Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[F:10][C:11]1[N:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:10][C:11]1[N:16]=[CH:15][C:14]([N:4]2[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]2=[O:7])=[CH:13][CH:12]=1
Reactant: CC1(C)NC(=O)NC1=O
Reactant: OB(O)c1ccc(F)nc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)NC(=O)N(c2ccc(F)nc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
Two reactions were set up in parallel. For each of them, to a solution of 5,5-dimethyl-2,4-imidazolidinedione (1.5 g, 11.71 mmol) in dry dichloromethane (100 mL), (6-fluoro-3-pyridinyl)boronic acid (1.980 g, 14.05 mmol), copper(II) acetate (2.126 g, 11.71 mmol) and pyridine (1.420 mL, 17.56 mmol) were added. The reaction was left under stirring under air atmosphere at room temperature overnight. The two reaction mixtures were combined and the solid was filtered off. The resulting solution was washed with water (90 mL). The aqueous phase was extracted twice with dichloromethane (twice 90 mL). The organic phases were combined and washed with brine and dried over anhydrous sodium sulphate. Removal of the solvent afforded a residue which was purified by silica gel chromatography (Biotage system, 100 g SNAP column) using as eluent a gradient and cyclohexane/ethyl acetate from 65/35 to 50/50 to afford the title compound as a white solid (1.27 g).
Reaction SMILES: [CH2:1]([C:3]([CH2:16]C)([CH3:15])[CH2:4][C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11](Br)=[CH:10][C:8]=2[N:9]=1)C.[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[CH:19]=[CH2:20].C(N(CC)C(C)C)(C)C>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:16][C:3]([CH3:1])([CH3:15])[CH2:4][C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([CH:20]=[CH:19][C:18]([O:22][CH2:23][CH3:24])=[O:21])=[CH:10][C:8]=2[N:9]=1
Reactant: C=CC(=O)OCC
Reactant: CCC(C)(CC)Cc1nc2cc(Br)ccc2o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C=Cc1ccc2oc(CC(C)(C)C)nc2c1
Temperature: 100 °C
Yield: 98.1 %

Procedure:
A mixture of 2-(2,2-diethylpropyl)-5-bromobenzoxazole (0.60 g, 0.00225 mol), ethyl acrylate (1.08 g, 0.0108 mol), palladium acetate (0.051 g, 0.00023 mol), trintolylphosphine (0.135 g,0.0045 mol) and N,N-diisopropylethylamine (0.585 g, 0.0045 mol) was heated at 100° C. for 6 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic extracts were dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate:dichloromethane 3:97, to give ethyl 3-[2-(2,2-dimethylpropyl)benzoxazol-5-yl]propenoate (0.634 g).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[N:4]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[N:3]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:47]([O:51][CH2:52][CH2:53][OH:54])([CH3:50])([CH3:49])[CH3:48].[F-].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:47]([O:51][CH2:52][CH2:53][O:54][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[N:4]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[N:3]=1)([CH3:50])([CH3:49])[CH3:48]
Reactant: COc1ccc(Cn2nc(I)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)ccnc32)cc1
Reactant: CC(C)(C)OCCO
Agent: [F-]
Agent: [K+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2nc(OCCOC(C)(C)C)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)ccnc32)cc1
Temperature: 25 °C
Yield: 68 %

Procedure:
tert-Butyl 4-(3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.12 g, 0.218 mmol), Cu(I)I (0.0416 g, 0.218 mmol), 1,10-phenanthroline (0.0394 g, 0.218 mmol), 2-tert-butoxyethanol (0.774 g, 6.55 mmol) and KF on Al2O3 (40%; 0.222 g, 1.53 mmol) in toluene (4 mL) were stirred at 120° C. for 40 hours. The reaction was then cooled to room temperature. Ethyl acetate (10 mL) was then added. The reaction was filtered through a pad of celite and concentrated to dryness. The resulting residue was purified by chromatography (hexane:ethyl acetate, 3:1) to give tert-butyl 4-(3-(2-tert-butoxyethoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.080 g, 68%) as a solid. MS APCI (+) m/z 540.5 detected.
Reaction SMILES: C([O:8][C:9]1[CH:29]=[CH:28][C:12]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[C:11]([CH:30]=[CH2:31])[CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH2:30]([C:11]1[CH:10]=[C:9]([OH:8])[CH:29]=[CH:28][C:12]=1[O:13][CH2:14][CH2:15][C:16]1[N:17]=[C:18]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:19][C:20]=1[CH3:21])[CH3:31]
Reactant: C=Cc1cc(OCc2ccccc2)ccc1OCCc1nc(-c2ccccc2)oc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCc1cc(O)ccc1OCCc1nc(-c2ccccc2)oc1C
Yield: 63.6 %

