Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C[Al](C)C.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[N:20]1[C:25]2[N:26]=[C:27]([NH:38][CH2:39][C:40](OC)=[O:41])[N:28]=[C:29]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[CH3:37])[C:24]=2[CH:23]=[CH:22][C:21]1=[O:44]>>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[N:20]1[C:25]2[N:26]=[C:27]([NH:38][CH2:39][C:40](=[O:41])[N:4]3[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]3)[N:28]=[C:29]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[CH3:37])[C:24]=2[CH:23]=[CH:22][C:21]1=[O:44]
Reactant: O=C1CNCCN1
Reactant: COC(=O)CNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: C[Al](C)C
Product: Cc1cc(F)ccc1-c1nc(NCC(=O)N2CCNC(=O)C2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 29 %

Procedure:
Following the general procedure outlined in Example 193, piperazine-2-one (165 mg, 1.65 mmol), trimethylaluminum (0.83 mL, 1.65 mmol) and the product of Example 190 (150 mg, 0.33 mmol) were reacted to give the crude material. Preparative HPLC, eluting with acetonitrile/H2O (10/90, v/v to 90/10, v/v, over 10 min), followed by recrystallization from dichloromethane and hexane, gave the desired product 50 mg (29%). LC-MS: 523.2 (MH+, m/z), 1.68 (Rt, min).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:22]=[CH:21][C:20]=4[F:29])[CH2:15][CH2:14]3)=[O:12])=[N:9][N:10]=2)[CH:7]=1.[CH3:30][N:31](C=O)C>C(=O)(O)[O-].[Na+].[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:29][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([F:28])([F:27])[F:26])[C:19]=1[CH:16]1[CH2:17][CH2:18][N:13]([C:11]([C:8]2[N:6]3[CH:7]=[C:2]([C:30]#[N:31])[CH:3]=[CH:4][C:5]3=[N:10][N:9]=2)=[O:12])[CH2:14][CH2:15]1
Reactant: O=C(c1nnc2ccc(Br)cn12)N1CCC(c2c(F)cccc2C(F)(F)F)CC1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [C-]#N
Product: N#Cc1ccc2nnc(C(=O)N3CCC(c4c(F)cccc4C(F)(F)F)CC3)n2c1
Temperature: 130 °C
Yield: 33 %

Procedure:
A solution of (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-fluoro-6-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (80 mg, 0.17 mmol) in DMF (2.0 mL) with zinc cyanide (40 mg, 0.34 mmol) was sparged with Ar for 15 min. To the solution was added Pd(PPh3)4 (19 mg, 0.017 mmol) and the vessel was sealed and heated to 130° C. with microwaves for 30 min. The mixture was diluted with saturated sodium bicarbonate solution (20 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with a saturated brine solution (2×30 mL) and concentrated to dryness under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 50% EtOAc in hexanes) followed by HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 15 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA) and was washed with saturated sodium bicarbonate solution, and freeze dried to give 3-(4-(2-fluoro-6-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile as a white solid (23 mg, 33%): 1H NMR (500 MHz, DMSO-d6) δ 9.54-9.52 (m, 1H), 8.14-8.11 (m, 1H), 7.82-7.78 (m, 1H), 7.64-7.59 (m, 1H), 7.57-7.50 (m, 2H), 5.17-5.10 (m, 1H), 4.79-4.72 (m, 1H), 3.40-3.24 (m, 2H, overlaps with H2O), 3.07-2.98 127 (m, 1H), 2.30-2.19 (m, 1H), 2.14-2.03 (m, 1H), 1.91-1.79 (m, 2H); ESI MS m/z 418 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[C:16]([OH:17])=[CH:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][CH:20]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][CH:20]=[C:19]2[O:17][C:16]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][N:10]=2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1cc2cccnc2nc1-c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc4cccnc4nc3-c3ccccc3)c2cc1OC
Temperature: 140 °C
Reaction time: 5.5 h
Yield: 68.4 %

Procedure:
2-Phenyl-[1,8]naphthyridin-3-ol (23 mg), 4-chloro-6,7-dimethoxyquinoline (69 mg), and 4-dimethylaminopyridine (38 mg) were suspended in o-dichlorobenzene (2 ml), and the mixture was stirred at 140° C. for 5.5 hr. The reaction solution was cooled to room temperature. Water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (29 mg, yield 71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15].[Br:16]Br>C(Cl)(Cl)Cl>[Br:16][CH:11]1[CH2:12][CH2:13][CH2:14][CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:10]1=[O:15]
Reactant: COc1ccccc1C1CCCCC1=O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COc1ccccc1C1CCCC(Br)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.1 %

