Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=O.[Si](Cl)(C(C)(C)C)(C)C.CCN(C(C)C)C(C)C.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1.[F-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCCC1>[OH:1][C:2]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[S:43]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1ccc(N2CCOCC2)cc1O
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=S)c1ccc(N2CCOCC2)cc1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-hydroxy-4-morpholin-4-yl-benzamide (102 mg; 0.46 mmol) and t-butyldimethylsilyl chloride (73 mg; 0.48 mmol) in dry tetrahydrofuran (4 mL) was added Hunig's base (0.084 mL; 0.48 mmol) via syringe at room temperature under a nitrogen atmosphere. After stirring at room temperature for 4 hours, Lawesson's reagent was added (117 mg; 0.28 mmol) in one portion and the resulting solution was stirred for 16 hours. Benzyl trimethyl ammonium fluoride (1.84 mmol) then was added and stirring was continued for 2 hours longer. The reaction was concentrated at reduced pressure, and the residue re-dissolved in EtOAc (10 mL) and washed with water, 10% citric acid, 5% NaHCO3, and brine then dried (Na2SO4), filtered and concentrated in vacuo. The residue was then recrystallized from EtOAc/hexanes to provide the thioamide as a yellow solid (31 mg; 28%).
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:10]([O:17][C:18]1[CH:19]=[C:20](/[C:24](=[N:26]/[S@@:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28])/[CH3:25])[CH:21]=[CH:22][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)C>O1CCCC1.[Zn]>[CH2:6]([O:5][C:3](=[O:4])[C:2]([F:9])([F:8])[C@@:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:19]=1)([NH:26][S@@:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28])[CH3:25])[CH3:7]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: C/C(=N\[S@](=O)C(C)(C)C)c1cccc(OCc2ccccc2)c1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(F)(F)[C@](C)(N[S@](=O)C(C)(C)C)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
Zinc (5.07 g, 77.5 mmol) and cuprous chloride (2.64 g, 25.8 mmol) were stirred in a dried apparatus and heated for 1 minute with a heat gun under a flow of argon. After cooling to room temperature, tetrahydrofuran (85.1 ml) was added. The reaction mixture was stirred in a 70° C. oil bath for 30 minutes, then cooled to room temperature. A solution of ethyl bromodifluoroacetate (13.5 g, 8.54 ml, 64.6 mmol) in tetrahydrofuran (25.5 ml) was added dropwise while maintaining the temperature between 26 and 29° C. After stirring for 10 minutes at 23° C., a solution of (R,E)-N-(1-(3-(benzyloxy)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (intermediate A2.6) (8.51 g, 25.8 mmol) in tetrahydrofuran (25.5 ml) was added dropwise and stirring continued for 24 hours at room temperature. For the workup, the reaction mixture was cooled to 0° C. and ethanol (3 ml) was added dropwise. The mixture was filtered through a pad of Dicalite® and washed with ethyl acetate. The filtrate was concentrated at reduced pressure. The residue was taken in ethyl acetate (40 ml) and water was added. The emulsion was filtered again through a pad of Dicalite®. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and evaporated at reduced pressure. The crude product (13.7 g, yellow oil) was purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 50:50 as the eluent. The (R)-3-(3-benzyloxy-phenyl)-2,2-difluoro-3-((R)-2-methyl-propane-2-sulfinylamino)-butyric acid ethyl ester (7.72 g, 66% yield) was obtained as a yellow oil. MS (ISP): m/z=454.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](C)([C:14]([O-])=O)[C:9]([O:11]CC)=[O:10])[CH:5]=[CH:4][C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C.Cl>O>[CH3:14][CH:8]([C:9]([OH:11])=[O:10])[C:6]1[CH:5]=[CH:4][C:3]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:2]([F:1])[CH:7]=1
Reactant: CCOC(=O)C(C)(C(=O)[O-])c1ccc(-c2ccccc2)c(F)c1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Temperature: 25 °C
Yield: 66.8 %

