Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH:6]1[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][CH2:7]1.C(N(C(C)C)CC)(C)C.[CH3:25][C:26]1([CH3:39])[C:30]2([CH2:34][S:35](Cl)(=[O:37])=[O:36])[C:31]([CH2:33][CH:27]1[CH2:28][CH2:29]2)=[O:32]>ClCCl>[O:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][CH2:7][CH:6]1[CH2:5][NH:4][CH2:3][CH2:2][NH:1][S:35]([CH2:34][C@@:30]12[C:26]([CH3:25])([CH3:39])[CH:27]([CH2:28][CH2:29]1)[CH2:33][C:31]2=[O:32])(=[O:37])=[O:36]
Reactant: NCCNCC1COc2ccccc2O1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)Cl)C(=O)C2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C2CC[C@]1(CS(=O)(=O)NCCNCC1COc3ccccc3O1)C(=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
To a solution of 2.1 g (10 mmole) of 2-{N-(2-aminoethyl)]aminomethyl-2,3-dihydrobenzodioxin and 1.3 g (10 mmole) of diisopropylethylamine in 100 ml of dichloromethane stored in an ice bath was added 1.8 g (7.2 mmole) (-)-10-camphorsulfonyl chloride. The mixture was allowed to stir overnight at room temperature. The reaction was next washed with saturated aqueous sodium bicarbonate, with saturated sodium chloride, dried over sodium sulfate, filtered and evaporated in vacuum. Column chromatography on 100 g of silica gel with chloroform as eluant, followed by crystallization from isopropanol gave 1.3 g of the title compound, m.p. 149°-152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](=[O:26])[NH:15][C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:10]=[C:9]2[CH2:27][C:28](O)=[O:29])=[C:4]([C:31]([F:34])([F:33])[F:32])[CH:3]=1.O.ON1C2C=CC=CC=2N=N1.[CH3:46][NH:47][CH3:48].C1COCC1>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]([CH2:27][C:28]([N:47]([CH3:48])[CH3:46])=[O:29])=[CH:10][C:11]([C:14]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)=[O:26])=[C:12]2[CH3:13])=[C:4]([C:31]([F:33])([F:32])[F:34])[CH:3]=1
Reactant: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)cc(CC(=O)O)n1-c1ccc(Cl)cc1C(F)(F)F
Reactant: CNC
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)cc(CC(=O)N(C)C)n1-c1ccc(Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of the above (1-[4-chloro-2-(trifluoromethyl)phenyl]-5-methyl-4-{[4-(methylsulfonyl)phenyl]carbamoyl}-1H-pyrrol-2-yl)acetic acid (30 mg, 0.518 mmol) in DMF (0.58 mL), 1-hydroxybenzotriazole monohydrate (18 mg, 0.12 mmol) and hydrochloric acid 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide (23 mg, 0.12 mmol) were successively added, and the mixture was stirred at room temperature for 1 hour. Thereafter, a 2M dimethylamine/THF solution was added to the mixture, and the mixture was stirred overnight. After the reaction, it was diluted with ethyl acetate, and the organic layer was washed with 1M hydrochloric acid, water and saturated brine. Thereafter, it was dried with sodium sulfate, filtration was carried out, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (17 mg, 54%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[S:5][C:6]=1[N:7](C)[C:8](=O)C(F)(F)F.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[N:3]=[C:4]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[S:5][C:6]=1[NH:7][CH3:8]
Reactant: CN(C(=O)C(F)(F)F)c1sc(-c2cccnc2)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CNc1sc(-c2cccnc2)nc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 86.4 %

