Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].F[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: O=Cc1ccc(F)cc1
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Yield: 112 %

Procedure:
A slurry of 4-cyanophenol (1.24 g, 10.4 mmol), potassium carbonate (3.3 g, 23.9 mmol), and 4-fluoro benzaldehyde (1.0 g, 8 mmol) in dry DMF (50 mL) was stirred at 100° C. overnight under nitrogen atmosphere. After the reaction is completed it was cooled to room temperature and poured in to ice cold water. The mixture was extracted with ethyl acetate (100 mL×2), the combined organic layers were washed with water (50 mL×2), and brine, then dried over anhydrous sodium sulphate and concentrated. The residue was purified by column chromatography using 3% ethyl acetate in hexane to obtain the title compound (2 g, 86%)
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:14]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=1>C(O)C.O1CCOCC1.ClCCl>[Cl:1][C:2]1[C:3]([CH:14]([S:23]([C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)(=[O:25])=[O:24])[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=1
Reactant: COC(=O)/C=C/c1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Solvent: C1COCCO1
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)CCc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
A Raney nickel suspension (“R-100”, product of Nikko Rika Corporation) was washed sequentially with water and ethanol to give a corresponding ethanol suspension. The resulting ethanol suspension (2 ml) was added to a solution of methyl(E)-3-[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]acrylate (770 mg, 1.55 mmol) in a mixture of ethanol (10 ml) and 1,4-dioxane (5 ml). Under a hydrogen atmosphere of 1 atmospheric pressure, the resulting mixture was stirred vigorously for 30 minutes. After the reaction mixture was filtered, the filtrate was concentrated under reduced pressure. The residue thus obtained was dissolved in dichloromethane (15 ml). The resulting solution was dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (720 mg, 1.44 mmol, 93%) as a white powder.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][N:10]=1)[C:6]#[N:7]>CCO.[Pd]>[NH2:7][CH2:6][C:5]1[CH:8]=[CH:9][N:10]=[C:3]([NH:2][CH3:1])[CH:4]=1
Reactant: CNc1cc(C#N)ccn1
Agent: [Pd]
Solvent: CCO
Product: CNc1cc(CN)ccn1

Procedure:
A suspension of 2-Methylamino-isonicotinonitrile (5.6 g) and Pd/C (10%, 4 g) in EtOH (150 mL) and TEA (40 mL) was placed in a 500 mL Parr Hydrogenation bottle and hydrogenated at or below 60 psi H2 pressure over night. After filtering through a pad of Celite®, the reaction mixture was concentrated in vacuo to give a yellow oil as the desired compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[NH2:10][NH2:11]>C(O)C>[C:1](=[N:10][NH2:11])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: NN
Reactant: CC(=O)c1ccccc1
Solvent: CCO
Product: CC(=NN)c1ccccc1
Reaction time: 2 h
Yield: 68.8 %

Procedure:
acetophenone (2.0 g, 16 mmol) is diluted in 16 ml of absolute ethanol and then hydrazine (2.3 ml, 48 mmol) is added. The mixture is heated to reflux temperature. After 2 h, the solvent is evaporated and the residue is taken up in ether (150 ml). The medium is washed with water (100 ml). After drying over Na2SO4, the ether is evaporated off. A pale yellow oil (1.5 g, 11 mmol, 69%) is obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]([OH:15])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1.[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>Cl.C(O)CCC>[ClH:1].[ClH:1].[Cl:14][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[Cl:13])[O:6][CH2:5][CH:4]([OH:15])[CH2:3][CH2:2][N:25]1[CH2:26][CH2:27][N:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:23][CH2:24]1
Reactant: OC(CCCl)COc1ccc(Cl)c(Cl)c1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCCCO
Product: OC(CCN1CCN(c2ccccc2)CC1)COc1ccc(Cl)c(Cl)c1

