Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:6]2[N:7]=[C:8]([CH:20]([CH3:22])[CH3:21])[C:9]([CH2:18][OH:19])=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:5]2=[CH:4][CH:3]=1.[H-].[Na+].[C:25](OCCBr)(=[O:27])[CH3:26]>CN(C)C=O>[C:25]([O:19][CH2:18][C:9]1[C:8]([CH:20]([CH3:22])[CH3:21])=[N:7][N:6]2[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]2[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OCCBr
Reactant: CC(C)c1nn2c(Cl)ccc2c(-c2ccc(F)cc2)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1c(C(C)C)nn2c(Cl)ccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.8 %

Procedure:
To a solution of (7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl)methanol (40 mg) in N,N-dimethylformamide (1 mL) was added 40% sodium hydride in oil (55 mg) in an ice-water bath. After 20 minutes, to the mixture was added 2-bromoethyl acetate (31 mg) at the temperature. After 15 minutes, the reaction mixture was stirred at ambient temperature for 5 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water three times and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by p-TLC (hexane-ethyl acetate=10-1) to give [7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]methyl acetate as a pale yellow solid (42 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:35][O:36][C:37]1[C:42]2[N:43]=[C:44]([NH2:46])[S:45][C:41]=2[C:40]([CH:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[CH:39][CH:38]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[CH3:35][O:36][C:37]1[C:42]2[N:43]=[C:44]([NH:46][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][C:2]([CH3:1])=[N:3][CH:4]=3)[S:45][C:41]=2[C:40]([CH:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[CH:39][CH:38]=1
Reactant: COc1ccc(C2CCOCC2)c2sc(N)nc12
Reactant: Cc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccc(C)nc3)nc12

Procedure:
From 6-methylnicotinic acid, HATU and N-diethylisopropylamine in THF, then treatment with 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-ylamine in dioxane and DMF. ES-MS m/e (%): 384 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=[CH:17][C:4]=2[O:3]1.ClC1C=CC=C(C(OO)=[O:31])C=1>ClCCl>[CH3:21][O:20][C:18]([C:15]1[CH:16]=[CH:17][C:4]2[O:3][C:2]([CH3:22])([CH3:1])[CH2:7][CH:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=3[O-:31])[C:5]=2[CH:14]=1)=[O:19]
Reactant: COC(=O)c1ccc2c(c1)C(c1ccccn1)CC(C)(C)O2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)C(c1cccc[n+]1[O-])CC(C)(C)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
313 mg of methyl 3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran-6-carboxylate were dissolved in 10 ml of dichloromethane at room temperature and 283 mg of m-chloroperbenzoic acid were added. After stirring at room temperature for 2 hours the mixture was washed with sodium o bisulphite solution and sodium bicarbonate solution. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using initially 2% (v/v) methanol/ethyl acetate and finally 5% (v/v) methanol/ethyl acetate for the elution. There were obtained 250 mg of 2-[3,4-dihydro-6-(methoxycarbonyl)-2,2-dimethyl-2H-1-benzopyran-4-yl]pyridine N-oxide as an oil which solidified upon trituration with diethyl ether. After recrystallization from toluene the product melted at 128-130° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH2:8].[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH:23]=[CH:24][CH2:25]Br)=[CH:12][CH:11]=1.O>CN(C)C=O>[F:9][C:10]1[CH:11]=[CH:12][C:13]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH:23]=[CH:24][CH2:25][NH:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:14][CH:15]=1
Reactant: NOC1CCCCO1
Reactant: Fc1ccc(Sc2ccccc2C=CCBr)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(Sc2ccccc2C=CCNOC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To O-tetrahydropyranyl hydroxylamine (2.77 g; 23.6 mmol) in 10 ml of dry dimethylformamide was added 1-[2-(4-fluorophenylthio)phenyl]-3-bromoprop-1-ene (2.54 g; 7.87 mmol) in 10 ml of dimethylformamide dropwise. The reaction mixture was stirred overnight at room temperature. The mixture was poured into 200 ml of water and extracted twice with diethyl ether. The organics were collected, washed twice with water and then with brine, dried over K2CO3 and concentrated. The crude subtitle compound was chromatographed by HPLC using 3:1 hexane/ethyl acetate and then 2:1 hexane/ethyl acetate to afford the subtitle compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Mg].[OH:11][C:12]1[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[C:16]([CH:19]=1)[CH:17]=[O:18].[Cl-].[NH4+]>O1CCCC1>[OH:11][C:12]1[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[C:16]([CH:17]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[OH:18])[CH:19]=1
Reactant: COc1ccc(Br)cc1
Reactant: COc1ccc(O)cc1C=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2cc(O)ccc2OC)cc1
Yield: 99.4 %

