Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].[CH3:16][N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:22][OH:23]>O1CCCC1>[CH3:16][N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:22][O:23][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CN1CCC[C@H]1CO
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC[C@H]1COc1ccc(C(F)(F)F)cc1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a solution of 2-fluoro-5-(trifluoromethyl)benzonitrile (8.0 g, 42.3 mmol, Aldrich) in tetrahydrofuran (50 mL) were added sodium hydride (1.9 g, 46.5 mmol) and (S)-(1-methylpyrrolidin-2-yl)methanol (5.5 mL, 46.5 mmol, Aldrich). After stirring at room temperature for 3 h, the reaction mixture was quenched with saturated NaHCO3 (30 mL). The aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to afford 12.0 g (100%) of the title compound. LCMS (APCI+) m/z 285 (M+H)+.
Reaction SMILES: O[C:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.O>O1CCOCC1>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:2](=[CH2:6])[C:3]([OH:5])=[O:4])=[CH:12][CH:11]=1
Reactant: COc1ccc(C(C)(O)C(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: C=C(C(=O)O)c1ccc(OC)cc1
Yield: 78.2 %

Procedure:
2-Hydroxy-2-(4-methoxyphenyl)propionic acid (35 g, 178 mmol) was dissolved in dioxane (700 ml) and concentrated sulfuric acid (60 ml) was added thereto. The reaction mixture was refluxed for 2 hours under heating. The reaction solution was cooled and, after adding water, extracted with ethyl acetate. The organic layer was washed with saturated sodium thiosulfate solution and water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 24.8 g (yield: 72%) of the title compound as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[N+](C1C=CC=CC=1)([O-])=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(=O)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.8 %

Procedure:
To a solution of 4-bromo-benzoyl chloride (3.3 g, 15 mmol) and AlCl3 (2.6 g, 20 mmol) in nitrobenzene (20 mL) was added a solution of methoxy-benzene (1.5 g, 14.5 mmol) in nitrobenzene (5 mL) slowly at 0° C. The resulting mixture was allowed to warm to rt and stir at rt for 16 h. The mixture was poured onto 150 mL ice-water solution and extracted with CH2Cl2 (5×100 mL). The combined organic layers were washed with water (2×100 mL) and brine (50 mL). and dried over anhy. Na2SO4. The solvent was removed in vacuo to obtain the crude product which was purified by recrystallization from cyclohexane to yield the title product (4.0 g, 91%) as a solid; 1H NMR (500 MHz, CDCl3); δ 3.90 (s, 3H), 6.97 (d, J=8.5, 2H), 7.63 (d, J=2.0, 4H), 7.79 (d, J=9.0, 2H).
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].N1C=CC=CC=1.[CH3:18][O:19][CH2:20][CH2:21][OH:22].Cl>CN(C1C=CN=CC=1)C.ClCCl>[S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)([O:22][CH2:21][CH2:20][O:19][CH3:18])(=[O:3])=[O:2]
Reactant: COCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.3 %

Procedure:
To tosyl chloride (50.0 g, 0.263 mol) at 0° C. and under nitrogen were added anhydrous dichloromethane (80 ml), anhydrous pyridine (23 ml, 24.3 g, 0.29 mol), 2-methoxyethanol (21.0 ml, 20.0 g, 0.263 mol) and a catalytic quantity of DMAP. After 10 minutes the mixture was warmed to room temperature, at which it was stirred for 16 hours. Dichloromethane (100 ml) and 1 M aqueous hydrochloric acid (50 ml) were added. The organic layer was isolated and washed with 1 M aqueous hydrochloric acid (4×30 ml) and water (4×30 ml), dried (Na2SO4) and concentrated in vacuo to give the title compound (51.68 g, 85%) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 4 h
Yield: 70.1 %