Procedure:
A solution of 4-[2-(4-benzyloxy-2-vinylphenoxy)ethyl]-5-methyl-2-phenyloxazole (1.30 g, 3.16 mmol) in ethanol (100 mL) was treated with 5% Pd/C (160 mg) and hydrogen (60 psi) at ambient temperature for 18 h. The mixture was filtered and concentrated in vacuo to give a tan solid (0.65 g, 64%): 1H NMR (400 MHz, CDCl3) δ 7.99 (dd, J=8.3 Hz, 2.0 Hz, 2H), 7.45-7.38 (m, 3H), 6.63 (d, J=2.4 Hz, 1H), 6.50-6.41 (m, 2H), 5.98 (br s, 1H), 4.10 (t, J=6.4 Hz, 2H), 2.95 (t, J=6.4 Hz, 2H), 2.85-2.51 (m, 2H), 2.39 (s, 3H), 1.08 (t, J=7 Hz, 3H); HRMS: Calc'd=324.1599; Found=324.1597.
Reaction SMILES: C[Li].C[Si](Cl)(C)C.[C:8]1(=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])/[CH2:9][CH2:10][C:11]2[C:16]/1=[CH:15][CH:14]=[CH:13][CH:12]=2.[CH2:23]1C2C(=CC=CC=2)C(CC(OCC)=O)=C1>C(OCC)C.C(Cl)Cl.[Cu](I)I>[CH3:23][C:8]1([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1
Reactant: CCOC(=O)CC1=CCc2ccccc21
Reactant: CCOC(=O)/C=C1\CCc2ccccc21
Agent: I[Cu]I
Agent: C[Si](C)(C)Cl
Agent: [Li]C
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)CC1(C)CCc2ccccc21
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a suspension of copper iodide (1.9 g, 9.9 mmol) in diethyl ether (10 mL) was added methyl lithium (12.4 mL, 19.8 mmol, 1.6M in diethyl ether) at 0° C. and the mixture was stirred for 10 min. The solvent was removed under reduced pressure at 0° C. and then CH2Cl2 (10 mL) was added. The reaction mixture was stirred for 5 minutes at 0° C., and then the solvent was removed again under reduced pressure at 0° C. To the residue was added pre-cooled CH2Cl2 (75 mL), cooled to −78° C., and then added trimethylsilyl chloride (1.3 mL, 9.9 mmol) and a solution of a mixture of (E)-ethyl 2-(2,3-dihydro-1H-inden-1-ylidene)acetate and ethyl 2-(1H-inden-3-yl)acetate (1:1 mixture, 1 g, 4.9 mmol) in CH2Cl2 (10 mL), successively. The resulted mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched by addition of a mixture of aqueous saturated NH4Cl and 28% NH4OH (1:1, 50 mL). The mixture was extracted with diethyl ether (3×50 mL) and the combined extracts were washed with water, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (Hexanes-EtOAc, 0 to 10%) to give 0.47 g of the title compound. Additionally, 0.17 g of unreacted ethyl 2-(1H-inden-3-yl)acetate was recovered. MS (DCI/NH3) m/z 236 (M+NH4)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[CH:15]([CH3:20])[C:16](=O)[CH2:17][CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([NH:24][NH2:25])[CH3:23]>C(#N)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:24]([CH2:22][CH3:23])[N:25]=[C:16]([CH2:17][CH3:18])[C:15]=2[CH3:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNN
Reactant: CCC(=O)C(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CC#N
Solvent: O
Product: CCc1nn(CC)c(C2CCN(C(=O)OC(C)(C)C)CC2)c1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 1-(tert-butoxycarbonyl)-4-(1,3-dioxo-2-(R/S)-methylpent-1-yl)piperidine (435 mg, 1.5 mmol) (from Step D) in 2:1 v/v acetonitrile/water (12 mL) was treated with ethylhydrazine (34% sol'n in water, 0.28 mL, 1.6 mmol) and the resulting mixture was stirred at rt for 20 h. The reaction mixture was partitioned between 75 mL of ether and 25 mL of sat'd sodium chloride and the layers were separated. The organic layer was dried over magnesium sulfate and concentrated. MPLC (Biotage) on a 40S silica cartridge using 4:1 v/v, then 1:1 v/v hexanes/ethyl acetate as the eluent afforded the title compound:
Reaction SMILES: [N:1]1[N:12]2[C:4]([N:5]=[C:6]3[C:10](=[C:11]2[C:13]2[CH:14]=[CH:15][C:16]4[O:20][C:19]([CH2:21][CH2:22]OS(C)(=O)=O)=[CH:18][C:17]=4[CH:28]=2)[CH2:9][CH2:8][CH2:7]3)=[CH:3][CH:2]=1.[CH3:29][CH:30]1[CH2:34][CH2:33][CH2:32][NH:31]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:29][CH:30]1[CH2:34][CH2:33][CH2:32][N:31]1[CH2:22][CH2:21][C:19]1[O:20][C:16]2[CH:15]=[CH:14][C:13]([C:11]3[N:12]4[C:4](=[CH:3][CH:2]=[N:1]4)[N:5]=[C:6]4[C:10]=3[CH2:9][CH2:8][CH2:7]4)=[CH:28][C:17]=2[CH:18]=1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3c4c(nc5ccnn35)CCC4)ccc2o1
Reactant: CC1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1CCCN1CCc1cc2cc(-c3c4c(nc5ccnn35)CCC4)ccc2o1
Temperature: 70 °C

