Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][P:3]([CH2:7][C:8]([CH3:25])=[CH:9][CH2:10][C:11]1[C:12]([OH:24])=[C:13]2[C:17](=[C:18]([CH3:22])[C:19]=1[O:20][CH3:21])[CH2:16][O:15][C:14]2=[O:23])(=[O:6])[O:4]C.C[Si](Br)(C)C.N1C(C)=CC=CC=1C>C(#N)C>[OH:24][C:12]1[C:11]([CH2:10][CH:9]=[C:8]([CH3:25])[CH2:7][P:3](=[O:2])([OH:6])[OH:4])=[C:19]([O:20][CH3:21])[C:18]([CH3:22])=[C:17]2[C:13]=1[C:14](=[O:23])[O:15][CH2:16]2
Reactant: COc1c(C)c2c(c(O)c1CC=C(C)CP(=O)(OC)OC)C(=O)OC2
Agent: C[Si](C)(C)Br
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: COc1c(C)c2c(c(O)c1CC=C(C)CP(=O)(O)O)C(=O)OC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
To a solution of [4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-phosphonic acid dimethyl ester (18 mg, 0.049 mmol) in acetonitrile (2 mL) was added TMSBr (63 μL, 0.49 mmol) and 2,6-lutidine (85 μL, 0.73 mmol) at 0° C. The reaction solution was allowed to warm to room temperature and stirred for 2 hours when completion of the reaction was observed by LCMS. The reaction was cooled to 0° C. and quenched by the addition of MeOH. The reaction mixture was concentrated under reduced pressure and the residue was purified by RP HPLC using a C18 column with a gradient of H2O-acetonitrile (5-0%) over 20 minutes to provide 12.2 mg (73%) of the product. 1H NMR (300 MHz, CD3OD) δ 1.95 (s, 3H), 2.15 (s, 3H), 2.48 (d, 2H, J=22 Hz), 3.44 (t, 2H, J=6 Hz), 3.79 (s, 3H), 5.24 (s, 2H), 5.38 (q, 1H, J=7 Hz), 6.87 (br s, 1H) ppm; MS (m/z) 341 [M−H]−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)[C:8]2[C:23](=[O:24])[N:22]3[CH2:25][CH2:26][CH2:27][N:21]3[C:9]=2[NH:10][C:11]=1[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[O:5])[CH3:2].C(Cl)Cl>C(#N)C.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:35][CH:36]=2)=[C:8]2[C:23](=[O:24])[N:22]3[CH2:25][CH2:26][CH2:27][N:21]3[C:9]2=[N:10][C:11]=1[CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(CCc2ccc(F)cc2)Nc2c(c(=O)n3n2CCC3)C1c1ccc(C(=O)O)cc1
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1c(CCc2ccc(F)cc2)nc2c(c1-c1ccc(C(=O)O)cc1)c(=O)n1n2CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of ceric ammonium nitrate (228 mg, 0.42 mmol) in acetonitrile (1 mL) and water (0.2 mL) was added dropwise to a solution of the product from Step D (102 mg, 0.21 mmol) in acetonitrile (1 mL). The resulting solution was stirred at rt for 2 h and then concentrated at reduced pressure. Trituration of the remaining material with a mixture of CH2Cl2 and water provided E as a light yellow solid (75 mg, 0.15 mmol, 73%): 1H NMR (400 MHz, DMSO-d6) δ 13.05 (br, 1H), 7.95 (d, 2H, J=8), 7.41 (d, 2H, J=8), 7.22 (dd, 2H, J=8, 6), 7.07 (t, 2H, J˜9), 3.87 (m, 4H), 3.77 (t, 2H, J=7), 3.07 (m, 2H), 2.99 (m, 2H), 2.54 (quint., 2H, J=7), 0.75 (t, 3H, J=7) ppm; ESI-MS m/z 490 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)O)=[C:4]([CH3:16])[CH:3]=1.CC(C)=[O:19].P(=O)(O)(O)O>O>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]2[C:13](=[O:12])[CH:14]=[CH:15][CH:11]2[OH:19])=[C:4]([CH3:16])[CH:3]=1
Reactant: Cc1cc(F)cc(C)c1C(O)c1ccco1
Reactant: CC(C)=O
Agent: O=P(O)(O)O
Solvent: O
Product: Cc1cc(F)cc(C)c1C1C(=O)C=CC1O
Temperature: 120 °C

