Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][C:5]([CH3:17])([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[C:4]1=[O:18])[CH3:2].C(O)C.[H][H]>[Pd].CCCCCC.CCOC(C)=O>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2([CH3:17])[CH2:6][CH2:7][N:3]([CH2:1][CH3:2])[C:4]2=[O:18])=[CH:9][CH:10]=1
Reactant: [H][H]
Reactant: CCN1CCC(C)(c2ccc([N+](=O)[O-])cc2)C1=O
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCN1CCC(C)(c2ccc(N)cc2)C1=O

Procedure:
A mixture of 770 mg (3.1 mmol) (±)-1-ethyl-3-methyl-3-(4-nitrophenyl)pyrrolidin-2-one, 50 mg of 10% palladium on carbon, and 50 mL of absolute ethanol was shaken with hydrogen (initial hydrogen pressure 46 psig) in a pressure vessel for 2.5 hours. The catalyst was removed by filtration through Celite under nitrogen, and the filter cake was washed with additional ethanol. Concentration of the filtrate in vacuo gave 684 mg (quantitative) of an extremely pale pink oil; essentially homogeneous by TLC in 1:1 hexane-EtOAc. 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (PB-NH3/CI): m/e=219.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:30])[CH3:29])[C:23]=1[N:31]=[C:32]=[O:33])([CH3:21])[CH3:20]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]([C:10]2[CH:11]=[CH:12][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:14][CH:15]=2)[C:32]([NH:31][C:23]2[C:22]([CH:19]([CH3:20])[CH3:21])=[CH:27][CH:26]=[CH:25][C:24]=2[CH:28]([CH3:30])[CH3:29])=[O:33])=[CH:6][CH:7]=1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CC(C)c1ccc(NCc2ccc(Br)cc2)cc1
Product: CC(C)c1ccc(N(Cc2ccc(Br)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 26.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using [(4-bromophenyl)methyl](4-isopropylphenyl)amine (2.7 g) and 2,6-diisopropylphenyl isocyanate (2.1 g) as starting materials, N-[(4-bromophenyl)methyl]-N′-(2,6-diisopropylphenyl)-N-(4-isopropylphenyl)urea (1.2 g) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1OCC[N:14]=1.O.[ClH:16]>>[ClH:16].[OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][NH2:14])=[CH:4][CH:3]=1
Reactant: Oc1ccc(S)cc1
Reactant: CC1=NCCO1
Agent: Cl
Solvent: O
Product: NCCSc1ccc(O)cc1
Yield: 11 %

Procedure:
A mixture of 4-hydroxythiophenol (2.48 g, 19.7 mmol) and 2-methyl-2-oxazoline (1.67 g, 1.69 mL, 19.7 mmol) were refluxed (neat) under argon for two hours. Upon cooling, the crude sticky solid was re-suspended in concentrated hydrochloric acid (aq) and refluxed for 12 hours. The mixture was then poured into water (20 mL) and extracted with diethyl ether (2×20 mL). The aqueous liquors were concentrated to dryness and twice re-dissolved in water and re-concentrated. Re-crystallisation of the resultant solid (ethanolidiethyl ether) gave the product as a cream solid (0.45 g, 11%); m.p. 130–31 ° C. (lit.11 128–29° C.); 1H (400 MHz, D2O) δ 3.07 (4H, br s, 2×CH2), 6.87 (2H, d, J 11.9 Hz, Ar), 7.41 (2H, d, J 11.9 Hz, Ar)
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:18])[C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])[CH:5]=[CH:4][N:3]=1.[O:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH:29]=[C:28]([NH2:30])[CH:27]=[N:26]2)[CH2:21][CH2:20]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>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].O1CCOCC1>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=1[C:9]([NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:30][C:28]2[CH:27]=[N:26][N:25]([CH:22]3[CH2:23][CH2:24][O:19][CH2:20][CH2:21]3)[CH:29]=2)[CH:7]=1)=[O:18]
Reactant: Nc1cnn(C2CCOCC2)c1
Reactant: O=C(Nc1ccnc(Br)c1)c1c(Cl)cccc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C(Nc1ccnc(Nc2cnn(C3CCOCC3)c2)c1)c1c(Cl)cccc1Cl
Temperature: 25 °C
Yield: 25.1 %

