Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:14]([OH:15])=[C:13]([F:16])[C:12]([F:17])=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7].Cl[CH:19]([F:21])[F:20]>CN(C)C=O>[F:20][CH:19]([F:21])[O:15][C:14]1[C:4]([F:3])=[C:5]([CH:11]=[C:12]([F:17])[C:13]=1[F:16])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: FC(F)Cl
Reactant: CCOC(=O)c1cc(F)c(F)c(O)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(F)c(F)c(OC(F)F)c1F

Procedure:
1.76 g (0.044 moles) of a 60% w/w suspension of sodium hydride in mineral oil was added in small portions, whilst stirring and ice-cooling, to a solution of 8.83 g (0.04 moles) of ethyl 2,4,5-trifluoro-3-hydroxybenzoate [(XXIV), X=X'=F, R16 =C2H5O] [prepared as described in step (a) above] in 40 ml of dimethylformamide and, after the addition was complete, the mixture was stirred, whilst ice-cooling, for an additional 30 minutes. At the end of this time, the reaction mixture was transferred into a 200 ml stainless steel autoclave, and then 100 ml of dimethylformamide containing 28.0 g (0.32 moles) of chlorodifluoromethane were added thereto, and the mixture was stirred under pressure at 95°-100° C. for 5 hours. At the end of this time, the dimethylformamide was removed by distillation under reduced pressure, and water was added to the residue, which was extracted with toluene. The extract was washed with water and dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography, using toluene as the eluent, to give 4.85 g of ethyl 3-difluoromethoxy-2,4,5-trifluorobenzoate as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:25])[N:4]([CH3:24])[CH:5]=[C:6]([C:8]([OH:23])([C:19]([F:22])([F:21])[F:20])[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2[Cl:18])[CH3:10])[CH:7]=1.[Cl:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[C:33]([O:35][CH3:36])=[O:34]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH3:36][O:35][C:33](=[O:34])[C:32]1[CH:31]=[CH:30][C:29]([O:17][C:14]2[CH:15]=[CH:16][C:11]([CH:9]([CH3:10])[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[C:3](=[O:25])[N:4]([CH3:24])[CH:5]=3)([OH:23])[C:19]([F:21])([F:22])[F:20])=[C:12]([Cl:18])[CH:13]=2)=[CH:28][C:27]=1[Cl:26]
Reactant: COC(=O)c1ccc(B(O)O)cc1Cl
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1cc(Cl)c(=O)n(C)c1)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3cc(Cl)c(=O)n(C)c3)C(F)(F)F)c(Cl)c2)cc1Cl

Procedure:
In analogy to Example 151, step 8, 3-chloro-5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one was reacted with 3-chloro-4-methoxycarbonylphenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a colorless foam. MS (m/e)=564.1 [M+H+].
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].S(Cl)([Cl:21])=O>>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]([Cl:21])=[O:18])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)O)CC2)CC1
Reactant: O=S(Cl)Cl
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)Cl)CC2)CC1
Reaction time: 1 h

Procedure:
10 ml of thionyl chloride was added to 0.02 mol (5.0 g) of trans-4-(trans-4'-propyl cyclohexyl)-cyclohexane carboxylic acid and heated. They became homogeneous within about 1 hour, and then they were treated further for about an hour. Thereafter, excess thionyl chloride was removed under reduced pressure to leave trans-4-(trans-4'-propyl cyclohexyl)-cyclohexane carboxylic acid chloride. On the other hand, 3.9 g of 4-4'-cyanophenyl phenol is dissolved in 10 ml of pyridine and the acid chloride was added therein. It was stirred well and left to stand for one night. 200 ml of toluene was added thereto, and the toluene layer was washed with 6N HCl at first, then with 2N aqueous NaOH solution, and finally with water until the wash washing water became neutral. After it was dried with anhydrous sodium sulfate, toluene was removed completely under reduced pressure. The yielded crystals were then recrystallized from acetone to obtain 5.8 g of crystals of trans-4-(trans-4'-propyl cyclohexyl)-cyclohexane carboxylic acid 4"'-cyanobiphenyl ester. Yield: 68%. Its physical properties and elemental analysis are shown n Table 1.
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].[O:5]([CH2:12][CH2:13][CH2:14]Br)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)C>[O:5]([CH2:12][CH2:13][CH2:14][S:3][CH2:1][CH3:2])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrCCCOc1ccccc1
Reactant: CC[S-]
Agent: [Na+]
Solvent: CCO
Product: CCSCCCOc1ccccc1