Procedure:
A solution of N-(4-chloro-2-pyridin-3-yl-thiazol-5-yl)-2,2,2-trifluoro-N-methyl-acetamide (0.337 g, 1 mmol) in ice-cold methanol (18 mL) was treated with potassium carbonate (0.434 g, 3.1 mmol) and stirred under nitrogen for 20 min. The solids were removed by filtration, and the filtrate was concentrated under reduced pressure and it was adsorbed onto silica gel. Purification by silica gel chromatography eluting with a gradient of ethyl acetate in hexanes afforded a bright yellow solid (0.195 g, 82%): mp 79° C. (dec); 1H NMR (400 MHz, CDCl3) δ 8.97 (d, J=2.1 Hz, 1H), 8.55 (dd, J=4.8, J=1.5 Hz, 1H), 8.08 (ddd, J=8.1, 2.0, 2.0 Hz, 1H), 7.32 (dd, J=8.1, 4.8 Hz, 1H), 4.07 (br m, 1H), 3.03 (d, J=5.3 Hz, 3H); ESIMS m/z 228.23 (M+2); IR 1540 cm−1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:18])=[O:5])[CH3:2].[C:19]1(=O)[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)=[CH:9][S:8][C:7]=1[N:18]1[C:22](=[O:23])[C:21]2[C:20](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]1=[O:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2cccc(C)c2)csc1N
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2cccc(C)c2)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 63 %

Procedure:
A mixture of 2-amino-4-(3-methylphenyl)thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 2 & 3, Part B) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) was heated at reflux overnight. After cooling to room temperature, the acetic acid was removed in vacuo and the residue triturated with petroleum ether. The crude product was collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue was dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization from petroleum ether afforded the desired product as a yellow solid in 63% yield.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)C.C(O)C.O.[NH2:17][NH2:18]>O>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([NH:17][NH2:18])=[O:3])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc(Br)cc1
Temperature: 78 °C
Yield: 96 %

Procedure:
Into a 200 mL three-neck flask was put 25 g (0.19 mol) of ethyl-4-bromobenzoate, 50 mL of ethanol was added thereto, and the mixture was stirred. After that, 20 mL of hydrazine monohydrate was added to the mixture, and then the mixture was stirred while being heated at 78° C. for 5 hours to be reacted. After the reaction, water was added to the reaction mixture, and a precipitated solid was collected by suction filtration. The obtained solid was washed with water and collected by suction filtration, whereby 24 g of a white solid of 4-bromobenzoylhydrazine, which was the object of the synthesis, was obtained in a yield of 96% (synthesis scheme (a-1)).
Reaction SMILES: [CH:1]1[C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[N:4]=[CH:3][CH:2]=1.O.NN.[Cl-].[Na+]>C(O)COCCO>[CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[N:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2-c2ncccc21
Agent: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: OCCOCCO
Product: c1ccc2c(c1)Cc1cccnc1-2
Temperature: 168 °C
Reaction time: 3 h
Yield: 98.8 %

Procedure:
Subsequently, in a stream of argon, 500 mL of diethylene glycol was added to 16.8 g (92.6 mmol) of 4-azafluorene-9-one and 25 mL (370 mmol) of hydrazine monohydrate, and was heated and stirred at 168° C. for 3 hours. After the reaction liquid was cooled to room temperature, an aqueous solution of sodium chloride was added to the reaction liquid, and then, was extracted with ethyl acetate. The organic phase was washed with water, dried over sodium sulfate and concentrated, to thereby obtain 15.3 g of 4-azafluorene (99% yield).
Reaction SMILES: N1C=CC=CC=1.C([O-])([O-])=O.[Ca+2].[CH3:12][Si:13](F)([CH3:15])[CH3:14].C(O)=O.[OH2:20]>>[CH3:12][Si:13]([CH3:15])([CH3:14])[O:20][Si:13]([CH3:15])([CH3:14])[CH3:12]
Reactant: O
Reactant: C[Si](C)(C)F
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: c1ccncc1
Solvent: O=CO
Product: C[Si](C)(C)O[Si](C)(C)C
Temperature: 0 °C

