Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[CH:26]1([CH2:29][O:30][C:31]2[C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=[CH:33][N:32]=2)[CH2:28][CH2:27]1>CCCCCCC.CCOC(C)=O>[CH:26]1([CH2:29][O:30][C:31]2[C:36]([C:2]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[N:8]([CH3:25])[C:9](=[O:24])[C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=3)=[CH:35][CH:34]=[CH:33][N:32]=2)[CH2:27][CH2:28]1
Reactant: CC1(C)OB(c2cccnc2OCC2CC2)OC1(C)C
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1I
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1cccnc1OCC1CC1

Procedure:
The title compound was prepared in analogy to example 72, from N-(4-iodo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 98, intermediate a) and 2-(cyclopropylmethoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (CAS RN 848243-26-5) and using a gradient of n-heptane:EtOAc (100:0 to 30:70) for the chromatographic purification. Light yellow oil (63%). MS (ESI): m/z=498.146 [M+H]+.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][CH3:12].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1.CCOC(C)=O>[CH2:11]([S:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][OH:2])[CH3:12]
Reactant: CCSc1ccccc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCSc1ccccc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of methyl-2-(ethylthio)benzoate (5.0 g, 25.5 mmol) in dry THF (67 mL) was added to a stirred solution of LAH (17.5 mL of a 1.0 M solution in THF) in an additional 50 mL dry THF at 0° C. under Ar. The reaction was allowed to warm to room temperature while stirring overnight. The resulting clear solution was diluted with EtOAc (140 mL). The mixture was poured into water (300 mL) and the resulting precipitate was filtered off. The filtrate was extracted with ether (3×200 mL) and the combined organic extracts were dried over MgSO4, filtered, concentrated in vacuo and dried overnight on a high vacuum line to yield the title compound as a pale yellow oil:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)[CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([N:22]=[C:23]=[O:24])[CH:18]=[C:19]([Cl:21])[CH:20]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:23]([NH:22][C:17]2[CH:18]=[C:19]([Cl:21])[CH:20]=[C:15]([Cl:14])[CH:16]=2)=[O:24])=[C:4]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)[CH:3]=1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: Nc1ccc(Cl)cc1-c1nnn[nH]1
Solvent: Cc1ccccc1
Product: O=C(Nc1cc(Cl)cc(Cl)c1)Nc1ccc(Cl)cc1-c1nnn[nH]1
Yield: 73.4 %

Procedure:
4-Chloro-2-(1H-tetrazol-5-yl)-phenylamine (500 mg) dissolved in toluene (15 ml) was treated with 3,5-dichlorophenylisocyanate (500 mg) and stirred for a week. The precipitated product was filtered, washed with toluene, dissolved in acetone, filtered through celite, precipitated again with water, filtered and dried. This residue was slurried in 96% EtOH, and adjusted to basic pH with 10 N NaOH. The solution was filtered through celite and re-acidified with 4N HCl and a little water. The precipitated product was filtered and washed with water to afford 1-[4-Chloro-2-(1H-tetrazol-5-yl)-phenyl]-3-(3,5-dichloro-phenyl)-urea as a white solid (720 mg ). Mp.=234-236° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH2:9][CH3:10])[C:5](N)=[C:4]([CH2:11][CH3:12])[CH:3]=1.Cl.N([O-])=O.[Na+].C(=O)(O)[O-].[Na+].[Cu][C:24]#[N:25].[C-]#N.[K+]>O.C(Cl)Cl>[Br:1][C:2]1[CH:8]=[C:7]([CH2:9][CH3:10])[C:5]([C:24]#[N:25])=[C:4]([CH2:11][CH3:12])[CH:3]=1
Reactant: N#C[Cu]
Reactant: CCc1cc(Br)cc(CC)c1N
Agent: Cl
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: O
Solvent: ClCCl
Product: CCc1cc(Br)cc(CC)c1C#N
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
4-Bromo-2,6-diethylaniline (4.80 g, 21.0 mmol) was suspended in a mixture of water (25 mL) and concentrated hydrochloric acid (8.0 mL) then sonicated for 10 minutes. The resultant suspension was cooled to 0° C. and a solution of sodium nitrite (1.60 g, 23.1 mmol) in water (5 mL) was slowly added, maintaining the reaction temperature below 5° C. After 30 minutes, the reaction mixture was neutralised by the careful addition of sodium bicarbonate, then the resultant suspension was added in aliquots to a solution of copper (I) cyanide (2.26 g, 25.2 mmol) and potassium cyanide (3.43 g, 52.6 mmol) in water (25 mL) at 70° C. After complete addition, heating at 70° C. was continued for 1 h then the reaction mixture was cooled to ambient temperature. Water and DCM were added then the organic phase was collected, dried over anhydrous sodium sulfate and concentrated in vacuo to afford a brown residue that was purified by flash chromatography (silica, 80 g column, ISCO, 0-10% ethyl acetate in cyclohexane) to afford the title compound as an off-white solid (4.43 g, 88%). 1H NMR (DMSO-D6, 300 MHz): 7.58 (s, 2H), 2.78 (q, J=7.6 Hz, 4H), 1.21 (t, J=7.6 Hz, 6H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][C:14]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>Cl>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:13][C:14]3[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:15]=3[C:16]([OH:18])=[O:17])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: Cc1cccc(C(=O)O)c1N
Agent: Cl
Product: Cc1cccc(C(=O)O)c1Nc1ccnc2cc(Cl)ccc12