Procedure:
To a microwave tube was added N-(2-bromopyridin-4-yl)-2,6-dichlorobenzamide (0.083 g, 0.24 mmol), 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine (0.048 g, 0.29 mmol), Pd2(dba)3 (0.022 g, 0.024 mmol), XantPhos (0.028 g, 0.048 mmol), Cs2CO3 (0.16 g, 0.48 mmol) and dioxane (2 mL). The mixture was degassed with N2 for 10 min. The resulting mixture was irradiated in a microwave reactor at 140° C. for 3 hours and then cooled to room temperature. The mixture was filtered through Celite and concentrated under reduced pressure. The residue was dissolved in DMF and purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to give the desired product as a white solid (26 mg, yield: 25%). 1H NMR (500 MHz, d6-DMSO): δ 10.87 (s, 1H), 8.83 (s, 1H), 8.02 (d, J=5.5 Hz, 1H), 7.97 (s, 1H), 7.60 (d, J=3.0 Hz, 2H), 7.53 (t, J=3 Hz, 1H), 7.43 (s, 1H), 7.24 (s, 1H), 6.77 (d, J=5.0 Hz, 1H), 4.34 (m, 1H), 3.98-3.94 (m, 2H), 3.49-3.45 (m, 2H), 1.95-1.91 (m, 4H). LCMS (ESI) m/z: 432.0 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:24])[N:12]([CH2:20][C:21]([NH2:23])=O)[C:13]([CH:17]([CH3:19])[CH3:18])=[N:14]2)=[CH:9][CH:8]=1.C(=O)([O-])O.[Na+]>CN(C)C=O.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:24])[N:12]([CH2:20][C:21]#[N:23])[C:13]([CH:17]([CH3:19])[CH3:18])=[N:14]2)=[CH:9][CH:8]=1
Reactant: CC(C)c1nc2cc(OCc3cccc(F)c3)ccc2c(=O)n1CC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)c1nc2cc(OCc3cccc(F)c3)ccc2c(=O)n1CC#N
Temperature: -78 °C
Yield: 52.9 %

Procedure:
To a mixture of 2-[7-(3-fluoro-benzyloxy)-2-isopropyl-4-oxo-4H-quinazolin-3-yl]-acetamide (50 mg, 0.14 mmol) in dimethylformamide (0.5 mL), dichloromethane (2 mL) was added N-ethyl-N,N-diispropylamine (26.2 mg, 0.2 mmol) and the resulting mixture cooled to −78° C. Then trifluorosulfonic anhydride (49.6 mg, 0.18 mmol) was added and the reaction mixture allowed to warm up to rt over 30 min. The resulting mixture was then poured into sodium hydrogen carbonate (sat. 5 mL), and the mixture extracted with diethylether (3×5 mL). The combined extracts were then washed with brine, dried and evaporated to leave a light yellow solid. Purification by chromatography (SiO2, EtOAc:heptane 1:1 to 85:15) afforded the title compound (26 mg, 55%) as a white solid. MS: m/e=352.2 (M+H+).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=2[O:2]1.Br[C:14]1[CH:18]=[CH:17][S:16][C:15]=1[S:19]([N:22]1[CH:26]=[CH:25][CH:24]=[CH:23]1)(=[O:21])=[O:20]>>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:14]3[CH:18]=[CH:17][S:16][C:15]=3[S:19]([N:22]3[CH:26]=[CH:25][CH:24]=[CH:23]3)(=[O:20])=[O:21])=[CH:4][C:3]=2[O:2]1
Reactant: O=S(=O)(c1sccc1Br)n1cccc1
Reactant: OB(O)c1ccc2c(c1)OCO2
Product: O=S(=O)(c1sccc1-c1ccc2c(c1)OCO2)n1cccc1
Yield: 90 %