Procedure:
In a 200 ml round-bottom flask is placed 15.03 g (~43.7 mmol) of ethyl 2-(2-fluoro-4-biphenylyl)-2-methylmalonate, 62 ml of glacial acetic acid, and 22 ml of 6 N aqueous hydrochloric acid. The mixture is refluxed under nitrogen for 24 hours. On cooling to room temperature, the solution is diluted with 250 ml of water and the mixture is extracted with 4×50 ml of methylene chloride. The combined extracts are washed with 2×100 ml of water and then with 8×40 ml (0.2 N) of aqueous potassium hydroxide solution. Extracts 1-4 are combined, acidified to pH <1 with concentrated hydrochloric acid, and the resulting solution is extracted with 3×50 ml of methylene chloride. The organic extracts are dried over sodium sulfate and concentrated in vacuo to give 7.13 g (38.8% overall) crude flurbiprofen. Extract 5 is backwashed with 3×15 ml methylene chloride, acidified with concentrated hydrochloric acid, and the resulting mixture is extracted with 3×20 ml methylene chloride to give 1.84 g (10.0%) crude flurbiprofen. Fractions 6-8 are combined and the pH is adjusted to ~9.0. After washing with 3×30 ml methylene chloride, the aqueous is acidified with concentrated hydrochloric acid and is then extracted with 3×50 ml of methylene chloride. Drying and concentration of the extracts gives 0.53 g (4.0%) crude flurbiprofen Ib.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:22][C:23]1[CH:24]=[C:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH:26]=[CH:27][CH:28]=1>C(#N)C.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:22][C:23]3[CH:24]=[C:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH:26]=[CH:27][CH:28]=3)[CH:10]=2)[O:3]1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CBr)c1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cccc(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.4 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.88 g, 4.54 mmol) in acetonitrile (20 mL) was added cesium carbonate (4.43 g, 13.61 mmol) and tert-butyl 3-(bromomethyl)phenylcarbamate (1.298 g, 4.54 mmol). The reaction was stirred at room temperature for 3 h. After this time, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The aqueous phase was extracted with CHCl3. The combined organic layer was dried over anhydrous MgSO4, filtered, and concentrated. The resulting residue was purified by (0-100% ethyl acetate:hexanes) to afford the title compound (1.06 g, 2.65 mmol, 59% yield) as a colorless oil. LCMS, [M+H]+=400.3.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH2:4][C:5](=O)[CH2:6][CH3:7])[CH3:3].C(OC(=O)CC)(=[O:18])CC.[Cl-].C([Mg]Cl)C(C1C=CC=CC=1)(C)C>C1(C)C=CC=CC=1.C(OCC)C>[CH3:1][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH:4]=[CH:5][CH2:6][CH3:7])[CH2:3][OH:18]
Reactant: CCC(=O)OC(=O)CC
Reactant: CCC(=O)CC(C)(C)c1ccccc1
Agent: CC(C)(C[Mg]Cl)c1ccccc1
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCC=CC(C)(CO)c1ccccc1

Procedure:
A process for preparing 2-methyl-2-phenyl-4-hexanone having the structure: ##STR47## comprising the step of intimately admixing propionic anhydride having the structure: ##STR48## with neophymagnesium chloride having the structure: ##STR49## in the presence of an inert solvent selected from the group consisting of diethylether, toluene and tetrahydrufuran, the reaction taking place in the presence of or in the absence of a cuprous chloride catalyst; the mole ratio of propionic anhydride:neophylmagnesium chloride being from 0.5:1 up to about 2:1; the temperature of reaction being from -10° C. up to 0° C.; the concentration of propionic anhydride in solvent being from about 1 up to about 5 moles of propionic anhydride per liter of solvent; the time of addition of one reactant to the other varying from 0.5 hours up to 4 hours and the time of aging of the reaction mass being from 0.5 up to 4 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]([NH:11][C@H:12]([C:33]([OH:35])=[O:34])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:32])[N:22]([CH3:31])[C:23]([CH3:30])=[CH:24][C:25]=2[C:26]([F:29])([F:28])[F:27])=[CH:16][CH:15]=1)=[O:10].C(=O)(O)[O-].[Na+].[C:41]([O:44][CH:45](Cl)[CH3:46])(=[O:43])[CH3:42].O>CN(C=O)C>[C:41]([O:44][CH:45]([O:34][C:33](=[O:35])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:32])[N:22]([CH3:31])[C:23]([CH3:30])=[CH:24][C:25]=2[C:26]([F:28])([F:29])[F:27])=[CH:18][CH:19]=1)[NH:11][C:9]([C:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[O:10])[CH3:46])(=[O:43])[CH3:42]
Reactant: CC(=O)OC(C)Cl
Reactant: Cc1cc(C(F)(F)F)c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)O)cc2)c(=O)n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OC(C)OC(=O)[C@H](Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.2 %

