Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])=[C:8]([O:23][CH2:24][CH3:25])[CH:7]=2.[NH:36]1[CH2:41][CH2:40][CH:39]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)[CH2:38][CH2:37]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:24]([O:23][C:8]1[CH:7]=[C:6]2[C:11]([C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:3]([CH2:2][N:36]3[CH2:41][CH2:40][CH:39]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[CH2:38][CH2:37]3)[C:4]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)=[N:5]2)=[CH:10][C:9]=1[S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[CH3:25]
Reactant: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CBr)c(C(=O)OC)c2cc1S(=O)(=O)C(C)C
Reactant: C1CC(N2CCOCC2)CCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)OC)c2cc1S(=O)(=O)C(C)C
Yield: 32.2 %

Procedure:
A solution of methyl 3-(bromomethyl)-7-(ethyloxy)-6-[(1-methylethyl)sulfonyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (3.5 g, 6.09 mmol), 4-(4-piperidinyl)morpholine (1.778 g, 7.31 mmol), and N,N-diisopropylethylamine (2.13 mL, 12.19 mmol) in acetonitrile (50 mL) was stirred at room temperature for 1.5 h. The solvent was removed under reduced pressure, and the residue was partitioned between a 10% sodium carbonate solution and methylene chloride. The organic phase was separated and washed with Na2CO3. The organic phase was extracted with 2N HCl (three times). The aqueous extracts were cooled in an ice bath and adjusted to pH 12 with 6N NaOH. The precipitated solid was extracted with methylene chloride (three times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to afford methyl 7-(ethyloxy)-6-[(1-methylethyl)sulfonyl]-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.3 g, 31% yield) as a yellow solid. This material was used without further purification. MS (m/z) 664.2 (M+H+).
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:16])[C:8]3[N:9]2[C:12](=[O:15])[NH:13][N:14]=3)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[CH:20]([C:23]1[NH:24][CH:25]=[CH:26][N:27]=1)([CH3:22])[CH3:21]>>[CH:20]([C:23]1[N:24]([C:2]2[CH:11]=[C:10]3[C:5]([NH:6][C:7](=[O:16])[C:8]4[N:9]3[C:12](=[O:15])[NH:13][N:14]=4)=[CH:4][C:3]=2[N+:17]([O-:19])=[O:18])[CH:25]=[CH:26][N:27]=1)([CH3:22])[CH3:21]
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c(F)cc2n2c(=O)[nH]nc12
Reactant: CC(C)c1ncc[nH]1
Product: CC(C)c1nccn1-c1cc2c(cc1[N+](=O)[O-])[nH]c(=O)c1n[nH]c(=O)n12

Procedure:
The title compound was prepared from 8-fluoro-7-nitro[1,2,4]triazolo[4,3-a]quinoxaline-1,4(2H,5H)-dione and 2-isopropylimidazole by a method analogous to the method described in example 11. M.p. 240° C. decomp.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[C:14](=[O:15])[CH2:13][CH2:12][C@H:11]1[CH:16]=[CH:17][CH:18]([O:26]C(=O)C)[CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C[O-].[Na+].C(O)(=O)C>CO>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[C:14](=[O:15])[CH2:13][CH2:12][C@H:11]1[CH:16]=[CH:17][CH:18]([OH:26])[CH2:19][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: COC(=O)CCCCCC[C@@H]1C(=O)CC[C@H]1C=CC(CC1CCCCC1)OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)CCCCCC[C@@H]1C(=O)CC[C@H]1C=CC(O)CC1CCCCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of trans-2-(4-cyclohexyl-3-acetoxy-1-butenyl)-5-oxocyclopentaneheptanoic acid methyl ester (265 g), prepared as described in Example 9, in methanol (287 ml) is added a solution of sodium methoxide (prepared from 172 g of sodium and 148 ml of methanol). The reaction mixture is stirred at room temperature for 90 min. then rendered neutral with one equivalent of acetic acid. The solvent is evaporated. The residue is taken up in ether. The ether solution is washed with water, dried and the solvent removed to yield the title compound, νmaxCHCl3 3,450, 1,735 cm-1.