Procedure:
Sodium ethanethiolate (6 mmol, 0.5 g) and 3-phenoxypropyl bromide (5 mmol, 1.1 g) in ethanol were refluxed overnight. After removal of solvent, Ether was added, washed with H20 and evaporated to give 3-phenoxypropylethyl sulfide. It was treated with 1 equivalent of acrylic acid in acetone in the presence of 4 equivalents of 12 N HCl under N2 at room temperature overnight and then at 50° C. for 3 h, affording 3-(S-ethyl-3-phenoxypropylsulfoniumyl)propionic acid chloride as a white powder. It was then subjected to the general procedure 1 to give compound 573 as a white powder (0.58 g, 25% overall yield). Anal. (C14H22Na2O8P2S.0.5 H2O) C, H.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].Cl[C:7]([O:9][CH2:10][Cl:11])=[O:8].N1C=CC=CC=1>C(OCC)C>[C:7](=[O:8])([O:9][CH2:10][Cl:11])[O:5][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: O=C(Cl)OCCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCOC(=O)OCCl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
A solution of butyl alcohol (50 mmol) and chloromethyl chloroformate (4.5 mL, 50 mmol) in diethyl ether (200 mL) was cooled to 0° C. under argon. Pyridine (5.7 mL, 50 mmol) was added dropwise with stirring over 5 min. The solution was stirred at 0° C. for 15 min, then allowed to warm to room temperature and stirred for three additional hours. The ether solution was filtered, washed with 1 M HCl, and then twice with water, dried over MgSO4, filtered, and concentrated on a rotary evaporator to give butyl chloromethyl carbonate (7 g, 85%).
Reaction SMILES: [O:1]([CH:8]=[CH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(C(OO)=[O:24])=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[O:1]([CH:8]=[CH:9][CH2:10][C:11]12[O:24][CH:16]1[CH:15]=[CH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C(=COc1ccccc1)Cc1ccccc1
Reactant: O=C(OO)c1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: C1=CC2OC2(CC=COc2ccccc2)C=C1
Reaction time: 96 h
Yield: 58 %

Procedure:
5.8 g of o-phenoxyallylbenzene was added to 70 ml of chloroform solution containing perbenzoic acid prepared from 17 g of benzoyl peroxide and the mixture was allowed to stand at about 5° C for 4 days. The resulting mixture was washed with sodium hydroxide solution, Mohr's salt solution, then water and dried on anhydrous sodium sulfate. The solvent was evaporated and the concentrated was chromatographed over a silica gel, eluted with benzene, there was obtained 3.6 g (yield 58%) of o-phenoxyallylbenzene oxide.
Reaction SMILES: [Na].ClC1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7](=[O:46])[N:6]([CH2:47][CH2:48][CH3:49])C(=O)C=1.[CH2:51]([OH:54])[CH2:52][CH3:53]>>[CH2:47]([N:6]1[C:51](=[O:54])[CH:52]=[C:53]([O:54][CH2:51][CH2:52][CH3:53])[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]1=[O:46])[CH2:48][CH3:49]
Reactant: CCCO
Reactant: CCCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Agent: [Na]
Product: CCCOc1cc(=O)n(CCC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 69 %

Procedure:
To a solution of sodium (0.09 g) in propanol was added 6-chloro-3-propyl-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (0.8 g) was added and the mixture was heated under reflux for 14 hours. The reaction mixture was concentrated to dryness. The resulting residue was dissolved in methylene chloride-water. The aqueous layer was acidified with 1N hydrochloric acid and extracted with methylene chloride. The organic layer was washed with water, dried, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give colorless amorphous powders (0.38 g, 69%).
Reaction SMILES: [OH:1]O.[CH3:3][C:4]1([CH3:31])[O:9][C:8](=[O:10])[CH:7]([CH:11]([C:15]2[CH:20]=[CH:19][C:18]([S:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[C:12]#[C:13][CH3:14])[C:6](=[O:30])[O:5]1.O.Cl>CC(O)=O>[CH3:3][C:4]1([CH3:31])[O:9][C:8](=[O:10])[CH:7]([CH:11]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[O:1])=[CH:17][CH:16]=2)[C:12]#[C:13][CH3:14])[C:6](=[O:30])[O:5]1
Reactant: OO
Reactant: CC#CC(c1ccc(SCc2ccccc2C)cc1)C1C(=O)OC(C)(C)OC1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC#CC(c1ccc(S(=O)Cc2ccccc2C)cc1)C1C(=O)OC(C)(C)OC1=O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 47.1 %