Procedure:
Working up of the HF/pyridine reaction solution takes place suitably with a suspension of excess finely powdered CaCO3 in ice water with vigorous stirring and filtration of the resultant calcium fluoride. Further, excess hexamethyldisiloxane can be added to the crude reaction mixture with vigorous stirring, so that the phases are at least somewhat mixed, and the volatile trimethylsilyl fluoride (boiling point 17° C.) and water format temperatures between -20° C. and 24° C. The trimethylsilyl fluoride can be cleaved in a receiver with alkaline solution to form alkali fluorides and hexamethyldisiloxane. The working up with hexamethyldisiloxane is particularly suitable for the reaction of the 5'-phosphates.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:11]1([NH:5][C:4]2[CH:6]=[CH:7][C:8]([CH3:9])=[C:2]([CH3:1])[CH:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1ccc(N)cc1C
Reactant: Brc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Cc1ccc(Nc2ccccc2)cc1C
Temperature: 105 °C

Procedure:
Into a 250 mL round bottom flask was placed palladium acetate (120 mg) and Cytop-216 (120 mg) and was stirred in toluene (20 mL) for 1 hour at room temperature under agron. To this was added, in order, 3,4-dimethylaniline (3.27 g), bromobenzene (6 mL), sodium t-butoxide (7.9 g) and a further (20 mL) of toluene. The resulting mixture was heated at 100-110° C. for between 4 and 6 hours. The mixture was cooled to room temperature and diluted with 20 mL of toluene, filtered to remove insolubles, and 10-20 g of Al2O3 was added. The resulting slurry was heated to −80° C. and filtered while hot. The toluene was removed by rotary evaporation and the residue was recrystallized from 150 mL of isopropyl alcohol. The solid produced on cooling was filtered by suction, washed with a further 100 mL of isopropyl alcohol, and dried overnight. Yield was 5.1 g with a purity >99% which was determined by HPLC and NMR.
Reaction SMILES: [OH:1][CH:2]([CH2:20][CH3:21])[C:3]([N:5]1[CH2:10][CH2:9][C:8]2[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][C:7]=2[CH2:6]1)=[O:4].N1C=CN=C1.[C:27]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28].C(Cl)Cl>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:27]([Si:31]([CH3:33])([CH3:32])[O:1][CH:2]([CH2:20][CH3:21])[C:3]([N:5]1[CH2:10][CH2:9][C:8]2[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][C:7]=2[CH2:6]1)=[O:4])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCC(O)C(=O)N1CCc2nc(-c3ccccc3)oc2C1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCC(O[Si](C)(C)C(C)(C)C)C(=O)N1CCc2nc(-c3ccccc3)oc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
710.00 mg (2.48 mmol) 2-hydroxy-1-(2-phenyl-6,7-dihydro-4H-oxazolo[5,4-c]pyridin-5-yl)-butan-1-one are placed in 10 mL DMF and combined with 340.00 mg (4.99 mmol) imidazole. Then 600.00 mg (3.98 mmol) tert.-butyl-chloro-dimethyl-silane and 30.00 mg (0.25 mmol) DMAP are added and the mixture is stirred overnight at RT. The DMF is eliminated i.V., the residue is added to DCM and extracted 1 time each with H2O, 1N HCl and saturated sodium chloride solution. The solvent of the org. phase is eliminated in vacuo and the residue is purified on silica gel. (Eluant: cyclohexane/EA).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:21]3[C:22]([O:26][CH3:27])=[CH:23][CH:24]=[CH:25][C:20]=3[F:19])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14]
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(Br)cccc12
Reactant: COc1cccc(F)c1B(O)O
Product: COc1cccc(F)c1-c1cccc2c(N)c(C(=O)NC3CC3)nnc12
Yield: 59.7 %