Procedure:
To a suspension of N-[(2,6-dichlorophenyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine (145 mg, 0.275 mmol) and sodium bicarbonate (185 mg, 2.2 mmol) in DMF (2 mL) was added 1-chloroethyl acetate (270 mg, 2.2 mmol) at room temperature. The mixture was stirred for 48 h at room temperature. Then, the reaction mixture was poured into water (30 mL) and was extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with brine solution (60 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave the crude product, which was purified by silica gel chromatography using a Biotage (40s) column to afford 110 mg (65% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine 1-(acetoxy)ethyl ester as an amorphous white solid. ES-HRMS m/e calcd for C28H25Cl2F3N2O6 (M+Na) 635.0931, found 635.0932.
Reaction SMILES: Cl.[CH:2]1([CH2:5][NH:6][C:7](=[O:15])[CH:8]=[C:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:4][CH2:3]1.[F:16][C:17]1[CH:31]=[CH:30][C:20]([CH:21](Cl)[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH:21]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[N:12]2[CH2:13][CH2:14][C:9](=[CH:8][C:7]([NH:6][CH2:5][CH:2]3[CH2:4][CH2:3]3)=[O:15])[CH2:10][CH2:11]2)=[CH:30][CH:31]=1
Reactant: Fc1ccc(C(Cl)c2ccc(F)cc2)cc1
Reactant: O=C(C=C1CCNCC1)NCC1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(C=C1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)NCC1CC1
Yield: 77.8 %

Procedure:
A mixture of N-(cyclopropylmethyl)-2-(piperidin-4-ylidene)acetamide hydrochloride (80.0 mg, 0.347 mmol) prepared in EXAMPLE 22e, 4,4′-difluorobenzhydryl chloride (0.105 ml, 0.555 mmol), K2CO3 (105 mg, 0.763 mmol) and KI (5.8 mg, 0.035 mmol) in acetonitrile (5 ml) was stirred under reflux for 12 hours. The reaction was quenched with H2O (20 ml), extracted with chloroform (30 ml×2), dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexane:30/70 to 50/50) to give 2-(1-(bis(4-fluorophenyl)methyl)piperidin-4-ylidene)-N-(cyclopropylmethyl)acetamide (107 mg, 78%) as a white solid: LCMS: 397 {M+1}+. 1H NMR (DMSO-d6)□ δ: 0.11 (m, 2H), 0.38 (m, 2H), 0.87 (m, 1H), 2.22 (m, 2H), 2.32 (m, 2H), 2.36 (m, 2H), 2.93 (m, 4H), 4.47 (s, 1H), 5.61 (s, 1H), 7.13 (m, 4H), 7.43 (m, 4H), 7.87 (t, 1H).
Reaction SMILES: [C:1]([CH2:9][C:10]([CH3:12])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:15](OC)[N:16](C)[CH3:17]>>[CH3:15][N:16]([CH3:17])[C:9]([CH:10]=[CH2:12])=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)CC(=O)c1ccccc1
Product: C=CC(=Cc1ccccc1)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A mixture of 1-benzoylacetone (24.00 g, 0.15 mole) and dimethylformamide dimethylacetal were stirred overnight at room temperature under argon. The resulting reddish-colored mixture was concentrated on the rotary evaporator, then dissolved in THF (tetrahydrofuran). The resulting solution was stirred and heated to boiling and slowly diluted with hexane. At the point of turbidity heating was discontinued. An orange gum precipitated and rapidly solidified. The mixture was chilled in an ice bath and filtered yielding 25.25 g (78%) of 2-(dimethyl-amino)-1-phenyl-1,3-butanediene m.pt. 72°-74° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17](Br)[CH:18]=[C:13]3[C:12]([C:20]3[CH:24]=[CH:23][O:22][CH:21]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Sn](CCCC)(CCCC)[C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)CCC.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C1(C)C=CC=CC=1.Cl[Pd]Cl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)[CH:18]=[C:13]3[C:12]([C:20]3[CH:24]=[CH:23][O:22][CH:21]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccoc2)c2cc(Br)cnc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: Cl[Pd]Cl
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)n1cc(-c2ccoc2)c2cc(-c3cccs3)cnc21
Yield: 78 %

