27](=[CH2:31])[C:28]([O:18][C:9]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1)([C:10]([F:11])([F:12])[F:13])[C:14]([F:17])([F:15])[F:16])=[O:29]
Reactant: C=C(F)C(=O)Cl
Reactant: Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1C
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=C(F)C(=O)OC(c1ccc(C)c(C)c1)(C(F)(F)F)C(F)(F)F
Temperature: 20 °C
Reaction time: 3.5 h
Yield: 51.4 %

Procedure:
A solution of 27.3 g (0.1 mol) Of 2-(3,4-dimethylphenyl)hexafluoro-2-propanol and 10.1 g (0.1 mol) of triethylamine in 50 ml of dry diethyl ether was added dropwise with stirring at a temperature of 20° C. to a solution of 20 g (0.184 mol) of α-fluoroacryloyl chloride (obtained according to Example 4) in 50 ml of dry diethyl ether in the course of 35 minutes. The reaction mixture was then stirred at a temperature of 20° C. for a further 3.5 hours. The resulting solid was filtered off. The filtrate was distilled under reduced pressure after addition of 0.01 g of hydroquinone monomethyl ether. 17.7 g (51 percent of theory) of 2-(3,4-dimethylphenyl)-hexafluoro-2-propyl α-fluoroacrylate having a boiling point of 72° to 73° C. (under 0.4 mbar) were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([F:15])=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16](=[O:18])=[O:17]>>[C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([C:16]([OH:18])=[O:17])=[CH:11][C:12]([F:15])=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)nc1
Product: CC(C)(C)OC(=O)Nc1cnc(F)cc1C(=O)O
Yield: 25 %

Procedure:
Reaction of 5-[N-(tert-butoxycarbonyl)amino]-2-fluoropyridine (5.3 g, 25 mmol) sequentially with n-Butyl and CO2 as described in the following example gives 5-(N-(tert-butoxycarbonyl)amino]-2-fluoropyridine-4-carboxylic acid (1.60 g, 25%). 1H NMR (DMSO) δ 9.83 (1H, brs) 8.84 (1H, s), 7.49 (1H, d, J=2.9 Hz), 1.47 (9H, s).
Reaction SMILES: C([O:5][C:6](=[O:39])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:31]2[N:36]=[CH:35][C:34]([CH2:37][CH3:38])=[CH:33][N:32]=2)[CH2:19][C:20]2[CH:21]=[N:22][N:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:24]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:37]([C:34]1[CH:33]=[N:32][C:31]([N:18]([CH2:19][C:20]2[CH:21]=[N:22][N:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:24]=2)[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:39])=[O:5])[S:12][CH:13]=2)=[N:36][CH:35]=1)[CH3:38]
Reactant: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2cnn(-c3ccccc3)c2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)O)n2)Cc2cnn(-c3ccccc3)c2)nc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 76 %

Procedure:
2-{[4-(2-{(5-Ethylpyrimidin-2-yl)[(1-phenyl-1H-pyrazol-4-yl)methyl]amino}ethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (7.3 g) obtained in Example 326-1 was dissolved in dichloromethane (80 mL), trifluoroacetic acid (20 mL) was added, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution (at this time point, the object product had been extracted in the ethyl acetate layer). The ethyl acetate layer was washed with aqueous 10% citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1) to give the title compound (5.0 g) as a white solid.
Reaction SMILES: [C:1]([NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:26]2)=CC=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[C:1]([NH:5][C:6](=[S:26])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)NC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=S)c1ccc([N+](=O)[O-])cc1
Yield: 68 %

