Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1.II.Cl[P:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([CH3:26])([CH3:25])[CH3:24]>CCOCC>[C:23]([P:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: FC(F)(F)c1ccc(-c2ccccc2Br)cc1
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)(C)P(c1ccccc1-c1ccc(C(F)(F)F)cc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 10.7 %

Procedure:
An oven dried Schlenk tube was evacuated and backfilled with argon and charged with magnesium turnings (90 mg, 3.69 mmol), 2-bromo-4′-(trifluoromethyl)biphenyl (1.01 g, 3.35 mmol), and a crystal of iodine. The tube was purged with argon for 5 minutes, then THF (6 mL) was added through a rubber septum and the reaction mixture was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature and cuprous chloride (365 mg, 3.69 mmol) and chloro-di-t-butylphosphine (0.765 mL, 4.03 mmol) were added. Heating was resumed for 14 hours. The reaction mixture was then cooled to room temperature and diluted with ether (40 mL). The suspension was filtered to isolate the solid. The solid was partitioned between ethyl acetate (60 mL) and 38% ammonium hydroxide (75 mL). The aqueous layer was extracted with ethyl acetate (60 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, decanted, and concentrated in vacuo. The product was crystallized from MeOH (10 mL) to afford 131 mg (11%) of pale yellow needles. A second crop was isolated by concentrating the mother liquor and recrystallizing the solid from MeOH (20 mL) and water (2 mL) to afford 260 mg (21%) of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:22])=[C:6]([C:8]2[CH2:12][CH2:11][CH2:10][C:9]=2[C:13]2[N:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][CH:14]=2)[CH:7]=1.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][O:20][C:19]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([C:9]3[CH2:10][CH2:11][CH2:12][C:8]=3[C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:22][CH2:28][C:27]3[CH:30]=[CH:31][C:24]([Cl:23])=[CH:25][CH:26]=3)[N:18]=2)=[O:21])=[CH:26][CH:25]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: O=C(O)c1cccc(C2=C(c3cc(Cl)ccc3O)CCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(OCc1ccc(Cl)cc1)c1cccc(C2=C(c3cc(Cl)ccc3OCc3ccc(Cl)cc3)CCC2)n1

Procedure:
6-[2-(5-Chloro-2-hydroxyphenyl)cyclopent-1-enyl]pyridine-2-carboxylic acid (97 mg, 0.30 mmol) was refluxed in 2-butanone (4 mL) with 4-chlorobenzyl bromide (140 mg, 0.70 mmol) and potassium carbonate (1.0 g) under nitrogen for five hours. The reaction mixture was then filtered through highflo, evaporated down to an oil and chromatographed on a Water's sep-pak (10 g) with ether/isohexane (15/85) to give the title compound. (160 mg, 92%). LC/MS [MH+] 556 Rt=5.5 min.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[H-].[Na+].Br[CH2:15][C:16]([O:18][CH3:19])=[O:17].O>C1COCC1.CN(C=O)C>[CH3:19][O:18][C:16](=[O:17])[CH2:15][O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: COc1cc(C=O)ccc1O
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(C=O)cc1OC

Procedure:
(4-Formyl-2-methoxy-phenoxy)-acetic acid methyl ester was prepared by dissolving vanillin (4.1 mmol) (Aldrich) in dry THF (10 mL) and dry DMF (1 mL). Sodium hydride (109 mg, 4.5 mmol) was then added to the solution slowly and the resulting mixture was stirred at room temperature for 1 h at which time methyl bromoacetate (5 mmol) (Aldrich) was added dropwise. The reaction was stirred at room temperature for 14 h at which time water (10 mL) was added and the THF was evaporated in vacuo. The aqueous layer was then extracted with ethyl acetate (3×15 mL), and the combined organic layers were dried over magnesium sulfate and concentrated. The resulting (4-formyl-2-methoxy-phenoxy)-acetic acid methyl ester was purified via flash column chromatography (SiO2, 230-400 mesh) with ethyl acetate/hexane.
Reaction SMILES: [CH2:1]1[O:7][CH2:6][C@@H:4](O)[C@H:2]1O.[Na].[CH2:9]([N:16]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([BH3-])#N.[Na+]>O.C(#N)C>[CH2:9]([N:16]1[CH2:20][CH2:19][C@@H:18]([N:21]2[CH2:4][CH2:6][O:7][CH2:1][CH2:2]2)[CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: O[C@@H]1COC[C@@H]1O
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CC#N
Product: c1ccc(CN2CC[C@@H](N3CCOCC3)C2)cc1
Reaction time: 16 h
Yield: 27.1 %