Procedure:
Hydrogen peroxide (20 μL, 0.05 mmol) was added to a 0° C. solution of 28.3 (20 mg, 0.05 mmol) in AcOH (2 mL). The reaction was stirred at 80° C. for 1.5 hours, then cooled to room temperature and stirred for 16 hours. The reaction mixture was poured into cold water and the resulting solution was acidified to pH=2 with 6N HCl(aq). The aqueous layer was extracted with ethyl acetate and sec-butanol. The combined organic layers were concentrated to yield 10 mg (50%) of 2,2-Dimethyl-5-[1-(4-o-tolylmethanesulfinyl-phenyl)-but-2-ynyl]-[1,3]dioxane-4,6-dione (29.1). LC/MSD m/e: 383.0 (consistent with di-acid-H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][C:5]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[Cl:22]N1C(=O)CCC1=O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([Cl:22])[C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][C:5]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCOc1cc(NC(C)=O)ccc1C(=O)OC
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CCCCCCOc1cc(NC(C)=O)c(Cl)cc1C(=O)OC
Temperature: 70 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
To a stirred solution of 4-acetylamino-2-hexyloxybenzoic acid methyl ester (2.6 g) in dimethylformamide (20 ml) is added N-chlorosuccinimide (1.4 g), and the resulting mixture is stirred at 70° C. for 1 hour. The reaction mixture is poured into ice-water and extracted with diethyl ether. The organic layer is washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate, and evaporated to give 4-acetylamino-5-chloro-2-hexyloxybenzoic acid methyl ester (2.1 g) as an oil.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[C:5]1=[O:29])[CH:2]=C.I([O-])(=O)(=O)=[O:32].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[Cl:16][C:12]1[CH:11]=[C:10]([C@@H:8]2[C@@H:7]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:6]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[C:5](=[O:29])[C@:4]([CH2:1][CH:2]=[O:32])([CH3:30])[CH2:9]2)[CH:15]=[CH:14][CH:13]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(CC)CC)C1=O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)N1C(=O)[C@@](C)(CC=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a solution of 240 mg (0.54 mmol) of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(pentan-3-yl)piperidin-2-one (Example 71, Step E) in THF (8 mL) and water (2.8 mL) added a catalytic amount of osmium tetroxide. After 1.25 h, 323 mg (1.51 mmol) of sodium periodate were added. The resulting light brown slurry was stirred at room temperature for 18.5 h, and then filtered through a fritted funnel. The filtrate was partially concentrated under reduced pressure, then was diluted with water and extracted with ethyl acetate (2×). The combined organic layers were washed with saturated aqueous sodium thiosulfate and then saturated aqueous sodium chloride. The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated. The crude title compound was used directly in the next step.
Reaction SMILES: [S:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11]C(=O)C)=[CH:7][N:6]=1)(=[O:4])(=[O:3])[NH2:2]>[OH-].[Na+]>[S:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: CC(=O)Nc1ccc(S(N)(=O)=O)nc1
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(S(N)(=O)=O)nc1
Temperature: 25 °C
Yield: 70 %

