Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:14])[CH2:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23]>CN(C)C=O.C(OCC)(=O)C>[CH2:23]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:14])[CH2:7][C:8]([CH3:12])([CH3:13])[O:9]2)=[CH:4][CH:3]=1)[CH:22]=[CH2:21]
Reactant: CC1(C)CC(=O)c2ccc(O)cc2O1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOc1ccc2c(c1)OC(C)(C)CC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
9.74 g of 7-hydroxy-2,2-dimethyl-4-oxochroman (CAS#: 17771-33-4) was dissolved in 150 ml of N,N-dimethylformamide. Thereafter, 10.5 g of potassium carbonate and 7.36 g of allyl bromide were added to the reaction solution, and the obtained mixture was stirred at room temperature overnight. Thereafter, the reaction solution was diluted with ethyl acetate, and then washed with water and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was then purified by silica gel column chromatography (hexane-ethyl acetate), so as to obtain 11.0 g of the subject compound.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH:21]([CH3:23])[CH3:22])[C:4]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1)=O.[S-:24][C:25]#[N:26].[Na+].Cl>C(O)(=O)C>[C:17]([C:8]1[CH:7]=[C:6]([C:4]2[NH:26][C:25](=[S:24])[NH:2][C:3]=2[CH:21]([CH3:23])[CH3:22])[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]=1[OH:16])([CH3:20])([CH3:19])[CH3:18]
Reactant: N#C[S-]
Reactant: CC(C)C(N)C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)c1[nH]c(=S)[nH]c1-c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 23.2 %

Procedure:
By following the same procedure as in Example 8 using 3.4 g of 2-amino-1-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-methyl-1-butanone hydrochloride, 1.6 g of sodium thiocyanate, 1 ml of concentrated hydrochloric acid, and 31 ml of acetic acid and recrystallizing the reaction product from water-containing isopropanol, 0.8 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-isopropyl-2-thioxo-4-imidazoline was obtained.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14](=[O:22])[CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>C(OCC)(=O)C>[CH3:6][N:4]([CH3:5])[CH:3]=[C:15]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[C:14]([C:10]1[O:9][CH:13]=[CH:12][CH:11]=1)=[O:22]
Reactant: COC(OC)N(C)C
Reactant: O=C(Cc1ccncc1)c1ccco1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CN(C)C=C(C(=O)c1ccco1)c1ccncc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
N,N-Dimethylformamide dimethylacetal (5 mL) was added to 1-(2-furyl)-2-(4-pyridyl)-1-ethanone (2.0 g, 10.7 mmol), followed by stirring at 100° C. for 2 hours. After cooling as it was, the reaction solution was diluted with ethyl acetate and an aqueous saturated solution of ammonium chloride. The aqueous layer was extracted with ethyl acetate (×6). The combined organic layer was dried over anhydrous sodium sulfate and concentrated, to give the title compound (2.5 g, 97%) as a reddish brown oil.
Reaction SMILES: Br[C:2]12[CH2:12][C:6]3([CH3:13])[CH2:7][C:8]([CH3:11])([CH2:10][C:4]([C:14]45[CH2:24][C:18]6([CH3:25])[CH2:19][C:20]([CH3:23])([CH2:22][C:16](Br)([CH2:17]6)[CH2:15]4)[CH2:21]5)([CH2:5]3)[CH2:3]1)[CH2:9]2.[C:27]1([OH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O>[OH:33][C:27]1[CH:32]=[CH:31][C:30]([C:2]23[CH2:12][C:6]4([CH3:13])[CH2:7][C:8]([CH3:11])([CH2:10][C:4]([C:14]56[CH2:24][C:18]7([CH3:25])[CH2:19][C:20]([CH3:23])([CH2:22][C:16]([C:30]8[CH:31]=[CH:32][C:27]([OH:33])=[CH:28][CH:29]=8)([CH2:17]7)[CH2:15]5)[CH2:21]6)([CH2:5]4)[CH2:3]2)[CH2:9]3)=[CH:29][CH:28]=1
Reactant: Oc1ccccc1
Reactant: CC12CC3(C)CC(Br)(C1)CC(C14CC5(C)CC(C)(CC(Br)(C5)C1)C4)(C2)C3
Solvent: O
Product: CC12CC3(C)CC(c4ccc(O)cc4)(C1)CC(C14CC5(C)CC(C)(CC(c6ccc(O)cc6)(C5)C1)C4)(C2)C3
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 99.1 %