Procedure:
A mixture of bromide 30 (40.3 mg, 0.1 mmol), tributylthiophen-2-yl-stannane (62 μL, ca 0.2 mmol), PdCl2.(MeCN)2 (3.6 mg, 0.014 mmol), and tri-o-tolyl-phosphane (6.6 mg, 0.022 mmol) in toluene (0.9 mL) was stirred under N2 for 2 h. The reaction mixture was cooled and separated by PTLC with CH2Cl2 as eluent to afford 33 (31.7 mg, 78%) as yellowish solid. 1H NMR (400 MHz; CDCl3) δ 6.71 (dd, J=2.0, 1.0 Hz, 1H), 7.12 (dd, J=5.1, 3.6 Hz, 1H), 7.32 (dd, J=3.6, 1.2 Hz, 1H), 7.35 (dd, J=5.1, 1.2 Hz, 1H), 7.48-7.63 (m, 4H), 7.82 (m, 1H), 7.84 (s, 1H), 8.09 (d, J=2.2 Hz, 1H), 8.22-8.26 (m, 2H), 8.73 (d, J=2.2 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH:3]([C:5]1[C:14]2[C:9](=[C:10]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([CH3:24])[CH:6]=1)[OH:4].[CH3:27][N:28]=[C:29]=[O:30].C(N(CC)CC)C>ClCCl>[F:26][C:2]([F:1])([F:25])[CH:3]([O:4][C:29](=[O:30])[NH:28][CH3:27])[C:5]1[C:14]2[C:9](=[C:10]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([CH3:24])[CH:6]=1
Reactant: Cc1cc(C)c(-c2cccc3c(C(O)C(F)(F)F)cc(C)nc23)c(C)c1
Reactant: CN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)OC(c1cc(C)nc2c(-c3c(C)cc(C)cc3C)cccc12)C(F)(F)F

Procedure:
A mixture of 2,2,2-trifluoro-1-[2-methyl-8-(2,4,6-trimethyl-phenyl)quinolin-4-yl]-ethanol (50 mg), methyl isocyanate (0.5 ml), triethylamine (0.1 ml) in dichloromethane (2 ml) was heated at reflux for 2 hrs. The mixture was quenched with water and extracted with chloroform. The organic layer was separated, dried and concentrated to give the crude material which was purified by silica gel column chromatography using chloroform as eluent to give the title compound as a white solid.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([O:14][CH3:15])[CH:5]=1)[NH2:3].CO[CH:18](OC)[CH2:19][C:20](=O)[CH3:21]>Cl.O.CO>[CH3:15][O:14][C:6]1[CH:5]=[C:4]([N:2]2[CH:18]=[CH:19][C:20]([CH3:21])=[N:3]2)[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(CC(C)=O)OC
Reactant: COC(=O)c1ccc(NN)cc1OC
Agent: Cl
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(-n2ccc(C)n2)cc1OC
Temperature: 90 °C
Yield: 53.7 %

Procedure:
To a stirred solution of 4-hydrazino-2-methoxybenzoic acid, methyl ester hydrochloride (0.88 g) from Example 104 and one drop of concentrated hydrochloric acid in a 1:1 water/methanol (10 ml) mixture was added acetylacetaldehyde dimethylacetal (0.53 g). The reaction was heated to 90° C. for 5 minutes. The reaction was concentrated in vacuo and partitioned between 1 N sodium hydroxide (10 ml) and ethyl acetate (50 ml). The organic phase was removed and washed with brine, dried over anhydrous magnesium sulfate and filtered. Evaporation of the solvent in vacuo afforded a brown oil which was combined with a previous lot (0.54 g) and recrystallized three times from diisopropyl ether to give 2-methoxy4-(3-methyl-pyrazol-1-yl)-benzoic acid, methyl ester (0.5 g). m.p. 167-169° C., MS, m/z: 246 (M)+.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:27]=[CH:28][C:29]([O:41][CH3:42])=[C:30]([S:32]([NH:35][C:36]([CH3:40])([CH3:39])[CH2:37][OH:38])(=[O:34])=[O:33])[CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:27]=[CH:28][C:29]([O:41][CH3:42])=[C:30]([S:32]([NH:35][C:36]([CH3:39])([CH3:40])[CH2:37][OH:38])(=[O:34])=[O:33])[CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: COc1ccc(Br)cc1S(=O)(=O)NC(C)(C)CO
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: COc1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1S(=O)(=O)NC(C)(C)CO