Procedure:
This compound was prepared according to the procedure of Example 25. A mixture of 8.1 g (0.03 mole) of 4-chloro-1-(3,4-dichlorophenoxy)-2-butanol, 4.9 g (0.03 mole) of 1-phenylpiperazine, 16.0 g (0.15 mole) of anhydrous sodium carbonate and 0.3 g (0.002 mole) of potassium iodide in a total volume of 200 ml of 1-butanol gave a golden oil as residue. The hydrochloric acid salt was formed in ethereal hydrogen chloride and the collected solid was recrysrallized from methanol-ethyl ether to give 5.1 g (37%) of white solid, m.p. 210°-213° C.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.N1(C2C=CN=CC=2)CCCC1.[CH3:27][C:28]1[O:32][CH:31]=[C:30](/[CH:33]=[C:34](/[CH:36]=[CH:37]/[CH:38]=[C:39](/[C@H:41]([O:70][CH3:71])[C@H:42]([C@H:44]2[O:62][C:60](=[O:61])[C@@H:58]3[O:59][C@H:57]3[CH2:56][C@H:55]3[CH2:63][C:64]([O:66][C@H:53]([CH2:54]3)[C@H:52]([CH3:67])[CH:51]=[CH:50][C@H:48]3[O:49][C@:47]3([CH3:68])[C@@H:46]([OH:69])[CH2:45]2)=[O:65])[CH3:43])\[CH3:40])\[CH3:35])[N:29]=1.[I:72][CH2:73][CH2:74][C:75]([OH:77])=[O:76]>C1(C)C=CC=CC=1>[CH3:27][C:28]1[O:32][CH:31]=[C:30](/[CH:33]=[C:34](/[CH:36]=[CH:37]/[CH:38]=[C:39](/[C@H:41]([O:70][CH3:71])[C@H:42]([C@H:44]2[O:62][C:60](=[O:61])[C@@H:58]3[O:59][C@H:57]3[CH2:56][C@H:55]3[CH2:63][C:64]([O:66][C@H:53]([CH2:54]3)[C@H:52]([CH3:67])[CH:51]=[CH:50][C@H:48]3[O:49][C@:47]3([CH3:68])[C@@H:46]([OH:69])[CH2:45]2)=[O:65])[CH3:43])\[CH3:40])\[CH3:35])[N:29]=1.[I:72][CH2:73][CH2:74][C:75]([O-:77])=[O:76]
Reactant: O=C(O)CCI
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CO[C@@H](/C(C)=C/C=C/C(C)=C/c1coc(C)n1)[C@@H](C)[C@@H]1C[C@H](O)[C@@]2(C)O[C@@H]2/C=C/[C@@H](C)[C@H]2C[C@H](CC(=O)O2)C[C@@H]2O[C@H]2C(=O)O1
Agent: CO[C@@H](/C(C)=C/C=C/C(C)=C/c1coc(C)n1)[C@@H](C)[C@@H]1C[C@H](O)[C@@]2(C)O[C@@H]2C=C[C@@H](C)[C@H]2C[C@H](CC(=O)O2)C[C@@H]2O[C@H]2C(=O)O1
Solvent: Cc1ccccc1
Product: O=C([O-])CCI
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.03 g of DCC and a catalytic amount of 4-pyrrolidinopyridine were added to a solution of 1.25 g of rhizoxin and 1.20 g of 3-iodopropionic acid in toluene, and the resulting mixture was stirred at room temperature for 2 hours. At the end of this time, the reaction mixture was treated in the same manner as described in Example 1, to give 1.33 g of rhizoxin 3-iodopropionate. The whole of this ester was immediately dissolved in 20 ml of acetonitrile, and 0.92 g of the silver salt of methylmercaptan prepared at the time of use was added. The resulting mixture was stirred at room temperature for 8 hours, after which the precipitate was filtered off. The solvent was then removed by distillation under reduced pressure, and ethyl acetate was added to the residue. The resulting mixture was washed with a 5% w/v aqueous solution of sodium bicarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography, using a 1:1 by volume mixture of cyclohexane and ethyl acetate as eluent, to give 970 mg of the title product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]([CH3:18])[CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][C:6]=1[N+:19]([O-])=O.[H][H]>CO.[Pd]>[NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]([CH3:18])[CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][C:6]=1[NH2:19]
Reactant: CC1CC(=O)NN=C1c1ccc(NCCN)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1CC(=O)NN=C1c1ccc(NCCN)c(N)c1
Yield: 50.9 %

Procedure:
3.0 g (10.3 mmol) of 6-[4-(2-aminoethyl)amino-3-nitro-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone in 200 ml of methanol are hydrogenated under a hydrogen pressure of 2 bar at room temperature in the presence of 0.5 g of palladium charcoal (10% Pd) until uptake of hydrogen ceases. After removal of the catalyst by filtration, the solution is concentrated by evaporation under vacuum. The residue is chromatographed on silica gel with methanol/conc. ammonia (95/5) as solvent. The main fraction is concentrated by evaporation under vacuum and the solid obtained is recrystallized from ethanol. 1.37 g (51%) of a beige coloured solid, m.p. 176°-177° C. are obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([CH3:12])=[CH:7][C:6]=1[CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)(=[O:3])[CH3:2].S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].Cl.C(OC(C)C)(C)C>C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([CH3:12])=[C:7]2[C:6]=1[CH2:13][CH2:14][CH2:15][C:16]2=[O:18])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(F)c(C)cc1CCCC(=O)O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CC(C)OC(C)C
Product: CC(=O)Nc1cc(F)c(C)c2c1CCCC2=O
Reaction time: 0.25 h
Yield: 75.4 %