Procedure:
N-(6-Mercapto-pyridin-3-yl)-acetamide (30 g, 17.3 mmol) was dissolved in cold concentrated hydrochloric acid solution (225 ml), followed by the addition of ice water (50 ml). Chlorine was bubbled into solution, and the temperature was kept below 10° C. The solution became dark brown first, and the chlorination was complete after 3 hours when the temperature no longer rose and the color of the solution lightened. The reaction was diluted with ice and water (1.2 kg) while keeping the temperature below 10° C. The product, 5-acetylamino-pyridine-2-sulfonyl chloride, was collected by filtration and air-dried. This was then suspended in chloroform (CHCl3) (200 mL), followed by the addition of 30% ammonia solution (100 ml), and the resulting reaction mixture was stirred for 2 hours. The solvent was removed in vacuo to give a black solid, 2-sulfamyl-5-acetylamino-pyridine. 2-Sulfamyl-5-acetylamino-pyridine was dissolved in 0.85 N NaOH solution (500 ml), and the resulting solution was stirred at refluxing temperature for 3.5 hours. After cooled down to room temperature, the reaction mixture was extracted with 3:1 of CHCl3/MeOH solution (3×200 ml). The aqueous layer was neutralized to pH 7, and water was removed in vacuo to give the crude product which was recrystallized from water to afford the title compound (21.6 g, 70%).
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:26])[CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[C:19]1[CH:24]=[CH:23][C:22](=[O:25])[NH:21][N:20]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:27](O)[CH3:28].Cl>>[C:1]([NH:5][CH2:6][CH:7]([OH:26])[CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([O:16][CH2:27][CH3:28])=[O:15])=[CH:12][C:11]=1[C:19]1[CH:24]=[CH:23][C:22](=[O:25])[NH:21][N:20]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NCC(O)COc1ccc(C(=O)O)cc1-c1ccc(=O)[nH]n1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccc(OCC(O)CNC(C)(C)C)c(-c2ccc(=O)[nH]n2)c1

Procedure:
4-(3-t-Butylamino-2-hydroxypropoxy)-3-(1,6-dihydro-6-oxo-3-pyridazinyl)benzoic acid was esterified with ethanol-hyrogen chloride to give ethyl 4-(3-t-butylamino-2-hydroxypropoxy)-3(1,6-dihydro-6-oxo-3-pyridazinyl)benzoate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([CH3:16])=[CH:10]2)[CH3:2].Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[O:26][C:27]=1[CH3:28]>>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:22][C:23]1[N:24]=[C:25]([C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=3)[O:26][C:27]=1[CH3:28])[C:11]([CH3:16])=[CH:10]2)[CH3:2]
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCl
Reactant: CCOC(=O)C(Cc1ccc2[nH]c(C)cc2c1)OCC
Product: CCOC(=O)C(Cc1ccc2c(c1)cc(C)n2Cc1nc(-c2ccc(C(F)(F)F)cc2)oc1C)OCC

Procedure:
In analogy to the procedures described in examples 36a) and 36b), rac-2-ethoxy-3-(2-methyl-1H-indol-5-yl)-propionic acid ethyl ester (preparation 5) was reacted with 4-chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole to give rac-2-ethoxy-3-{2-methyl-1-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-1H-indol-5-yl}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless oil.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH:22]1[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]1)=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH:22]1[CH2:23][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CC(ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)C1
Yield: 91.9 %

Procedure:
To a solution of tert-butyl 3-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]azetidine-1-carboxylate 37 (0.15 g, 0.34 mml) in methanol (15 mL) was added 5% Pd/C (0.3 g). The mixture was hydrogenated under 35 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give tert-butyl 3-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]azetidine-1-carboxylate 38 (0.11 g, 91%) as a colorless foam.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:9]=[C:8](I)[N:7]=[CH:6]2)[CH2:3][CH2:2]1.C([Mg]Cl)(C)C.[CH2:16]([Sn:20]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])Cl)[CH2:17][CH2:18][CH3:19]>C1COCC1>[CH:1]1([CH2:4][N:5]2[CH:9]=[C:8]([Sn:20]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:16][CH2:17][CH2:18][CH3:19])[N:7]=[CH:6]2)[CH2:3][CH2:2]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Ic1cn(CC2CC2)cn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn(CC2CC2)cn1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 78.2 %