Procedure:
4,7-Dichloroquinoline and 2-amino-3-methyl benzoic acid are refluxed in dilute hydrochloric acid for 1 hour to give 2-(7-chloro-4-quinolylamino)-3-methyl benzoic acid.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:35][CH2:36]I>O1CCOCC1>[Cl:35][CH2:36][O:15][C:14](=[O:16])[C@H:9]([C@H:10]([CH2:12][CH3:13])[CH3:11])[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: ClCI
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCl
Reaction time: 0.25 h
Yield: 74.3 %

Procedure:
To a solution of N-BOC-L-isoleucine (23.1 g, 0.1 mol) in dioxane (500 mL), was added dropwise a 40% aqueous solution of tetrabutylammonium hydroxide (65.6 mL, 0.1 mol). After stirring for 15 min, the solution was evaporated to dryness through co-evaporation with dioxane and toluene. The residue was dissolved in dichloromethane (500 mL) and then chloroiodomethane (72.8 mL, 1 mol) was added and the solution was stirred for 6 h at room temperature. The solution was concentrated under reduced pressure and the residue was shaken with hexane/ethyl acetate (1:1 v/v, 400 mL). The yellow crystalline solid was filtered off and the filtrate was washed with aqueous solution of sodium thiosulfate (0.1 M) and then filtered through anhydrous sodium sulfate and evaporated to dryness. The residue was column chromatographed (silica gel, 1-2% MeOH in CH2Cl2), to give 20.8 g of N-BOC-L-isoleucine chloromethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:13])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[O:14]1[CH2:19][CH2:18][CH:17](O)[CH2:16][CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)cc(O)c1C
Reactant: OC1CCOCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)cc(OC2CCOCC2)c1C
Temperature: 55 °C

Procedure:
A 100 mL round bottom flask was charged with methyl 5-chloro-3-hydroxy-2-methylbenzoate (500 mg, 2.492 mmol), tetrahydro-2H-pyran-4-ol (318 mg, 3.12 mmol), triphenylphosphine (1307 mg, 4.98 mmol) and tetrahydrofuran (20 mL). The reaction was maintained for 15 min, at which time DIAD (1.454 mL, 7.48 mmol) was added in one portion. The resulting solution was heated at 55° C. for 24 h and then concentrated in vacuo. Purification of the residue by column chromatography (10-50% EtOAc/hexanes) gave methyl 5-chloro-2-methyl-3-((tetrahydro-2H-pyran-4-yl)oxy)benzoate as an orange-oil, which was used directly in the next step. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.42 (d, J=2.02 Hz, 1H), 6.98 (d, J=2.02 Hz, 1H), 4.51 (tt, J=3.73, 7.39 Hz, 1H), 3.99 (ddd, J=3.66, 7.01, 11.31Hz, 2H), 3.91 (s, 3H), 3.64 (ddd, J=3.28, 7.77, 11.43 Hz, 2H), 2.38-2.45 (m, 3H), 1.99-2.10 (m, 2H), 1.74-1.92 (m, 2H). MS(ES) [M+H]+ 285.0
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:21][C:22]1[CH:41]=[CH:40][C:25]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([O:38]C)=[O:37])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.[OH-].[Na+]>CN(C)C=O.C(OCC)(=O)C.O1CCCC1.CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:30][CH:29]=3)=[CH:24][CH:23]=1)[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(OCc2ccc(Cn3ccc4cc(OCc5ccccc5)ccc43)cc2)cc1
Temperature: 0 °C
Yield: 52.2 %