Procedure:
A mixture of (4-fluoro-2,6-dimethylphenyl)furan-2-ylmethanol (6 g, 27 mmol), acetone (150 ml), water (24 ml) and orthophosphoric acid (0.6 ml) is heated under microwave conditions at 120° C. for 50 minutes. The organic solvent is evaporated under vacuo, diluted with water (150 ml) and extracted with ethylacetate (3×100 ml). The combined organic extracts are combined, washed with water and brine, dried over anhydrous sodium sulphate, filtered and the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel to give 5-(4-fluoro-2,6-dimethylphenyl)-4-hydroxy cyclopent-2-enone (3 g).
Reaction SMILES: [N:1]1([S:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[C:16]4[N:22]=[C:21]([CH2:23][CH2:24][CH:25]5[NH:31][C:30](=O)[CH2:29][CH2:28][CH2:27][CH2:26]5)[NH:20][C:17]4=[N:18][CH:19]=3)=[CH:10][CH:9]=2)(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>>[N:1]1([S:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[C:16]4[N:22]=[C:21]([CH2:23][CH2:24][CH:25]5[NH:31][C:30](=[S:42])[CH2:29][CH2:28][CH2:27][CH2:26]5)[NH:20][C:17]4=[N:18][CH:19]=3)=[CH:10][CH:9]=2)(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CCCCC(CCc2nc3cc(-c4ccc(S(=O)(=O)N5CCC5)cc4)cnc3[nH]2)N1
Product: O=S(=O)(c1ccc(-c2cnc3[nH]c(CCC4CCCCC(=S)N4)nc3c2)cc1)N1CCC1
Yield: 37.1 %

Procedure:
The title compound is synthesized as described for 7-[2-(6-{4-cyano-phen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-thione (compound A2) from 258 mg of 7-(2-{6-[4-(azetidine-1-sulfonyl)-phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-azepan-2-one (compound B6) and 242 mg of Lawesson's reagent. Purification by chromatography on flash silica gel (eluent gradient: dichloromethane/0-5 vol. % ethanol) affords 99 mg of the title compound as a beige foam. ESI-MS: 470.2 (MH+). TLC: Rf=0.45 (dichloromethane/ethanol 10:1 parts by volume).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15](OS(C(F)(F)F)(=O)=O)[C:14]([C:29]3[CH:33]=[CH:32][O:31][CH:30]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:34]([NH:41][CH2:42][C:43]#[CH:44])([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].C(N(CC)CC)C>C(#N)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([C:44]#[C:43][CH2:42][NH:41][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:14]([C:29]3[CH:33]=[CH:32][O:31][CH:30]=3)=[CH:13][CH:12]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1C#CCNC(=O)OC(C)(C)C
Temperature: 70 °C
Yield: 29.5 %

Procedure:
Methyl 6-(benzenesulphonylmethyl)-3-(furan-3-yl)-2-(trifluoromethanesulphonyloxy)-benzoate (Intermediate 123, 0.756 g), N-Boc-propargylamine (0.698 g), copper (I) iodide (0.014 g) and bis(triphenylphosphine)palladium(II)chloride (0.026 g) were added to a solution of triethylamine (0.152 g) in acetonitrile (10 ml) and the mixture was heated at 70° C., under nitrogen, for 17 hours. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and DCM with a gradient of 0-10%. After evaporation of the appropriate fractions, the resulting residue was triturated with diethyl ether and the solid was collected by filtration to give methyl 6-(benzenesulphonylmethyl)-2-(3-t-butyoxycarbonylaminoprop-1-yn-1-yl)-3-(furan-3-yl)benzoate (0.225 g) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12]([OH:14])=[O:13])[CH2:6][CH2:5]2.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[K].[OH-].[K+].Cl>O.[I-].[Na+].C(O)C>[CH2:15]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12]([OH:14])=[O:13])[CH2:6][CH2:5]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)C1CCc2cc(O)ccc2C1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(O)C1CCc2cc(OCc3ccccc3)ccc2C1
Temperature: 100 °C
Yield: 92.8 %