Procedure:
To the Grignard reagent prepared from 4-bromoanisole (286 g) and magnesium turnings (38.5 g) in dry tetrahydrofuran (480 ml) was added, dropwise, with vigorous stirring, a solution of 5-hydroxy-2-methoxybenzaldehyde (100 g) in dry tetrahydrofuran (1 liter). The mixture was heated on a steam bath for 3 hours, cooled and decomposed with saturated ammonium chloride solution. The organic layer was removed and the aqueous extracted with ethyl acetate (twice). The combined organics were washed with water, dried with anhydrous magnesium sulphate and evaporated to dryness. The residue was stirred with water (4 liters), and the buff coloured solid collected and dried to give crude 1-(5-hydroxy-2-methoxyphenyl)-1-(4-methoxy- phenyl)-methanol (170 g, 99%), m.p. 62°-68°. This carbinol (85 g) was dissolved in ethanol (700 ml) and 10% palladium on charcoal (10 g) added. The mixture was hydrogenated in a Parr apparatus at 45° until hydrogen uptake ceased. The mixture was filtered, the filtrate evaporated to dryness and the residue filtered through a column containing silica gel, eluting with dichloromethane, to give 2,4'-dimethoxy-5-hydroxydiphenylmethane (46 g, 58%), m.p. 56°-58° (from petroleum spirit (60°-80°)).
Reaction SMILES: C[O-].[Na+].C(=O)(O)O.[NH2:8][C:9]([NH2:11])=[NH:10].[NH2:12][C:13]1[C:29]([O:30][CH3:31])=[CH:28][C:16]([CH2:17][C:18](=[CH:21]N2CCOCC2)[C:19]#[N:20])=[CH:15][C:14]=1[O:32][CH3:33]>CS(C)=O.O>[NH2:10][C:9]1[N:11]=[C:19]([NH2:20])[C:18]([CH2:17][C:16]2[CH:15]=[C:14]([O:32][CH3:33])[C:13]([NH2:12])=[C:29]([O:30][CH3:31])[CH:28]=2)=[CH:21][N:8]=1
Reactant: COc1cc(CC(C#N)=CN2CCOCC2)cc(OC)c1N
Reactant: N=C(N)N
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1N
Temperature: 120 °C
Reaction time: 60 h