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2)(337 mg, 1.0 mmol) and 5-Bromo-N-(2-hydroxy-1,1-dimethyl-ethyl)-2-methoxy-benzenesulfonamide (example B.7) (440 mg, 1.3 mmol) according to general procedure II. Obtained as a yellow solid (135 mg, 23%). MS (ISP) 595.3[(M+H)+]; mp 178-180° C.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH2:9]([S-:11])[CH3:10].[Na+]>CN(C=O)C.O>[CH2:9]([S:11][CH:3]([CH3:4])[CH2:2][C:1]([O:6][CH2:7][CH3:8])=[O:5])[CH3:10]
Reactant: C/C=C/C(=O)OCC
Reactant: CC[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(C)SCC
Temperature: 25 °C
Yield: 14 %

Procedure:
Ethyl crotonate (commercially available, for example, from Aldrich) (2.37 g, 20.8 mmol) was dissolved in DMF (60 ml) and stirred at room temperature. Sodium ethanethiolate (commercially available, for example, from Aldrich) (1.66 g, 19.7 mmol) was added portionwise. On completion of the addition, the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with EtOAc (×3). The combined organic solutions were dried (MgSO4), and concentrated in vacuo, for an extensive period of time to remove excess DMF. The residue was applied to a silica cartridge (50 g), eluting with a gradient of EtOAc-cyclohexane (2%-6%) to give the title compound as a colourless oil (527 mg, 14%): 1H NMR δ (CDCl3) 4.16 (2H, q, J=9 Hz), 3.28-3.18 (1H, m), 2.66-2.55 (3H, m), 2.44 (1H, dd, J=15, 8 Hz), 1.33 (3H, d, J=7 Hz), 1.31-1.23 (6H, m).
Reaction SMILES: [CH3:1][N:2]([CH2:26][C:27]1[O:28][C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=2[C:31]=1[CH3:32])[C:3](=[O:25])/[CH:4]=[CH:5]/[C:6]1[CH:24]=[N:23][C:9]2[NH:10][CH2:11][CH2:12][CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][C:8]=2[CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:10]1[CH2:11][CH2:12][CH2:13][NH:14][CH2:15][C:8]2[CH:7]=[C:6](/[CH:5]=[CH:4]/[C:3]([N:2]([CH3:1])[CH2:26][C:27]3[O:28][C:29]4[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=4[C:31]=3[CH3:32])=[O:25])[CH:24]=[N:23][C:9]1=2
Reactant: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(C(=O)OC(C)(C)C)CCCN3)oc2ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CNCCCN3)oc2ccccc12
Reaction time: 1.5 h

Procedure:
(E)-tert-butyl 8-(3-(methyl((3-methylbenzofuran-2-yl)methyl)amino)-3-oxoprop-1-enyl)-1,2,3,4-tetrahydropyrido[2,3-b][1,5]diazocine-5(6H)-carboxylate (49 mg, 0.1 mmol) was dissolved in 5 mL of DCM followed by the addition of trifluoroacetic acid (5 mL). The solution was stirred for 1.5 h, then concentrated in vacuo, and subjected to prep HPLC purification to obtain the product as a white solid. Yield 25 mg (64%); 1H NMR (400 MHz, CDCl3) δ 10.1 (bs, 1H), 8.01 (m, 2H), 7.50-7.22 (m, 6H), 6.86 (d, J=16.0 Hz, 1H), 4.79 (s, 2H), 4.66 (s, 2H), 3.88 (s, 2H), 3.25 (s, 2H), 3.10 (s, 3H), 2.29 (bs, 5H); ESI MS m/z 391 [C23H26N4O2+H]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](I)[CH:7]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(O)CO>C(O)(C)C.[Cu]I>[Br:1][C:2]1[CH:7]=[C:6]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)[CH:5]=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1cncc(I)c1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: CC(C)(C)OC(=O)N1CCN(c2cncc(Br)c2)CC1
Temperature: 25 °C
Yield: 36.7 %