Procedure:
A mixture of 10.60 g (50 mmol) of 1,2,3,4-tetrahydro-6-hydroxynaphthalene-2-carboxylic acid, 12.85 g (75 mmol) of benzyl bromide, 6.6 g (100 mmol) of 85% potassium hydrooxide, 0.525 g (3.5 mmol) of sodium iodide, 200 ml of ethanol and 25 ml of distilled water was heated under reflux at 100° C. for 12 hours. To this reaction mixture was added 50 ml of 10% potassium hydroxide, followed by heating under reflux at that temperature for 2 hours. After allowing the reaction system to cool up to room temperature, the reaction mixture in cold water was acidified with 36% hydrochloric acid. The resulting deposited product was filtered, and recrystallized from toluene to obtain 13.08 g (46.4 mmol) of 1,2,3,4-tetrahydro-6-benzyloxynaphthalene-2-carboxylic acid.
Reaction SMILES: CC([N:5]([C@H:9]([CH2:27][N:28]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]1=[O:38])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]3[C:24]([Br:25])=[CH:23][CH:22]=[CH:21][N:20]3[CH:26]=2)=[CH:13][CH:12]=1)[C:6](=O)[O-:7])(C)C.Cl.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:51]=[C:52]([CH:67]=[CH:68][C:69]=1[O:70][CH:71]([CH3:73])[CH3:72])C(OC1C(F)=C(F)C(F)=C(F)C=1F)=O>O1CCOCC1.C(OCC)(=O)C>[Br:25][C:24]1[C:19]2[N:20]([CH:26]=[C:17]([C:14]3[CH:13]=[CH:12][C:11]([CH2:10][C@H:9]([NH:5][C:6](=[O:7])[C:52]4[CH:67]=[CH:68][C:69]([O:70][CH:71]([CH3:72])[CH3:73])=[C:50]([Cl:49])[CH:51]=4)[CH2:27][N:28]4[C:29](=[O:38])[C:30]5[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:36]4=[O:37])=[CH:16][CH:15]=3)[N:18]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)N(C(=O)[O-])[C@@H](Cc1ccc(-c2cn3cccc(Br)c3n2)cc1)CN1C(=O)c2ccccc2C1=O
Reactant: CC(C)Oc1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(C(=O)N[C@@H](Cc2ccc(-c3cn4cccc(Br)c4n3)cc2)CN2C(=O)c3ccccc3C2=O)cc1Cl
Temperature: 25 °C

Procedure:
A solution of 1,1-dimethylethyl{(1S)-2-[4-(8-bromoimidazo[1,2-a]pyridin-2-yl)phenyl]-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2yl)methyl]ethyl)carbamate (3.5 mmol) and hydrogen chloride in 1,4-dioxane (20 mL, 4.0 M) was stirred for 1 h at RT. The reaction was concentrated to dryness and redissolved in N,N-dimethylformamide (35 mL). Added to the solution was diisopropylethylamine (10.5 mmol) and pentafluorophenyl 3-chloro-4-[(1-methylethyl)oxy]benzoate (3.8 mmol), followed by stirring at RT for half an hour. The reaction was dissolved in ethyl acetate (80 mL) and washed with water (3×50 mL) and brine (1×50 mL). To the separated organic layer was added hexanes (150 mL) upon which a precipitate was formed, filtered, and dried to afford the title compound as an off white solid (65%). ESMS [M+H]+: 672.2.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[O:20][CH3:21])=[CH:9][CH:8]=1)=[O:6])[CH3:3].CN1CCOCC1.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1>C1COCC1>[CH2:2]([O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([NH:19][C:32]([CH:29]3[CH2:31][CH2:30]3)=[O:33])[CH:16]=[CH:15][C:14]=2[O:20][CH3:21])=[CH:9][CH:8]=1)=[O:6])[CH3:3]
Reactant: O=C(Cl)C1CC1
Reactant: CCOC(=O)c1ccc(-c2cc(N)ccc2OC)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCOC(=O)c1ccc(-c2cc(NC(=O)C3CC3)ccc2OC)cc1
Reaction time: 18 h
Yield: 93.5 %