Procedure:
To a solution of 1,4-anhydroerythritol (1.9 g, 18 mmol) in water (10 ml) was added sodium periodiate (0.7 g, 18 mmol) and the reaction stirred for 16 h. Acetonitrile (10 ml) was added to the mixture and the reaction was filtered to remove precipitated salts. (R)-1-benzyl-pyrrolidin-3-ylamine (1.0 g, 6 mmol) was added as a solution in acetonitrile (5 ml) to the filtrate, followed by sodium cyanoborohydride (1.1 g, 18 mmol). The reaction was stirred for 10 minutes after which time the reaction the acetonitrile removed by evaporation, the mixture made basic by addition of NaHCO3, and repeatedly extracted with CH2Cl2. The combined organic extracts were dried (Na2SO4) and concentrated. Purification by flash column chromatography (CH2Cl2:MeOH 9:1) afforded the title product (0.4 g, 28%) as a brown gum. MS: 247.2 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:48]=[CH:47][C:7]([O:8][C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([C:17]3[C:22]([F:23])=[C:21]([F:24])[C:20]([O:25][C:26]4[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[C:28]([O:35]CC5C=CC=CC=5)[CH:27]=4)=[C:19]([F:43])[C:18]=3[F:44])=[C:11]([F:45])[C:10]=2[F:46])=[CH:6][C:5]=1[O:49]CC1C=CC=CC=1)([O-])=O.[H][H]>O1CCCC1.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:48]=[CH:47][C:7]([O:8][C:9]2[C:10]([F:46])=[C:11]([F:45])[C:12]([C:17]3[C:22]([F:23])=[C:21]([F:24])[C:20]([O:25][C:26]4[CH:31]=[CH:30][C:29]([NH2:32])=[C:28]([OH:35])[CH:27]=4)=[C:19]([F:43])[C:18]=3[F:44])=[C:13]([F:16])[C:14]=2[F:15])=[CH:6][C:5]=1[OH:49]
Reactant: O=[N+]([O-])c1ccc(Oc2c(F)c(F)c(-c3c(F)c(F)c(Oc4ccc([N+](=O)[O-])c(OCc5ccccc5)c4)c(F)c3F)c(F)c2F)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2c(F)c(F)c(-c3c(F)c(F)c(Oc4ccc(N)c(O)c4)c(F)c3F)c(F)c2F)cc1O
Reaction time: 168 h

Procedure:
72 g of 4,4'-Bis(4-nitro-3-benzyloxyphenoxy)octafluorobiphenyl prepared as described in Example 1 (0.09 mol) are dissolved in 600 ml of a mixture of tetrahydrofuran and ethyl acetate (volume ratio 1:1), and 7 g of Pd/C (palladium/carbon) are added to the solution. The mixture is then hydrogenated at room temperature in an autoclave with vigorous stirring using hydrogen at a pressure of 1 bar; after 7 days, the reaction is terminated. The yellow-beige solution is evaporated to half in a rotary evaporator and left to stand overnight at room temperature, during which the reaction product precipitates in crystalline form. The reaction product is then collected and dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 96%0).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][N:10]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]CC(O)=O)[C:9]2=[O:28])=[CH:4][CH:3]=1.[OH-:29].[Na+].[CH2:31]([OH:33])[CH3:32]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][N:10]([CH:19]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:32][C:31]([OH:29])=[O:33])[C:9]2=[O:28])=[CH:6][CH:7]=1
Reactant: O=C(O)CCCCCCn1cc(-c2ccccc2)n(-c2ccc(Cl)cc2)c1=O
Reactant: CCO
Reactant: [OH-]
Agent: [Na+]
Product: CCCCC(CC(=O)O)n1cc(-c2ccccc2)n(-c2ccc(Cl)cc2)c1=O

Procedure:
The product is produced as described in example 18 from 13.5 g of 7-[3-(4-chlorophenyl)-2-oxo-4-phenyl-4-imidazolin-1-yl] enanthic acid ethel ester, 1.28 g of NaOH in 60 cc. of ethanol.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9](I)([F:11])[F:10].OO>[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Fe+2].CS(C)=O>[OH:1][C:2]1[C:7]([C:9]([F:11])([F:10])[F:8])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: FC(F)(F)I
Reactant: Oc1ccccn1
Agent: [Fe+2]
Agent: OO
Agent: c1cc[cH-]c1
Solvent: CS(C)=O
Product: Oc1ncccc1C(F)(F)F
Temperature: 25 °C
Yield: 64 %