Reaction SMILES: [CH:1]1([S:4]([N:7]2[CH2:12][CH2:11][N:10](C(O)=O)[CH2:9][CH2:8]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Cl:16]CCl.Cl>O1CCOCC1>[ClH:16].[CH:1]1([S:4]([N:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: ClCCl
Reactant: O=C(O)N1CCN(S(=O)(=O)C2CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=S(=O)(C1CC1)N1CCNCC1
Reaction time: 2.5 h

Procedure:
14.37 g of tert-butyl ester of 4-cyclopropanesulfonyl-piperazine-1-carboxylic acid is put in a 2-liter three-necked flask, under nitrogen atmosphere. 412 ml of dichloromethane is added. The reaction mixture is cooled in an ice bath and 4M hydrochloric acid in solution in dioxane is added dropwise. The reaction mixture is allowed to return gradually to room temperature. The reaction mixture is stirred for 2.5 h, then evaporated and concentrated. The residue is taken up in a small amount of ethyl ether, triturated and then filtered and dried. 10.25 g of 1-cyclopropanesulfonyl-piperazine hydrochloride is obtained in the form of a white powder.
Reaction SMILES: O[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25](=[O:59])[N:26]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]3[N:36]=[CH:37][N:38](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:39]=3)=[CH:30][N:29]=2)[CH:27]=1.CCN(C(C)C)C(C)C.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[CH:24][C:25](=[O:59])[N:26]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]3[N:36]([CH2:2][C:3]4[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH2:12][CH2:13][CH2:14][C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[CH:4]=4)[CH:37]=[N:38][CH:39]=3)=[CH:30][N:29]=2)[CH:27]=1
Reactant: N#Cc1ccc(CO)cc1OCCCc1ccccc1
Reactant: O=c1ccc(Cl)cn1-c1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cn1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)cc1OCCCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled solution (-78° C.) of 4-hydroxymethyl-2-(3-phenyl-propoxy)-benzonitrile from step 3 (35 mg, 0.13 mmol) and 5-chloro-5'-(1-trityl-1H-imidazol-4-ylmethyl)-[1,2']bipyridinyl-2-one from Example 23, Step 5 (70 mg, 0.13 mmol) in CH2Cl2 (650 μl) was added DIEA (50 μl, 0.27 mmol) followed immediately by the addition of Tf2O (33 μl, 0.19 mmol). The reaction mixture was stirred at -78° C. for 1 hour and was then transferred to an ice bath and stirred at 0° C. for another hour. The solvent was removed in vacuo. The residue was then dissolved in MeOH (650 μl) and heated to 60° C. for 14 hours. The MeOH was then removed in vacuo and the residue treated with saturated NaHCO3 (5 mL) and extracted with CH2Cl2 (2×10 mL). The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography [4% MeOH(5% NH4OH)/CH2Cl2) to yield the final product.