Procedure:
To a solution of 5-(benzyloxy)-1H-indole (0.19 g, 0.86 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 35 mg, 0.86 mmol) with stirring at 0° C., and the mixture was stirred at the same temperature for 10 min. Methyl 3-(4-{[4-(chloromethyl)benzyl]oxy}phenyl)propanoate (0.25 g, 0.78 mmol) was added to the obtained mixture and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate, and the mixture washed with 5% aqueous potassium hydrogensulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=3/1) to give an oil. Then, a mixture of the obtained oil, 1 N aqueous sodium hydroxide solution (1.6 mL), methanol (3.0 mL) and tetrahydrofuran (6.0 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with 5% aqueous potassium hydrogensulfate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=1/2) to give the title compound (200 mg, yield 49%) as beige crystals. MS (APCI−): 490 (M−H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[C:15]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:14][C:13]([Cl:30])=[CH:12][N:11]=2)=[O:9])[CH:5]=[CH:4][CH:3]=1.[Si](N=C=O)(C)(C)C.[CH3:38][C:39](O)=[O:40]>C1COCC1.C(#N)C>[C:26]([C:23]1[CH:22]=[CH:21][C:20]([S:17]([NH:16][C:15]2[C:10]([C:8]([C:6]3[N:7]=[C:2]([NH:1][C:39](=[O:40])[CH3:38])[CH:3]=[CH:4][CH:5]=3)=[O:9])=[N:11][CH:12]=[C:13]([Cl:30])[CH:14]=2)(=[O:18])=[O:19])=[CH:25][CH:24]=1)([CH3:27])([CH3:29])[CH3:28]
Reactant: CC(=O)O
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2cccc(N)n2)cc1
Agent: C[Si](C)(C)N=C=O
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(C(=O)c2ncc(Cl)cc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
N-[2-(6-Amino-pyridine-2-carbonyl)-5-chloro-pyridin-3-yl]-4-tert-butyl-benzenesulfonamide (26 mg, 0.05 mmol) in THF (2 mL) was treated with TMS-isocyanate (100 mg) and AcOH (0.5 mL), and then stirred at 80° C. for 2 h. The mixture was subsequently diluted with acetonitrile (1 mL) and purified via HPLC to afford the title compound: 1H NMR (400 MHz, CDCl3) δ 11.1 (s, 1H), 8.48 (d, 1H), 8.32 (d, 1H), 8.24 (m, 2H), 7.86 (m, 3H), 7.55 (d, 2H), 5.30 (s, 2H), 4.75 (s, 2H), 1.22 (s, 9H); ESMS m/z (relative intensity): 488.1 (M+H)+ (100).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]([NH:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16](Cl)[N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].O.CCOC(C)=O.[CH3:32][N:33](C=O)C>[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>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]([NH:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16]([C:32]#[N:33])[N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C[C@@H](Nc1nc(Cl)ccc1[N+](=O)[O-])c1ccccc1
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: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C[C@@H](Nc1nc(C#N)ccc1[N+](=O)[O-])c1ccccc1
Temperature: 120 °C
Reaction time: 72 h
Yield: 96 %

