Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[CH3:2][O:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([C:12]2[O:13][CH2:14]C(C)(C)[N+]=2C)=[C:6]([CH:20]([CH3:28])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:5]=1.[OH-:29].[Na+].Cl.C[Si](C=[N+]=[N-])(C)C>CO.C1C=CC=CC=1>[CH3:14][O:13][C:12](=[O:29])[C:7]1[CH:8]=[C:9]([O:10][CH3:11])[C:4]([O:3][CH3:2])=[CH:5][C:6]=1[CH:20]([CH3:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1cc(C2=[N+](C)C(C)(C)CO2)c(C(C)Cc2ccccc2)cc1OC
Reactant: [OH-]
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Agent: [I-]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1cc(OC)c(OC)cc1C(C)Cc1ccccc1
Temperature: 0 °C
Yield: 88.3 %

Procedure:
To a solution of 2-[4,5-dimethoxy-2-(1-methyl-2-phenyl-ethyl)-phenyl]-3,4,4-trimethyl-4,5-dihydro-oxazolium iodide (5.132 g, 10.4 mmol) in 52 mL methanol was added 4 M NaOH (5.2 mL, 20.7 mmol). The solution was warmed to reflux. After 16 hours the solution was cooled to 0° C. and acidified to pH=1 with concentrated HCl. The mixture was extracted with ethyl acetate, washed with H2O and washed with brine. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give a crude acid (3.228 g). A portion of this acid (2.919 g, 9.73 mmol) was dissolved in a mixture of 70 mL benzene and 20 mL MeOH. Trimethylsilyldiazomethane (6.3 mL, 2.0 M in hexanes) was added drop-wise. After 30 minutes the solution was concentrated in vacuo to give 4,5-dimethoxy-2-(1-methyl-2-phenyl-ethyl)-benzoic acid methyl ester as an oil (2.886 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15](Cl)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:30])([F:29])[C:21]1[N:26]=[CH:25][C:24]([CH2:27][NH2:28])=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:28][CH2:27][C:24]3[CH:25]=[N:26][C:21]([C:20]([F:30])([F:19])[F:29])=[CH:22][CH:23]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccc(C(F)(F)F)nc1
Reactant: Clc1ncnc2c1CN(Cc1ccccc1)CC2
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1ccc(CNc2ncnc3c2CN(Cc2ccccc2)CC3)cn1
Yield: 86 %