Procedure:
Methanesulfonic acid 2-[5-(6,7-dihydro-5H-1,4,8a-triaza-s-indacen-8-yl)-benzo-furan-2-yl]-ethyl ester (0.085 mmol) was dissolved in acetonitrile (2 ml) followed by addition of 2-methylpyrrolidine (0.85 mmol) and potassium carbonate (0.425 mmol) and heated to 70° C. for 24 hours. The reaction was cooled, filtered and concentrated. The residue was purified via preparative HPLC to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[C:10]2[O:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2c1OCC2=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1COc2c(CBr)cccc21
Temperature: 25 °C
Yield: 44.8 %

Procedure:
A solution of 7-methylbenzofuran-3(2H)-one (0.759 g, 5.12 mol) in carbon tetrachloride (50 mL) was added with N-bromosuccinimide (1.00 g, 5.63 mmol) and benzoyl peroxide (0.0830 g, 0.256 mmol), and the mixture was refluxed for 4 hours by heating. The reaction mixture was cooled to room temperature, and then filtered, and the resulting filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 7-bromomethylbenzofuran-3(2H)-one (0.573 g, 49%).
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])[CH3:2].[CH2:14]([O:21][C:22]([C:24]1([CH2:30][N:31]2[CH2:36][CH2:35][C:34]([CH2:38][NH:39][C:40](=O)[O:41]C(C)(C)C)([F:37])[CH2:33][CH2:32]2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:22]([C:24]1([CH2:30][N:31]2[CH2:32][CH2:33][C:34]([CH2:38][NH:39][C:40]([N:6]3[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[N:4]([CH:1]([CH3:3])[CH3:2])[C:5]3=[O:13])=[O:41])([F:37])[CH2:35][CH2:36]2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)n1c(=O)[nH]c2ccccc21
Reactant: CC(C)(C)OC(=O)NCC1(F)CCN(CC2(C(=O)OCc3ccccc3)CCOCC2)CC1
Product: CC(C)n1c(=O)n(C(=O)NCC2(F)CCN(CC3(C(=O)OCc4ccccc4)CCOCC3)CC2)c2ccccc21