Procedure:
0.19 g (2.0 mmol) of 2-hydroxypyridine and 0.11 g (0.6 mmol) of ferrocene were weighed and placed in a two-neck flask and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 8.0 ml of dimethyl sulfoxide, 2.0 ml of a 3.0 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide and 0.4 ml of a 30% hydrogen peroxide aqueous solution, and the mixture was stirred for 20 minutes. During the stirring, the temperature of the reaction system rose up in the range of from 40° C. to 50° C. Thereafter, the resulting solution was cooled to room temperature. Formation of 2-hydroxy-3-trifluoromethylpyridine (19F-NMR yield: 64%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard. The subsequent procedure was conducted in the same manner as in Example 1 and 2-hydroxy-3-trifluoromethylpyridine was obtained as a white solid (0.081 g, yield: 50%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[N:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[C:17]=3[NH:16][C:15]2=[O:27])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:18]3[CH:19]=[N:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[C:17]=3[NH:16][C:15]2=[O:27])[CH2:12][CH2:13]1
Reactant: [H][H]
Reactant: O=c1[nH]c2c3ccccc3ncc2n1C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: O=c1[nH]c2c3ccccc3ncc2n1C1CCNCC1

Procedure:
A mixture of 44.0 g (0.123 mol) 3-(1-benzylpiperidin-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one and 10.0 g palladium (Pd/C 10%) in 500 mL methanol was hydrogenated for 16 h at 50 C in a hydrogen atmosphere of 50 psi. After filtration of the reaction mixture the solvent was eliminated in vacuo. The product was precipitated out by the addition of isopropanol. It was filtered off and dried.
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[S:21]([NH2:24])(=[O:23])=[O:22].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CS(C)=O>[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[S:21]([NH:24][C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)(=[O:22])=[O:23]
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: NS(=O)(=O)c1cccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=S(=O)(Nc1nc2ccccc2nc1Cl)c1cccc(Cl)c1Cl
Temperature: 150 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
2,3-Dichloroquinoxaline (1.00 g, 5.02 mmol), 2,3-dichlorobenzenesulfonamide (1.41 g, 5.02 mmol) and potassium carbonate (694 mg, 5.02 mmol) were suspended in dimethyl sulfoxide (30 mL) and the mixture was stirred at 150° C. for 3 hours. The reaction mixture was slowly added to a mixture (300 ml) of a 1% aqueous acetic acid solution and ice, and the mixture was stirred for 3 hours. The resulting solid was collected by filtration and washed with water. Then, slurry purification was performed using diisopropyl ether, to give 2,3-dichloro-N-{3-chloroquinoxalin-2-yl}benzenesulfonamide (Compound AA) (1.53 g, yield: 78%).
Reaction SMILES: [F:1]/[C:2](/[C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10]1)=[C:3](/[F:8])\[Si](C)(C)C.[F-].[K+].O>C(#N)C>[F:1]/[C:2](/[C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10]1)=[CH:3]/[F:8]
Reactant: CCC[C@H]1CC[C@H](/C(F)=C(\F)[Si](C)(C)C)CC1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCC[C@H]1CC[C@H](/C(F)=C\F)CC1

Procedure:
Then, 18.2 g (0.07 mol) of the obtained (Z)-1,2-difluoro-1-(trans-4-n-propylcyclohexyl)-2-trimethylsilylethylene was dissolved in 50 ml of acetonitrile, and then 8.12 g (0.14 mol) of potassium fluoride and 3.78 g (0.21 mol) of water were added thereto. The mixture was reacted for one hour at 50° C. The reaction mixture was cooled, and then 200 ml of water was added thereto. The mixture was extracted with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over CaCl2. After filtration, the solvent and low boiling substances were distilled off, and the residue was further distilled under reduced pressure to obtain 10.5 g (yield: 80%) of (E)-1,2-difluoro-1-(trans-4-n-propylcyclohexyl)ethylene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[N:12]2)=[S:10])=[CH:4][CH:3]=1.I[CH3:33]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]=[C:9]([S:10][CH3:33])[N:11]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:26][CH:27]=3)=[N:12]2)=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(C2=NN(C(=S)Nc3ccc(Cl)cc3)CC2c2ccccc2)cc1
Reactant: CI
Product: CSC(=Nc1ccc(Cl)cc1)N1CC(c2ccccc2)C(c2ccc(C(F)(F)F)cc2)=N1
Reaction time: 8 h