Reaction SMILES: [CH:1]1([C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2C(O)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23](=[O:26])([O-])[O-].[Na+].[Na+].O>CO>[CH:1]1([C:7]2[C:8]3[O:9][C:10]4[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:23](=[O:26])[C:19]=3[CH:20]=[CH:21][CH:22]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccccc1Oc1ccccc1C1CCCCC1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=c1c2ccccc2oc2c(C3CCCCC3)cccc12
Reaction time: 2 h
Yield: 77 %

Procedure:
A mixture of 18.4 g (65 mmol) of 2-(2-cyclohexylphenoxy)benzoic acid and 190 g of polyphosphoric acid is kept at 100° C. for 2 hours. The reaction mixture is then diluted with 200 ml of methanol, neutralized with sodium carbonate and poured onto about 800 ml of water. The product which has precipitated is filtered off, washed with water and dried under a high vacuum. 14.6 g (77%) of 4-cyclohexylxanthone, melting point 122°-124° C., result as a beige powder.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([CH2:8][C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[N:12]=[N:11][N:10]=2)[CH2:6][CH2:5][NH:4][C:3]1=[O:24].I[CH2:26][CH3:27].[H-].[Na+]>CN(C)C=O>[CH2:26]([N:4]1[CH2:5][CH2:6][N:7]([CH2:8][C:9]2[N:13]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)[N:12]=[N:11][N:10]=2)[C@H:2]([CH3:1])[C:3]1=[O:24])[CH3:27]
Reactant: C[C@@H]1C(=O)NCCN1Cc1nnnn1-c1ccc(C(F)(F)F)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCN(Cc2nnnn2-c2ccc(C(F)(F)F)cc2)[C@H](C)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (3R)-3-methyl-4-({1-[4-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-2-piperazinone (100 mg, 0.294 mmol, intermediate 18), in N,N-Dimethylformamide (DMF) (1 mL) was added iodoethane (0.026 mL, 0.323 mmol) and sodium hydride (23.5 mg, 0.588 mmol). The resulting reaction mixture was stirred at room temperature for 24 hours.
Reaction SMILES: [I:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.N1C=CN=C1.[CH3:23][C:24]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C)C=O>[Si:27]([O:13][CH2:12][C@H:11]1[O:14][C@@H:7]([N:6]2[CH:15]=[C:2]([I:1])[C:3](=[O:17])[NH:4][C:5]2=[O:16])[CH2:8][C@@H:9]1[OH:10])([C:24]([CH3:26])([CH3:25])[CH3:23])([CH3:29])[CH3:28]
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(I)c(=O)[nH]c2=O)C[C@@H]1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of 5-iodo-2′-deoxyuridine (5.0 g, 14 mmol) in 70 ml in dry N,N-dimethylformamide (DMF) was added imidazole (1.09 g, 16 mmol), followed by (2.41 g, 16 mmol) TBDMSCl at 0° C. The mixture was left in the ice bath and stirred overnight. The reaction was quenched with sat. aq. NaCl solution and extracted with EtOAc. After drying (MgSO4), the solvent was removed and the crude mixture was purified by chromatography on silica (EtOAc:petroleum ether 3:7). The product (33) (5.9 g, 90%) was obtained as a colourless solid. 1H NMR (d6 DMSO) δ 0.00 (s, 3H, CH3), 0.79 (s, 9H, tBu), 1.88-1.97 (m, 1H, H-2′), 2.00-2.05 (m, 1H, H-2′), 3.59-3.71 (m, 2H, H-5′), 3.75 (br s, 1H, H-4′), 4.06 (br s, 1H, H-3′), 5.18 (d, J=4.0 Hz, 1H, OH), 5.98 (t, J=5.9 Hz, 1H, H-1′), 7.89 (s, 1H, H-6), 11.62 (s, 1H, NH). Mass (−ve electrospray) calcd for C15H25IN2O5Si 468.06. Found 467.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:25][C:26](=[O:51])[C@H:27]([CH2:42][CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C@@H:28]([N:32]([CH:40]=[O:41])[O:33]C1CCCCO1)[CH2:29][CH2:30][CH3:31])[C:17](=[O:24])[NH:18][C:19]1[S:20][CH:21]=[N:22][N:23]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:25][C:26](=[O:51])[C@H:27]([CH2:42][CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C@@H:28]([N:32]([CH:40]=[O:41])[OH:33])[CH2:29][CH2:30][CH3:31])[C:17](=[O:24])[NH:18][C:19]1[S:20][CH:21]=[N:22][N:23]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC[C@@H]([C@@H](CCCc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)Nc1nncs1)N(C=O)OC1CCCCO1