Procedure:
A mixture of 3.7 g of N-(tert-butoxycarbonyl)piperazine, 2.5 g of bromodiphenylmethane, 6.9 g of potassium carbonate and 20 ml of hexamethylphosphoramide was stirred at 40° to 50° C. for 4 hours. After cooling, water was added and the reaction mixture was extracted with diethyl ether. The exact was washed and dried, and the solvent was removed under reduced pressure. Hexane was added to the precipitated crystals and the crystals were collected by filtration to give 2.5 g of 4-(tert-butoxycarbonyl)-1-diphenylmethylpiperazine (melting point: 129°-131° C.).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][C@H:18]1[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]1>CN(C=O)C>[CH3:23][C:20]1([CH3:24])[O:19][C@@H:18]([CH2:17][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:22][O:21]1
Reactant: O=Cc1ccc(O)cc1
Reactant: CC1(C)OC[C@H](CCl)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](COc2ccc(C=O)cc2)O1
Temperature: 150 °C

Procedure:
1.79 g (14.6 mmol) of p-hydroxybenzaldehyde are dissolved in absolute DMF (10 ml), and 14.2 g (102.5 mmol) of potassium carbonate and 3.3 g (22.0 mmol) of (R)-(+)-4-chloromethyl-2,2-dimethyl-1,3-dioxolane are added. The mixture is heated at 150° C. for 24 h. The mixture is then concentrated using a rotary evaporator, and the residue is partitioned between dichloromethane and water. The combined organic phases are extracted with dichloromethane (three times, 20 ml each), washed with sat. sodium chloride solution and dried over magnesium sulphate. After removal of the solvent on a rotary evaporator, the crude product is purified chromatographically on silica gel 60 (mobile phase: cyclohexane/ethyl acetate 5:1).
Reaction SMILES: CN(C)C=O.[CH2:6]([O:10][C:11]1[C:16]([F:17])=[C:15](Cl)[N:14]=[CH:13][N:12]=1)[C:7]#[C:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[CH3:25][C:26]1([CH3:31])[CH2:30][CH2:29][NH:28][CH2:27]1>C(OCC)(=O)C>[CH2:6]([O:10][C:11]1[C:16]([F:17])=[C:15]([N:28]2[CH2:29][CH2:30][C:26]([CH3:31])([CH3:25])[CH2:27]2)[N:14]=[CH:13][N:12]=1)[C:7]#[C:8][CH3:9]
Reactant: CC1(C)CCNC1
Reactant: CC#CCOc1ncnc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCOc1ncnc(N2CCC(C)(C)C2)c1F
Temperature: 80 °C
Reaction time: 6 h
Yield: 31.7 %

Procedure:
Into 4 ml of N,N-dimethylformamide was resolved 0.36 g of 4-(2-butynyloxy)-6-chloro-5-fluoropyrimidine, 0.62 g of potassium carbonate and 0.25 g of 3,3-dimethylpyrrolidine was added therein, and the mixture was stirred for 6 hours at 80° C. The reaction mixture was cooled to near room temperature, ethyl acetate was added therein, and the mixture was washed with a saturated sodium chloride aqueous solution three times. The organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.15 g of 4-(2-butynyloxy)-5-fluoro-6-(3,3-dimethylpyrrolidin-1-yl)pyrimidine (hereinafter, referred to as Compound (28)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:25])[C:7]3[C:14](=[O:15])[N:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)[C:12](=[O:24])[C:8]=3[NH:9][C:10]=2[CH:11]=1.CS(O)(=O)=O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:25])[C:7]3[C:14]([OH:15])=[N:13][N:16]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)[C:12](=[O:24])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: O=C1c2[nH]c3cc(Cl)ccc3c(=O)c2C(=O)N1Nc1ccc(F)cc1
Agent: CS(=O)(=O)O
Solvent: CO
Product: O=c1c2ccc(Cl)cc2[nH]c2c(=O)n(-c3ccc(F)cc3)nc(O)c12
Temperature: 25 °C
Yield: 26.7 %