Procedure:
2-(2-Methoxy-phenyl)-cyclohexanone (51 mg, 0.27 mmol) was dissolved in chloroform (1 mL). To this solution bromine (45.4 mg, 0.28 mmol) in chloroform (0.5 mL) was added drop wise at room temperature. The reaction was stirred for 3 hours at room temperature and the solvent was removed under reduced pressure to yield the crude title compound (49 mg) which was used directly in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[Na+].[Na+]>[I-].[K+].CN(C)C=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:3][CH:4]=1)=[O:7]
Reactant: CCOC(=O)C(C)Cl
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(C=O)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 92.8 %

Procedure:
6.1 g of 4-hydroxybenzaldehyde, 7 g of ethyl α-chloropropionate, 4 g of sodium carbonate, 0.2 g of potassium iodide and 20 g of dimethyl formamide, were mixed, and the mixture was stirred at 100° C. for 5 hours and then cooled to room temperature. The inorganic salts were filtered off, and the residue was washed with dimethylformamide. The solution from the washing was combined with the filtrate, followed by concentration and distillation under reduced pressure, whereby 10.3 g of ethyl 2-(4-formylphenoxy)propionate was obtained as a colorless transparent liquid. The boiling point was from 130° to 140° C./1 mmHg.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10](=[O:31])[CH:11]([N:15]1[C@H:18]([S:19][S:20][C:21]2[S:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)[CH2:17][C:16]1=[O:30])[C:12](=[CH2:14])[CH3:13]>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:31])[C:11]([N:15]1[C@H:18]([S:19][S:20][C:21]2[S:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)[CH2:17][C:16]1=[O:30])=[C:12]([CH3:14])[CH3:13]
Reactant: C=C(C)C(C(=O)OC)N1C(=O)C[C@H]1SSc1nc2ccccc2s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(=C(C)C)N1C(=O)C[C@H]1SSc1nc2ccccc2s1
Reaction time: 1.5 h

Procedure:
5 ml of triethylamine are added to a solution of 12 g of 2-[(4R)-4-(benzthiazol-2-yldithio)-2-oxoazetidin-1-yl]-3-methylenebutyric acid methyl ester in 500 ml of methylene chloride and the mixture is allowed to stand at room temperature for 90 minutes. The reaction mixture is washed with 5% aqueous citric acid solution, dried over sodium sulphate and freed of solvent in vacuo. The residue is purified by chromatography over silica gel (deactivated with 10% water) with toluene and toluene/ethyl acetate (19:1) and yields the title compound, which after recrystallization from diethyl ether/pentane has a melting point of 63°-66°.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[CH3:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>>[CH3:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:31])=[CH:25][CH:24]=1)(=[O:21])=[O:22]
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Product: CS(=O)(=O)c1ccc(CC(=O)Nn2nc(N3CCOCC3)c3ccccc3c2=O)cc1

Procedure:
The product of Example 1B and 2-(4-(methylsulfonyl)phenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.25-8.35 (m, 1H), 7.97-8.05 (m, 2H), 7.91-7.93 (m, 3H), 7.65-7.67 (m, 2H), 3.83 (s, 3H), 3.82 (d, J=8.4 Hz, 2H), 3.35-3.63 (m, 1H), 3.21 (s, 3H), 3.08-3.11 (m, 4H); MS (ESI+) M/Z 443 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].CO.[NH:6]1[CH:10]=[N:9][C:8]([S:11](F)(=[O:13])=[O:12])=[N:7]1>C(O)(=O)C>[CH2:1]([NH:3][S:11]([C:8]1[N:9]=[CH:10][NH:6][N:7]=1)(=[O:13])=[O:12])[CH3:2]
Reactant: CCN
Reactant: O=S(=O)(F)c1nc[nH]n1
Solvent: CC(=O)O
Solvent: CO
Product: CCNS(=O)(=O)c1nc[nH]n1
Temperature: 0 °C