Procedure:
Two 20 mL microwave vials were each charged with a half portion of 6-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (5.62 g, 21.6 mmol), (6-(trifluoromethyl)pyridin-3-yl)methanamine (5.0 g, 28 mmol), N,N-diisopropylethylamine (7.6 mL, 44 mmol) and acetonitrile (10 mL), and the mixture was subjected to a microwave irradiation at 200° C. for 3.5 h. LC-MS analysis showed the reaction was complete for both samples. The samples were combined, and partitioned between CH2Cl2 (150 mL) and 0.5M NaH2PO4 (pH 4; 120 mL). The organic layer was extracted with 2M HCl (60 mL, 30 mL). The combined acid extracts were basified with 50% KOH (25 mL), extracted with CH2Cl2 (2×100 mL), dried (Na2SO4), filtered and concentrated to yield a light brown oil, which was absorbed on silica (40 g) and purified by column (120 g silica gel, 0-7.5% MeOH/CH2Cl2) to afford a light yellow foam (7.42 g, 86%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]([F:35])=[C:22]4[C:26]=3[N:25]([CH3:27])[CH:24]=[C:23]4[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+].Cl>O1CCCC1.C(O)(C)C.O>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]([F:35])=[C:22]4[C:26]=3[N:25]([CH3:27])[CH:24]=[C:23]4[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: CCOC(=O)CCc1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)ccc(F)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3ccc(F)c4c(CCC(=O)O)cn(C)c34)no2)cc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
To a solution of ethyl 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-4-fluoro-1-methyl-1H-indol-3-yl]propanoate (D130) (349 mg) in tetrahydrofuran (THF) (10 mL), Isopropanol (5 mL) and water (2 mL), was added sodium hydroxide (293 mg). The reaction mixture was stirred at room temperature overnight. LCMS showed the reaction was complete. The reaction mixture was neutralized with 2 M HCl till pH ˜6.0. After removing part of organic solvent, the residue was purified by MDAP to give 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-4-fluoro-1-methyl-1H-indol-3-yl]propanoic acid (E96) (204 mg). δH (DMSO-d6, 400 MHz): 1.38 (6H, d), 2.61 (2H, t), 3.04 (2H, t), 3.63 (3H, s), 4.95-5.01 (1H, m), 6.96 (1H, dd), 7.23 (1H, s), 7.43 (1H, dd), 7.55 (1H, d), 8.42 (1H, dd), 8.53 (1H, d), 12.15 (1H, s); δF (DMSO-d6, 376 MHz): −120.5; MS (ES): C24H21FN4O4 requires 448; found 449.2 (M+H+).
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[N:7]=[C:8]([C:13]([NH:15][C@H:16]2[CH2:21][CH2:20][N:19]([C:22]3[S:23][C:24]([C:30]([O:32]CC)=O)=[C:25]([CH2:27][NH:28][CH3:29])[N:26]=3)[CH2:18][C@H:17]2[O:35][CH2:36][CH3:37])=[O:14])[NH:9][C:10]=1[CH2:11][CH3:12].Cl>C1(C)C=CC=CC=1>[Cl:5][C:6]1[N:7]=[C:8]([C:13]([NH:15][C@H:16]2[CH2:21][CH2:20][N:19]([C:22]3[S:23][C:24]4[C:30](=[O:32])[N:28]([CH3:29])[CH2:27][C:25]=4[N:26]=3)[CH2:18][C@H:17]2[O:35][CH2:36][CH3:37])=[O:14])[NH:9][C:10]=1[CH2:11][CH3:12]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1CNC
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: CCO[C@@H]1CN(c2nc3c(s2)C(=O)N(C)C3)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 34.5 %

Procedure:
Trimethylaluminum (1.05 M solution in hexane) (0.76 mL, 0.80 mmol) was added to a solution of ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl)-4-[(methylamino)methyl]-1,3-thiazole-5-carboxylate obtained in Example (256a) (80 mg, 0.16 mmol) in toluene (3 mL), and the mixture was heated under reflux for 45 minutes. A 1 N aqueous hydrochloric acid solution was added to the reaction solution, followed by stirring. Then, the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: dichloromethane/methanol=20/1) to obtain 25 mg of the title compound as a pale yellow solid (35%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([OH:15])[C:12]=1[O:13][CH3:14])[C:6]([O:8][CH3:9])=[O:7].[CH2:16](Cl)[C:17]#[CH:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.[I-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:15][CH2:18][C:17]#[CH:16])[C:12]=1[O:13][CH3:14])[C:6]([O:8][CH3:9])=[O:7]
Reactant: C#CCCl
Reactant: COC(=O)c1cc(O)c(OC)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1cc(C(=O)OC)cc(OC)c1OC
Yield: 45.6 %