Procedure:
A mixture of 5′-amino-2′methoxy-biphenyl-4-carboxylic acid ethyl ester hydrochloride (100 mg), N-methylmorpholine (0.1 ml) and cyclopropanecarbonyl chloride (29 mg) in dry THF (3 ml) was stirred at 20 C for 18 h. The mixture was then evaporated and the residue partitioned between sodium bicarbonate solution and ethyl acetate. The dried extracts were then evaporated giving the title compound as a dark oil (88 mg)
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([C:9](O)([CH3:11])[CH3:10])=[CH:5][CH:4]=1.C(O)(=O)C>CO.[OH-].[Pd+2].[OH-]>[CH:9]([C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:13])[F:14])=[CH:4][CH:5]=1)([CH3:11])[CH3:10]
Reactant: CC(C)(O)c1ccc(C(F)(F)F)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)c1ccc(C(F)(F)F)cc1

Procedure:
2-(4-(Trifluoromethyl)phenyl)-2-propanol (233 mg, 1.14 mmol), acetic acid (0.50 mL) and 20% palladium(II) hydroxide (120 mg) were combined in 2.0 mL of methanol and subjected to hydrogenation at 48 psi on a Parr shaker overnight. The mixture was centrifuged and the supernatant was filtered through 0.45 micron filter. The catalyst was washed with 3.0 mL of methanol followed by 2×3.0 mL of pentane. The combined filtrates were diluted with 20 mL of pentane and washed with 35 mL of saturated sodium bicarbonate. After extracting the aqueous layer with 2×20 mL of pentane, the combined organic layers were dried over sodium sulfate. The solvents were removed by distillation at atmospheric pressure to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:36]([F:39])([F:38])[F:37])=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([OH:12])[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][C:22]([NH:24][S:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)(=[O:27])=[O:26])=[O:23])=[CH:15][CH:14]=3)[C:6]=2[CH:35]=1>C(Cl)Cl.O=[Mn]=O>[C:10]([C:8]1[N:7]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][C:22]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])=[O:23])=[CH:15][CH:14]=2)[C:6]2[CH:35]=[C:2]([Cl:1])[C:3]([C:36]([F:38])([F:39])[F:37])=[CH:4][C:5]=2[N:9]=1)(=[O:12])[CH3:11]
Reactant: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3c(C(C)O)nc4cc(C(F)(F)F)c(Cl)cc43)cc2)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(=O)c1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.5 %

Procedure:
A solution of 1-[6-chloro-1-[4-(2-chloroethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazol-2-yl]ethanol (Example 367, step 1, 400 mg, 1 mmol) in CH2Cl2 was added MnO2 (2.7 g, 32 mmol) . The mixture was stirred at room temperature for 24 h. This was directly purified by flash column chromatography eluting with hexane/ethyl acetate (4:1) to afford 350 mg (88%) of the title compound as white solids.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7]([OH:9])=[O:8].C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:32]([NH:34][NH:35][CH:36]=O)=O>CN(C=O)C>[N:34]1[N:35]=[CH:36][N:1]([C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[O:5][CH2:6][C:7]([OH:9])=[O:8])[CH:32]=1
Reactant: O=CNNC=O
Reactant: Nc1cccc(OCC(=O)O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(O)COc1cccc(-n2cnnc2)c1
Temperature: 25 °C
Yield: 29.7 %