Procedure:
N-{[3-(3,4-Methylenedioxy)phenyl]thiophene-2-sulfonyl}pyrrole was prepared in the same manner as described in Example 13C using 3,4-methylenedioxyphenylboronic acid and N-(3-bromothiophene-2-sulfonyl)pyrrole. The crude product was purified by flash column chromatography on silica gel using 2% EtOAc in hexane as the eluent resulting in N-{[3-(3,4-methylenedioxy)phenyl]thiophene-2-sulfonyl}-pyrrole in a 90% yield.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[S:14][CH2:13][C:12]3([CH2:18][CH2:17][CH2:16][CH2:15]3)[N:11]2[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:5]([CH2:24][CH3:25])[CH:4]=1)=O.[O:26]=[C:27]([CH3:37])[CH2:28]P(=O)(OCC)OCC>>[CH2:24]([C:5]1[CH:4]=[C:3](/[CH:1]=[CH:28]/[C:27](=[O:26])[CH3:37])[CH:8]=[CH:7][C:6]=1[N:9]=[C:10]1[S:14][CH2:13][C:12]2([CH2:15][CH2:16][CH2:17][CH2:18]2)[N:11]1[CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH3:25]
Reactant: CCOP(=O)(CC(C)=O)OCC
Reactant: CCc1cc(C=O)ccc1N=C1SCC2(CCCC2)N1C1CCCC1
Product: CCc1cc(/C=C/C(C)=O)ccc1N=C1SCC2(CCCC2)N1C1CCCC1

Procedure:
1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method C1e to give 2-(4-cyano-2-ethylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2-ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The nitrile was reduced according to Method D11a to give 2-(4-formyl-2-ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The aldehyde was reacted with diethyl (2-oxopropyl)phosphonate according to Method D12a according to afford 2-(2-ethyl-4-((1E)-2-acetylvinyl)phenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[NH:15][CH2:14][C@H:13]([N:16]([O:29][CH2:30][CH:31]=[CH2:32])S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH:12]=[C:11]1[CH3:33])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].SCC(O)=O.[Li+].[OH-]>CN(C)C=O.O>[Si:1]([O:8][CH2:9][C@H:10]1[NH:15][CH2:14][C@H:13]([NH:16][O:29][CH2:30][CH:31]=[CH2:32])[CH:12]=[C:11]1[CH3:33])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: C=CCON([C@@H]1C=C(C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C(O)CS
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCON[C@@H]1C=C(C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of N-[(3R,6S)-6-[[(tert-butyldimethylsilyl)oxy]methyl]-5-methyl-1,2,3,6-tetrahydropyridin-3-yl]-2-nitro-N-(prop-2-en-1-yloxy)benzene-1-sulfonamide (Intermediate 146, 12 g, 24.11 mmol, 1.00 equiv) in N,N-dimethylformamide (100 mL), 2-sulfanylacetic acid (4.4 g, 47.77 mmol, 2.00 equiv). This was followed by the addition of LiOH (5.8 g, 242.17 mmol, 10.00 equiv), in portions. The resulting solution was stirred for 2 h at room temperature. The resulting solution was diluted with 500 mL of water. The resulting solution was extracted with 5×200 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×200 mL of brine and 2×200 mL of sodium bicarbonate (aq.). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 8.4 g (crude product) of the title compound as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][CH2:20][N:19]([S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=4)(=[O:25])=[O:24])[C:18]=3[CH:33]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].F[C:35]1C=C(S(Cl)(=O)=O)C=C[CH:40]=1>>[CH2:35]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][CH2:20][N:19]([S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=4)(=[O:25])=[O:24])[C:18]=3[CH:33]=2)=[O:13])=[CH:10][C:2]=1[F:1])[CH3:40]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: O=C(Nc1ccc(C(=O)O)c(F)c1)c1ccc2c(c1)N(S(=O)(=O)c1cccc(F)c1)CCO2
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(F)c2)CCO3)cc1F