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one and tert-Butyl ({1-[(4-benzyloxycarbonyltetrahydro-2H-pyran-4-yl)methyl]-4-fluoropiperidin-4-yl}methyl)carbamate (step 5 of Example 15).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[CH3:16][O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>>[CH3:16][O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([C:13]1[S:12][C:11]([C:3]2[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:10])[F:9])[O:5][N:4]=2)=[CH:15][CH:14]=1)=[O:21]
Reactant: COc1ccccc1C(=O)Cl
Reactant: Cc1c(-c2cccs2)noc1C(F)(F)F
Product: COc1ccccc1C(=O)c1ccc(-c2noc(C(F)(F)F)c2C)s1
Yield: 54 %

Procedure:
Prepared from 4-Methyl-3-thiophen-2-yl-5-trifluoromethyl-isoxazole and 2-methoxybenzoyl chloride by the method described in Example 3. Crude product was chromatographed on silica gel with EtOAc/hexanes (15 then 25%) as eluant to afford product as a yellow-tinted oil (100 mg, 54%). 1H NMR (CDCl3) 2.39 (d, J=1.3, 3H), 3.82 (s, 3H), 7.01-7.08 (m, 2H), 7.27-7.54 (m, 4H). 13C NMR 8.0, 55.9, 111.9, 115.9 (q, J=151), 120.7, 128.2, 129.0, 129.6, 132.7, 135.0, 136.3, 147.1, 155.4 (q, J=41), 157.3, 158.0, 188.2. 19F NMR −63.1. LC/MS 7.50 min, [M+1]+ 368.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:5]=2[N:6]=1.[C:13]([O:16][CH2:17][C:18](Cl)=[O:19])(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:16][CH2:17][C:18]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:5]=2[N:6]=1)=[O:19])(=[O:15])[CH3:14]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1cc2nc(N)sc2cc1C
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)Nc1nc2cc(C)c(C)cc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Amino-5,6-dimethylbenzothiazole (4.5 g) is dissolved in pyridine (80 ml) and thereto is added dropwise acetoxyacetyl chloride (3.0 ml) at room temperature. After the mixture is stirred at room temperature for 2 hours, the solvent is distilled off. The resulting oil is solidified with addition of water. The obtained solids are filtered off and washed with water, then with diethyl ether, dried and recrystallized from ethanol to give the title compound (5.4 g) having the following physical properties.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[C:17](=O)([O-])[O-].[Na+].[Na+]>CO>[F:6][C:7]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:8]=1[C:9]([O:11][CH3:17])=[O:10]
Reactant: Cc1ccc(C(=O)O)c(F)c1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(C)cc1F
Yield: 75 %

Procedure:
Sulfuric acid (2 mL) was added to the solution of 2-fluoro-4-methylbenzoic acid (0.848 g; 5.34 mmol) in methanol (30 mL). The mixture was refluxed for 24 hours. After cooling, the solution was made alkaline by addition of an aqueous solution of sodium carbonate, concentrated under reduced pressure in order to remove methanol, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and was concentrated under reduced pressure to give 0.672 g (75%) of methyl 2-fluoro-4-methylbenzoate as a solid.
Reaction SMILES: [N:1]1[C:2]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.S(Cl)(Cl)=O.[CH3:19]O>>[N:1]1[C:2]([CH2:10][CH2:11][C:12]([O:14][CH3:19])=[O:13])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CO
Reactant: O=C(O)CCc1cn2ccccc2n1
Solvent: O=S(Cl)Cl
Product: COC(=O)CCc1cn2ccccc2n1
Temperature: 60 °C
Reaction time: 3.5 h