Procedure:
Into a 5 liter four-necked separable flask equipped with a thermometer, a stirrer, an inlet for nitrogen gas and a reflux condenser, 48.4 g (0.1 mole) of 3,3′-dibromo-5,5′,7,7′-tetramethyl-1,1′-biadamantane and 688 g (7.3 moles) of phenol were placed, and the resultant mixture was heated under the refluxing condition at 155° C. for 30 minutes. After the mixture was cooled at the room temperature, 4.3 liters of pure water was added, and the obtained mixture was heated under the refluxing condition at 80° C. for 10 minutes. The formed precipitates were separated by filtration, and the solid substance was mixed with 7 liters of pure water and stirred for 10 minutes. The solid substance was separated by filtration and dried at 60° C. under a reduced pressure for 24 hours, and 50.6 g of 3,3′-bis(4-hydroxyphenyl)(5,5′,7,7′-tetramethyl)-1,1′-biadamantane was obtained (the yield: 99%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:15].Br[CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21]>>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:6]1=[O:15]
Reactant: COC(=O)CC1Cc2ccccc2NC1=O
Reactant: CC(C)CCBr
Product: COC(=O)CC1Cc2ccccc2N(CCC(C)C)C1=O

Procedure:
Following a similar N-alkylation procedure described in example 9, the (2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-acetic acid methyl ester (0.068 mmol) obtained in the previous step is alkylated with 1-bromo-3-methylbutane to give the crude [1-(3-methyl-butyl)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]-acetic acid methyl ester, which is used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[C@H:12]([CH2:13][OH:14])[CH2:11][CH2:10][S:9]2(=[O:16])=[O:15])[CH:5]=[C:4]([F:17])[C:3]=1[C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][N:27]=2)[CH2:22][CH2:21]1)=[O:19].[H-].[Na+].S(C1C=CC(C)=CC=1)(O[CH3:40])(=O)=O.O>O1CCCC1>[F:17][C:4]1[CH:5]=[C:6]([N:8]2[C@H:12]([CH2:13][O:14][CH3:40])[CH2:11][CH2:10][S:9]2(=[O:15])=[O:16])[CH:7]=[C:2]([F:1])[C:3]=1[C:18]([N:20]1[CH2:21][CH2:22][N:23]([C:26]2[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][N:27]=2)[CH2:24][CH2:25]1)=[O:19]
Reactant: Cc1cnc(N2CCN(C(=O)c3c(F)cc(N4[C@H](CO)CCS4(=O)=O)cc3F)CC2)c(C)c1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC[C@@H]1CCS(=O)(=O)N1c1cc(F)c(C(=O)N2CCN(c3ncc(C)cc3C)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1.8 %