Procedure:
In a microwave reaction vessel was dissolved (R)-3-(6-chloro-3-nitro-pyridin-2-ylamino)-3-phenyl-propionic acid ethyl ester (0.75 g, 2.14 mmol) in DMF (12 ml). Added the zinc cyanide (0.15 g, 1.29 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.25 g, 0.21 mmol). Reaction mixture was degassed using a stream of nitrogen and capped. Reaction was heated in a microwave at 120° C. for 1 hour and then stirred at room temperature for 72 hours. After this time the reaction was poured into water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (3×). The combined organics were dried (MgSO4), filtered and concentrated to give the crude product which was purified via silica gel flash column chromatography (12 g silica gel, 5-20% EtOAc/hexanes) to afford 0.70 g (96%) of the title compound.
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].[C:9]([C:11]1[CH:12]=[CH:13][C:14]([C@@H:21]2[C:26]([C:27]#[N:28])=[C:25]([CH3:29])[N:24]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[C:23](=[O:40])[N:22]2[CH3:41])=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:16]=1)#[N:10]>C1COCC1>[C:9]([C:11]1[CH:12]=[CH:13][C:14]([C@@H:21]2[C:26]([C:27]#[N:28])=[C:25]([CH3:29])[N:24]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[C:23](=[O:40])[N:22]2[CH3:41])=[C:15]([S:17]([C:2]([F:4])([F:3])[F:1])(=[O:19])=[O:18])[CH:16]=1)#[N:10]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cl)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: C[Si](C)(C)C(F)(F)F
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)C(F)(F)F)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The reaction was carried out under argon. Tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF; 18.4 mg, 66.7 μmol; 1.1 eq.) and (trifluoromethyl)trimethylsilane (2 M solution in THF, 60.6 μl, 121 μmol) were initially charged in THF (1.45 ml) at 0° C. 5-Cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfonyl chloride (30 mg, 60.6 μmol) was added, and the mixture was stirred at RT overnight. More tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF; 16.7 mg, 60.6 μmol; 1.0 eq.) and (trifluoromethyl)trimethylsilane (2 M solution in THF, 65 μl, 130 μmol) were then added at 0° C., and the mixture was again stirred for 15 h with gradual warming to RT. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). The title compound was obtained as a solid (3.3 mg, 10% of theory).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([CH:28]=[CH2:29])=[N:20][N:21]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[C:15]=2[CH:14]=1.I[C:31]1[CH:32]=[N:33][N:34]([CH2:36][CH2:37][O:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][O:40]2)[CH:35]=1.ClCCl.O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](/[CH:28]=[CH:29]/[C:31]3[CH:32]=[N:33][N:34]([CH2:36][CH2:37][O:38][CH:39]4[CH2:44][CH2:43][CH2:42][CH2:41][O:40]4)[CH:35]=3)=[N:20][N:21]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[C:15]=2[CH:14]=1
Reactant: Ic1cnn(CCOC2CCCCO2)c1
Reactant: C=Cc1nn(C2CCCCO2)c2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)ncc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)c(Cl)c(-c2cc3c(cn2)c(/C=C/c2cnn(CCOC4CCCCO4)c2)nn3C2CCCCO2)c1Cl
Temperature: 95 °C
Reaction time: 3 h
Yield: 50.9 %

Procedure:
To a solution of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-pyrazolo[4,3-c]pyridine (0.1 mmol) in DMF (0.5 mL) was added 4-iodo-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-pyrazole (44 mg, 0.14 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (7.5 mg, 0.0092 mmol), and water (0.05 mL). The mixture was degassed and sealed. It was stirred at 95° C. for 3 h. After cooling the solid was filtered off, washed with acetonitrile. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (32 mg). LCMS (M+H)+=628.2/630.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:17][C:18]=2[CH3:19])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].OC1C=CC(C=O)=C(OC)C=1.CC1OC(C2C=CC=CC=2)=NC=1CCOS(C)(=O)=O.[CH2:56]([C@H:63]1[CH2:67][O:66][C:65](=[O:68])[N:64]1[C:69](=[O:74])[CH2:70][O:71][CH2:72][CH3:73])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1.B(OS(C(F)(F)F)(=O)=O)(CCCC)CCCC>>[CH2:56]([C@H:63]1[CH2:67][O:66][C:65](=[O:68])[N:64]1[C:69](=[O:74])[C@@H:70]([O:71][CH2:72][CH3:73])[C@H:5]([OH:6])[C:4]1[CH:7]=[CH:8][C:9]([O:11][CH2:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:17][C:18]=2[CH3:19])=[CH:10][C:3]=1[O:2][CH3:1])[C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1
Reactant: COc1cc(OCCc2nc(-c3ccccc3)oc2C)ccc1C=O
Reactant: CCOCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: CCCCB(CCCC)OS(=O)(=O)C(F)(F)F
Agent: COc1cc(O)ccc1C=O
Agent: Cc1oc(-c2ccccc2)nc1CCOS(C)(=O)=O
Product: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1OC