Procedure:
The preparation of Example 1 was repeated with the changes that N-tert-butyl 4-nitrobenzamide (3.00 g, 0.0135 mole) and 2,4-bis (4-methoxyphenyl) -1,3 -dithia-2,4-diphosphetane-2,4-disulfide (3.28 g, 0.0081 mole) were the starting reactants and the reaction was carried out by refluxing in 50 mL dry toluene solvent for 3 hours. In addition, the solvent was removed in vacuo leaving a yellow viscous oil. The oil was taken up into ethyl acetate and the solution filtered through silica gel. The solvent was removed in vacuo, the residue taken up into ethanol, and the mixture filtered through fluted filter paper. Recrystallization from ethanol produced 2.20 g golden crystals of the desired product (68% yield), mp 136°-138° C. Proton nuclear magnetic resonance (89.55 MHz) showed absorptions at 8.21 ppm (d, 8.0 Hz, 2H; 3,5-aryl H); 7.76 ppm (d, 8.0 Hz, 2H; 2,6-aryl H); 1.67 ppm (s, 9H; tert-butyl H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[N:19]=[C:18](Cl)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:21][CH3:22])[CH:16]=2)[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([NH2:33])[C:24]1[CH:32]=[CH:31][C:30]2[O:29][CH2:28][O:27][C:26]=2[CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C>[CH2:1]([O:8][CH2:9][C:10]1[N:19]=[C:18]([NH:33][CH2:23][C:24]2[CH:32]=[CH:31][C:30]3[O:29][CH2:28][O:27][C:26]=3[CH:25]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:21][CH3:22])[CH:16]=2)[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: COc1ccc2nc(COCc3ccccc3)nc(Cl)c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: COc1ccc2nc(COCc3ccccc3)nc(NCc3ccc4c(c3)OCO4)c2c1
Reaction time: 6 h
Yield: 98 %