Procedure:
(S)-[2,6-difluoro-4-(3-hydroxymethyl-1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl][4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (270 mg) described in Example 35 was dissolved in tetrahydrofuran, sodium hydride (48 mg) was added, and the mixture was stirred at room temperature for 30 min. Then, to the reaction mixture was added methyl tosylate (203 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (5 mg).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[N:28]=[C:27]([NH2:29])[N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][NH:24]2.C(N(C(C)C)C(C)C)C>CCCCO>[C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:20]2[N:28]=[C:27]([NH2:29])[N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][NH:24]3)[CH3:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](N)c1nc2ccccc2n1-c1ccccc1
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1nc(N)nc2[nH]cnc12)c1nc2ccccc2n1-c1ccccc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
Into a 25-mL round-bottom flask was placed a solution of (S)-1-(1-phenyl-1H-benzo[d]imidazol-2-yl)ethanamine from Example 4 (238 mg, 1.00 mmol, 1.00 equiv) in n-BuOH (8 mL), 6-chloro-9H-purin-2-amine (155 mg, 0.91 mmol, 0.91 equiv, 98%) and N-ethyl-N-isopropylpropan-2-amine (390 mg, 2.96 mmol, 2.95 equiv, 98%). The resulting solution was stirred overnight at 130° C. and concentrated under vacuum. The residue was eluted onto a C18 column (water/acetonitrile) to afford 0.150 g (40%) of 149 as a white solid. LC-MS (ES, m/z): 371 [M+H]+. H-NMR (300 MHz, CD3OD, ppm): δ 7.71 (d, 2H), 7.51 (s, 5H), 7.29 (m, 2H), 7.10 (d, 1H), 5.67 (s, 1H), 1.69 (d, 3H)
Reaction SMILES: Br[CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH3:13])[C:3]1=O.Cl.[NH:16]1[CH:20]=[C:19]([CH2:21][C:22]([NH2:24])=[S:23])[N:18]=[CH:17]1>>[NH:16]1[CH:20]=[C:19]([CH2:21][C:22]2[S:23][C:2]3[CH2:11][CH2:10][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][C:8]=4[O:12][CH3:13])[C:3]=3[N:24]=2)[N:18]=[CH:17]1
Reactant: NC(=S)Cc1c[nH]cn1
Reactant: COc1cccc2c1CCC(Br)C2=O
Agent: Cl
Product: COc1cccc2c1CCc1sc(Cc3c[nH]cn3)nc1-2

Procedure:
Starting compounds: 2-bromo-5-methoxy-1-tetralone, 4-imidazolylthioacetamide hydrochloride
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[CH3:9][C:10]1[NH:14][CH:13]=[N:12][C:11]=1/[CH:15]=[CH:16]/[C:17]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)=[O:18]>CO.[Pd]=O>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[CH3:9][C:10]1[NH:14][CH:13]=[N:12][C:11]=1[CH2:15][CH2:16][C:17]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)=[O:18]
Reactant: Cc1[nH]cnc1/C=C/C(=O)c1ccc2ccccc2c1
Agent: O=[Pd]
Agent: O=C(O)/C=C\C(=O)O
Solvent: CO
Product: Cc1[nH]cnc1CCC(=O)c1ccc2ccccc2c1
Yield: 69.6 %

Procedure:
A solution of (E)-3-(5-methyl-1H-imidazol-4-yl)-1-(2-naphthalenyl)-2-propen-1-one maleate (300 mg) in hot methanol (90 ml) was hydrogenated at room temperature and atmospheric pressure over a stirred suspension of pre-reduced 10% palladium oxide on carbon (50% aqueous paste; 30 mg) in methanol (10 ml) for 16 h. The suspension was filtered, evaporated in vacuo, and the residual oil (ca. 350 mg) was partitioned between dichloromethane (3×50 ml) and 2N sodium carbonate (50 ml). The combined organic extracts were dried and evaporated in vacuo. The residual oil (300 mg) was dissolved in absolute ethanol (6 ml) and treated with a solution of maleic acid (100 mg) in ethanol (1 ml). Dilution with dry ether (ca. 75 ml) afforded the title compound (210 mg) as a solid, m.p. 137°-138°, t.l.c. (System A, 89:10:1) Rf 0.33.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.Cl[CH2:25][CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29]>C1COCC1>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[CH2:25][CH2:26][CH2:27][S:28]2(=[O:30])=[O:29])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCN2CCCS2(=O)=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-Boc-4-(2-aminoethyl)-piperazine (1.26 g, 6.8 mmol) and triethylamine (1 mL) in THF (10 ML), 3-chloro-propylsulfonyl chloride (Aldrich, 0.68 mL, 6.94 mmol) was added slowly at room temperature. The mixture was stirred for 30 minutes at and the reaction was quenched with water. The new mixture was extracted with ethyl acetate and the extracts were combined and dried (Na2SO4). The solution was concentrated and the residue was dissolved in THF (20 mL) and Cs2CO3 (500 mg), NaI (80 mg) were added and the mixture was stirred at reflux overnight. The mixture was cooled to room temperature and poured into water. The new mixture was extracted with ethyl acetate (3×15 mL) and the extracts were combined and dried (Na2SO4). Removal of the solvent on a rotary evaporator gave a solid. 2.01 g.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=O)=[CH:5][CH:4]=[N:3]1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[CH3:1][N:2]1[C:6]([CH2:7][NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][CH:11]=2)=[CH:5][CH:4]=[N:3]1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Cn1nccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cn1nccc1CNc1ccc(C(F)(F)F)cc1
Reaction time: 0.17 h
Yield: 81.1 %