Procedure:
Using Method H, 4-amino-8-bromo-N-cyclopropyl-cinnoline-3-carboxamide (120 mg, 0.39 mmol) and 2-fluoro-6-methoxyphenylboronic acid (250 mg, 1.47 mmol) were reacted (refluxed 2 hours). After purification the title compound (82 mg, 60% yield) was obtained as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.52 (bm, 1H), 7.93 (m, 1H), 7.75 (m, 1H), 7.36 (apparent q, J=7.0 Hz, 1H), 6.84 (m, 2H), 3.69 (s, 3H), 2.96 (m, 1H), 0.85 (m, 2H), 0.63 (m, 2H). MS APCI, m/z=353 (M+H) HPLC 1.74 min.
Reaction SMILES: C(OC(=O)[NH:10][CH:11]([C:24](=[O:41])[N:25]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:26][CH:27]([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:15][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[NH2:10][CH:11]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[CH:17][CH:18]=1)[C:24]([N:25]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH2:26][CH:27]([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[O:41]
Reactant: CCOC(CN(Cc1ccccc1)C(=O)C(Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCc1ccccc1)OCC
Agent: [Pd]
Solvent: CO
Product: CCOC(CN(Cc1ccccc1)C(=O)C(N)Cc1ccc(OC(C)(C)C)cc1)OCC
Reaction time: 2 h

Procedure:
To a solution of [1-[Benzyl-(2,2-diethoxy-ethyl)-carbamoyl]-2-(4-tert-butoxy-phenyl)-ethyl]-carbamic acid benzyl ester (3.32 g, 5.76 mmol) in MeOH (50 mL) was added Pd/C (500 mg). After 2 h of stirring under H2 atmosphere, the solution was filtered on Celite and the solvent was evaporated to afford 2-Amino-N-benzyl-3-(4-tert-butoxy-phenyl)-N-(2,2-diethoxy-ethyl)-propionamide, which was used next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH:4]=[O:5].[CH:12](=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].O.O.[Cl-].[Ca+2].[Cl-].CO.[OH-].[K+].Cl>>[OH:1][C:2]1[C:9]([CH:12]([OH:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:8]([OH:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH:4]=[O:5]
Reactant: CCCCCCCCCCCC=O
Reactant: Cc1cc(O)cc(O)c1C=O
Agent: Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCC(O)c1c(O)cc(C)c(C=O)c1O
Yield: 28.7 %