Procedure:
In analogy to the procedures described in examples 11 a] to 11 c], 2-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde (prepared from 4-hydroxy-2-methoxy-benzaldehyde and methanesulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester in analogy to the procedure described in example 114 b]) was reacted with (S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one and nBu2BOTf to yield (S)-4-benzyl-3-((2S,3R)-2-ethoxy-3-hydroxy-3-{2-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one (according to NMR, one of the four isomers is strongly predominating; the configuration was tentatively assigned as 2S, 3R according to Tetrahedron Asymmetry 1999, 1353). Reduction of (S)-4-benzyl-3-((2S,3R)-2-ethoxy-3-hydroxy-3-{2-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one with triethylsilane in trifluoroacetic acid then gave (S)-4-benzyl-3-((2S)-2-ethoxy-3-{2-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one. The (S)-4-benzyl-3-((2S)-2-ethoxy-3-{2-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one was subsequently saponified with 1N NaOH in THF to yield (2S)-2-ethoxy-3-{2-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid as colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([O:14][CH2:15][C@H:16]2[CH2:18][O:17]2)[C@H:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]#[N:37])=[CH:21][CH:20]=2)[C@@H:10]([O:38][CH2:39][C:40]2[CH:49]=[C:48]([O:50][CH3:51])[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:41]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+]>COCCO>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@H:10]([O:38][CH2:39][C:40]2[CH:49]=[C:48]([O:50][CH3:51])[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:41]=2)[C@@H:11]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]#[N:37])=[CH:23][CH:24]=2)[C@H:12]([O:14][CH2:15][C@H:16]([OH:17])[CH2:18][O:17][CH2:16][CH2:15][O:14][CH3:12])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(CO[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](OC[C@H]3CO3)[C@@H]2c2ccc(OCCCOc3ccccc3C#N)cc2)cc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: COCCO
Product: COCCOC[C@@H](O)CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](OCc2cc(OC)c3ccccc3c2)[C@H]1c1ccc(OCCCOc2ccccc2C#N)cc1

Procedure:
In analogy to the procedure described in example 1 (k) the (3R,4R,5S)-4-[4-[3-(2-cyano-phenoxy)-propoxy]-phenyl]-3-(4-methoxy-naphthalen-2-ylmethoxy)-5-[(2R)-oxiranylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester was treated with sodium 2-methoxy-ethylate (prepared from 2-methoxy-ethanol and sodium hydride) to give the (3S,4R,5R)-4-[4-[3-(2-cyano-phenoxy)-propoxy]-phenyl]-3-[(2R)-2-hydroxy-3-(2-methoxy-ethoxy)-propoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester as colorless oil; MS: 771 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].[SH2:7].[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]2[C:23](=[O:24])[C:18]3[N:19]=[C:20]([CH3:22])O[C:17]=3[CH2:16][CH2:15][C:14]=2[CH:25]=1)[CH3:9].Cl>CN(C)C=O>[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]2[C:23](=[O:24])[C:18]3[N:19]=[C:20]([CH3:22])[S:7][C:17]=3[CH2:16][CH2:15][C:14]=2[CH:25]=1)[CH3:9]
Reactant: CCc1ccc2c(c1)CCc1oc(C)nc1C2=O
Reactant: S
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ccc2c(c1)CCc1sc(C)nc1C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred suspension of potassium tert-butoxide (1.80 g) in dry N,N-dimethylformamide (20 ml) was cooled to 5° C. and saturated with hydrogen sulphide. The product from example 3 step (vi) (1.00 g) was added and the reaction stirred at room temperature for 1 hour. The mixture was poured into ice, acidified to pH4 with 2N hydrochloric acid and extracted with ethyl acetate. The extracts were washed with brine, dried (MgSO4) and evaporated to give an orange solid which was purified by chromatography eluting with 50% ethyl acetate in isohexane.