Procedure:
Acetic acid (0.87 mL) was added to a chloroform (10 mL) solution that contained 1-methyl-1H-pyrazol-5-carbaldehyde (1.00 g) and 4-aminobenzotrifluoride (1.76 g) at a room temperature, and the obtained solution was then stirred for 10 minutes. Thereafter, sodium triacetoxyborohydride (2.89 g) was added to the reaction solution, and the obtained mixture was then stirred for 5.5 hours. Thereafter, a saturated sodium hydrogencarbonate aqueous solution was added to the reaction solution, and the obtained mixture was then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and was then concentrated under a reduced pressure. The obtained solid was washed with diisopropyl ether, so as to obtain the title compound (1.88 g) in the form of a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].[F:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1.N>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][C:19]=2[OH:23])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: Oc1cccc(F)c1
Agent: N
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(Cc1ccc(Cl)cc1)c1ccc(F)cc1O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-chlorophenylacetyl chloride (27.6 g, 0.15 mol) in 1,2-dichloroethane (200 ml), cooled to 0° C. in an ice bath, under nitrogen is added slowly AlCl3 (21.8 g, 0.16 mol). The reaction mixture is stirred at 0° C. for 20 min. 3-fluorophenol (12.2 g, 0.11 mol) is added, and the reaction mixture is allowed to warm to room temperature, then heated at 90° C. for 16 h. The reaction mixture is cooled to room temperature, then poured cautiously into aqueous ammonia solution (500 ml) with vigourous stirring. The mixture is diluted with CH2Cl2 (250 ml) and filtered through Celite. The organic phase is separated, washed with water, brine and dried (MgSO4). The solvent is removed in vacuo, and the crude product is purified by flash chromatography on silica gel using iso-hexane:ethyl acetate (10:1 to 4:1) as the eluent to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([C@H:13]([OH:15])[CH3:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:16][N:17]1[C:21](S(C)(=O)=O)=[N:20][N:19]=[C:18]1[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([C@H:13]([O:15][C:21]3[N:17]([CH3:16])[C:18]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[N:19][N:20]=3)[CH3:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(-c2cccnc2)nnc1S(C)(=O)=O
Reactant: C[C@@H](O)c1cc(-c2cccc(Cl)c2)on1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](Oc1nnc(-c2cccnc2)n1C)c1cc(-c2cccc(Cl)c2)on1
Temperature: 60 °C
Yield: 77.2 %