Procedure:
Methyl 3,4-dimethoxy-5-hydroxybenzoate (E. Spath and H. Roder, Mon. f. Chem. 1922, 43, 93; G. J. Kapadia, Y. N. Vaishnav, M. B. E. Fayez, J. Pharm. Sci. 1969, 9, 1157) (0.54 g, 2.54 mmol), propargyl chloride (0.23 g, 3.04 mmol), sodium iodide (3 mg, 0.02 mmol) and potassium carbonate (0.53 g, 3.81 mmol) were refluxed in acetone (10 mL) for 18 hr, cooled, filtered and concentrated. The resulting oil was dissolved in ethyl acetate (20 mL) and washed with water (3×10 mL). The organic layer was dried (Na2SO4), concentrated and recrystallized from alcohol (2.5 mL)/hexane (20 mL) to give methyl 3,4-dimethoxy-5-(2-propynyloxy)benzoate (0.29 g, 49%); mp 72°-73.5°. Anal. Calcd for C13H14O5 : C, 62.39; H, 5.64. Found: C, 62.28; H, 5.68.
Reaction SMILES: [CH:1]1([NH:4][CH:5]([P:14](=[O:21])([O:18]CC)[O:15]CC)[P:6](=[O:13])([O:10]CC)[O:7]CC)[CH2:3][CH2:2]1.CO.CC(C)=O>C(O)(=O)C.Br>[CH:1]1([NH:4][CH:5]([P:14](=[O:15])([OH:18])[OH:21])[P:6](=[O:7])([OH:13])[OH:10])[CH2:2][CH2:3]1
Reactant: CCOP(=O)(OCC)C(NC1CC1)P(=O)(OCC)OCC
Agent: Br
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: O=P(O)(O)C(NC1CC1)P(=O)(O)O
Temperature: 45 °C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
1.28 g of tetraethyl (cyclopropylamino)methylenebis(phosphonate) was dissolved in 13 ml of 25% hydrogen bromide acetic acid solution and the mixture was stirred at 45° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and 20 ml of purified water was added to the residue. Then, the mixture was again concentrated under reduced pressure. The oily product thus obtained was solidified by methanol and acetone and subjected to the filtration. The solid was washed with acetone to give 0.42 g of (cyclopropylamino)methylenebis(phosphonic acid) as a white solid.
Reaction SMILES: [O:1]1[C:3]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2]1.B(F)(F)F.CCOCC.CCCCCC.CCCCCC.C(OCC)(=O)C>CCOCC>[CH:3]1([CH:2]=[O:1])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: C1CCCCCC2(CCCCC1)CO2
Agent: FB(F)F
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=CC1CCCCCCCCCCC1
Yield: 32 %