Procedure:
A stirred suspension of 6-chloro-2-(4-fluoroanilino)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-trione (1.40 g, 3.90 mM) in a solution of methanol (0.73 L) and methanesulfonic acid (73 mL) was refluxed for 16 hours and cooled to room temperature. The resulting orange suspension was filtered (the filtrate was saved for use in Example 26) and the collected solids were washed successively with methanol and ether to give the title compound (0.374 g, 27%) as a light orange powder, mp>400° C.; MS(CI): 358 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:19]([CH2:29][N+:30]#[C-:31])([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20].[C-]#N.[Na+]>>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:10]=1[C@H:11]1[O:12][CH:31]=[N:30][C@@H:29]1[S:19]([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C=O)c(OCc2ccccc2)c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [C-]#N
Agent: [Na+]
Product: COc1ccc([C@H]2OC=N[C@@H]2S(=O)(=O)c2ccc(C)cc2)c(OCc2ccccc2)c1

Procedure:
In a manner analogous to Preparation 1, 2-benzyloxy-4-methoxybenzaldehyde (2.54 g, 10.5 mmol), tosylmethylisocyanide (1.95 g, 10.0 mmol) and NaCN (49 mg, 1.00 mmol) gave the desired compound as a tan solid. MS(ES+) m/z 438.5 (M+H+).
Reaction SMILES: C(#N)C.N1C=CC=CC=1.F.[CH3:11][O:12][C:13]([C:15]1[CH2:29][C@@H:28]([O:30][Si](C(C)(C)C)(C)C)[C@H:27](/[CH:38]=[CH:39]/[C@@H:40]([O:48][Si](C(C)(C)C)(C)C)[CH2:41][C@H:42]([CH3:47])[CH2:43][CH2:44][CH2:45][CH3:46])[C:16]=1[S:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:14]>N1C=CC=CC=1>[CH3:11][O:12][C:13]([C:15]1[CH2:29][C@@H:28]([OH:30])[C@H:27](/[CH:38]=[CH:39]/[C@@H:40]([OH:48])[CH2:41][C@H:42]([CH3:47])[CH2:43][CH2:44][CH2:45][CH3:46])[C:16]=1[S:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:14]
Reactant: CCCC[C@@H](C)C[C@@H](/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(C(=O)OC)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCC[C@@H](C)C[C@H](O)/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(C(=O)OC)C[C@H]1O
Reaction time: 15 h
Yield: 79 %

Procedure:
To a solution of ice-cooled acetonitrile (1 mL) and pyridine (10 mL) was added a hydrogen fluoride-pyridine (0.1 mL). To this solution was added methyl (11R,12S,13E,15S,17R)-9-methoxycarbonyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate (67 mg, 0.097 mmol) in pyridine (0.1 mL). The ice bath was removed and the solution was agitated for 15 hours while returning it to room temperature. The reaction solution was poured into a mixture of ethyl acetate and saturated aqueous sodium hydrogencarbonate. The desired product was extracted from this mixed solution with ethyl acetate. The extract was washed with brine, then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, then was purified by silica gel column chromatography (40 to 50% ethyl acetate/hexane) to obtain methyl (11R,12S,13E,15S,17R)-9-methoxycarbonyl-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate (35 mg, 78%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:25][C@@:24]2([CH3:26])[C@@H:13]([CH2:14][CH2:15][C@:16]2([O:27][C:28](=[O:30])[CH3:29])[C:17](=[O:23])[CH2:18][O:19][C:20](=[O:22])[CH3:21])[C@H:12]2[C@H:3]1[C@:4]1([CH3:33])[C:9]([C@@H:10]([F:31])[CH2:11]2)=[CH:8][C:7](=[O:32])[CH2:6][CH2:5]1.O1CCOCC1>C(Cl)(Cl)Cl>[OH:1][C@H:2]1[CH2:25][C@@:24]2([CH3:26])[C@@H:13]([CH2:14][CH2:15][C@:16]2([O:27][C:28](=[O:30])[CH3:29])[C:17](=[O:23])[CH2:18][O:19][C:20](=[O:22])[CH3:21])[C@H:12]2[C@H:3]1[C@:4]1([CH3:33])[C:9]([C@@H:10]([F:31])[CH2:11]2)=[CH:8][C:7](=[O:32])[CH:6]=[CH:5]1
Reactant: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C