Procedure:
(1R)-1-[5-(3-chlorophenyl)isoxazol-3-yl]ethanol (5.40 g, 24.1 mmol) was dissolved in DMF (45 mL). To this 3-[4-methyl-5-(methylsulfonyl)-4H-1,2,4-triazol-3-yl]pyridine (5.75 g, 24.1 mmol) and cesium carbonate (10.1 g, 31.4 mmol) were added. After stirring over night at 60° C., water was added. The mixture was extracted with dichloromethane, followed by concentration of the organic layer in vacuo, to give a crude which was purified by column chromatography on silica using dichloromethane/methanol=98/2, to give the title compound (7.10 g, 77%). 1H NMR: 8.90 (d, 1H), 8.72 (m, 1H), 8.04 (dt, 1H), 7.76 (bs, 1H), 7.66 (m, 1H), 7.45 (m, 1H), 7.40 (m, 2H), 6.73 (s, 1H), 6.35 (q, 1H), 3.57 (s, 3H), 1.93 (d, 3H). 1H NMR (DMSO-d6): 8.90 (d, 1H), 8.71 (dd, 1H), 8.13 (dt, 1H), 7.99 (s, 1H), 7.86 (m, 1H), 7.58 (m, 3H), 7.40 (s, 1H), 6.19 (q, 1H), 3.54 (s, 3H), 1.81 (d, 3H). LC-MS (M++1)=382. [α]DRT (2.92 g/L, CDCl3)=−46.575°
Reaction SMILES: C(N(CC)CC)C.[O:8]([C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]2[C@@H:31]([CH2:32][CH2:33][C@@H:34]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[OH:35])[C:30](=[O:43])[N:29]2[C:44]2[CH:49]=[CH:48][C:47](I)=[CH:46][CH:45]=2)=[CH:24][CH:23]=1)[C@@H:9]1[O:17][C@H:16]([C:18]([O:20][CH3:21])=[O:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]1[OH:11].[CH2:51]([NH:54][S:55]([CH3:58])(=[O:57])=[O:56])[C:52]#[CH:53]>CN(C=O)C.[Cu](I)I>[O:8]([C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]2[C@@H:31]([CH2:32][CH2:33][C@@H:34]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[OH:35])[C:30](=[O:43])[N:29]2[C:44]2[CH:49]=[CH:48][C:47]([C:53]#[C:52][CH2:51][NH:54][S:55]([CH3:58])(=[O:57])=[O:56])=[CH:46][CH:45]=2)=[CH:24][CH:23]=1)[C@@H:9]1[O:17][C@H:16]([C:18]([O:20][CH3:21])=[O:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]1[OH:11]
Reactant: C#CCNS(C)(=O)=O
Reactant: COC(=O)[C@H]1O[C@@H](Oc2ccc([C@@H]3[C@@H](CC[C@H](O)c4ccc(F)cc4)C(=O)N3c3ccc(I)cc3)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1O[C@@H](Oc2ccc([C@@H]3[C@@H](CC[C@H](O)c4ccc(F)cc4)C(=O)N3c3ccc(C#CCNS(C)(=O)=O)cc3)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 18 h