Procedure:
To a solution of ethylamine in methanol (2 M, 2.4 mmol, 4.8 mmol) was added 1H-1,2,4-triazole-3-sulfonyl fluoride (200 mg, 1.18 mmol, J. Heterocycl. Chem. 1988, 25, 1857). After ten minutes the reaction was concentrated in vacuo to give a yellow oil. Ice-cold water (2-3 mL) was added and the resulting solution was sonicated for approximately one minute. Several drops of acetic acid were added which immediately caused precipitation of the title compound which was obtained as a white solid after filtration (57 mg).
Reaction SMILES: [CH3:1][Mg+].[Br-].[Cl:4][C:5]1[CH:6]=[C:7]([C:11]2[O:15][N:14]=[C:13]([CH:16]=[O:17])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1>C1COCC1>[Cl:4][C:5]1[CH:6]=[C:7]([C:11]2[O:15][N:14]=[C:13]([CH:16]([OH:17])[CH3:1])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: C[Mg+]
Reactant: O=Cc1cc(-c2cccc(Cl)c2)on1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)c1cc(-c2cccc(Cl)c2)on1
Reaction time: 3 h
Yield: 124.2 %

Procedure:
MeMgBr (3M in THF, 313 mL, 937.2 mmol) was added dropwise at 0° C. to 5-(3-chlorophenyl)isoxazole-3-carbaldehyde (177 g, 252 mmol) in THF (3 L). The mixture was allowed to attain room temperature, stirred at that temperature for 3 h and then quenched with aq. NH4Cl at 0° C. and the solvent was distilled off. To the remaining was added EtOAc and filtered through a plug of celite. The organic layer was washed with water, saturated brine and concentrated. The crude product was purified by flash column chromatography on silica using heptane/EtOAc=80:20, to give the title compound (70 g, 37%) as a white-yellow solid. 1H NMR: 7.73 (m, 1H), 7.63 (m, 1H), 7.38 (m, 2H), 6.57 (s, 1H), 5.07 (q, 1H), 2.44 (s, 1H), 1.59 (d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:22][N:23]([CH3:27])[C:24](Cl)=[S:25]>C(#N)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:24](=[S:25])[N:23]([CH3:27])[CH3:22])=[C:6]([C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=1
Reactant: COC(=O)c1ccc(O)c(C(C)(C)C)c1
Reactant: CN(C)C(=S)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1ccc(OC(=S)N(C)C)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
A solution of 3.0 g (14.4 mmol) of 3-tert-butyl-4-hydroxy-benzoic acid methyl ester (Aust. J. Chem., 1978;31:907-916), cesium carbonate (7.04 g, 21.6 mmol), and acetonitrile (50 mL) was heated to reflux and then treated with N,N-dimethylthiocarbamoyl chloride (2.67 g, 21.6 mmol) all at once. The mixture was refluxed for 2 hours, cooled to room temperature. and quenched with 1N HCl. The solution was extracted with EtOAc; the organic layer was washed with 1N NaOH and brine, dried (MgSO4), and concentrated. The residue was chromatographed over silica gel, eluting with 3:2 hexane:EtOAc, to give 3-tert-butyl-4-dimethylthiocarbamoyloxy-benzoic acid methyl ester.
Reaction SMILES: C[O-].[Na+].Cl.[CH3:5][O:6][CH2:7][C:8]([NH2:10])=[NH:9].[Cl:11][CH2:12][C:13](=O)[CH2:14][C:15](OCC)=[O:16].Cl>CO.O.CCOCC>[Cl:11][CH2:12][C:13]1[N:10]=[C:8]([CH2:7][O:6][CH3:5])[N:9]=[C:15]([OH:16])[CH:14]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: COCC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: COCc1nc(O)cc(CCl)n1
Reaction time: 3 h
Yield: 94.4 %

Procedure:
Sodium methylate (11.90 g, 0.22 mole) was added to a solution of methoxyacetamidine hydrochloride (12.45 g, 0.1 mole) and ethyl 4-chloroacetoacetate (16.50 g, 0.1 mole) in methanol (50 ml) at 5° to 10° C. with stirring. The resulting orange reaction mixture was stirred at 5° to 10° C. for 2 hours and then at 20° C. for 3 hours, and neutralized with conc. hydrochloric acid. The precipitate was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue which was then dissolved in water (300 ml). The aqueous solution was extracted with chloroform, and the chloroform extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crystalline residue. The residue was suspended in ether and then filtered to obtain 17.8 g of 6-(chloromethyl)-4-hydroxy-2-(methoxymethyl)pyrimidine as pale brown needle-like crystals (m.p. 124.0°-125.5° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:22]2[CH:26]=[N:25][NH:24][C:23]2=[O:27])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1.CS(C)=O.[OH-].[K+].Br[CH:35]([CH2:37][CH3:38])[CH3:36]>O>[Br:1][C:2]1[CH:3]=[C:4]([N:22]2[CH:26]=[N:25][N:24]([CH:35]([CH3:36])[CH2:37][CH3:38])[C:23]2=[O:27])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1
Reactant: CCC(C)Br
Reactant: COc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cc3Br)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCC(C)n1ncn(-c2ccc(N3CCN(c4ccc(OC)cc4)CC3)c(Br)c2)c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 29.8 %