Procedure:
A mixture of 3 g of 11β-hydroxy-17α,21-diacetoxy-6α-fluoro-pregn-4-ene-3,20-dione [compound 4, the product of Example 3] , 2.5 g of 2,3-dichloro-4,5-dicyanobenzoquinone, and 30 ml of dioxan was heated under reflux for 2 hours. The resulting dark colored suspension was cooled, filtered from dichloro-dicyanohydroquinone, and then evaporated to dryness. The residue so obtained was dissolved in chloroform and filtered through neutral alumina (50 g). The solvent was evaporated under reduced pressure. The residue crystallized from methanol as colorless prisms, m.p.: 235°-240°, λmax, 241 nm (ε= 14,200). The analytical sample of 11β-hydroxy-17α,21-diacetoxy-6α-fluoro-pregna-1,4-diene-3,20-dione (compound 5) was obtained by an additional recrystallization from methanol.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:14]OS(C)(=O)=O)[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C-:22]#[N:23].[Na+]>CS(C)=O.O>[F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:14][C:22]#[N:23])[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)OCC1(c2ccc(C(F)(F)F)cc2)CCCC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCC1(c2ccc(C(F)(F)F)cc2)CCCC1
Temperature: 140 °C
Reaction time: 6 h
Yield: 60 %

Procedure:
To a stirred solution of methanesulfonic acid 1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl ester (240) (7 g, 21.73 mmol) in dimethyl sulfoxide (200 mL) were added KI (0.361 g, 2.17 mmol) and NaCN (1.6 g, 32.6 mmol). The reaction mixture was then stirred at 140° C. for 6 h. After completion of the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate (2×300 mL) and the organic layer was washed with water and brine. It was then dried over Na2SO4 and concentrated. The crude product was purified by 100-200 silica column chromatography using 5% ethyl acetate in hexane as the eluent to give [1-(4-trifluoromethyl-phenyl)-cyclopentyl]-acetonitrile (241) (3.3 g, 60%) as a colorless thick liquid.
Reaction SMILES: [CH:1]1([C:5]2[C:12]([C:13]3[NH:17][C:16]([O:18][CH2:19]C)=[N:15][N:14]=3)=[CH:11][C:8]([C:9]#[N:10])=[C:7]([CH3:21])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.CO>CCO>[CH:1]1([C:5]2[C:12]([C:13]3[NH:17][C:16]([O:18][CH3:19])=[N:15][N:14]=3)=[CH:11][C:8]([C:9]#[N:10])=[C:7]([CH3:21])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCOc1nnc(-c2cc(C#N)c(C)cc2C2CCC2)[nH]1
Solvent: CCO
Solvent: CO
Product: COc1nnc(-c2cc(C#N)c(C)cc2C2CCC2)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzonitrile (compound 219.7), except MeOH was used as the solvent instead of EtOH. m/z (ES+) 269 (M+H)+. 1H NMR (400 MHz, Chloroform-d) δ 10.96 (br, 1H), 7.82 (s, 1H), 7.35 (s, 1H), 4.11 (s, 3H), 4.15-4.05 (m, 1H), 2.59 (s, 3H), 2.31-2.16 (m, 2H), 2.14-1.89 (m, 3H), 1.87-1.71 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Si:8]([CH3:17])([O:13][CH:14]([CH3:16])[CH3:15])[O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[Mg].[I:19]I>C1COCC1>[I:19][C:2]1[CH:7]=[CH:6][C:5]([Si:8]([CH3:17])([O:13][CH:14]([CH3:16])[CH3:15])[O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: II
Reactant: CC(C)O[Si](C)(OC(C)C)c1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)O[Si](C)(OC(C)C)c1ccc(I)cc1
Reaction time: 1 h
Yield: 84 %