Procedure:
To a solution of 3-imidazo[1,2-a]pyridin-2-ylpropanoic acid (472 mg) in methanol (24.8 mL) was added thionyl chloride (0.215 mL), and the mixture was stirred at 60° C. for 3.5 hr. To the reaction mixture was added, under ice-cooling, saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (402 mg).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([CH2:15][CH3:16])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[Pd+2].[OH-]>[CH2:15]([CH:10]1[CH:11]([OH:14])[CH2:12][CH2:13][NH:8][CH2:9]1)[CH3:16]
Reactant: [H][H]
Reactant: CCC1CN(Cc2ccccc2)CCC1O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCC1CNCCC1O

Procedure:
A mixture of 1-benzyl-3-ethyl-4-hydroxypiperidine (5.0 g, 22.0 mmole) and palladium hydroxide (1.5 g) in methanol (100 ml) was stirred at 5.0 g, 22.0 mmole) and palladium hydroxide (1.5 g) in methanol (100 ml) was stirred at 50-55° C. in hydrogen atmosphere (1 atm.) for 20 hr. The catalyst was filtered off, washed with methanol, and filtrate was concentrated to dryness to give 3-ethyl-4-hydroxypiperidine as oil. Yield 2.9 g (94%), C7H15NO, m/z 130 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[O:25]([CH2:24][CH2:23][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCCOc1ccccc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CCOc3ccccc3)CC1)O2

Procedure:
Compound 140 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2-bromoethoxy)benzene and conditions outlined in procedure V. LCMS: 422 [M+H]; Rt=1.01 min.
Reaction SMILES: [CH2:1]([O:3][CH:4]=[CH:5][C:6]#[N:7])[CH3:2].C([Li])CCC.[C:13]1([CH2:23][CH2:24][CH2:25]I)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.C(Cl)Cl>O1CCCC1>[CH2:1]([O:3][CH:4]=[C:5]([C:6]#[N:7])[CH2:25][CH2:24][CH2:23][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[CH3:2]
Reactant: ICCCc1cccc2ccccc12
Reactant: CCOC=CC#N
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC=C(C#N)CCCc1cccc2ccccc12
Temperature: 25 °C
Yield: 26.9 %