Procedure:
In a round bottomed flask 1-cyclopropylmethyl-4-iodo-1H-imidazole (570 mg, 2.3 mmol) was dissolved in THF (10 mL). The solution was cooled to 0° C. and isopropylmagnesium chloride (2.0 M in THF, 1.15 mL, 2.3 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 1.5 h. Tributylchlorostannane (0.62 mL, 2.3 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated NH4Cl solution and extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 20% to 50% EtOAc/heptane (containing 0.5% triethylamine) to isolate 740 mg (78%) of 1-cyclopropylmethyl-4-tributylstannanyl-1H-imidazole as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][S:18]([NH2:21])(=[O:20])=[O:19])[C:12](=[O:22])[N:11]([CH3:23])[C:10]=3[N:9]=[C:8]2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:35])([F:34])[F:33])[CH:26]=2)=[CH:4][CH:3]=1.IC.[C:40](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][S:18]([NH:21][CH3:40])(=[O:20])=[O:19])[C:12](=[O:22])[N:11]([CH3:23])[C:10]=3[N:9]=[C:8]2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:34])([F:33])[F:35])[CH:26]=2)=[CH:36][CH:37]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1c(=O)n(CS(N)(=O)=O)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CNS(=O)(=O)Cn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.3 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)methanesulfonamide (0.1 g, 0.18 mmol, example 18) in DMF (3 mL) was added iodomethane (16 mg, 0.18 mmol) and potassium carbonate (36 mg, 0.26 mmol). The reaction was stirred at room temperature overnight. The mixture was partitioned between ethyl acetate and water. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative-HPLC to give 1-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8 (3-(trifluoromethoxy)-phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-methylmethanesulfonamide (23 mg, 22.3% yield) as a white solid. 1H-NMR (DMSO-d6) δ 7.63(t, 1H), 7.50(d, 1H), 7.41-7.46(m, 4H), 7.34-7.37(m, 1H), 7.19-7.23(m, 1H), 5.45(s, 2H), 5.20(s, 2H), 3.31(s, 3H), 2.60(d, 3H). LCMS retention time 3.097 min; LCMS MH+ 574
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5]([F:16])([F:15])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)C.[OH-].[Na+].Cl>>[F:15][C:5]([F:16])([C:6]1[CH:7]=[CH:8][C:9]([N+:12]([O-:14])=[O:13])=[CH:10][CH:11]=1)[C:4]([OH:17])=[O:3]
Reactant: CCOC(=O)C(F)(F)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(F)(F)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
According to the above-described scheme, 2,2-difluoro-2-(4-nitrophenyl)acetic acid ethyl ester (Compound 2b; 147 mg, 0.6 mmol) and 1N NaOH solution (3 mL) were put into an eggplant flask, and the mixture was stirred at room temperature for 19 hours. After the reaction, the reaction mixture was neutralized with 5% HCl solution, extracted with ethyl acetate and washed with water, and an organic layer was dried with anhydrous sodium sulfate. Ethyl acetate was distilled away under reduced pressure, and by carrying out purification by silica gel column chromatography, 2,2-difluoro-2-(4-nitrophenyl)acetic acid (Compound 4b) was obtained with a yield of 93%.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:41])[CH2:7][C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH2:38][CH3:39])([C:23]3[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([CH2:35][CH3:36])([OH:34])[CH2:32][CH3:33])=[C:25]([CH3:37])[CH:24]=3)[CH2:21][CH3:22])=[CH:16][C:15]=2[CH3:40])=[N:12][CH:13]=1)C>CO>[CH2:21]([C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:11]2[N:10]=[CH:9][C:8]([CH2:7][C:6]([OH:41])=[O:5])=[CH:13][N:12]=2)=[C:15]([CH3:40])[CH:16]=1)([C:23]1[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([CH2:32][CH3:33])([OH:34])[CH2:35][CH3:36])=[C:25]([CH3:37])[CH:24]=1)[CH2:38][CH3:39])[CH3:22]
Reactant: CCOC(=O)Cc1cnc(-c2ccc(C(CC)(CC)c3ccc(/C=C/C(O)(CC)CC)c(C)c3)cc2C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3ncc(CC(=O)O)cn3)c(C)c2)cc1C)CC
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.10 mL) was added to a solution of [2-(4-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-pyrimidin-5-yl]-acetic acid ethyl ester (Example 83-(1); 26.8 mg, 0.0507 mmol) in methanol (0.68 mL) at room temperature, and the mixture was stirred at room temperature for three hours. The solvent was distilled off and saturated aqueous ammonium chloride solution was added to the residue, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give the title compound (25 mg, 100%).