Procedure:
A solution of 4-bromo-1-(methyldiisopropyloxysilyl)benzene (13.35 g, 42.1 mmol) in THF (85 ml) was added slowly dropwise at 0° C. to a suspension of magnesium chips (1.53 g, 63.1 mmol) in THF (10 ml). After one hour, the Grignard reagent of 4-bromo-1-(methyldiisopropyloxysilyl)benzene was added dropwise at 0° C. to iodine (13.87 g, 54 mmol) dissolved in 50 ml of dry THF. After stirring during four hours, the solvent was pumped off and the residue was extracted with dry pentane (200 ml) and filtered. The yellow solution was concentrated to afford 4-iodo-1-(methyldiisopropyloxysilyl)benzene as a yellow oil of in 84% yield. 1H NMR (CDCl3, δ, ppm) 7.76 (2H, d); 7.42 (2H, d); 4.21 (2H, heptuplet); 1.23 (12H, t); 0.37 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13]CC(C)(C)N=2)=[CH:8][CH:7]=1)=[O:5].Cl.[OH2:24]>>[CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:13])=[O:24])=[CH:10][CH:11]=1)=[O:5]
Reactant: Cc1ccccc1C(=O)c1ccc(C2=NC(C)(C)CO2)cc1
Reactant: O
Agent: Cl
Product: Cc1ccccc1C(=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C

Procedure:
2-[4-(2-Methylbenzoyl)phenyl]-4,4-dimethyl-2-oxazoline (2.86 g) and 4.5M hydrochloric acid (150 ml) are refluxed for 8 hours. The mixture is cooled to room temperature, and thereto is added water. The precipitates are collected by filtration to give 4-(2-methylbenzoyl)benzoic acid (2.23 g) as white powder.
Reaction SMILES: [OH-:1].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]#[N:29])=[C:26]([C:30]([OH:33])([CH3:32])[CH3:31])[N:25]=[C:24]2[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:18][CH:17]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C(O)C>[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]([NH2:29])=[O:1])=[C:26]([C:30]([OH:33])([CH3:32])[CH3:31])[N:25]=[C:24]2[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:18][CH:17]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: [OH-]
Reactant: CCCCc1nc(C(C)(C)O)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Solvent: CCO
Product: CCCCc1nc(C(C)(C)O)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
10 ml of a 1N aqueous solution of sodium hydroxide were added to a solution of 232 mg of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carbonitrile [prepared as described in Example 10(a)]in 10 ml of ethanol, and the resulting mixture was heated under reflux for 3 hours. At the end of this time, the reaction mixture was worked up in a similar manner to that described in Example 45(c), to afford 185 mg of the title compound as an amorphous solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([C:21]1[CH:25]=[CH:24][S:23][CH:22]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].O>CN(C=O)C>[Br:1][C:22]1[S:23][CH:24]=[CH:25][C:21]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCc1ccsc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCc1ccsc1Br
Reaction time: 24 h
Yield: 94.8 %

Procedure:
A solution of N-bromosuccinimide (NBS) (48 g; 0.27 mol) dissolved in DMF (160 ml) was slowly added to a solution of 3-dodecylthiophene (68 g; 0.27 mol) dissolved in DMF (110 ml). After the reaction solution was stirred for one day, 750 ml of water was added thereto. An organic material was extracted by using ethyl ether (3×300 ml), and washed with brine and water, and then the residual moisture was removed over anhydrous magnesium sulfate. After removing the solvent, the residue was distilled off under reduced pressure at 125° C./˜5 mmHg to obtain a product (84.85 g, yield of 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:13][C:12](=[O:14])[C:11]([C:15]([OH:17])=[O:16])=[CH:10][C:9]=1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1.S(=O)(=O)(O)O.[CH3:30]O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:13][C:12](=[O:14])[C:11]([C:15]([O:17][CH3:30])=[O:16])=[CH:10][C:9]=1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)[nH]c1=O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)[nH]c1=O
Temperature: 25 °C