Procedure:
In 50 ml of methylene chloride, 5.0 g of 4-(2 -acetylamino-4-fluoro-5-methylphenyl)butanoic acid was suspended. To the suspension, 4.3 ml of thionyl chloride was added dropwise over 2 minutes at an internal temperature of 3° to 4° C., followed by stirring at the same temperature for 15 minutes and then at room temperature for 45 minutes. To the resulting mixture, 6.6 g of aluminum chloride were added over 5 minutes at an internal temperature of 4° to 6° C., followed by stirring for one hour at the same temperature and then stirring for 24 hours at room temperature. After the completion of the reaction, a 5% aqueous hydrochloric acid solution and ice were added gradually to the reaction mixture and they were stirred for a while. The reaction mixture was extracted with chloroform. The chloroform layer was washed sufficiently with water and a saturated aqueous solution of sodium bicarbonate, and was then dried over potassium carbonate. The solvent was removed under reduced pressure. To the residue so obtained, isopropyl ether was added. The crystals so precipitated were collected by filtration, whereby 3.5 g of the title compound was obtained.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH2:10][CH2:11][NH2:12])=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.[Cl:26][C:27]1[N:32]=[C:31](Cl)[CH:30]=[CH:29][N:28]=1>C(O)(C)C>[Cl:26][C:27]1[N:32]=[C:31]([NH:12][CH2:11][CH2:10][CH2:9][O:8][C:7]2[CH:13]=[CH:14][C:4]([O:3][C:2]([F:15])([F:16])[F:1])=[CH:5][CH:6]=2)[CH:30]=[CH:29][N:28]=1
Reactant: NCCCOc1ccc(OC(F)(F)F)cc1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: FC(F)(F)Oc1ccc(OCCCNc2ccnc(Cl)n2)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 60.2 %

Procedure:
To a solution of 3-(4-(trifluoromethoxy)phenoxy)propan-1-amine (450 mg, 1.91 mmol) in isopropanol (8 mL, 3 mL/mmol) was added DIPEA (0.5 mL, 2.86 mmol) and 2,4-dichloropyrimidine (340 mg, 2.29 mmol) and the mixture was stirred at 80° C. for 24 h. Then reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2×30 mL) and water (2×30 mL). The EtOAc layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography provided 2-chloro-N-(3-(4-(trifluoromethoxy)phenoxy)propyl)pyrimidin-4-amine (400 mg, 60%) as a solid. Observed mass (M+1): 348.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([F:23])[CH:15]=2)[CH2:10][CH:9]1[CH2:24][OH:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26]I.[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([F:23])[CH:15]=2)[CH2:10][CH:9]1[CH2:24][O:25][CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(F)cc([N+](=O)[O-])c2)CC1CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC1CC(Oc2cc(F)cc([N+](=O)[O-])c2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
To 22.7 g of 4-(3-fluoro-5-nitrophenoxy)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (6), 250 mL of anhydrous DMF, and 36.3 g of MeI at 0° C. was added 3.9 g of 60% NaH, in several portions. The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated to remove excess MeI then diluted with H2O. The mixture was diluted with 500 mL of saturated NH4Cl and extracted 3 times with 500 mL of EtOAc. The combined organic layers were dried and concentrated to yield 23 g of 4-(3-fluoro-5-nitro-phenoxy)-2-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (7).
Reaction SMILES: [CH:1]1([CH:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C@H:18]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:19]1>>[C:25]1([CH2:24][CH2:23][N:20]2[CH2:21][CH2:22][C@H:18]([NH:17][C:8](=[O:10])[CH:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:19]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Reactant: O=C(O)C(C1CCCCC1)C1CCCCC1
Product: O=C(N[C@H]1CCN(CCc2ccccc2)C1)C(C1CCCCC1)C1CCCCC1