Solvent: O
Solvent: CC(=O)O
Product: CCC[C@@H]([C@@H](CCCc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)Nc1nncs1)N(O)C=O
Yield: 68.5 %

Procedure:
A solution of (2R,3S)-3-(formyl-2-tetrahydropyranyloxyamino)-2-(3-phenyl-1-propyl)hexanoic acid [(1s)-5-benzyloxycarbonylamino-1-(1,3,4-thiadiazol-2-ylcarbamoyl)-1-pentyl]amide (23 mg, 0.032 mmol) in acetic acid-water (4:1, 1 mL) is heated to 50° C. for 16 h. The reaction mixture is concentrated, then dissolved in toluene and concentrated in vacuo. The procedure is repeated once again to afford the crude product which is recrystallized from dichloromethane-methanol-diethyl ether to provide (2R,3S)-3-(formyl-hydroxyamino)-2-(3-phenyl-1-propyl)hexanoic acid [(1S)-5-benzyloxycarbonylamino-1-(1,3,4-thiadiazol-2-ylcarbamoyl)-1-pentyl]amide as a solid (14 mg, 69% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4]([CH2:7][CH2:8][C:9]([NH:12]C(=O)OCC1C=CC=CC=1)([CH3:11])[CH3:10])(=[O:6])=[O:5].[H][H]>CO.[Pd]>[NH2:12][C:9]([CH3:11])([CH3:10])[CH2:8][CH2:7][S:4]([CH2:3][CH2:2][OH:1])(=[O:6])=[O:5]
Reactant: CC(C)(CCS(=O)(=O)CCO)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(N)CCS(=O)(=O)CCO
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of benzyl 4-(2-hydroxyethylsulfonyl)-2-methylbutan-2-ylcarbamate (790 mg, 2.40 mmol) in methanol (30 ml) was purged with nitrogen and palladium on carbon (10%, 120 mg) was added. The solution was put under a blanket of hydrogen (1.3 atmospheres) and stirred for 1.5 hours at room temperature. The suspension was filtered through 0.45 um PTFE and concentrated in vacuo to afford the title compound which was used without further purification. LRMS (ESI/APCI) m/z 196 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[F:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1>>[F:10][C:7]1[CH:6]=[C:3]([C:4]#[N:5])[C:2]([C:13]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=2[F:11])=[CH:9][CH:8]=1
Reactant: N#Cc1cc(F)ccc1Br
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Product: N#Cc1cc(F)ccc1-c1cc([N+](=O)[O-])ccc1F

Procedure:
2-Bromo-5-fluorobenzonitrile was coupled to 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane as described in Example 51 to give 4,2′-difluoro-5′-nitrobiphenyl-2-carbonitrile as a black solid: δH (360 MHz, CDCl3) 7.38-7.56 (4H, m), 8.33-8.40 (2H, m).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[C@H:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([O:30][CH3:31])=[CH:28][C:27]([CH2:32]OCC)=[CH:26][C:25]=2[O:36][CH3:37])=[CH:20][CH:19]=1)[NH:6][C:7](=[O:16])[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:59]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:38])[C@H:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([O:30][CH3:31])=[CH:28][C:27]([CH2:32][Br:59])=[CH:26][C:25]=2[O:36][CH3:37])=[CH:20][CH:19]=1)[NH:6][C:7](=[O:16])[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])[CH3:2]