Procedure:
To 5.0 g (25.5 mmol) of 1-oxaspiro[2.11]tetradecane in 50 ml of dry ether at 0° C. is slowly added 1.8 ml (2.1 g, 14.6 mmol) of boron trifluoride etherate. The ice bath is removed and after 15 minutes at room temperature the solution is partitioned between ether and saturated sodium bicarbonate. The organic phase is evaporated to give a clear oil. Flash chromatography over silica gel using a hexane to hexane:ethyl acetate (9:1) gradient give 1.6 g (34%) of a clear oil: NMR (CDCl3) δ 1.28-1.8 (m, 18 H), 2.03 (s, 1 H), 2.42 (m, 1 H), 9.62 (s, 1 H)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[NH2:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[NH2:20])[C:15]#[N:16]>CS(C)=O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]1[NH:11][C:12]2[CH:13]=[C:14]([C:15]#[N:16])[CH:17]=[CH:18][C:19]=2[N:20]=1
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: N#Cc1ccc(N)c(N)c1
Solvent: CS(C)=O
Product: N#Cc1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a 20 ml scint. vial was added 0.500 g (2.86 mmol) of 2,6-Dichloro-benzaldehyde, 0.3804 g (2.86 mmol) of 3,4-diamino-benzonitrile, and 6 mL DMSO. To the brown solution was added 0.1995 g (1.23 mmol) of FeCl3. Allowed stir at r.t. open to air for 18 h. Extracted with EtOAc and washed with water, and brine. Dried and purified on silica gel column chromatography (EtOAc/Hep, 1:9 to 7:3) to give of the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.62-7.72 (m, 4 H) 7.79 (br. s., 1 H) 8.27 (br. s., 1 H) 13.48 (br. s., 1 H). MS (m/z) 288.1 M (+1), tR=1.18, Meth 10
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C:6]1[CH2:25][S:24][C@@H:9]2[C@H:10]([NH:13]C(CCC[C@@H](N)C(O)=O)=O)[C:11](=[O:12])[N:8]2[C:7]=1[C:26]([OH:28])=[O:27])=[O:3].[Na].C(N(CC)C1C=CC=CC=1)C.C(Cl)(=O)C.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.ClCl.Cl>C(Cl)Cl.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.O.C(O)C(C)C>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:26]([OH:28])=[O:27])=[C:6]([CH2:5][O:4][C:2](=[O:3])[CH3:1])[CH2:25][S:24][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CCC[C@@H](N)C(=O)O)[C@H]2SC1
Agent: Cl
Agent: ClCl
Agent: [Na]
Solvent: CCN(CC)c1ccccc1
Solvent: O
Solvent: CC(C)CO
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: -35 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
4.8 gm (10 mmol) of cephalosporin C, sodium salt, dihydrate was suspended in 80 ml of methylene chloride (cyclohexane stabilized, dried over 4A molecular sieves). Diethyl aniline (dried over KOH), 7.4 gm (8 ml, 50 mmol), and acetyl chloride, 4.7 gm (4.3 ml, 60 mmol), were added. The mixture was stirred in an ice bath at 30° to 40° C. for 1 hour and then at room temperature for 2 hours. Filtration removed 1.65 gm of undissolved material. The reaction solution was cooled in an ice-alcohol bath before addition to a solution of the triphenyl phosphite-chlorine kinetic compound prepared as follows: triphenyl phosphite, 6.8 gm (5.8 ml, 22 mmol), was added to 100 ml of dry methylene chloride and cooled to ice-alcohol temperature before the addition of chlorine gas until a yellow coloration persisted. The addition of a few drops of triphenyl phosphite gave a colorless solution. After mixing the two above described solutions at ice alcohol temperature, diethyl aniline, 3.3 gm (3.5 ml, 22 mmol), in 20 ml of dry methylene chloride was added dropwise over a period of 10 minutes. The reaction mixture was stirred in the cold for 2 hours, then cooled further to about -35° C. and treated with isobutanol (dried over 3A molecular sieves), 6.0 gm (7.4 ml, 80 mmol). A stream and dry hydrogen chloride was then passed through the reaction mixture for about 30 seconds. The reaction mixture was refrigerated overnight. Twenty ml of water was then added to the methylene chloride solution. The resulting 2-phase mixture was stirred vigorously for 5 minutes. The methylene chloride layer was separated and washed with 20 ml of water. The aqueous layer and the aqueous wash were combined, washed with ethyl acetate and then adjusted to pH 3.8 with saturated ammonium bicarbonate solution. After 30 minutes at ice bath temperature the aqueous slurry was filtered to provide 1.5 gm (vacuum dried, 83%) of 7-ACA.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1.C(Cl)(=O)C(Cl)=O.[C:22]1([O:28][CH3:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(Cl)Cl.CN(C=O)C>[CH3:29][O:28][C:22]1[CH:27]=[CH:26][C:25]([C:10]([C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:15])=[CH:14][CH:13]=2)=[O:12])=[CH:24][CH:23]=1
Reactant: COC(=O)CCc1ccc(C(=O)O)cc1
Reactant: COc1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)CCc1ccc(C(=O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
4-[3-(Methyloxy)-3-oxopropyl]benzoic acid (66) (1.0 g, 4.80 mmol) was dissolved in CH2Cl2 (25 mL). Oxalyl chloride (0.86 mL, 9.61 mmol) was added dropwise, followed by addition of two drops of DMF. The reaction mixture was stirred at room temperature for 2 h. Methylene chloride and the excess of oxalyl chloride were removed under vacuum. The residue was dissolved in CH2Cl2 (15 mL) with anisole (1.05 mL, 9.60 mmol). Cooled in an ice bath, AlCl3 (0.97 g, 7.20 mmol) was added in portions. The mixture was stirred at 0° C. for 3.5 h, then stirred at room temperature for 1.5 h. Poured into 1 N HCl (25 mL) with ice, the mixture was extracted with CH2Cl2 (3×50 mL). The combined CH2Cl2 extract was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give brown oil. The crude product was purified by chromatography on a silica gel column eluted with hexanes:EtOAc (8:1 to 5:1) to give 0.90 g (63%) of the title compound 167 as cotton-like white solid. 1H NMR (400 MHz, CDCl3): δ 2.68 (t, J=7.7 Hz, 2H), 3.03 (t, J=7.7 Hz, 2H), 3.68 (s, 3H), 3.89 (s, 3H), 6.96 (d, J=8.8 Hz, 2H), 7.30 (d, J=8.1 Hz, 2H), 7.70 (d, J=8.1 Hz, 2H), 7.81 (d, J=8.8 Hz, 2H)+. LCMS (ESI): m/z 299 (M+H)+.
Reaction SMILES: Cl.CO[C:4]([C@@H:6]1[C@@H:10]([OH:11])[CH2:9][CH2:8][NH:7]1)=[O:5].[Cl:12][C:13]1[C:20]([CH3:21])=[C:19]([N:22]=[C:23]=[O:24])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]>>[Cl:12][C:13]1[C:20]([CH3:21])=[C:19]([N:22]2[C:4](=[O:5])[C@H:6]3[C@@H:10]([OH:11])[CH2:9][CH2:8][N:7]3[C:23]2=[O:24])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: COC(=O)[C@H]1NCC[C@@H]1O
Reactant: Cc1c(N=C=O)ccc(C#N)c1Cl
Agent: Cl
Product: Cc1c(N2C(=O)[C@H]3[C@@H](O)CCN3C2=O)ccc(C#N)c1Cl