Procedure:
Dicyclohexylacetic acid and (S)-3-amino-1-(2-phenylethyl)pyrrolidine were reacted under the same conditions as in Example 23 to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)dicyclohexylacetamide.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[NH:11][C:12]([C:17]3[CH:22]=[C:21]([O:23][CH2:24][CH3:25])[CH:20]=[CH:19][N:18]=3)=[CH:13][C:14](=[O:16])[CH:15]=2)[CH:5]=1)[CH3:2].[H-].[Na+].[CH3:28]I.O>CN(C)C=O>[CH2:24]([O:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([C:12]2[CH:13]=[C:14]([O:16][CH3:28])[CH:15]=[C:10]([C:6]3[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=[CH:8][N:7]=3)[N:11]=2)[CH:22]=1)[CH3:25]
Reactant: CCOc1ccnc(-c2cc(=O)cc(-c3cc(OCC)ccn3)[nH]2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccnc(-c2cc(OC)cc(-c3cc(OCC)ccn3)n2)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In an argon atmosphere, 506 mg (1.5 mmol) of 4,4″-diethoxy-1′H-[2,2′;6′,2″]terpyridin-4′-one (L17, Example 23) are added at 0° C. to a suspension of 78 mg (approximately 60% dispersion in paraffin oil, 1.95 mmol) of sodium hydride in 15 ml of absolute N,N-dimethylformamide. The mixture is then stirred for 15 minutes at 0° C. and for 15 minutes at room temperature. After cooling again, 0.12 ml (1.95 mmol) of methyl iodide is added. Stirring is then carried out at room temperature for a further 45 minutes. 15 ml of water are added and filtration is carried out, yielding 4,4″-diethoxy-4′-methoxy-[2,2′;6′,2″]terpyridine in the form of a beige powder. 1H-NMR (360 MHz, CDCl3): 1.39 (t, 6H, J=7.2 Hz); 3.90 (s, 3H); 4.12 (q, 4H, J=7.2 Hz); 6.73 (dd, 2H, J=5.6, 2.5 Hz); 7.88 (s, 2H); 8.01 (d, 2H, J=2.5 Hz); 8.39 (d, 2H, 5.6 Hz). MS (EI pos, 70 eV), m/z=351 (90, [M+]); 350 (70); 336 (100); 323 (70); 295 (45).
Reaction SMILES: [F:1][C:2]([F:15])([O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11])[CH:3]([F:5])[F:4].[O:16]([C:23]1[CH:24]=[C:25]([NH:29][CH2:30][CH:31](O)[C:32]([F:35])([F:34])[F:33])[CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[O:16]([C:23]1[CH:24]=[C:25]([N:29]2[CH2:30][CH:31]([C:32]([F:33])([F:34])[F:35])[O:11][CH:10]2[C:9]2[CH:12]=[CH:13][CH:14]=[C:7]([O:6][C:2]([F:15])([F:1])[CH:3]([F:4])[F:5])[CH:8]=2)[CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Reactant: OC(CNc1cccc(Oc2ccccc2)c1)C(F)(F)F
Solvent: Cc1ccccc1
Product: FC(F)C(F)(F)Oc1cccc(C2OC(C(F)(F)F)CN2c2cccc(Oc3ccccc3)c2)c1
Yield: 91.7 %