Procedure:
A mixture of 6.5 g of sodium methylate, 21.6 g of guanidine carbonate and 12.8 g of α-(4-amino-3,5-dimethoxy-benzyl)-β-morpholino - acrylonitrile in 120 ml of absolute dimethyl sulphoxide was stirred at 120° C. for 60 hours. Subsequently, the mixture was diluted with 1.2 liters of water and extracted with two 2 liter portions of ethyl acetate. The ethyl acetatae extract was washed with two 1 liter portions of water, dried over magnesium sulphate and evaporated in vacuo. After recrystallisation of the residue from methanol, there was obtained 2,4-diamino-5-(4-amino-3,5-dimethoxy-benzyl)-pyrimidine of melting point 215°-216° C.
Reaction SMILES: [CH2:1]1COCC1.[C:6]([NH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16](=O)[CH2:15][CH2:14][CH2:13]2)(=[O:8])[CH3:7].[Cl-].C[CH:23]=[N+:24]=[CH:25]C>C(#N)C>[C:6]([NH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]([CH2:23][N:24]([CH3:25])[CH3:1])[CH2:14][CH2:13]2)(=[O:8])[CH3:7]
Reactant: C1CCOC1
Reactant: CC=[N+]=CC
Reactant: CC(=O)Nc1ccc2c(c1)CCCC2=O
Agent: [Cl-]
Solvent: CC#N
Product: CC(=O)Nc1ccc2c(c1)CCC(CN(C)C)C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A THF solution (40 ml) of 6-acetylamino-1-tetralone (1.692 g) was added to an acetonitrile solution (40 ml) of N,N-dimethylmethylene ammonium chloride (2.04 g), then stirred at room temperature for 24 hours, and concentrated. An aqueous solution of 10% potassium carbonate was added to the residue, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried, and concentrated. The residue was dissolved in methanol (50 ml), to which was added sodium borohydride (0.86 g). The reaction mixture was stirred at room temperature for 1 hour, and water was added thereto, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried, and concentrated. The residue was dissolved in methanol (50 ml), to which were added 10% palladium-carbon (0.4 g) and 1 N hydrochloric acid (20 ml). Then, this was catalytically reduced under a hydrogen pressure of 1 atmosphere, for 12 hours. The palladium-carbon was removed from the reaction mixture through filtration, the filtrate was concentrated, and an aqueous solution of 10% potassium carbonate was added thereto to form a free form compound. Then, this was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried, and concentrated. The resulting crude crystals were recrystallized from ethyl acetate-hexane to obtain the entitled compound (1.862 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[C@@H:10]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:9]2)=[N:6][C:5]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[NH:33][N:32]=[C:31]3[CH3:37])=[CH:4][N:3]=1.Cl>ClCCl.O1CCOCC1>[NH2:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:9]2)=[N:6][C:5]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[NH:33][N:32]=[C:31]3[CH3:37])=[CH:4][N:3]=1
Reactant: Cc1n[nH]c2ccc(-c3cnc(N)c(N4CCN(C(=O)OC(C)(C)C)[C@@H](Cc5ccccc5)C4)n3)cc12
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1n[nH]c2ccc(-c3cnc(N)c(N4CCN[C@@H](Cc5ccccc5)C4)n3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of 2-amino-3-[(S)-4-Boc-3-benzylpiperazinyl]-5-(3-methyl-1H-indazol-5-yl)pyrazine 109 (20 mg, 0.04 mmol) in dichloromethane (2 mL) was added a 4 M solution of HCl in dioxane (2 mL). The reaction mixture was stirred at room temperature for 1 hour. The organic solvent was evaporated under reduced pressure. The crude product was purified by RP-HPLC to yield the desired 2-amino-3-[(S)-3-benzylpiperazinyl]-5-(3-methyl-1H-indazol-5-yl)pyrazine 110 (12 mg, 0.03 mmol).
Reaction SMILES: [CH3:1][Si:2]([CH3:21])([CH3:20])[C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]=1.[CH2:22]([Li])CCC.CI>CCOCC>[CH3:17][Si:16]([CH3:19])([CH3:18])[C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[C:5](=[CH:4][C:3]([Si:2]([CH3:21])([CH3:20])[CH3:1])=[CH:15][CH:14]=3)[CH:6]([CH3:22])[C:7]=2[CH:8]=1
Reactant: C[Si](C)(C)c1ccc2c(c1)Cc1cc([Si](C)(C)C)ccc1-2
Reactant: [Li]CCCC
Solvent: CCOCC
Solvent: CI
Product: CC1c2cc([Si](C)(C)C)ccc2-c2ccc([Si](C)(C)C)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.7 %