Procedure:
The title compound was prepared from compound 1A and compound 23E in a manner similar to that described in Example 19. mp 237-238° C.; HPLC: 100% at 2.11 and 2.36 min (retention time) (Conditions: Phenomenex Luna C18 (4.6×50 mm); Eluted with 0% to 100% B, 4 min gradient (A=90% H2O-10% MeOH-0.1% H3PO4 and B=10% H2O-90% MeOH-0.1% H3PO4); Flow rate at 4 mL/min. UV detection at 220 nm). Chiral HPLC: retention time=15.9 min (100%); Conditions: OD (4.6×250 mm); Eluted with 20% isopropanol in hexane for 30 min at 1 mL/min, MS (ES) m/z 306 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].[F:15][C:16]([Si](C)(C)C)([F:18])[F:17]>CN(C)C=O>[F:15][C:16]([F:18])([F:17])[CH:7]([C:6]1[S:5][CH:4]=[N:3][C:2]=1[CH3:1])[OH:8]
Reactant: Cc1ncsc1C=O
Reactant: C[Si](C)(C)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ncsc1C(O)C(F)(F)F
Yield: 84.5 %

Procedure:
According to Reference Example 8-2, by use of 4-methylthiazole-5-carbaldehyde (300 mg, 2.36 mmol) dissolved in N,N-dimethylformamide (4 mL), potassium carbonate (65 mg, 0.47 mmol) and (trifluoromethyl)trimethylsilane (0.419 mL, 2.83 mmol), the mixture was stirred and reacted at room temperature for 2.2 hours. Then, purification by preparative thin-layer chromatography (chloroform/methanol=15/1) was performed to give 2,2,2-trifluoro-1-(4-methylthiazol-5-yl)ethanol (Compound DT) (393 mg, yield: 84%).
Reaction SMILES: C1(C)C=C(C)C=C(C)C=1S(O[NH2:13])(=O)=O.[Br:15][C:16]1[CH:21]=[N:20][C:19]([C:22]#[C:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[CH:18][N:17]=1.C([O-])([O-])=O.[K+].[K+].NN1C=CN=CC1>C(Cl)Cl.CN(C=O)C>[Br:15][C:16]1[N:17]=[CH:18][C:19]2[N:20]([N:13]=[C:23]([Si:24]([CH3:26])([CH3:25])[CH3:27])[CH:22]=2)[CH:21]=1
Reactant: C[Si](C)(C)C#Cc1cnc(Br)cn1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Agent: NN1C=CN=CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[Si](C)(C)c1cc2cnc(Br)cn2n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 7.6 %

Procedure:
O-(Mesitylenesulfonyl)hydroxylamine (680 mg, 3.2 mmol) was added in one portion to a stirred solution of 2-bromo-5-trimethylsilanylethynyl-pyrazine (Step 1, 3 mmol) in CH2Cl2 (3 ml) at 0° C. The mixture was stirred at 0° C. for 30 minutes, at RT for 4 hours, then evaporated. The N-amino adduct was used without further manipulation. K2CO3 (410 mg, 3 mmol) was added to a stirred solution of the N-aminopyrazine from above in dry DMF (5 ml) at RT under nitrogen. After 6 hours the mixture was partitioned between EtOAc/H2O. The organic layer was washed with brine (×2), then evaporated. The residue was taken up in CH2Cl2 and passed through a phase separating cartridge. The filtrate was evaporated and the residue was purified by chromatography on silica (2→4% EtOAc/Petrol) to give the title compound (62 mg, oil) MS: [M+H]+ 270/272.
Reaction SMILES: O=[O+][O-].[Si:4]([O:11][CH2:12][CH2:13][C@H:14]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C:15](C)=[CH2:16])([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCC.CC[O:52]CC>O=O.ClCCl>[Si:19]([O:18][C@@H:14]([CH2:13][CH2:12][O:11][Si:4]([C:7]([CH3:8])([CH3:9])[CH3:10])([CH3:5])[CH3:6])[C:15](=[O:52])[CH3:16])([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:20])[CH3:21]
Reactant: CCOCC
Reactant: C=C(C)[C@H](CCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: O=O
Agent: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCC
Product: CC(=O)[C@H](CCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Yield: 70 %