Procedure:
A mixture of 0.54 g of the compound from Step C and 0.1 mL of iodomethane were stirred overnight after which time the precipitated solids were filtered and dried. This product was suspended in 2 mL of chloroform and 2 mL of 5% aqueous sodium bicarbonate was added. After stirring overnight the layers were separated and the chloroform extracts dried over magnesium sulfate and concentrated to afford 0.12 g of the title compound as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14](O)[CH2:15][OH:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:15]1[O:16][C:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)([CH3:9])[O:10][CH2:14]1
Reactant: OCCO
Reactant: CC(=O)c1ccc(O)c([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1(c2ccc(O)c([N+](=O)[O-])c2)OCCO1

Procedure:
A solution of 4'-hydroxy-3'-nitroacetophenone (known compound, 12.1 g, 67.0 mmol), benzene (100 ml), ethylene glycol (5.61 ml, 100 mmol) and p-toluenesulfonic acid hydrate (catalytic amount) was refluxed overnight removing the resulting water by azeotropic distillation with benzene. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel to give the object compound (1) as an oil. Yield 14.6 g (97%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:20][C:21]([OH:23])=[O:22])=[C:7]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][CH:15]=[C:14](Cl)[CH:13]=3)[NH:8]2)=[CH:4][CH:3]=1.[Br:24]C1C=CC(I)=CC=1>>[Br:24][C:15]1[CH:16]=[CH:17][C:12]([C:11]([C:7]2[NH:8][C:9]3[C:5]([C:6]=2[CH2:20][C:21]([OH:23])=[O:22])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)=[O:19])=[CH:13][CH:14]=1
Reactant: Brc1ccc(I)cc1
Reactant: O=C(O)Cc1c(C(=O)c2cccc(Cl)c2)[nH]c2cc(Cl)ccc12
Product: O=C(O)Cc1c(C(=O)c2ccc(Br)cc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 7 from 6-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (Example 7, step 1) and 4-bromoiodobenzene.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30](F)=[CH:29][CH:28]=[CH:27][C:26]=4F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.CN(C)CCO[C:39]1[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=1>>[CH2:2]1[C:40]2[C:39](=[CH:45][CH:44]=[C:42]([NH:43][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:41]=2)[CH2:5][CH2:4][NH:3]1
Reactant: CN(C)CCOc1ccc(N)cc1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 4-{[2-(dimethylamino)ethyl]oxy}aniline in a manner analogous to Example 64. 1H NMR (400 MHz, DMSO-d6) δ 2.30 (s, 6H), 2.71 (t, 2H, J=5.7 Hz), 4.05 (t, 2H, J=5.7 Hz), 6.54 (d, 1H, J=5.2 Hz), 6.87 (d, 2H, J=9.0 Hz), 7.15 (t, 1H, J=6.9 Hz), 7.29 (t, 2H, J=7.9 Hz), 7.37 (d, 1H, J=7.7 Hz), 7.47-7.66 (m, 5H), 7.86 (d, 1H, J=8.0 Hz), 8.04 (s, 1H), 8.26 (d, 1H, J=5.2 Hz), 8.46 (bd, 1H, J=8.9 Hz), 8.87 (d, 1H, J=6.9 Hz), 9.39 (s, 1H), 10.98 (s, 1H); ESIMS (M+H)+=606.
Reaction SMILES: [CH:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4])=[CH2:2].[C:13]([C:17]1[CH:22]=[CH:21][C:20]([S:23]Cl)=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].C(Cl)(Cl)(Cl)[Cl:26]>>[C:13]([C:17]1[CH:18]=[CH:19][C:20]([S:23][CH:1]([S:3]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2)(=[O:4])=[O:5])[CH2:2][Cl:26])=[CH:21][CH:22]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: C=CS(=O)(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)c1ccc(SCl)cc1
Reactant: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1ccc(SC(CCl)S(=O)(=O)c2ccc(Cl)cc2)cc1
Reaction time: 144 h
Yield: 61 %

Procedure:
To a solution of 26.1 g (0.129 mole) of p-chlorophenyl vinyl sulfone in 100 ml of carbon tetrachloride at 25° C. was added 25.9 (0.129 mole) of p-t-butylbenzenesulfenyl chloride. The reaction mixture was allowed to stand for six days in a closed flask. Removal of the solvent by evaporation gave 55 g (106%) of crude product, m.p. 52°-68°. Recrystallization from 300 ml ethylacetatepentane (1:5) gave 31.5 g (61%) of pure product, m.p. 65°-67°.
Reaction SMILES: [F:1][C:2]1([F:22])[CH2:6][C@H:5]([CH2:7][OH:8])[N:4]([CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)[C:3]1=[O:21].FC1(F)C[C@H](CO)N(CCCCCCC(OC)=O)C1=O>ClCCl.CO>[F:22][C:2]1([F:1])[CH2:6][C@H:5]([CH:7]=[O:8])[N:4]([CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)[C:3]1=[O:21]
Reactant: COC(=O)c1ccc(CCN2C(=O)C(F)(F)C[C@@H]2CO)cc1
Agent: COC(=O)CCCCCCN1C(=O)C(F)(F)C[C@@H]1CO
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(CCN2C(=O)C(F)(F)C[C@@H]2C=O)cc1