Procedure:
To a round bottom flask was added (3-amino-phenoxy)-acetic acid 2 (167 mg, 1.0 mmol, 1.0 eq.), toluene (5.0 mL), DMF (0.5 mL), p-toluene sulfonic acid monohydrate (209 mg, 1.1 mmol, 1.1 eq.), and sym-diformyl hydrazine (96.8 mg, 1.1 mmol, 1.1 eq.). The mixture was refluxed overnight. Upon cooling to RT, the reaction mixture separated out into two layers with product in the bottom brown oil layer and toluene in the clear top layer. The toluene layer was removed; water was added to the brown oil and then extracted with EtOAc 3×. The combined organic layers were then dried with Na2SO4, concentrated via rotary evaporation, and then triturated with ether to give (3-[1,2,4]Triazol-4-yl-phenoxy)-acetic acid 24 as an orange solid (65.0 mg, 30% yield). LC/MSD (HP Series 1100 MSD) MS (ES+) m/z 220.1 (M+H)+1 1H-NMR, Varian 400 MHz (DMSO-d6) δ 9.10 (s, 2H), 7.48 (m, 1H), 7.39 (t, 1H), 7.31 (dd, 1H), 7.00 (dd, 1H), 4.80 (s, 2H) ppm.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][N:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][O:5][C:6]1[N:7]=[CH:8][C:9]([CH2:10][OH:11])=[CH:13][CH:14]=1
Reactant: CC(C)CCOc1ccc(C(=O)O)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)CCOc1ccc(CO)cn1

Procedure:
[6-(3-Methyl-butoxy)-pyridin-3-yl]-methanol was prepared from 6-(3-methylbutoxy)nicotinic acid (0.24 g) and lithium aluminium hydride (0.5M, THF, 3.5 ml) according to the method described in Example 54 to give the product as a yellow oil (0.19 g, 86%): δH (400 MHz, CDCl3) 8.08 (1H, d, J 2.5 Hz), 7.59 (1H, dd, J 8.5, 2.5 Hz), 6.71 (1H, d, J 8.5 Hz), 4.60 (2H, s), 4.30 (2H, t, J 6.5 Hz), 1.81 (1H, nonet, J 6.7 Hz), 1.66 (3H, q, J 7 Hz) and 0.96 (6H, d, J 6.5 Hz); HPLC (XTERRA, 50/80, 235 nm) 86% (2.54 min).
Reaction SMILES: Cl.C([O:9][C:10]1[C:15](=[O:16])[CH:14]=[CH:13][N:12]([CH2:17][CH2:18][OH:19])[C:11]=1[CH2:20][CH3:21])C1C=CC=CC=1.C(N(CC)CC)C.[C:29](Cl)(=[O:33])[CH:30]([CH3:32])[CH3:31].CCO>CN(C)C=O.CCOC(C)=O>[CH2:20]([C:11]1[N:12]([CH2:17][CH2:18][O:19][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:13]=[CH:14][C:15](=[O:16])[C:10]=1[OH:9])[CH3:21]
Reactant: CC(C)C(=O)Cl
Reactant: CCc1c(OCc2ccccc2)c(=O)ccn1CCO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CN(C)C=O
Product: CCc1c(O)c(=O)ccn1CCOC(=O)C(C)C
Reaction time: 0.25 h
Yield: 40 %

Procedure:
To a solution of 3-benzyloxy-2-ethyl-1-(2-hydroxyethyl)pyridin-4-one hydrochloride (3.1 g, 0.01 mole; prepared as described in Example 2) in 100 ml of dry dimethylformamide was added dropwise triethylamine (7 ml, 0.05 mole) whilst stirring over 15 minutes under N2. Isobutyryl chloride (4.2 ml, 0.04 mole) was then added dropwise and the mixture was heated at 75°-78° C. overnight under N2. The reaction was monitored by tlc (silica; 50% EtOH:50% EtOAc) and after filtration the dimethylformamide was removed under high vacuum by rotary evaporation. The solid residue was dissolved in 100 ml of dichloromethane and washed with 5% w/v aqueous NaHCO3 (3×100 ml) and water (2×100 ml). The organic layer was dried over Na2SO4, filtered and rotary evaporated to give a crude solid. Purification was achieved by recrystallization using activated charcoal in ethyl acetate. The filtrate was used for further crystallization of the solid from ethyl acetate to give the title compound in 40% yield, δ(DMSO): 0.8-1.12 (15H, m), 2.3-2.8 (4H, m), 4.15 (4H, s), 5.9-6.1 (1H, d, 7 Hz), 7.5-7.7 (1H, d, 8 Hz).
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OC)=O.CCCCCC.[C:43]([O:46]CC)(=[O:45])[CH3:44]>C(Cl)Cl>[C:43]([OH:46])(=[O:45])/[CH:44]=[CH:1]/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCC/C=C/C=O
Reactant: CCOC(C)=O
Agent: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCCCCC/C=C/C=C/C(=O)O
Reaction time: 2 h