Procedure:
0.74 g (2.4 mmol) of the 2-benzyloxymethyl-4-chloro-6-methoxyquinazoline prepared in Example 246, 0.55 g (3.6 mmol) of piperonylamine and 0.50 g of sodium carbonate were mixed with 20 ml of isopropyl alcohol. The obtained mixture was heated under reflux. After 6 hours, the reaction mixture was distilled under a reduced pressure to remove the solvent and the residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) and recrystallized from chloroform/n-hexane to give 1.01 g of the title compound as a yellow crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:7][C:8]=1[CH3:9].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH2:28]([O:35][C:36]1[CH:69]=[CH:68][C:39]([C:40]([O:42][C:43]2[CH:48]=[CH:47][C:46]([CH2:49][N:50]([CH2:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[C:51](=[O:59])[C:52]3[CH:57]=[CH:56][C:55]([NH2:58])=[CH:54][CH:53]=3)=[CH:45][CH:44]=2)=[O:41])=[CH:38][CH:37]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CN(C=O)C>[CH2:28]([O:35][C:36]1[CH:69]=[CH:68][C:39]([C:40]([O:42][C:43]2[CH:48]=[CH:47][C:46]([CH2:49][N:50]([CH2:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[C:51](=[O:59])[C:52]3[CH:53]=[CH:54][C:55]([NH:58][C:11](=[O:13])[CH2:10][C:5]4[CH:6]=[CH:7][C:8]([CH3:9])=[C:3]([O:2][CH3:1])[CH:4]=4)=[CH:56][CH:57]=3)=[CH:45][CH:44]=2)=[O:41])=[CH:38][CH:37]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: COc1cc(CC(=O)O)ccc1C
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)OC(C)(C)C)C(=O)c3ccc(N)cc3)cc2)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)OC(C)(C)C)C(=O)c3ccc(NC(=O)Cc4ccc(C)c(OC)c4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Prepared using General Procedures 6 and 8: To 2-(3-methoxy-4-methylphenyl)acetic acid (14.1 mg, 0.08 mmol) were added HOBT (12.0 mg, 0.08 mmol) in DMF (0.1 mL) and EDC (15.0 mg, 0.08 mmol) in DMF (0.1 mL). After stirring at room temperature for 30 min, 4-((4-amino-N-(2-(tert-butoxy)-2-oxoethyl)benzamido)methyl)phenyl 4-(heptyloxy)benzoate INT-4 (30 mg, 0.05 mmol) and TEA (0.019 mL, 0.10 mmol) in DMF (0.3 mL) were added. The reaction was stirred for 18 h then purified by preparative HPLC to provide 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(3-methoxy-4-methylphenyl)acetamido)benzamido)methyl)phenyl 4-(heptyloxy)benzoate. To 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(3-methoxy-4-methylphenyl)acetamido)benzamido)methyl)phenyl 4-(heptyloxy)benzoate in DCM (1.0 mL) was added TFA (0.2 mL). The reaction was stirred at 30° C. for 6 h. The reaction was concentrated to afford 22.3 mg (65%) of 2-(N-(4-((4-(heptyloxy)benzoyl)oxy)benzyl)-4-(2-(3-methoxy-4-methylphenyl)acetamido)benzamido)acetic acid 4. LCMS-ESI (m/z) calculated for C40H44N2O8: 680; no m/z observed, tR=11.45 min (Method 2). 1H NMR (400 MHz, DMSO) δ 10.32 (s, 1H), 8.06 (d, J=8.8 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H), 7.43 (d, J=7.2 Hz, 1H), 7.40-7.28 (m, 3H), 7.24 (d, J=8.5 Hz, 2H), 7.17-7.02 (m, 3H), 6.91 (s, 1H), 6.79 (d, J=7.5 Hz, 1H), 4.62 (d, J=36.2 Hz, 2H), 4.08 (t, J=6.5 Hz, 2H), 3.95 (d, J=28.6 Hz, 2H), 3.77 (s, 3H), 3.60 (s, 2H), 2.10 (s, 3H), 1.74 (dd, J=9.8, 4.8 Hz, 2H), 1.48-1.24 (m, 8H), 0.86 (d, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].C(=O)([O-])[O-].[Na+].[Na+].[CH2:11]([O:18][C:19](Cl)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC(C)=O.O>[CH2:11]([O:18][C:19]([NH:1][CH2:2][CH2:3][OH:4])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(NCCO)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
2-Aminoethanol (20 g.) and sodium carbonate (84.8 g.) is dissolved in acetone-water (1:1) (500 ml.) and benzylchloroformate (83.9 g.) is added dropwise to the stirred solution at 0° C. over a period of 0.5 hours. The mixture is stirred at 0° C. for a further 2.5 hours. The solids are filtered off and washed with acetone and the filtrate is evaporated to dryness. The resulting gum is taken up in chloroform and filtered. The filtrate is evaporated to dryness. The residue is chromatographed on a silica gel column (140×5 cm.) using chloroform and then 10% methanol in chloroform as the eluant to give 2-benzyloxycarbonylaminoethanol, which crystallizes from hexane as colorless needles; m.p. 53°-55° C.; γ max (CCl4) 3450, 3325, 1720, 1510, 1245 cm-1 ; δ (CDCl3) 3.29 (2H, m HOCH2CH2NH--), 3.57 (2H, m, HOCH2CH2NH--), 5.07 (2H, s, --CH2C6H5) and 7.31 ppm (5H, s, --CH2C6H5).
Reaction SMILES: Cl.[CH:2]([N:5]1[C:9]([C:10]2[N:19]=[C:18]3[N:12]([CH2:13][CH2:14][O:15][C:16]4[CH:23]=[C:22]([C@H:24]5[CH2:29][CH2:28][NH:27][CH2:26][C@H:25]5[OH:30])[CH:21]=[CH:20][C:17]=43)[CH:11]=2)=[N:8][CH:7]=[N:6]1)([CH3:4])[CH3:3].[CH3:31][N:32]([CH3:37])[C:33](=[O:36])[CH2:34]Cl>>[OH:30][C@H:25]1[C@@H:24]([C:22]2[CH:21]=[CH:20][C:17]3[C:18]4[N:12]([CH:11]=[C:10]([C:9]5[N:5]([CH:2]([CH3:4])[CH3:3])[N:6]=[CH:7][N:8]=5)[N:19]=4)[CH2:13][CH2:14][O:15][C:16]=3[CH:23]=2)[CH2:29][CH2:28][N:27]([CH2:34][C:33]([N:32]([CH3:37])[CH3:31])=[O:36])[CH2:26]1
Reactant: CN(C)C(=O)CCl
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc([C@H]3CCNC[C@H]3O)cc1OCC2
Agent: Cl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc([C@H]3CCN(CC(=O)N(C)C)C[C@H]3O)cc1OCC2
Yield: 56 %