Procedure:
(R)-methyl 4-(2-(3,3-difluoro-5-formyl-2-oxopyrrolidin-1-yl)ethyl)benzoate was prepared from 12b using the oxidation procedure (Step K) described for the preparation of intermediate 13a from intermediate 12a; TLC Rf 0.4 (solvent system: 95:5 v/v dichloromethane-methanol); 1H-NMR (CDCl3) δ 9.2 (s, 1H), 7.9 (dd, 2H), 7.24 (dd, 2H), 3.98-3.91 (m, 1H), 3.87 (s, 3H), 3.74-3.48 (m, 2H), 3.51-3.46 (m, 2H), 3.1-2.8 (m, 2H), 2.48-2.22 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:21][CH2:20][C@H:19]([CH2:22]O)[C@@H:18]([CH2:24]O)[C@@H:17]2[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[CH3:33])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:48]([NH2:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:48]([N:55]1[CH2:24][C@H:18]2[C@H:17]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[CH3:33])[C@@H:16]([O:15][C@@H:13]([C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:6]=3)[CH3:14])[O:21][CH2:20][C@@H:19]2[CH2:22]1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: Cc1cc(F)ccc1[C@@H]1[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@H](CO)[C@H]1CO
Reactant: NCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(F)ccc1[C@@H]1[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@@H]2CN(Cc3ccccc3)C[C@H]21
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
The intermediate from step I (2.44 g, 4.87 mmol) was combined with DMAP (0.15 g, 1.2 mmol) and dissolved in 38 mL DCM. The reaction vessel was cooled 0° C. followed by the sequential addition of triethylamine (2.72 mL, 19.5 mmol) and methanesulfonyl chloride (0.95 mL, 12.2 mmol). After 5 minutes, the reaction vessel was warmed to ambient temperature where it remained for 0.5 hr. The reaction was quenched by the addition of a saturated solution of NaHCO3. The aqueous mixture was extracted several times with DCM. The combined organic extracts were washed with 1 M HCl, brine, dried over Na2SO4, filtered through a fritted funnel and concentrated in vacuo. The crude bis-mesylate was dissolved in 50 mL n-butanol followed by the addition of benzylamine (3.19 mL, 29.2 mmol). The reaction vessel was heated to 100° C. for 3.5 hr. The volatiles were removed in vacuo and the crude residue was purified on silica gel and eluted with a combination of EtOAc/hexanes (35-95% EtOAc/hexanes linear gradient) which furnished the title compound. MS: (MH)+582.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[Si:9]([O:16][CH2:17][CH2:18][C@H:19]([OH:23])[C:20]([CH3:22])=[CH2:21])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CN=C1.OS([O-])(=O)=O.[K+]>CN(C=O)C>[Si:9]([O:16][CH2:17][CH2:18][C@H:19]([O:23][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7])[C:20]([CH3:22])=[CH2:21])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=C(C)[C@@H](O)CCO[Si](C)(C)C(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=C(C)[C@H](CCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.9 %

Procedure:
946 mg (6.28 mmol, 1.3 equivalents) of tert-butyldimethylchlorosilane is added to a solution of 1.173 g (4.83 mmol) of (S)-1-[(tert-butyldimethylsilyloxy)]-4-methyl-4-penten-3-ol 10and 855 mg (12.56 mmol, 2.6 equivalents) of imidazole in 15.0 ml of absolute DMF. The mixture is stirred for 16 hours at room temperature. It is mixed with 50 ml of an aqueous 1 M KHSO4 solution and extracted four times with 50 ml of Et2O each. The combined ether extracts are dried on MgSO4. After the solvent is distilled off in a vacuum, the residue is flash-chromatographed by a silica gel column with pentane/Et2O (20:1). As an alternative to this aqueous working-up, the reaction mixture can be chromatographed directly. By the two variations of working-up procedure, 1.643 g (4.73 mmol, 98%) of 11 is obtained.