Procedure:
2,4-Dihydroxy-6-methylbenzaldehyde (91 mg, 0.60 mmol) described in M. M. Joullie et al., J. Org. Chem., 50, 3997 (1985), dodecanal (133 mg, 0.72 mmol) and calcium chloride dihydrate (59 mg, 0.40 mmol) were stirred in a 0.4 M potassium hydroxide methanol solution (2 ml) at 0° C. for 24 hours. The reaction mixture was made acidic with 1 M hydrochloric acid. After extractive workup with ethyl acetate, the crude product was purified by silica gel thin-layer chromatography (hexane:ethyl acetate=3:1) to obtain 2,4-dihydroxy-3-(1-hydroxydodecyl)-6-methylbenzaldehyde (58 mg, yield 28%).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([O:10]C)=[O:9])=[CH:5][C:4]=1[C:12]1[N:16]2[N:17]=[CH:18][CH:19]=[CH:20][C:15]2=[N:14][CH:13]=1)=[CH2:2].C1COCC1.[OH-].[K+]>CO>[CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][C:4]=1[C:12]1[N:16]2[N:17]=[CH:18][CH:19]=[CH:20][C:15]2=[N:14][CH:13]=1)=[CH2:2]
Reactant: C=Cc1sc(C(=O)OC)cc1-c1cnc2cccnn12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=Cc1sc(C(=O)O)cc1-c1cnc2cccnn12
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Methyl 5-ethenyl-4-(imidazo[1,2-b]pyridazin-3-yl)thiophene-2-carboxylate (130 mg, 0.456 mmol) was dissolved in methanol (2.28 mL) and THF (2.28 mL) and 1M KOH in MeOH (1.38 mL, 1.38 mmol) was added to the mixture. The solution was left to stir at 60° C. for 18 h. The reaction was cooled to room temperature and concentrated under reduced pressure. 1N HCl was added to the residue and the precipitate filtered. The precipitate was then dried under high vacuum affording the title compound as a yellow solid. 1H NMR (500 MHz, CD3SOCD3) δ 13.37 (s, 1H, br); 8.62 (d, 1H); 8.23 (d, 1H); 8.07 (s, 1H); 7.96 (s, 1H); 7.33 (dd, 1H); 6.91 (dd, 1H); 5.84 (d, 1H); 5.41 (d, 1H). LRMS (APCI) calc'd for (C13H9N3O2S) [M+H]+, 272.0. found 272.0.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[O-]CC.[Na+].Br[CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(O)C>[CH3:21][Si:20]([CH3:22])([O:19][CH2:18][CH2:17][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CCO[Si](C)(C)C(C)(C)C)C(=O)OCC
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of diethyl malonate (5.14 g, 32.1 mmol) in anhydrous ethyl alcohol (100 mL) was reacted with 96% sodium ethoxide (2.28 g, 32.2 mmol) at 76° C. for 1 h. After the solution cooled to room temperature, (2-bromoethoxy)-tert-butyldimethylsilane (7.68 g, 32.1 mmol) was added. The resulting solution was heated at 76° C. for 15.5 h and then concentrated. The residue was partitioned between dichloromethane and water. The organic layer was dried (Na2SO4) and concentrated to give the title compound as a brown oil (10.22 g, 100%). 1H NMR (CDCl3) δ 4.19-4.11 (m, 4H), 3.62 (t, 2H, J=6.0 Hz), 3.55 (t, 1H, J=7.3 Hz), 2.10-2.06 (m, 2H), 1.23 (t, 6H, J=7.1 Hz), 0.85 (s, 9H), 0.01 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10](=[O:17])OCC(Cl)(Cl)Cl)=[CH:5][CH:4]=1.[C:20]1([C:26]2[N:30]=[C:29]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:28][N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:20]1([C:26]2[N:30]=[C:29]([N:31]3[CH2:36][CH2:35][N:34]([C:10]([NH:9][C:6]4[CH:7]=[N:8][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:4][CH:5]=4)=[O:17])[CH2:33][CH2:32]3)[S:28][N:27]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1ccc(C(F)(F)F)nc1)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1ccc(C(F)(F)F)nc1)N1CCN(c2nc(-c3ccccc3)ns2)CC1

Procedure:
A solution of 2,2,2-trichloroethyl [6-(trifluoromethyl)pyridin-3-yl]carbamate (200 mg, 0.593 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (146 mg, 0.593 mmol), diisopropylethylamine (0.207 ml, 1.19 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 48 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product as a solid. This was recrystallized from a mixed solvent of tetrahydrofuran, ethyl acetate and hexane to obtain the desired product (110 mg, 42.8%) as a solid.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[S:3]([O:6][C:7]1[CH:15]=[CH:14][C:13]([O:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])=[CH:12][C:8]=1[C:9]([O-])=O)(=[O:5])=[O:4].[C:26]([C:30]1C=C(OS(C(F)(F)F)(=O)=O)C=[CH:32][C:31]=1OS(C(F)(F)F)(=O)=O)(C)(C)[CH3:27].OC1C=CC(C(C2C=CC(O)=CC=2)(C)C)=CC=1>>[F:25][C:2]([F:24])([F:1])[S:3]([O:6][C:7]1[CH:15]=[CH:14][C:13]([O:16][S:17]([C:20]([F:23])([F:21])[F:22])(=[O:19])=[O:18])=[CH:12][C:8]=1[C:9]1[CH:32]=[CH:31][CH:30]=[CH:26][CH:27]=1)(=[O:5])=[O:4]
Reactant: CC(C)(C)c1cc(OS(=O)(=O)C(F)(F)F)ccc1OS(=O)(=O)C(F)(F)F
Reactant: O=C([O-])c1cc(OS(=O)(=O)C(F)(F)F)ccc1OS(=O)(=O)C(F)(F)F
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Product: O=S(=O)(Oc1ccc(OS(=O)(=O)C(F)(F)F)c(-c2ccccc2)c1)C(F)(F)F