Procedure:
To a solution of 1.0 g of 2,7-bis(trimethylsilyl)fluorene in 15 mL of dry ether was added dropwise 2.8 mL of 1.3 M n-butyllithium at 0° C. The mixture was stirred at room temperature for 3 hours, cooled to 0° C., and treated with a solution of 0.25 mL of methyl iodide in 5 mL of dry ether over a period of 5 minutes. The mixture was stirred at room temperature for 8 hours and washed with 2% Na2S2O3 (10 mL) and water (2×10 mL). The pooled aqueous layer was extracted with ether (2×15 mL). The combined organic extracts were dried over MgSO4 and the solvent was evaporated under reduced pressure to give 1.03 g (98.7%) of the crude 2,7-bis(trimethylsilyl)-9-methylfluorene as a yellow oil which was chromatographed on silica gel (230-400 mesh, 2×40-cm packed column) with an eluant consisting of Skelly B--dichloromethane (6:1) to give 0.78 g (74.7%) of the crude hydrocarbon as a colorless oil. Crystallization from 95% ethanol gave 0.69 g (66.1%) of the pure 2,7-bis(trimethyl-silyl)-9-methylfluorene as white needles, m.p. 107°-108.5° C.; 1H NMR (CDC13): δ 0.34 (s, 18H, SiMe3), 1.58 (d, 3H, CH3), 3.96 (q, 1H, CH), 7.40-7.90 (m, 6H, aryl).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Br[CH2:8][CH2:9][C@@:10]([CH3:20])([S:16]([CH3:19])(=[O:18])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.CCOC(C)=O>[CH3:20][C@@:10]([S:16]([CH3:19])(=[O:17])=[O:18])([CH2:9][CH2:8][N:4]1[CH:3]=[C:2]([CH3:1])[CH:6]=[N:5]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)[C@@](C)(CCBr)S(C)(=O)=O
Reactant: Cc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@](C)(CCn1cc(C)cn1)S(C)(=O)=O
Temperature: 55 °C
Reaction time: 8 h

Procedure:
To a solution of the 4-methylpyrazole (143 mg, 1.74 mmol, 1 eq) and (R)-ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate (500 mg 1.74 mmol, 1 eq) in THF (10 mL) was added cesium carbonate (2.27 g, 6.96 mmol, 4 eq). The resulting suspension was heated to 55° C. and allowed to stir overnight. The reaction was then diluted with EtOAc (10 mL) and the mixture filtered through a pad of celite, which was eluted with ˜10 mL of EtOAc. The crude material was purified by flash chromatography on a 40 g silica gel column eluting with an heptane/ethyl acetate/MeOH gradient) to give ethyl (2R)-2-methyl-4-(4-methyl-1H-pyrazol-1-yl)-2-(methylsulfonyl)butanoate which was used directly in the next step. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.27 (s, 1H), 7.13 (s, 1H), 4.30-4.11 (m, 2H), 3.03 (s, 3H), 2.80-2.71 (m, 1H), 2.51-2.41 (m, 1H), 2.04 (s, 3H), 1.66 (s, 3H). LC-MS M+H+289.4.
Reaction SMILES: Cl[C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[SH:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22].CC(C)([O-])C.[K+]>C1COCC1>[CH3:24][O:23][C:21](=[O:22])[CH2:20][CH2:19][S:18][C:2]1[CH:17]=[CH:16][C:5]([C:6](=[O:7])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:4][N:3]=1
Reactant: O=C(Nc1ccc(F)cc1)c1ccc(Cl)nc1
Reactant: COC(=O)CCS
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CCSc1ccc(C(=O)Nc2ccc(F)cc2)cn1
Temperature: 0 °C
Reaction time: 3 h
Yield: 3.9 %

Procedure:
To a solution of 6-chloro-N-(4-fluorophenyl)nicotinamide (0.25 g, 1.0 mmol) in 3 mL of THF was added methyl 3-mercaptopropionate (0.16 mL, 1.5 mmol) then potassium tert-butoxide (0.22 g, 2.0 mmol). The mixture was stirred for 3 h then poured into ice water and the solids washed with water and collected. Purification by trituration using ethyl acetate gave 13 mg (4%) of the titled product as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.94 (m, 1H), 8.09 (m, 1H), 7.74 (m, 2H), 7.43 (m, 1H), 7.17 (m, 2H), 3.59 (s, 3H), 3.37 (m, 2H), 2.75 (m, 2H); MS (EI) m/z 333.10 (M−H)−.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][NH:6]1)[CH3:3].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](O)=[O:24])=[CH:18][CH:17]=1.C1(N=C=NC2CCCCC2)CCCCC1.C(Cl)[Cl:42]>>[ClH:42].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([N:6]2[CH2:7][CH2:8][C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:5]2[CH2:4][N:2]([CH3:1])[CH3:3])=[O:24])=[CH:18][CH:17]=1
Reactant: ClCCl
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: CN(C)CC1NCCc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CN(C)CC1c2ccccc2CCN1C(=O)Cc1ccc(Br)cc1
Product: Cl