Procedure:
A 250 mL rb flask equipped with a magnetic stir bar was charged with 6.68 g (19.0 mmol) of the product of Step A, 100 mL methanol, 3 mL of concentrated sulfuric acid and the suspension was refluxed overnight. The resulting clear solution was then cooled to room temperature and evaporated. The residue was partitioned between EtOAc and 5% aqueous Na2CO3 and separated. The organic layer was washed with water, brine, dried (MgSO4), filtered and evaporated to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.C([O:14][C@@H:15]1[C@@H:28]([O:29]C(=O)C)[C@H:27]([O:33]C(=O)C)[CH2:26][S:25][C@H:16]1[O:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22](Br)[CH:23]=1)(=O)C>>[O:17]([C:18]1[CH:19]=[N:20][CH:21]=[C:22]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:23]=1)[C@@H:16]1[S:25][CH2:26][C@@H:27]([OH:33])[C@H:28]([OH:29])[C@H:15]1[OH:14]
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Product: O[C@@H]1[C@@H](O)[C@H](Oc2cncc(-c3cccc(F)c3)c2)SC[C@H]1O

Procedure:
By following a procedure analogous to Example 122 starting from 3-fluoro-phenylboronic acid and 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside, 5-(3-fluorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=67%).
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([C:9]([CH3:18])=[C:10]([CH3:17])[C:11](=[O:16])[O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Br:19]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([C:9]([CH3:18])=[C:10]([CH2:17][Br:19])[C:11](=[O:16])[O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Oc1ccc2c(C)c(C)c(=O)oc2c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Oc1ccc2c(C)c(CBr)c(=O)oc2c1C
Temperature: 25 °C

Procedure:
A mixture of 7-acetoxy-3,4,8-trimethylcoumarin (6.22 g, 25.3 mmol), N-bromosuccinimide (4.61 g, 25.9 mmol) and benzoyl peroxide (390 mg) were refluxed in carbon tetrachloride for 3.5 hours. The mixture was cooled to room temperature and partitioned between CH2Cl2 and water. The organic layer was separated and washed with water several times, then washed with brine. The organic layer was then dried with anhydrous sodium sulfate and evaporated to give crude product (11.8 g) which was recrystallized twice in toluene to give 7-acetoxy-3-bromomethyl-4,8-dimethylcoumarin, a white crystalline solid (4.86 g, 59%). 1H NMR (CDCl3): δ7.54 (d; J=8.8 Hz, 1H), 7.05 (d, J=8.8 Hz, 1H), 4.57 (s, 2H), 2.50 (s, 3H), 2.37 (s, 3H), 2.28 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][O:10][C:6]=2[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.C([NH:21][CH2:22][CH2:23][CH2:24][NH2:25])(OC(C)(C)C)=O.Cl>CO.O1CCOCC1>[N+:11]([C:5]1[C:6]2[O:10][N:9]=[CH:8][C:7]=2[C:2]([NH:21][CH2:22][CH2:23][CH2:24][NH2:25])=[N:3][CH:4]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cnc(Cl)c2cnoc12
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NCCCNc1ncc([N+](=O)[O-])c2oncc12
Reaction time: 8 h

Procedure:
4-Chloro-7-nitro-[1,2,5]benzoxadiazole (100 mg, 0.501 mmol) was dissolved in methanol (5 ml). N-Boc-1,3-propanediamine (44 mg, 0.25 mmol) was then added and the reaction mixture stirred overnight. The solvent was evaporated and the residue was purified using silica gel chromatography with ethyl acetate:hexane (1:1) to afford dark brown solid. This material was then treated with a solution of 4.0 M HCl in dioxane (excess) overnight to remove the Boc group. The solution was evaporated to afford N1-(7-nitro-[1,2,5]benzoxadiazol-4-yl)propane-1,3-diamine as the hydrochloride salt, which was used without further purification. Yield: 60 mg (51%). MS (m/z): (M+H)=237.22.