Reactant: CCOCc1cc(OC)c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)OCC)cc2)c(OC)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc(-c2c(OC)cc(CBr)cc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the product obtained in Example 1 -(5) or Reference Example 3-(3) (3.0 g) in CH2Cl2 (80 ml) containing PPh3 (1.77 g) was added CBr4 (2.8 g) at 0° C. The mixture was stirred at room temperature for 3 hours and evaporated. The residue was purified by: column chromatography (silica gel; eluent:AcOEt/n-hexane 1:1) to yield N-(2,6-dichlorobenzoyl)-4-(2,6-dimethoxy-4-bromomethylphenyl)-L-phenylalanine ethyl ester (3.15 g). IR (Nujol) 1731, 1654 cm−1; MS (APCI) m/z 59.6 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9]\[CH2:10][OH:11])=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[CH3:49][O:50][C:51](=[O:62])[CH2:52][O:53][C:54]1[CH:59]=[CH:58][C:57](O)=[CH:56][C:55]=1[CH3:61]>O1CCCC1>[CH3:49][O:50][C:51](=[O:62])[CH2:52][O:53][C:54]1[CH:59]=[CH:58][C:57]([O:11][CH2:10]/[CH:9]=[C:8](\[C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=2)/[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:56][C:55]=1[CH3:61]
Reactant: COC(=O)COc1ccc(O)cc1C
Reactant: OC/C=C(/c1ccccc1)c1ccc(I)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(/c2ccccc2)c2ccc(I)cc2)cc1C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of (Z)-3-(4-Iodo-phenyl)-3-phenyl-prop-2-en-1-ol (756 mg, 2.249 mmol) in dry tetrahydrofuran (40 mL) was added tributylphosphine (0.61 ml, 3.37 mmol). The mixture was cooled to 0° C. and added 1,1′-(azodicarbonyl)dipiperidine (850 mg, 3.37 mmol) and after 10 min (4-Hydroxy-2-methyl-phenoxy)-acetic acid methyl ester (485 mg, 2.47 mmol) was added. After 1.5 hr at 0° C. the reaction was allowed to warm up to ambient temperature and stirred overnight. The reaction mixture was added silica gel Fluka 60 (10 g) and evaporated in vacuo. The residue was purified by ISCO combiflash 16 (silica gel, DCM/MeOH 90:10) giving (Z)-{4-[3-(4-iodo-phenyl)-3-phenyl-allyloxy]-2-methyl-phenoxy}-acetic acid methyl ester as an oil.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@H:16]([CH2:24][CH3:25])[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18].[CH:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]2[N:34]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:35]=[C:36]([C:37]([O:39][CH3:40])=[O:38])[C:29]=12)=O>ClCCCl.C(O)(=O)C>[O:18]=[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[C@H:16]([NH:15][CH2:26][C:28]1[CH:33]=[CH:32][N:31]=[C:30]2[N:34]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:35]=[C:36]([C:37]([O:39][CH3:40])=[O:38])[C:29]=12)[CH2:24][CH3:25]
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(C=O)c12
Reactant: CC[C@@H](N)C(=O)N1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC[C@@H](NCc1ccnc2c1c(C(=O)OC)cn2C(=O)OC(C)(C)C)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A mixture of sodium triacetoxyborohydride (237 mg, 1.116 mmol) and (R)-2-amino-1-(pyrrolidin-1-yl)butan-1-one (131 mg, 0.837 mmol) in DCE (2 mL) was stirred at room temperature for 30 min. The reaction mixture was cooled to 0° C. A solution of 1-tert-butyl 3-methyl 4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (200 mg, 0.657 mmol) in DCE (2 mL) was added, followed by acetic acid (1 drop). The reaction was stirred at 0° C. for 30 min and then at room temperature for 3 h. Purification by silica column chromatography (EtOAc/DCM, 0-10%) afforded the title compound as a yellow oil (260 mg, 93%). [M+H] calc'd for C23H32N4O5, 445; found, 445.5.