Procedure:
Prepared as Ex. No. 1 by coupling 800 mg of 1-dimethylaminomethyl-1,2,3,4-tetrahydroisoquinoline and 1.05 g of (4-bromophenylaceticacid, dissolved in 35 ml of CH2Cl2, in the presence of 1.3 g of dicyclohexylcarbodiimide.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[C:16](O)(=[O:18])[CH3:17]>FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(Cl)(Cl)Cl>[C:11]([C:7]1[CH:8]=[C:9]([C:16](=[O:18])[CH3:17])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 1 h

Procedure:
A mixture of 2,6-di-t-butylphenol (1 g) in trifluoroacetic anhydride (5 ml) is carefully treated with 0.28 ml of glacial acetic acid and the reaction mixture is stirred at 20°-25° for 1 hr. The reaction mixture is diluted with chloroform and is separated, washed with saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product (1.39 g) is chromatographed on 180 g of silica gel. The column is packed and eluted with chloroform/acetone (99/1). An initial fraction of 200 ml is collected, followed by 7 ml fractions. Based on their TLC homogeniety, fractions 20-55 are combined and concentrated. Recrystallized from hexane gives the tire compound, mp 148°-150°; IR (mineral oil) 3581, 3007, 2956, 2925, 2871, 2856, 1663, 1596, 1581, 1465, 1463, 1442, 1423, 1370, 1364, 1356, 1320, 1305, 1274, 1239, 1232, 1138, 1124, 1108 an 886 cm-1 ; NMR (CDCl3, TMS) 7.84, 5.73, 2.56, and 1.47δ; CMR (CDCl3, TMS) 197.6, 158, 4, 135.8, 129.1, 126.1, 34.4, 30.2 and 26.3δ; MS (m/z) M+ (found)=248; other ions at m/z 233, 217, 205, 189, 178, 115, 57 and 43.
Reaction SMILES: F[H-]F.[NH4+].[C:5]1(=[O:12])[CH:10]=[CH:9][C:8](=[O:11])[CH:7]=[CH:6]1.C([Si](CC)(CC)[C:16]([F:19])([F:18])[F:17])C>C(#N)C>[OH:11][C:8]1([C:16]([F:19])([F:18])[F:17])[CH:9]=[CH:10][C:5](=[O:12])[CH:6]=[CH:7]1
Reactant: O=C1C=CC(=O)C=C1
Reactant: CC[Si](CC)(CC)C(F)(F)F
Agent: F[H-]F
Agent: [NH4+]
Solvent: CC#N
Product: O=C1C=CC(O)(C(F)(F)F)C=C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.4 %

Procedure:
A mixture of 74 mg (1.3 mmol) of ground ammonium bifluoride (NH4HF2), 119 mg (1.1 mmol) of 1,4-benzoquinone, and 2 mL of acetonitrile was treated with 239 mg (1.3 mmol) of triethyltrifluoromethylsilane and stirred vigorously at room temperature for 4 hours. The mixture was filtered and the filter cake was washed with dichloromethane. Concentration of the combined filtrates gave a black solid which was triturated with dichloromethane. The resulting mixture was filtered and the filter cake was washed with dichloromethane. Concentration of the combined filtrates afforded a brown solid which was purified by PTLC (one 2 mm silica gel plate eluted with a 2% methanol-98% dichloromethane) to give 83 mg (42% yield) of 4-hydroxy-4-trifluoromethyl-2,5-cyclohexadien-1-one.
Reaction SMILES: C1(S([O:10][C:11]2[CH:22]=[CH:21][C:14]3[S:15][CH:16]=[C:17]([C:18]([OH:20])=[O:19])[C:13]=3[CH:12]=2)(=O)=O)C=CC=CC=1.Cl>[OH-].[Na+]>[OH:10][C:11]1[CH:22]=[CH:21][C:14]2[S:15][CH:16]=[C:17]([C:18]([OH:20])=[O:19])[C:13]=2[CH:12]=1
Reactant: O=C(O)c1csc2ccc(OS(=O)(=O)c3ccccc3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1csc2ccc(O)cc12
Reaction time: 8 h
Yield: 96.6 %