Procedure:
To a stirred mixture of 45 parts of 4-[3-bromo-4-[4-(4-methoxyphenyl)-1-piperazinyl]-phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one and 90 parts of dimethyl sulfoxide were added 15 parts of potassium hydroxide (pulverized). Then there were added 6.2 parts of 2-bromobutane and the whole was stirred for 20 hours at room temperature. The reaction mixture was poured into water. The produce was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of methylbenzene and hexane (1:2 by volume). The precipitated product was filtered off and recrystallized from 80 parts of methanol. The product was filtered off and dried in vacuo at 60° C., yielding a first fraction of 14.7 parts (29.8%) of 4-[3-bromo-4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one; mp. 144.6° C. The less pure fractions were collected and the eluent was evaporated. The residue was further purified by column chromatography (HPLC) over silica gel using a mixture of ethyl acetate and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from methanol, yielding a second fraction of 4-[3-bromo-4-[4-(4-methoxyphenyl)-1-piperazinyl]-phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one; mp. 144.7° C. (int. 35).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1.Cl[CH2:20][C:21]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][N:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:20][C:21]3[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:3][C:4]2=[O:18])=[CH:11][CH:12]=1
Reactant: O=c1cc(O)ccn1CCc1ccc(CO)cc1
Reactant: Cc1cccnc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccnc1COc1ccn(CCc2ccc(CO)cc2)c(=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 500 mg (2.04 mmol) 4-hydroxy-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 2b) in 10 mL DMF is added 472 mg (2.65 mmol) 2-chloromethyl-3-methyl-pyridine and 845 mg (6.12 mmol) potassium carbonate. The reaction mixture is stirred overnight at RT, filtered and directly transferred to a reverse HPLC for purification (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.OC[C:27]#[C:28][C:29]1[CH:39]=[CH:38][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][CH:30]=1.O>C(Cl)Cl>[Br:5][CH2:1][C:27]#[C:28][C:29]1[CH:39]=[CH:38][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][CH:30]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCOC(=O)c1ccc(C#CCO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1ccc(C#CCBr)cc1
Reaction time: 13 h
Yield: 109.2 %

Procedure:
1.7 g of carbon tetrabromide and 1.15 g of triphenylphosphine were added to 10 ml of a solution of 0.70 g of ethyl 4-(3-hydroxy-1-propynyl)benzoate in methylene chloride at room temperature. The obtained mixture was stirred at that temperature for 13 hours, followed by the addition thereto of 20 ml of water. The obtained mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel chromatography (developer: 5% diethyl ether/n-hexane) to give 1.0 g of the title compound as a pale-yellow oil. 1H-NMR (400 MHz, CDCl3) δ(ppm); 1.38(t, J=7.2 Hz, 3H), 4.17(s, 2H), 4.36(q, J=7.2 Hz, 2H), 7.50(d, J=8.4 Hz, 2H), 7.99(d, J=8.4 Hz, 2H)
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22](Cl)=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(C1C=CC(C2C=CC(C(OC(C)C(C3C=CC(OCC=C)=CC=3)=O)=O)=CC=2)=CC=1)CCCCCC.[C:61]([O:67][CH:68]([CH3:78])[C:69]([C:71]1[CH:76]=[CH:75][C:74]([OH:77])=[CH:73][CH:72]=1)=[O:70])(=[O:66])[CH2:62][CH2:63][CH2:64][CH3:65]>CN(C1C=CN=CC=1)C>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:77][C:74]3[CH:75]=[CH:76][C:71]([C:69](=[O:70])[CH:68]([O:67][C:61](=[O:66])[CH2:62][CH2:63][CH2:64][CH3:65])[CH3:78])=[CH:72][CH:73]=3)=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCC(=O)OC(C)C(=O)c1ccc(O)cc1
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Agent: C=CCOc1ccc(C(=O)C(C)OC(=O)c2ccc(-c3ccc(CCCCCCC)cc3)cc2)cc1
Agent: CN(C)c1ccncc1
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3ccc(C(=O)C(C)OC(=O)CCCC)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 500 mg of 4'-octyloxy-biphenyl-4-yl-carboxylic acid chloride, 400 mg of (S) 4-(2-pentanoyloxy-1-keto-propyl)phenol, 600 mg of N,N-dicyclohexylcarbodiimide, and 20 mg of DMAP was stirred at room temperature for three hours. A solid material precipitated was removed by filtration. The organic layer thus obtained was washed with an acid, an alkali, and with water, dried, and then concentrated.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]2([O:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[FH:23].F.F.C(N(CC)CC)C>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]([F:23])([CH2:12][OH:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: F
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(F)(CO)CC1
Temperature: 120 °C
Reaction time: 6.5 h
Yield: 15.7 %