Procedure:
Following the procedures for Example 330, cis-racemic-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidin-3-ol hydrochloride (86 mg, 0.19 mmol) was reacted with N,N-dimethyl-2-chloroacetamide (26 mg, 0.21 mmol) to give 320 (51 mg, 57%). LCMS: RT=2.58 min, [M+H]+=480. 1H NMR 400 MHz (DMSO-d6) δ: 8.29 (1 H, d, J=8.29 Hz), 7.90-7.90 (2 H, m), 7.08 (1 H, dd, J=8.37, 1.72 Hz), 6.98 (1 H, d, J=1.65 Hz), 5.89-5.88 (1 H, m), 4.56-4.41 (4 H, m), 4.08 (1 H, br), 3.79 (1 H, br), 3.17 (2 H, m), 3.06 (3 H, s), 2.88 (2 H, m), 2.82 (3 H, s), 2.62 (1 H, m), 2.39 (1 H, m), 2.22 (2 H, m), 1.53 (1 H, m), 1.48 (6 H, d, J=6.61 Hz)
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15](=[O:36])[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[O:23][C:24]4[C:30]([CH:31]([CH3:33])[CH3:32])=[CH:29][C:28]([C:34]#[N:35])=[CH:27][C:25]=4[N:26]=3)=[CH:18][CH:17]=2)[CH2:9][CH:8]=1)(=O)=O.[F:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[C:34]([C:28]1[CH:29]=[C:30]([CH:31]([CH3:32])[CH3:33])[C:24]2[O:23][C:22]([C:19]3[CH:18]=[CH:17][C:16]([C:15]([NH:14][CH2:13][CH:10]4[CH2:11][CH2:12][C:7]([C:43]5[CH:44]=[CH:45][C:40]([F:39])=[CH:41][CH:42]=5)=[CH:8][CH2:9]4)=[O:36])=[CH:21][CH:20]=3)=[N:26][C:25]=2[CH:27]=1)#[N:35]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CC=C(OS(=O)(=O)C(F)(F)F)CC4)cc3)oc12
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CC=C(c5ccc(F)cc5)CC4)cc3)oc12
Yield: 83.5 %

Procedure:
To a mixture of 4-({[4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoyl]amino}methyl)cyclohex-1-en-1-yl trifluoromethanesulfonate (50 mg, 0.091 mmol, INTERMEDIATE 5) and 4-fluorophenyl boronic acid (25 mg, 0.179 mmol) in tetrahydrofuran (2 ml) and 1 M aqueous potassium carbonate (1 ml, 1.000 mmol) was added 1,1′-bis(di-t-butylphosphino)ferrocene palladium dichloride (1 mg, 5.64 μmol). The mixture was microwaved at 100° C. in a sealed tube for 10 min, cooled, and then resubmitted to the reaction conditions for 10 min, at which point LC/MS analysis showed no starting material. The organic phase of the reaction mixture was added directly to a 25 samplet and purified by flash chromatography on a Biotage Horizon, 25M column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 100% ethyl acetate in dichloromethane over 10 column volumes, to provide the title compound (37.5 mg, 0.076 mmol, 83% yield). Mass spectrum (ESI) 494.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.32 (d, J=8.5 Hz, 2H); 7.96 (d, J=8.0 Hz, 2H), 7.93 (d, J=1.5 Hz, 1H); 7.51 (s, 1H), 7.32 (ddd, J=2.0, 5.5, 8.5 Hz, 2H), 6.99 (t, J=9.0 Hz, 2H), 6.39 (br t, J=5.5 Hz, 1H), 6.03 (s, 1H), 3.42-3.58 (m, 3H), 2.34-2.56 (m, 3H), 1.96-2.08 (m, 3H), 1.46 (d, J=7.0 Hz, 6H), 1.44-1.62 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5](CC)[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([O:13][CH3:14])[CH:7]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].I[CH:25]([CH3:27])[CH3:26]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:25]([CH3:27])[CH3:26])=[C:8]([O:13][CH3:14])[CH:7]=1)[CH3:2]
Reactant: CC(C)I
Reactant: CCOC(=O)C(CC)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(OC(C)C)c(OC)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 88.6 %