Procedure:
A toluene solution (5 mL) of 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (0.45 g, 2.0 mol) and N-(3-phenoxyphenyl)-3-amino-1,1,1-trifluoro-2-propanol (0.60 g, 2.0 mmol) was refluxed in the presence of molecular sieves and Znl2 (˜5 mg) for 18 h under N2. The reaction mixture was filtered to remove the sieves, and the filtrate was diluted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated to give 0.92 g (92%) of the desired 3-(3-phenoxyphenyl)-2-[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]-5-(trifluoromethyl)oxazolidine product as a colorless oil. The formation of the desired product was monitored by the disappearance of the aldehyde peak (δ10) in the 1H NMR spectrum. HRMS calcd. 502.1253 [M+H]+, found: 502.1220.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[C:14]([CH:16]=O)[CH:13]=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:18]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:20][CH2:21][CH3:22])=[O:19]>CN(C=O)C>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[C:14]([CH:16]=[CH:23][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:13]=[CH:12][CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(C=O)n1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1cccc(CO[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
6-(t-Butyldimethylsilanyloxymethyl)pyridine-2-carboxaldehyde (4.29 g) was dissolved in 50 mL of DMF, and 7.14 g of (carbethoxymethylene)triphenylphosphorane was added to the solution, and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice-water, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. To the residue, 100 mL of a mixture of hexane-ethyl acetate (5:1) was added, the insoluble material was filtrated off, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (hexane-ethyl acetate=10:1) to give 5.45 g of ethyl 3-[6-(t-butyldimethylsilanyloxymethyl)pyridin-2-yl]acrylate as a light yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](=[O:20])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[N:14][C:15]([CH3:19])=[CH:16][CH:17]=4)[NH:12][CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:23][N:24]1[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]1.[ClH:37]>C(Cl)Cl.O1CCOCC1>[ClH:37].[ClH:37].[ClH:37].[OH:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](=[O:20])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[N:14][C:15]([CH3:19])=[CH:16][CH:17]=4)[NH:12][CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:23][N:24]1[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]1
Reactant: Cc1ccc2c(/C=C3\Oc4c(ccc(O)c4CN4CCN(C(=O)OC(C)(C)C)CC4)C3=O)c[nH]c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccc2c(/C=C3\Oc4c(ccc(O)c4CN4CCNCC4)C3=O)c[nH]c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A solution of tert-butyl (Z)-4-({6-hydroxy-2-[(6-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.023 g, 0.047 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. The mixture was azeotroped twice with toluene under reduced pressure, and then the residual solid was suspended in a mixed solvent of methylene chloride and diethyl ether and thereby washed to obtain (Z)-6-hydroxy-2-[(6-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one trihydrochloride (0.018 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:19][CH2:20][C:21]1([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(N1C=CN=C1)(N1C=CN=C1)=O.CN(C1C=CC=CN=1)C.ON1C2C=CC=CC=2N=N1.C(=O)([O-])[O-]>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[CH:7][C:3]=1[C:4]([NH:19][CH2:20][C:21]1([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:6]
Reactant: NCC1(O)CCCCCC1
Reactant: O=C(O)c1cc(-c2cc(C3CC3)[nH]n2)ccc1Cl
Agent: CN(C)c1ccccn1
Agent: O=C([O-])[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(NCC1(O)CCCCCC1)c1cc(-c2cc(C3CC3)[nH]n2)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-chloro-5-(5-cyclopropyl-1H-pyrazol-3-yl)-benzoic acid (0.06 g, 0.23 mmol), 1-aminomethyl-cycloheptanol ((0.082 g, 0.46 mmol), polystyrene supported carbonyldiimidazole (0.37 g, 0.46 mmol), polystyrene supported dimethylaminopyridine (0.32 g, 0.46 mmol) and 1-hydroxybenztriazole (0.06 g, 0.46 mmol) in N,N-dimethylformamide (3 mL) was shaken at room temperature for 16 h. MP-carbonate was added (0.5 g) and the resulting mixture was shaken at room temperature for 2 h. The mixture was filtered and the filtrate was concentrated in vacuo. the residue was purified by reverse phase chromatography to afford the title compound (0.02 g). LCMS (m/z) 388.4 M+1.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][NH:5][C:6]([C:8]1[C:9]([NH:15][CH2:16][C:17]([N:19]2[CH2:24][C@H:23]([CH3:25])[N:22]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:21][C@H:20]2[CH3:34])=[O:18])=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1)=[O:7].O.[OH-].[Li+]>O1CCCC1.CO.O>[Cl:14][C:12]1[CH:13]=[C:8]([C:6]([NH:5][CH2:4][C:3]([OH:35])=[O:2])=[O:7])[C:9]([NH:15][CH2:16][C:17]([N:19]2[CH2:24][C@H:23]([CH3:25])[N:22]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:21][C@H:20]2[CH3:34])=[O:18])=[N:10][CH:11]=1
Reactant: COC(=O)CNC(=O)c1cc(Cl)cnc1NCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CNc1ncc(Cl)cc1C(=O)NCC(=O)O
Reaction time: 8 h
Yield: 52.6 %

Procedure:
To a solution of [(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethylamino}-pyridine-3-carbonyl)-amino]-acetic acid methyl ester (0.043 g, 0.085 mmol) in tetrahydrofuran (1 mL), methanol (1 mL) and water (0.25 mL) was added lithium hydroxide monohydrate (0.018 g, 0.43 mmol). The reaction was stirred overnight. The reaction was then concentrated in vacuo, diluted with dichloromethane and passed through a fritted funnel. The filtrate was treated with saturated hydrogen chloride in diethyl ether and the white precipitate formed was collected by filtration to give the title compound (0.022 g, LRMS: 492.2).