Procedure:
2-Fluoro-4-{[4-(3-fluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid, MS (ISP): m/e=473.1 (M−H), was prepared as described for example 21, steps 1 to 8. Step 7 was performed using 3-fluoro-benzenesulfonyl chloride and yielded 2-fluoro-4-{[4-(3-fluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 8.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][N:3]=1.[Br:12][C:13]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:14]=1[O:15][C@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:10]([O:9][C:7]([C:5]1[O:6][C:2]([N:18]2[CH2:19][CH2:20][C@H:16]([O:15][C:14]3[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:13]=3[Br:12])[CH2:17]2)=[N:3][N:4]=1)=[O:8])[CH3:11]
Reactant: CCOC(=O)c1nnc(Br)o1
Reactant: Fc1ccc(Br)c(O[C@H]2CCNC2)c1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1nnc(N2CC[C@H](Oc3cc(F)ccc3Br)C2)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (0.5 g, 2.26 mmol) and (3S)-3-(2-bromo-5-fluorophenoxy)pyrrolidine (0.5 mL, 3.4 mmol) in THF (4.5 mL) was added DBU (0.5 mL, 3.4 mmol). The mixture was stirred at room temperature for 0.5 h then filtered and the filtrate concentrated. Purification by Combiflash (SiO2, gradient elution 70-100% EtOAc/Hexanes) afforded the desired product as solid.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:14]([OH:16])=O)[C:10]([CH3:13])([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:38][C:39]1[CH:44]=[C:43]([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH:42]=[CH:41][N:40]=1>C(Cl)Cl.C(N(CC)CC)C>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([C:14]([N:48]1[CH2:49][CH2:50][N:45]([C:43]2[CH:42]=[CH:41][N:40]=[C:39]([CH3:38])[CH:44]=2)[CH2:46][CH2:47]1)=[O:16])[C:10]([CH3:11])([CH3:12])[CH3:13])([CH3:5])([CH3:6])[CH3:7]
Reactant: Cc1cc(N2CCNCC2)ccn1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(N2CCN(C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)(C)C)CC2)ccn1
Yield: 90.1 %

Procedure:
To a solution of Boc-D-tert-leucine (0.23 g) in methylene chloride (5 ml) were added HOBt (0.20 g), WSC (0.29 g) and triethylamine (0.28 ml) under ice-cooling, and the reaction mixture was mixed at 0° C. for 15 minutes. Then, 1-(2-methyl-4-pyridinyl)piperazine (0.18 g) obtained in Example 114b) was added thereto, and further mixed at room temperature for 13 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The reaction mixture was washed with an aqueous potassium carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and then the residue was purified with basic silica gel column (ethyl acetate) to obtain the title compound as a colorless solid (0.35 g, 90%).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]#[C:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[Br:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:9]2[CH2:8][CH2:7][C:6]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]#[C:32][CH2:33][N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[CH:25][CH:24]=3)(=[O:22])=[O:21])([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OCC#CCN3CCOCC3)cc2)CCN(Cc2ccc(Br)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1(S(=O)(=O)c2ccc(OCC#CCN3CCOCC3)cc2)CCN(Cc2ccc(Br)cc2)CC1

Procedure:
1-(4-Bromo-benzyl)-4-[4-(4-morpholin-4-yl-but-2-ynyloxy)-benzenesulfonyl]-piperidine-4-carboxylic acid was prepared starting from 1-(4-bromo-benzyl)-4-[4-(4-morpholin-4-yl-but-2-ynyloxy)-benzenesulfonyl]-piperidine-4-carboxylic acid ethyl ester (2.87 g, 4.6 mmol) dissolved in THF:methanol (3:1, 150 ml) and 10 N NaOH (10 ml). The resulting reaction mixture was worked up as outlined in Example 1 (Step 7). Yield 2.26 g (83%); white powder; mp 198° C.; MS: 593.1 (M+H)+
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6]=[C:7](I)[NH:8][C:9]=1[CH2:10][CH2:11][CH3:12])=[O:4]>CO>[CH3:1][NH:2][C:3]([C:5]1[N:6]=[C:7]([C:7]2[NH:8][C:9]([CH2:10][CH2:11][CH3:12])=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[N:6]=2)[NH:8][C:9]=1[CH2:10][CH2:11][CH3:12])=[O:4]
Reactant: CCCc1[nH]c(I)nc1C(=O)NC
Solvent: CO
Product: CCCc1[nH]c(-c2nc(C(=O)NC)c(CCC)[nH]2)nc1C(=O)NC
Temperature: 25 °C
Yield: 40.1 %