Procedure:
A solution of 3-bromo-5-iodopyridine (13.0 g, 45.8 mmol), tert-butyl piperazine-1-carboxylate (8.53 g, 45.8 mmol), copper(I) iodide (0.871 g, 4.57 mmol), K3PO4 (19.46 g, 91.68 mmol), 1,2-ethanediol (5.1 mL, 91 mmol) in isopropyl alcohol (80 mL) in a sealed tube was heated at 80° C. in an oil bath for 2 days. After cooling to room temperature, the reaction mixture was filtered through celite. The filtrate was concentrated in vacuo. The residue was taken up in EtOAc and the solution was washed with saturated NaHCO3, dried (MgSO4) and concentrated. Purification by flash chromatography on silica gel (20% EtOAc/hexanes to 30% EtOAc/hexanes) afforded 5.75 g (37%) of desired product. MS calculated for C14H20BrN3O2: (M+H) 343; found 342.0, 344.0.
Reaction SMILES: [CH:1]([CH:3]([O:6][CH:7]([N:10]1[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]1=[O:17])[CH:8]=[O:9])[CH2:4][OH:5])=[O:2].[NH2:18][C:19]1[CH:23]=[CH:22][NH:21][N:20]=1>O>[OH:9][CH:8]1[C@H:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]2=[O:17])[O:6][C@H:3]([CH2:4][OH:5])[CH:1]([OH:2])[N:18]1[C:19]1[CH:23]=[CH:22][NH:21][N:20]=1
Reactant: O=CC(CO)OC(C=O)n1ccc(=O)[nH]c1=O
Reactant: Nc1cc[nH]n1
Solvent: O
Product: O=c1ccn([C@@H]2O[C@H](CO)C(O)N(c3cc[nH]n3)C2O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.8 %

Procedure:
[R-(R*, R*)]-α-(1-Formyl-2-hydroxyethoxy)-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidineacetaldehyde, (uridinedialdehyde), (2.4 g) was dissolved in water (10 ml). To the solution was added 3-aminopyrazole (0.83 g). The mixture was stirred at ambient temperature overnight. The precipitates were filtered and air-dried to give 1-[(2R, 6R)-3,5-dihydroxy-6-hydroxymethyl-4-(3-pyrazolyl)morpholin-2-yl]uracil (1.25 g).
Reaction SMILES: [C:1]([C:4]([CH2:21][C:22]#[C:23][CH:24]([O:30]C(=O)C)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])C(OCC)=O)(=[O:3])[CH3:2].[OH-].[Na+]>O.CO>[C:1]([CH:4]([CH2:21][C:22]#[C:23][CH:24]([OH:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])(=[O:3])[CH3:2]
Reactant: CCCCCC(C#CCC(CCCCCCC(=O)OCC)(C(C)=O)C(=O)OCC)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCC(O)C#CCC(CCCCCCC(=O)O)C(C)=O
Yield: 36.1 %

Procedure:
A solution of diethyl 2-acetyl-2-(4-acetoxy-2-nonyn-1-yl)azelate (59.7 g., 0.128 mole) and sodium hydroxide (30 g., 0.75 mole) in water (200 ml.) and methanol (800 ml.) is heated at 60° for 16 hours. Most of the methanol is then distilled at reduced pressure and the residue is dissolved in water. The solution is acidified to Congo Red with hydrochloric acid and the oily product taken up in ether and dried over sodium sulfate. Evaporation of the ether leaves 41.1 g. of the crude product as a redish viscous oil. The product is purified by chromatography on 650 g. of silica gel with 2% methanol in chloroform as eluant. Fifteen grams of pure 8-acetyl-12-hydroxy-10-heptadecynoic acid is obtained as a yellow viscous oil; pmr (CDCl3) δ 0.90 (3H,t), 2.20 (3H,s CH3CO), 4.37 (1H,t HCO).