Reaction SMILES: [CH2:1]([C:3]1([C:40]2[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=2)[CH:12]([CH2:13]CCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(O)=O)[C:11]2[C:6](=[CH:7][C:8]([OH:39])=[CH:9][CH:10]=2)[O:5][CH2:4]1)[CH3:2].[F:47][C:48]([F:72])([C:68]([F:71])([F:70])[F:69])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH:55]([CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH:66]=[CH2:67])[C:56]([O:58]CC)=[O:57]>>[CH2:1]([C:3]1([C:40]2[CH:41]=[CH:42][C:43]([OH:46])=[CH:44][CH:45]=2)[CH:12]([CH2:13][CH2:67][CH2:66][CH2:65][CH2:64][CH2:63][CH2:62][CH2:61][CH:55]([CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][C:48]([F:47])([F:72])[C:68]([F:69])([F:70])[F:71])[C:56]([OH:58])=[O:57])[C:11]2[C:6](=[CH:7][C:8]([OH:39])=[CH:9][CH:10]=2)[O:5][CH2:4]1)[CH3:2]
Reactant: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O
Reactant: C=CCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)OCC
Product: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 21 and the ethyl 2-(7,7,8,8,8-pentafluorooctyl)-8-nonenoate prepared in Example 12, the same procedure as shown in Example 21 was repeated to give 10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(7,7,8,8,8-pentafluorooctyl)decanoic acid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]#[C:11][CH:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](Cl)(=[O:20])[CH3:19].N1C=CC=CC=1.Cl>C(Cl)Cl>[C:18]([O:17][CH:12]([C:11]#[C:10][CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:13]([F:16])([F:15])[F:14])(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: OC(C#CCOCc1ccccc1)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC(C#CCOCc1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
In a three-necked flask of 50 ml in internal volume which was well dried under reduced pressure in nitrogen stream were charged 20 ml of methylene chloride, 3.57 g (13.0 mmol) of the above alcohol (3) and 1.20 ml (16.9 mmol) of acetyl chloride and then 1.37 ml (16.9 mmol) of pyridine was added thereto under ice-cooling, followed by stirring at room temperature overnight. The reaction was stopped by adding 1N aqueous hydrochloric acid solution and the reaction mixture was extracted with methylene chloride and dried over anhydrous magnesium sulfate. Solvent was distilled off to obtain a crude product, which was purified by silica gel column chromatography to obtain the above acetate (4).
Reaction SMILES: C(OC([NH:8][C@:9]([CH3:39])([CH2:20][CH2:21][C:22]1[O:23][C:24]([C:27](=[O:38])[CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:25][CH:26]=1)[CH2:10][CH2:11][P:12](=[O:19])([O:16]CC)[O:13]CC)=O)(C)(C)C.Br[Si](C)(C)C>ClCCl>[NH2:8][C@:9]([CH3:39])([CH2:20][CH2:21][C:22]1[O:23][C:24]([C:27](=[O:38])[CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:25][CH:26]=1)[CH2:10][CH2:11][P:12](=[O:13])([OH:16])[OH:19]
Reactant: CCOP(=O)(CC[C@@](C)(CCc1ccc(C(=O)CCCCc2ccccc2)o1)NC(=O)OC(C)(C)C)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: C[C@@](N)(CCc1ccc(C(=O)CCCCc2ccccc2)o1)CCP(=O)(O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.4 %

Procedure:
To a solution of diethyl (3R)-3-t-butoxycarbonylamino-3-methyl-5-[5-(5-phenylpentanoyl)furan-2-yl]pentylphosphonate (108.2 mg, 0.19 mmol) obtained in Example (29d) in dichloromethane (1.9 ml) was added bromotrimethylsilane (0.2.55 ml, 1.93 mmol), and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. After stirring, the reaction mixture was evaporated in vacuo, and the residue was diluted with aqueous ethanol, and then the resulting mixture was adjusted to pH 4 with aqueous ammonia and acetic acid. The crystals precipitated were collected by filtration, washed successively with water and ethanol and dried to afford the title compound (51.4 mg, yield: 66%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17](O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (35.94 mmol; 8.24 g) in dichloromethane (100 mL) was added benzyl alcohol (55.79 mmol; 4.73 mL), dimethylaminopyridine (0.72 mmol; 0.08 g) and dicyclohexylcarbodiimide (43.13 mmol; 8.27 g) and the resulting mixture was stirred for 3 hours at room temperature. The resulting solution was evaporated and the residue was dissolved in ethyl acetate (300 mL). The resulting solution was washed with a 1N hydrochloric acid solution (2×50 mL) and brine (50 mL), and dried over magnesium sulfate. After filtration and evaporation, the residue was purified via flash column chromatography ((eluent gradient: 0 to 50% EtOAc in heptane) to yield piperidine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester after evaporation. MS (ESI) m/z 320.19 [M+H]+.