Procedure:
A mixture of ethyl (4-hydroxy-3-methoxy-phenyl)-acetic acid ethyl ester (11.22 g, 53.4 mmol) and K2CO3 (22.13 g, 160 mmol) in DMF (100 ml) was heated at 60° C. 2-Iodopropane (9.06 ml, 91 mmol) was added and the mixture was vigorously stirred at 60° C. for 5 h. The reaction mixture was cooled to RT, diluted with AcOEt and washed with water. The aqueous phase was separated and further extracted with AcOEt. The combined organic fractions were dried over Na2SO4, filtered and evaporated to dryness. The resulting crude material was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, heptane/AcOEt 98:2→3:1) to yield the title compound (11.94 g, 47.3 mmol, 89%) as a colorless oil. TLC: RF=0.44 (heptane/AcOEt 7:3); HPLC: AtRet=2.14 min; LC-MS: m/z 253.4 [M+H]+; 1H NMR (400 MHz, CDCl3): 1.28 (t, J=7.1, 3H), 1.38 (d, J=6.1, 6H), 3.56 (s, 2H), 3.87 (s, 3H), 4.17 (q, J=7.1, 2H), 4.50 (h, J=6.1, 1H), 6.77-6.89 (m, 3H).
Reaction SMILES: [N:1]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32][CH2:31][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28](O)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4].[NH2:41][C@@H:42]([C:55]([NH:57][C@H:58]([C:63]([NH:65][C@H:66]([C:71]([NH2:73])=[O:72])[CH2:67][CH2:68][S:69][CH3:70])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>>[N:1]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32][CH2:31][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28]([NH:41][C@@H:42]([C:55]([NH:57][C@H:58]([C:63]([NH:65][C@H:66]([C:71]([NH2:73])=[O:72])[CH2:67][CH2:68][S:69][CH3:70])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]([O:50][C:51]([CH3:53])([CH3:54])[CH3:52])=[O:49])=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](N)CCCCNC(=O)OC(C)(C)C)C(N)=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Yield: 46 %

Procedure:
Condensation of BocPro-DTrp-PheOH (0.88 g.) and HDLys(Boc)-Leu-MetNH2 (0.68 g.) using dicyclohexylcarbodiimide and 1-hydroxybenzotriazole gave BocPro-DTrp-Phe-DLys(Boc)-Leu-MetNH2 in 46% yield. De-t-butoxycarbonylation of BocPro-DTrp-Phe-DLys(Boc)-Leu-MetNH2 (560 mg.) using trifluoroacetic acid in dimethyl sulfide and ethanedithiol gave HPro-DTrp-Phe-DLys-Leu-MetNH2, which was isolated as the amorphous white solid phosphate (1:1) acetate (1:3) salt in 26% yield.
Reaction SMILES: [CH2:1](Cl)[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[Mg].[CH3:13][Si:14]([CH3:17])(Cl)[Cl:15].[CH2:18]([Mg:28][Cl:29])[C:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:21])[CH3:20]>C1COCC1>[CH2:18]([Mg:28][Cl:29])[C:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:21])[CH3:20].[CH2:1]([Si:14]([CH3:17])([CH3:13])[Cl:15])[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(CCl)c1ccccc1
Reactant: C[Si](C)(Cl)Cl
Agent: CC(C)(C[Mg]Cl)c1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C[Si](C)(C)Cl)c1ccccc1
Yield: 73 %

Procedure:
Neophylmagnesium chloride was prepared by the careful addition of 500 g (2.96 mol) of neophyl chloride to 75 g (3.125 mol) of magnesium turnings in 1.25 liters of dry THF. A five liter, 4-necked flask equipped with an overhead stirrer, condenser, thermometer and addition funnel was charged with 387 g (3.125 mol) of dimethyldichlorosilane, 3.0 g of cuprous cyanide and 250 ml of THF. Neophylmagnesium chloride was added dropwise from the addition funnel at such a rate as to maintain a gentle reflux. After the 2 hr. addition and additional 1 hr. reflux the reaction mixture was cooled, filtered and the filter cake was washed with hexane (2×250 ml). The combined organic layers were concentrated at reduced pressure and diluted with 100 ml hexane and again filtered. Reduced pressure concentration and distillation of the product gave 493 g (73% of theory) of neophyldimethylchlorosilane.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:27]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([NH:34][CH:35]([CH3:37])[CH3:36])[N:29]=3)=[C:12]3[CH2:13][N:14](C(OCC4C=CC=CC=4)=O)[CH2:15][CH2:16][N:11]3[N:10]=2)=[CH:5][CH:4]=1>CO.[Pd]>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:27]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([NH:34][CH:35]([CH3:37])[CH3:36])[N:29]=3)=[C:12]3[CH2:13][NH:14][CH2:15][CH2:16][N:11]3[N:10]=2)=[CH:5][CH:4]=1
Reactant: CC(C)Nc1nccc(-c2c(-c3ccc(F)cc3)nn3c2CN(C(=O)OCc2ccccc2)CC3)n1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)Nc1nccc(-c2c(-c3ccc(F)cc3)nn3c2CNCC3)n1
Reaction time: 18 h