Procedure:
A solution of 100 mg (0.3 mmol) of the above obtained 5-benzenesulfonyloxybenzo[b]thiophene-3-carboxylic acid (2) in 1.2 ml of 1N sodium hydroxide was allowed to stand for 8 hours at 40° C. Hydrochloric acid (1N, 1.2 ml) was added thereto, and the precipitated crystals were filtered, washed with water, and dried to give 58 mg of 5-hydroxybenzo[b]thiophene-3-carboxylic acid (1). Yield 96.6% mp 262-263° C.
Reaction SMILES: C1COCC1.O.[C:7]([C:11]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14](=[O:21])[C:13](=[O:22])[C:12]=1[N+:23]([O-:25])=[O:24])([CH3:10])([CH3:9])[CH3:8].[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCOC(C)=O>[C:7]([C:11]1[C:12]([N+:23]([O-:25])=[O:24])=[C:13]([OH:22])[C:14]([OH:21])=[C:15]([C:17]([CH3:18])([CH3:19])[CH3:20])[CH:16]=1)([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)C1=CC(C(C)(C)C)=C([N+](=O)[O-])C(=O)C1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)c1cc(C(C)(C)C)c([N+](=O)[O-])c(O)c1O
Reaction time: 0.03 h
Yield: 73.5 %

Procedure:
In a separatory funnel was placed THF/H2O (1:1, 400 mL), 4,6-di-tert-butyl-3-nitrocyclohexa-3,5-diene-1,2-dione (4.59 g, 17.3 mmol) and Na2S2O4 (3 g, 17.3 mmol). The separatory funnel was stoppered and was shaken for 2 min. The mixture was diluted with EtOAc (20 mL). The layers were separated and the organic layer was washed with brine, dried over MgSO4 and concentrated to provide 4,6-di-tert-butyl-3-nitrobenzene-1,2-diol (3.4 g, 74%), which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.76 (s, 1H), 6.87 (s, 1H), 1.35 (s, 9H), 1.25 (s, 9H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH2:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Cl.COC(C1C=C2C(C(CC3C=CC(OCC4C=CC5C(=CC=CC=5)N=4)=CC=3)=CN2C)=CC=1)=O>>[CH3:13][O:12][C:10]([C:7]1[CH:8]=[C:9]2[C:4]([C:3]([CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([O:25][CH2:24][C:15]4[CH:16]=[CH:17][C:18]5[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=5)[N:14]=4)[CH:27]=3)=[CH:2][NH:1]2)=[CH:5][CH:6]=1)=[O:11]
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: COC(=O)c1ccc2c(Cc3ccc(OCc4ccc5ccccc5n4)cc3)cn(C)c2c1
Product: COC(=O)c1ccc2c(Cc3cccc(OCc4ccc5ccccc5n4)c3)c[nH]c2c1

Procedure:
This compound was prepared from methyl indole-6-carboxylate and 3-(quinolin-2-ylmethoxy)benzyl chloride (Example 5a) by the method described in Example 10, part ii.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[CH:15][C:13]([NH2:14])=[N:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19].CN(C=O)C>CO>[Si:21]([C@@:3]1([OH:4])[C@@H:5]([CH2:6][O:7][Si:21]([C:18]([CH3:20])([CH3:19])[CH3:17])([CH3:23])[CH3:22])[O:8][C@@H:1]([N:9]2[CH:16]=[CH:15][C:13]([NH2:14])=[N:12][C:10]2=[O:11])[CH2:2]1)([C:18]([CH3:20])([CH3:19])[CH3:17])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(N)nc2=O)C[C@@]1(O)[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2′-deoxycytidine dC (2.85 g, 12.54 mmol), imidiazole (6.49 g, 95.31 mmol), and TBSCl (7.18 g, 47.65 mmol) were added to anhydrous DMF (27 mL) and stirred at room temperature overnight under a N2 atmosphere. Methanol (20 mL) was added, and the mixture was stirred for 30 minutes and then concentrated in vacuo. Ethyl acetate (60 mL) and water (60 mL) were then added. The organic layer was separated and washed twice with water (20 mL), and the combined aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layer was dried with Na2SO4, concentrated in vacuo, and purified by silica gel chromatography to give 3′,5′-O-bis-tert-butyldimethylsilyl-2′-deoxycytidine dC.01 (4.79 g, 84%) as a white foam.