Procedure:
Ozone in O2 is directed at -78° C. through a solution of 1.610 g (4.67 mmol) of 11 in 200 ml of absolute dichloromethane (dry ice/acetone-cold bath). When starting compound 11 can no longer be detected by thin-layer chromatography in the solution, 3.89 g (14.83 mmol) of triphenylphosphine is added, and the cold bath is removed. The reaction batch is allowed to come slowly to room temperature, and the solvent is distilled off in a vacuum. Flash chromatography of the residue by a silica gel column with pentane/Et2O (50:1) yields 1.135 g (3.27 mmol, 70%) of 12.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[F:23])[NH2:19].FC1C=CC(NC2CCN(C(OC(C)(C)C)=O)CC2)=CC=1>>[F:15][C:16]1[CH:17]=[C:18]([NH:19][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: Nc1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)(C)OC(=O)N1CCC(Nc2ccc(F)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(F)c(F)c2)CC1

Procedure:
The title compound was prepared from 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate and 3,4-difluoroaniline using a method similar to that described for D1 although the crude product was purified by chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]#[N:10].C([O-])([O-])=O.[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.O>[CH2:17]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([CH:4]=1)[C:9]#[N:10])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#Cc1cc(O)ccc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(OCc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-bromo-3-cyanophenol (1 g, 5.05 mmol) was dissolved in DMF (10 ml) and K2CO3 (1.40 g, 10.10 mmol) and benzyl bromide (0.66 ml, 5.56 mmol) added. The mixture was stirred under N2 for 1 hr at RT. The mixture was diluted with water (15 mL) and extracted with EtOAc (2×10 mL). The organic fractions were combined, washed with brine (saturated, 1×8 mL), dried over MgSO4, filtered and the volatiles removed in vacuo. The residue was purified by chromatography on silica gel Biotage 25M, using a gradient eluant of EtOAc/Hexane (0-50%) to afford the title compound. LC/MS (m/z): 289 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH:14]=[CH:15][C:16]([O:18]CC)=[O:17])[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([CH:14]=[CH:15][C:16]([OH:18])=[O:17])[CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=Cc1cccc(-c2ccc(C)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2cccc(C=CC(=O)O)n2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.8 %

Procedure:
In methanol (5 ml) was suspended ethyl 6-(4-methylphenyl)-2-pyridineacrylate (465 mg, 1.74 mmol), and to the mixture was added at 0° C. 1N sodium hydroxide solution (5.22 ml). The mixture was stirred at room temperature for 20 hours. To the mixture was added at 0° C. 1N hydrochloric acid (5.22 ml), and methanol was evaporated under reduced pressure. The aqueous layer extracted with ethyl acetate (30 ml, 20 ml). The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. To the residue was added diisopropylether(5 ml), and Insoluble materials were filtered, which were washed with diisopropylether and dried under reduced pressure to give 6-(4-methylphenyl)-2-pyridineacrylic acid (344 mg, 1.44 mmol, 83%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)([CH3:23])=[CH2:22]>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([N:33]2[CH2:34][CH2:35][N:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[C:21]([CH3:23])=[CH2:22])[CH2:31][CH2:32]2)=[O:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: C=C(C)c1ccccc1N1CCNCC1
Reactant: COc1nc(C)c(C)cc1NC(=O)Oc1ccccc1
Product: C=C(C)c1ccccc1N1CCN(C(=O)Nc2cc(C)c(C)nc2OC)CC1
Yield: 62 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(2-isopropenylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.