Procedure:
Iodide 6a (0.35 g; 1.2 mmol) was used as starting material. After cooling to rt, the reaction mixture was diluted with CH3OH and filtered. The filtrate was evaporated under vacuum, and the residue was dissolved in CH2Cl2. Upon standing, a white solid precipitated. This material was collected by filtration and was washed with ice-cold CH2Cl2 to afford 0.080 g (43%) of 1a. mp>260 ÿC; TLC (EtOAc): Rf=0.32; 1H NMR (DMSO-d6): δ 0.83 (t, 6H), 1.61 (m, 4H), 2.73 (d, 6H), 2.89 (t, 4H), 7.50 (br t, 2H); 13C NMR (DMSO-d6): δ 13.1, 21.9, 24.7, 30.2, 130.3, 135.6, 163.0; UV/vis (CH3OH): λmax (ε M−1cm−1)=286 (18500), 294 (18200), 309 (9860); Anal. calcd for C16H24N6O2.0.25(CH2Cl2): C, 55.19; H, 6.98; N, 23.76; found: C, 54.93; H, 6.71; N, 23.74.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:15]([C:18]1[CH:19]=[CH:20][C:21]([F:26])=[C:22]([CH:25]=1)[C:23]#[N:24])(=[O:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:10]([F:13])([F:12])[F:11])=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]([F:26])=[C:22]([CH:25]=2)[C:23]#[N:24])=[O:17])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(=O)c1ccc(F)c(C#N)c1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: N#Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1F
Yield: 46 %

Procedure:
163 mg of 1-(3,5-Dichloro-phenyl)-2,2,2-trifluoro-ethanone (VIa) (Journal of Physical Organic Chemistry (1989), 2(4), 363-6), 486 mg of 5-acetyl-2-fluoro-benzonitrile (CAS:288309-07-9) and 276 mg of potassium carbonate in 5 ml of dry toluene were refluxed for 72 hours. The solvent was then evaporated under reduced pressure and the residue was purified on silica gel (eluent hexane/ethyl acetate 6:1) affording 5-[3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-fluoro-benzonitrile as a yellow resin in 46% yield (solidified on standing). 1H-NMR (CDCl3, δ in ppm): 8.05-8.11 (m, 2H), 7.33-7.43 (m, 3H), 7.15 (s, 2H).
Reaction SMILES: C([Li])(C)(C)C.[CH:6]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH2:7].[Cl:13][C:14]1[N:15]=[N:16][C:17](Cl)=[CH:18][CH:19]=1>CCCCC.C1COCC1.CCOC(C)=O.[Cl-].[Zn+2].[Cl-].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:9]([O:8][C:6]([C:17]1[N:16]=[N:15][C:14]([Cl:13])=[CH:19][CH:18]=1)=[CH2:7])[CH2:10][CH2:11][CH3:12]
Reactant: C=COCCCC
Reactant: Clc1ccc(Cl)nn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C(OCCCC)c1ccc(Cl)nn1
Temperature: -30 °C
Reaction time: 0.25 h