Procedure:
Polymerizations of 2,5bis(trifluoromethanesulfonyloxy)benzoate; 2,-tert-butyl-1,4-bis(trifluoromethanesulfonyloxy)benzene; bisphenol A, and 4,4'dihydroxy-1,1'-bisnapthyl are performed in the manner described in connection with EXAMPLE 6.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:13]([O:15][CH3:16])=[O:14].CN(C)CCN(C)C.C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:46])(=O)=O)=CC=1>O1CCCC1>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[C:12]([F:46])([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:13]([O:15][CH3:16])=[O:14]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: COC(=O)CCC(C(=O)OC)N1C(=O)c2ccccc2C1=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)CCC(F)(C(=O)OC)N1C(=O)c2ccccc2C1=O
Reaction time: 0.5 h

Procedure:
To a stirred solution of dimethyl 2-(1,3-dioxoisoindolin-2-yl)-pentane-1,5-dioate (1.0 g, 3.3 mmol) and tetramethylethylene diamine (0.5 g, 4.3 mmol) in tetrahydrofuran (10 mL) is added 2.5 M n-butyl lithium (1.6 mL, 4 mmol,) at -79° C. After 30 minutes, N-fluorobenzenesulfonimide (1 g, 3.2 mmol) is added to the mixture which then is allowed to reach room temperature. The solvent is removed in vacuo and the residue is stirred with methylene chloride (100 mL) for 10 minutes. The organic layer is washed with water and brine (30 mL each), and dried over sodium sulfate. The solvent is removed in vacuo to yield dimethyl 2-(1,3-dioxoisoindolin-2-yl)-2-fluoropentane-1,5-dioate which is further purified by chromatography and converted to 1,3-dioxo-2-(2,6-dioxo-3-fluoropiperidin-3-yl)isoindoline as described above in Part D of Example 9.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:47][C:48]1[CH:55]=[C:54]([CH3:56])[CH:53]=[CH:52][C:49]=1[CH2:50][NH2:51]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:51][CH2:50][C:49]4[CH:52]=[CH:53][C:54]([CH3:56])=[CH:55][C:48]=4[F:47])=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: Cc1ccc(CN)c(F)c1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NCc2ccc(C)cc2F)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 2-fluoro-4-methylbenzylamine (Jrd-Fluoro) to give the title product. LC-MS (ES+) 786 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][S:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])[CH3:10])[CH:5]=[CH:6][C:7]=1[NH2:8].C1N=CN([C:23](N2C=NC=C2)=[O:24])C=1.O>C1COCC1.C(Cl)Cl>[CH3:17][C:14]([S:12]([NH:11][CH:9]([C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:23](=[O:24])[NH:1][C:2]=2[CH:3]=1)[CH3:10])=[O:13])([CH3:16])[CH3:15]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(NS(=O)C(C)(C)C)c1ccc(N)c(N)c1
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CC(NS(=O)C(C)(C)C)c1ccc2[nH]c(=O)[nH]c2c1
Yield: 65 %

Procedure:
A mixture of N-[1-(3,4-diaminophenyl)ethyl]-2-methylpropane-2-sulfinamide and CDI (569 mg, 3.51 mmol) in THF-DCM (10 ml-10 ml) was refluxed for 6 hours. After cooling to the room temperture, water (10 mL) was added to the mixture. The mixture was extracted with EtOAc (150 ml) and organic layer was washed with brine (30 ml), dried over sodium sulfate and concentrated. The residue was recrystallized from EtOAc to afford 430 mg (65%) of the title compound as a pale brown solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.11 (9H, s), 1.38 (3H, d, J=7.3 Hz), 4.37-4.28 (1H, m), 5.53 (1H, d, J=6.6 Hz), 6.84 (1H, d, J=7.3 Hz), 6.93 (1H, d, J=8.1 Hz), 6.99 (1H, s), 10.54 (1H, br.s), 10.60 (1H, br.s). MS (ESI) m/z 282 (M+H)+, 280 (M−H)−.