Procedure:
1-Oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (144 mg, 679 μmol), triethylamine (1.10 mL, 6.79 mmol) and triethylamine trihydrofluoride (2.85 mL, 20.4 mmol) were mixed in a sealed test tube. This mixture was stirred at 120° C. for 6.5 hours. The reaction mixture was cooled, and then quenched with a 2 N aqueous NaOH solution and extracted with ethyl acetate three times. The organic layers were combined, washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-AcOEt) to give 4-fluoro-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (24.9 mg, 16%).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[C:12]=1[C:13]([NH:15][CH3:16])=[O:14]>O.CO.[Zn]>[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[C:13](=[O:14])[N:15]([CH3:16])[NH:21]2
Reactant: CNC(=O)c1c(-c2ccc(C)cc2C)cccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: Cc1ccc(-c2cccc3[nH]n(C)c(=O)c23)c(C)c1
Yield: 12 %

Procedure:
A solution of sodium hydroxide (0.035 g, 0.88 mmol) in water (2 ml) was added to a solution containing 0.095 g (0.33 mmol) of 2-(2,4-dimethylphenyl)-N-methyl-6-nitrobenzamide in methanol (1.5 ml). Zinc powder (0.03 g, 0.44 mmol) was then added to the mixture, which was heated under reflux for 24 h. After cooling, the zinc residue was separated by filtration and the methanol was partially evaporated. The residual solution was then adjusted to pH 7 with aqueous hydrochloric acid. The mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via biotage eluting with 40% ethyl acetate/hexanes gave 0.01 g (22%) of product.
Reaction SMILES: [Si](OC(COC1C=CC=CC=1)/C=C/[CH:12]1[CH2:19][CH2:18][CH:17]2[CH:13]1[CH2:14][CH2:15][C:16]2=[O:20])(C(C)(C)C)(C)C.OC(C1CC2C(CCC2)C1=O)CCCC(OC)=O>>[CH:13]12[CH2:14][CH2:15][C:16](=[O:20])[CH:17]1[CH2:18][CH2:19][CH2:12]2
Reactant: CC(C)(C)[Si](C)(C)OC(/C=C/C1CCC2C(=O)CCC12)COc1ccccc1
Agent: COC(=O)CCCC(O)C1CC2CCCC2C1=O
Product: O=C1CCC2CCCC12

Procedure:
By proceeding in a manner to that described in Reference Example 47, but replacing the starting material by the appropriate quantity of (E)-2-(3-tert-butyldimethylsilyloxy-4-phenoxybut-1-enyl)bicyclo[3,3,0]octan-6-one, prepared as described in Reference Example 52, and in the form of (±)-(E)-2β-[(mixture of 3α and 3β)-tert-butyldimethylsilyloxy-4-phenoxybut-1-enyl]bicyclo[3,3,0]octan-6-one, there was prepared 6-(E)-3-tert-butyldimethylsilyloxy-4-phenoxybut-1-enyl-3-(1-hydroxy-4-methoxycarbonylbut-1-yl)-bicyclo[3,3,0]octan-2-one, in the form of (±)-6β-[(E)-(mixture of 3α and 3β)-tert-butyldimethylsilyloxy-4-phenoxybut-1-enyl]-3-(1-hydroxy-4-methoxycarbonylbut-1-yl)bicyclo[3,3,0]octan-2-one.