Procedure:
To trans-2-undecenal (5.0 g) dissolved in methylene chloride (80 ml) was added (carbomethoxymethylene)-triphenylphosphorane (9.9 g), and the mixture was stirred for 2 hours. The reaction mixture was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 100:1 to 20:1) to give the methyl ester of trans,trans-2,4-tridecadienoic acid (5.2 g). Potassium hydroxide (6.5 g) was dissolved in a mixed solvent of ethanol-water (1:1) (100 ml). The methyl ester of trans,trans-2,4-tridecadienoic acid (5.2 g) was added to the mixture, and the resulting mixture was stirred at 60° C. for 40 minutes. After the reaction mixture was cooled, it was adjusted to the weak acidic range of pH with citric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give trans,trans-2,4-tridecadienoic acid (4.4 g). To trans,trans-2,4-tridecadienoic acid dissolved in N,N-dimethylformamide (DMF, 50 ml) were added para-nitrophenol (3.0 g) and N,N'-dicyclohexylcarbodiimide (4.4 g), and the mixture was stirred for 12 hours. After precipitates obtained were removed by filtration and the solvent (DMF) was removed by distillation, the residue was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 200:1 to 50:1) to give the active ester of trans,trans-2,4-tridecadienoic acid (2.4 g). To the active ester (880 mg) dissolved in DMF (30 ml) were added 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (800 mg) and triethylamine (2.0 ml). The mixture was stirred for 12 hours. After the solvent was removed by distillation, the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK281 in the yield of 380 mg.
Reaction SMILES: Cl[CH:2]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:3]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:6]=2[O:5][C:4]=1[CH3:14].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[CH:24][CH:23]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH:15]1([CH:2]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[CH:26][CH:27]=2)[C:3]2[C:7]3[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:6]=3[O:5][C:4]=2[CH3:14])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1ccc2c(C(Cl)C3CCCCC3)c(C)oc2c1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2c(C)oc3cc(OC)ccc23)C2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
To a mixture of 3-[chloro(cyclohexyl)methyl]-6-methoxy-2-methyl-1-benzofuran (530 mg) synthesized above, ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (498 mg) synthesized in Example 2(2) and N,N-dimethylformamide (10 mL) were added sodium iodide (408 mg) and sodium carbonate (288 mg), and the mixture was stirred at 80° C. overnight. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-70% ethyl acetate/hexane) to give the title object compound (781 mg, 85%) as a white solid.
Reaction SMILES: C(OC([N:8]1[C:17]2[CH:16]=[C:15]([CH2:18][CH2:19][O:20][Si](C(C)(C)C)(C)C)[CH:14]=[CH:13][C:12]=2[CH:11]2[CH2:28][CH2:29][CH2:30][C:10]2([F:31])[C:9]1=[O:32])=O)(C)(C)C>O1CCOCC1>[F:31][C:10]12[CH2:30][CH2:29][CH2:28][CH:11]1[C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][OH:20])=[CH:16][C:17]=1[NH:8][C:9]2=[O:32]
Reactant: CC(C)(C)OC(=O)N1C(=O)C2(F)CCCC2c2ccc(CCO[Si](C)(C)C(C)(C)C)cc21
Solvent: C1COCCO1
Product: O=C1Nc2cc(CCO)ccc2C2CCCC12F
Yield: 61.4 %

Procedure:
0.77 g (1.7 mmol) of 5-tert-butyloxycarbonyl-7-[2-(tert-butyldimethylsilyloxy)ethyl]-3a-fluoro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one is stirred in 10 ml of 4 M hydrochloric acidic dioxane for 2 hours at room temperature. The batch is concentrated by evaporation in a vacuum, the residue is taken up in ethyl acetate, washed with saturated NaHCO3, dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography on silica gel with hexane-ethyl acetate yields 0.26 g of product.