Procedure:
THF (24.0 mL) was added rapidly dropwise to tert-butyllithium (150 mL of a 1.7 M solution in pentane) at −78° C. After 15 min, n-butyl vinyl ether (14.0 mL, 109.4 mmol) was added, and the resulting mixture was warmed to −30° C., at which point modest gas evolution was observed. As gas evolution ceased, a second portion of n-butyl vinyl ether (14.0 mL, 109.4 mmol) was added, maintaining the reaction temperature at −30° C. After gas evolution had ceased, the reaction mixture was cooled to −78° C., and a solution of zinc chloride (29.8 g, 219 mmol) in THF (250 mL) was added rapidly dropwise. After 15 min, the reaction was warmed to −10° C. and transferred via cannula to a stirred solution of 3,6-dichloropyridazine (32.6 g, 219 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (16.0 g, 21.9 mmol) in THF (200 mL) at 0° C. After 1 h at 0° C., the reaction mixture was diluted with EtOAc and filtered through a short column of CELITE®, eluting with EtOAc. The filtrate was washed with water and brine, dried (sodium sulfate), and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (gradient elution; 0%-15% EtOAc/hexanes as eluent) to afford the title compound i-5a. 1HNMR (500 MHz, CDCl3): δ 7.80 (d, 1H, J=8.9 Hz), 7.52 (d, 1H, J=8.9 Hz), 5.76 (d, 1H, J=2.5 Hz), 4.55 (d, 1H, J=2.5 Hz), 3.97 (t, 2H, J=6.4 Hz), 1.83 (m, 2H), 1.57 (m, 2H), 1.02 (t, 3H, J=7.5 Hz).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][C@@H:8](O)[CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C@H:8]2[O:14][C:12](=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:17][CH:18]=1
Reactant: COC(=O)CCC[C@H](O)COc1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CCC[C@@H](COc2ccc(F)cc2)O1
Temperature: 40 °C
Reaction time: 12 h
Yield: 71.5 %

Procedure:
To a solution of methyl (S)-6-(4-fluorophenoxy)-5-hydroxy-hexanoate (0.8 g 3.12 mmol) in CH2Cl2 (20 ml), a catalytic amount of PTSA (10 mg) was added and the reaction mixture was stirred at 40° C. for 12 h. The reaction was then neutralised with sodium bicarbonate and the product extracted with dichloromethane. The organic layer was dried (Na2SO4) and concentrated. The crude product on purification on a silica gel (EtOAc-light petroleum (1:3) as eluent) gave (6S)-6-(4-fluorophenoxymethyl)-tetrahydropyran-2-one (0.5 g, 70%) as a colourless liquid. TLC:ethyl acetate-light petroleum (1:4), Rf=0.3. Optical rotation [α]D: +19° (c 0.9, CHCl3). 1H NMR (CDCl3, 200 MHz): δ 1.7-2.15 (m, 4H), 2.48-2.7 (m, 2H), 3.95-4.15 (m, 2H), 4.55-4.7 (m, 1H), 6.77-7.0 (m, 4H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[S:13]([O-:16])([OH:15])=[O:14].[Na+:17].C(O)C>O>[F:10][C:9]([F:12])([F:11])[C:5]1[CH:6]=[C:7]([Cl:8])[C:2]([S:13]([O-:16])(=[O:15])=[O:14])=[N:3][CH:4]=1.[Na+:17]
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)([O-])c1ncc(C(F)(F)F)cc1Cl
Yield: 103 %

Procedure:
In a flask, 2,3-dichloro-5-(trifluoromethyl)pyridine (10.8 g, 50 mmol), sodium hydrogen sulfite (20.8 g, 200 mmol), ethanol (100 ml) and water (100 ml) were charged and heated under reflux for 41 hours. After evaporating off the solvent from the reaction mixture, conc. hydrochloric acid was added to the residue and then evaporated to dryness. This residue was extracted with methanol, and the metanol phase was filtered and evaporated to dryness to obtain quantitatively sodium 5-trifluoromethyl-3-chloropyridine-2-sulfonate (14.6 g). Decomposition point, 322°-334° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][O:10][C:11](=[O:36])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:20](=[O:29])[C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:13]=1>>[CH3:9][O:10][C:11](=[O:36])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)/[C:21](=[C:22](/[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)\[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)/[C:20]2=[O:29])[CH:13]=1
Reactant: Clc1ccc(I)cc1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(/c3ccccc3)c3ccc(Cl)cc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-chloro-4-iodo-benzene (commercially available) and 3-{[phenyl-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (300 Hz, CDCl3): δppm 3.91 (s, 3H), 4.96 (s, 2H), 6.42 (d, 1H), 6.63-6.66 (m, 2H), 7.06 (t, 1H), 7.33-7.52 (m, 11H), 7.92 (d, 1H), 8.01 (s, 1H).