Procedure:
Palladium (10% on activated carbon, 25 mg) and 2 M hydrogen chloride in methanol (20 mL) were added to a solution of phenylmethyl 2-(4-fluorophenyl)-6,7-dihydro-3-[2-[(1-methylethyl)amino]-4-pyrimidinyl]pyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (i.e. the product of Step D) (0.50 g, 0.14 mmol) in methanol (30 mL). The resulting suspension was shaken on a Parr apparatus under hydrogen gas (68.9 kPa) for 18 h. The resulting suspension was filtered and concentrated to dryness to give 0.42 g of the title product, a compound of the present invention, as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[N:19]([CH3:20])[C:18]3[C:17](=[O:21])[N:16]([CH2:22][C:23]#[CH:24])[C:15](=[O:25])[N:14]([CH3:26])[C:13]=3[N:12]=2)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[N:19]([CH3:20])[C:18]3[C:17](=[O:21])[N:16]([CH2:22][C:23]#[CH:24])[C:15](=[O:25])[N:14]([CH3:26])[C:13]=3[N:12]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: C#CCn1c(=O)c2c(nc(C#Cc3cccc(OC)c3)n2C)n(C)c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C#CCn1c(=O)c2c(nc(C#Cc3cccc(O)c3)n2C)n(C)c1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 76 %

Procedure:
To a solution of 100 mg (0.28 mmol) 8-(3-methoxyphenylethynyl)-3,7-dimethyl-1-prop-2-ynyl-3,7-dihydropurine-2,6-dione in dichloromethane (25 mL) was added boron tribromide (0.5 mL, 5.3 mmol) at room temperature. After a few minutes precipitation of a yellow solid could be observed. The suspension was stirred for 0.5-1 h at room temperature until no starting material could be detected by TLC analyses (eluent: dichloromethane/methanol, 9.5:0.5). After hydrolysis with concentrated NaHCO3 solution (50 mL) the dichloromethane was removed under reduced pressure. The precipitate was filtered under reduced pressure, washed with water, dried at 70° C. and purified by column chromatography on silica gel (eluent: dichloro-methane/methanol, 9.5:0.5 or 9:1): colorless crystals (yield: 76%), m.p. 271° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:17]=[C:16]([CH3:18])[N:15]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=4)[N:14]=3)[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH:27]1[CH:31]=[CH:30][N:29]=[CH:28]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>C1(C)C=CC=CC=1.FC(F)(F)S([O-])(=O)=O.[Cu+].O.CN(C=O)C>[N:27]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:12]=[C:11]([C:13]4[CH:17]=[C:16]([CH3:18])[N:15]([CH2:19][C:20]5[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=5)[N:14]=4)[O:10][N:9]=3)=[CH:4][CH:3]=2)[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: c1c[nH]cn1
Reactant: Cc1ccc(Cn2nc(-c3nc(-c4ccc(I)cc4)no3)cc2C)cc1
Agent: [Cu+]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccc(-n5ccnc5)cc4)no3)cc2C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of 3-(4-iodophenyl)-5-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-1,2,4-oxadiazole (Example 13, 250 mg, 0.548 mmol), imidazole (56 mg, 0.822 mmol), caesium carbonate (197 mg, 0.603 mmol), copper-(I) trifluoromethanesulfonate (15 mg; 0.027 mmol), dibenzylideneacetone (6.7 mg, 0.027 mmol) and 1,10-phenanthroline (99 mg, 0.548 mmol) in toluene (1 mL) was heated to reflux under an inert atmosphere of argon over night. In order to increase solubility, DMF (100 μL) was added, and stirring was continued at 120° C. for 24 h. After being cooled to rt, water (5 mL) was added and the product was extracted with ethyl acetate. After the organic extract had been washed with brine and dried over anhydrous magnesium sulfate, it was filtered and concentrated in vacuo. The residue was subjected to preparative HPLC to afford the title compound in pure form (20 mg, 9%): 1H NMR (400 MHz, CDCl3) 8.33 (d, 2H), 7.98 (broad s, 1H), 7.53 (d, 2H), 7.38 (broad s, 1H), 7.26 (broad s, 1H, partially obscured by CHCl3 signal), 7.14 (d, 2H), 7.08 (d, 2H), 6.81 (s, 1H), 5.41 (s, 2H), 2.32 (s, 3H), 2.28 (s, 3H); ES-MS m/z 397, HPLC RT (Method K) 1.06 min.