Procedure:
Under a nitrogen atmosphere a stirred solution of 1.5 mL (0.014 mole) of 3-ethoxyacrylonitrile in 45 mL of tetrahydrofuran was cooled to about -110° C., and 6.2 mL (0.015 mole) of 2.5M n-butyllithium in hexanes was added dropwise at a rate to keep the reaction mixture temperature below -65° C. Upon completion of addition, the reaction mixture was stirred for about ten minutes, and then a solution of 4.0 grams (0.014 mole) of 3-(naphth-1-yl)propyl iodide in 15 mL of tetrahydrofuran was added dropwise. Upon completion of addition, the reaction mixture was stirred at about -78° C. for two hours. After this time the reaction mixture was allowed to warm to ambient temperature as it stirred for about 16 hours. The reaction mixture was concentrated under reduced pressure, yielding a dark residual oil. The oil was passed through a short column of silica gel using methylene chloride as the eluant. The eluate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished using 2:1 methylene chloride and petroleum ether. The appropriate fractions were combined and concentrated under reduced pressure, yielding 1.0 gram of 1-ethoxy-2-cyano-5-(naphth-1-yl)-1-pentene. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: CC(C)([O-])C.[Na+].[Br:7][CH:8]([Cl:13])[C:9]([F:12])([F:11])[F:10].[CH3:14][CH:15]([CH3:19])[CH:16]=[C:17]=[O:18].O1CCCC1>CN(C)C=O>[Br:7][C:8]([Cl:13])([C:9]([F:12])([F:11])[F:10])[CH:17]([OH:18])[CH:16]=[C:15]([CH3:19])[CH3:14]
Reactant: FC(F)(F)C(Cl)Br
Reactant: CC(C)C=C=O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)=CC(O)C(Cl)(Br)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
Sodium t-butoxide (1.39 g of a 42% solution in dry dimethyl formamide was added dropwise over a period of 5 minutes to a stirred mixture of 1-bromo-1-chloro-2,2,2-trifluoroethane (0.535 ml), 3-methylbut-1-en-1-al (0.538 ml) and dry tetrahydrofuran (10 ml) maintained at a temperature of -78° C. by external cooling under a nitrogen atmosphere. The mixture was then stirred for a further 40 minutes at the temperature after which the external cooling was removed and the reaction quenched by the dropwise addition of saturated aqueous ammonium chloride solution. The mixture was then partitioned between water and diisopropyl ether and the aqueous phase separated, washed with diisopropyl ether (3×25ml), and the washings combined with the organic phase. The organic phase was washed with brine and dried over anhydrous sodium sulphate and concentrated by evaporation under reduced pressure. After purification by a procedure similar to that set out in the previous Example there was obtained 5-bromo-5-chloro-4-hydroxy-2-methyl-6,6,6-trifluorohex-2-ene (1.39 g), identified by nuclear magnetic resonance and infra-red spectroscopy.
Reaction SMILES: [CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22](I)=[CH:21][C:20]=3[CH3:26])=[C:16]([F:27])[C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH:10]=2)=[O:8])[CH2:3][CH2:2]1.[C:28]([Si:30]([CH3:33])([CH3:32])[CH3:31])#[CH:29]>C(#N)C.C(N(CC)CC)C.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>[CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:29]#[C:28][Si:30]([CH3:33])([CH3:32])[CH3:31])=[CH:21][C:20]=3[CH3:26])=[C:16]([F:27])[C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: Cc1cc(I)ccc1Nc1c(C(=O)NOCC2CC2)cc2[nH]cnc2c1F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(C#C[Si](C)(C)C)ccc1Nc1c(C(=O)NOCC2CC2)cc2[nH]cnc2c1F
Temperature: 60 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-3H-benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide 11ccc (0.025 g, 0.052 mmol) is dissolved in 1:1 acetonitrile/triethylamine (0.50 mL). Ethynyl-trimethylsilane (0.013 mL, 0.092 mmol), Pd(PPh3)2Cl2 (0.004 g, 0.006 mmol), and CuI (0.002 g, 0.011 mmol) are added consecutively and the reaction mixture is stirred at 60° C. for 1 hour under N2. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue is purified by FCC (eluting with 20:1 methylene chloride:methanol) to yield 0.020 g (87%) of the desired product.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9]C)=O)(=O)[CH2:2][CH2:3][CH3:4].C(O)(=O)C.[NH2:15][NH2:16]>C(O)C>[CH2:2]([C:1]1[CH2:6][C:7](=[O:9])[NH:16][N:15]=1)[CH2:3][CH3:4]
Reactant: CCCC(=O)CC(=O)OC
Reactant: NN
Solvent: CCO
Solvent: CC(=O)O
Product: CCCC1=NNC(=O)C1
Reaction time: 2 h

Procedure:
Methyl butyrylacetate (4 g, 27.7 mmol) was stirred in ethanol and acetic acid (10:1, 8:0.8 mL) and treated with hydrazine (1.05 mL, 33.3 mmol). After 2 hrs, the resulting solid was filtered off and washed with a minimum amount of acetonitrile to yield 3-propyl-1H-pyrazol-5(4H)-one. Then, the 3-propyl-1H-pyrazol-5(4H)-one (4.68 g, 11.8 mmol) and 4-chloroquinoline N-oxide (1.5 g, 11.8 mmol) were stirred in acetic anhydride (20 mL) at ambient temperature for 30-40 minutes. The reaction mixture was concentrated, and the resulting solid filtered off, washed with a minimum amount of methanol, and treated with hydrazine (0.84 mL, 26.7 mmol) in methanol (12 mL) to yield Example 23 as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.97 (t, J=7.33 Hz, 3H) 1.66-1.76 (m, 2H) 3.02 (t, J=7.07 Hz, 2H) 7.62 (t, J=7.58 Hz, 1H) 7.80 (t, J=7.71 Hz, 1H) 7.93 (d, J=8.34 Hz, 1H) 8.10 (d, J=8.34 Hz, 2H); ESI-MS: m/z calc'd for C15H14ClN3O 287.74. found 288.2 (M+H)+.