Procedure:
Triethylamine (0.07 mL, 0.502 mmol) was added to a stirred solution of 4-[(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-(4-iodophenyl)-4-oxoazetidin-2-yl]phenyl methyl β-D-glucopyranosiduronate (i-7) (0.050 g, 0.071 mmol), N-prop-2-yn-1-ylmethanesulfonamide (i-5) (0.014 g, 0.105 mmol), tetrakistriphenylphosphine palladium(0) (0.012 g, 0.010 mmol) and copper iodide (0.005 g, 0.026 mmol) in DMF (0.5 mL) under a nitrogen atmosphere and the resulting solution aged at room temperature for 18 h. The volatiles were evaporated in vacuo and the crude residue purified by flash chromatography on silica gel (gradient elution; 0-25% methanol/methylene chloride as eluent) to afford the title compound; m/z (ES) 713 (MH+), 505.
Reaction SMILES: [CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:31]=[CH:30][C:20]([O:21][CH2:22][C:23]3(O)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[F:32][C@@H:33]([CH2:37][CH2:38][CH2:39][CH3:40])[C:34]([OH:36])=[O:35].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[F:32][C@@H:33]([CH2:37][CH2:38][CH2:39][CH3:40])[C:34]([O:36][C@H:26]1[CH2:27][CH2:28][C@H:23]([CH2:22][O:21][C:20]2[CH:30]=[CH:31][C:17]([C:14]3[N:13]=[CH:12][C:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:16][N:15]=3)=[CH:18][CH:19]=2)[CH2:24][CH2:25]1)=[O:35]
Reactant: CCCC[C@H](F)C(=O)O
Reactant: CCCCCCCCCCc1cnc(-c2ccc(OCC3(O)CCCCC3)cc2)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCCCc1cnc(-c2ccc(OC[C@H]3CC[C@H](OC(=O)[C@@H](F)CCCC)CC3)cc2)nc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
0.62 g of trans-4-[(p-(5-decyl-2-pyrimidinyl)phenoxymethyl]cyclohexanol, 0.196 g of (S)-2-fluorocaproic acid, 0.413 g of dicyclohexylcarbodiimide and 0.025 g of 4-(dimethylamino)pydidine were dissolved in 25 ml of methylene chloride and stirred at room temperature for 15 hours. The white suspension was subsequently filtered. The residue obtained after evaporation of the solvent from the filtrate was purified by chromatography on silica gel with ethyl acetate/petroleum ether (vol. 1:9). Subsequent crystallization from 10 ml of ethyl acetate and 50 ml of hexane gave 0.62 g of trans-4-[(p-(5-decyl-2-pyrimidinyl)phenoxy)methyl]cyclohexyl (S)-2-fluorohexanoate as colourless crystals, m.p. (C-S) 88.5° C., phase transitions (S-SC) 108.8° C., (SC -SA) 128° C., cl.p. (SA -I) 137.7° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH:22]3[CH2:24][CH2:23]3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:26])[CH3:2].[CH2:28]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[C:29]#[CH:30].C(OC(=O)COC1C=CC(SC2C=C(C#CC3C=CC(CO)=CC=3)C=C(OCCC3C=CC(Cl)=CC=3)C=2)=CC=1C)C>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:15]=[C:16]([C:30]#[C:29][CH2:28][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:17]=[C:18]([O:20][CH2:21][CH:22]3[CH2:24][CH2:23]3)[CH:19]=2)=[CH:9][C:8]=1[CH3:26])[CH3:2]
Reactant: C#CCN1CCOCC1
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OCC3CC3)c2)cc1C
Agent: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(OCC3CC3)c2)cc1C

Procedure:
The title product was prepared from [4-(3-Bromo-5-cyclopropylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (250 mg; 0.55 mmol) and 4-prop-2-ynyl-morpholine (208 mg; 1.7 mmol) applying the procedure described for {4-[3-[2-(4-Chlorophenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 205 mg; 75%. HPLC-MS: m/z: 496.1 (M+H)+; Rt: 2.04 min.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[Cl:13][C:10]1[CH:11]=[CH:12][C:3]([CH2:2][C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([F:14])[CH:20]=2)=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Cl)ccc1CBr
Reactant: OB(O)c1cccc(F)c1
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: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1cc(Cl)ccc1Cc1cccc(F)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 33.7 %

Procedure:
A mixture of methyl 2-(bromomethyl)-5-chlorobenzoate (step 1, 300 mg, 1.14 mmol) and tetrakis(triphenylphosphine)palladium (0) (132 mg, 0.11 mmol) in 1,2-dimethoxyethane (6 mL) was stirred at 50° C. under nitrogen for 30 min. Then 3-fluorophenylboronic acid (191 mg, 1.37 mmol) and 2 M sodium carbonate solution (2.28 mL, 4.55 mmol) was added, and the resulting mixture was heated at 90° C. under nitrogen for 16 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (50 mL) and washed with 1 M hydrochloric acid (30 mL), saturated sodium hydrogen carbonate aqueous (30 mL), and brine (30 mL). The organic layer was dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by TLC [hexane/ethyl acetate (8:1)] to give 107 mg (34%) of the title compound as colorless oil: 1H-NMR (CDCl3) δ 7.91 (1H, d, J=2.4 Hz), 7.41 (1H, dd, J=8.4, 2.4 Hz), 7.26–7.14 (2H, m), 6.91–6.79 (3H, m), 4.34 (2H, s), 3.84 (3H, s).