Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:8]([F:19])[C:7]=1[F:20].C([Li])(CC)C.[F:31][C:32]1[C:37]([F:38])=[C:36]([O:39][CH2:40][CH3:41])[CH:35]=[CH:34][C:33]=1[CH:42]1[CH2:47][CH2:46][C:45](=O)[CH2:44][CH2:43]1.Cl>C(OCC)(=O)C.C1COCC1>[F:20][C:7]1[C:8]([F:19])=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][C:3]1[CH:21]=[CH:22][C:23]([C:45]2[CH2:46][CH2:47][CH:42]([C:33]3[CH:34]=[CH:35][C:36]([O:39][CH2:40][CH3:41])=[C:37]([F:38])[C:32]=3[F:31])[CH2:43][CH:44]=2)=[C:24]([F:25])[C:2]=1[F:1]
Reactant: CCOc1ccc(C2CCC(=O)CC2)c(F)c1F
Reactant: CCCCCCOc1ccc(CCc2cccc(F)c2F)c(F)c1F
Agent: Cl
Agent: [Li]C(C)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCOc1ccc(CCc2ccc(C3=CCC(c4ccc(OCC)c(F)c4F)CC3)c(F)c2F)c(F)c1F
Temperature: 30 °C
Reaction time: 2 h

Procedure:
1-(2,3-Difluorophenethyl)-2,3-difluoro-4-(hexyloxy)benzene (s-24) (3.6 g) and THF (100 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to −74° C. sec-Butyllithium (1.00M; n-hexane and cyclohexane solution; 12 ml) was added dropwise in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. 1-(2,3-Difluoro-4-ethoxyphenyl)-cyclohexan-4-one (s-25) (2.6 g) in a THF (50 ml) solution was added dropwise in the temperature range of −75° C. to −70° C., and the stirring was continued for 8 hours while the mixture was allowed to return to 25° C. The resulting reaction mixture was poured into a vessel containing a 1N-HCl aqueous solution (100 ml) and ethyl acetate (100 ml) and mixed with them. The mixture was then allowed to stand until it had separated into organic and aqueous layers, and the extraction was carried out. The resulting organic layers were separated, and washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. p-Toluenesulfonic acid (0.19 g) and toluene (100 ml) were added, and the mixture was heated to reflux for 2 hours, while distilled water was removed. After the reaction solution had been cooled to 30° C., water (200 ml) and toluene (100 ml) were added and mixed with it. The mixture was then allowed to stand until it had separated into two layers of organic and aqueous layers, and the extraction into an organic layer was carried out. The resulting organic layers were separated, and washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The resulting solution was purified by column chromatography using silica gel as a stationary phase powder and toluene as an eluent, and further purified by recrystallization from a mixed solvent of Solmix A-11 and heptane (Solmix A-11:heptane=1:2 by volume) and dried to give 1-(2,3-difluoro-4-(hexyloxy)phenethyl)-4-(4-(4-ethoxy-2,3-difluorophenyl)cyclohex-1-enyl)-2,3-difluorobenzene (No. 487) (3.1 g). The yield based on the compound (s-24) was 33.8%.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:31]=[C:30]3[C:26]([CH2:27][C:28](=[O:32])[NH:29]3)=[CH:25][CH:24]=2)[CH:20]=[CH:21][CH:22]=1>N1CCCCC1.C(O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:31]=[C:30]3[C:26]([C:27](=[CH:12][C:9]4[NH:8][C:7]([CH3:14])=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:10]=4[CH3:11])[C:28](=[O:32])[NH:29]3)=[CH:25][CH:24]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]c(C)c(CCC(=O)O)c2C)c1
Yield: 91 %

Procedure:
3-(2-Carboxyethyl)-2,4-dimethyl-5-formylpyrrole (117 mg), 120 mg 6-(3-methoxyphenyl)-2-oxindole and 3 drops piperidine in 3 mL of ethanol were heated at 90° C. overnight. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 190 mg (91%) of the title compound as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4](F)[C:3]=1[F:11].[OH-].[NH4+:13]>O>[Br:1][C:2]1[C:3]([F:11])=[C:4]([C:5]([F:9])=[C:6]([F:8])[CH:7]=1)[NH2:13]
Reactant: [NH4+]
Reactant: Fc1cc(Br)c(F)c(F)c1F
Agent: [OH-]
Solvent: O
Product: Nc1c(F)c(F)cc(Br)c1F
Temperature: 150 °C

Procedure:
To a microwave tube was added 1-bromo-2,3,4,5-tetrafluorobenzene (1.0 g) and 28% aqueous ammonium hydroxide (5 mL). The mixture was heated under microwave irradiation at 150° C. for 2 hrs, then the mixture was poured into water and extracted with hexane. The organic layer was separated, dried with MgSO4, then concentrated. The residue was purified by silica gel flash chromatography (9:1 hexanes/ethyl acetate eluant) afford the title compound as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ 6.75 (m, 1H), 3.95 (br s, 2H) ppm; MS m/z: 226, 228 (M+H)+.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1.FC(F)(F)S(O[CH2:21][C:22]([F:25])([F:24])[F:23])(=O)=O.O>CN(C)C=O>[F:23][C:22]([F:25])([F:24])[CH2:21][O:3][CH:4]1[CH2:5][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(OCC(F)(F)F)C1
Reaction time: 0.5 h
Yield: 47.4 %

Procedure:
Sodium hydride (60 wt % dispersion in liquid paraffin, 151 mg, 3.46 mmol) in N,N-dimethylformamide (5 mL) was mixed with tert-butyl 3-hydroxyazetidine-1-carboxylate (500 mg, 2.89 mmol) in N,N-dimethylformamide (3 mL) under cooling with ice and stirred for 30 minutes, and the resulting reaction mixture was mixed with 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.499 mL, 3.46 mmol) under cooling with ice and then stirred at room temperature for 5 hours. After addition of water, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1→1/1(v/v)) to give the title compound as a colorless solid (350 mg, yield 48%).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:8][C:9]1[CH-:13][C:12]([CH3:14])=[C:11]([CH3:15])[C:10]=1[CH3:16].[Na+]>C1COCC1>[CH3:8][C:9]1[CH:13]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:12]([CH3:14])=[C:11]([CH3:15])[C:10]=1[CH3:16]
Reactant: CCOC(=O)CBr
Reactant: Cc1[cH-]c(C)c(C)c1C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1C(C)=C(C)C(C)=C1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3.822 g (22.89 mmol) ethyl bromoacetate in 25 mL THF was cooled to −78° C. and 3.000 g (20.80 g) sodium tetramethylcyclopentadienide in 50 mL THF was slowly added to it. The resulting slurry was allowed to warm to room temperature and was stirred overnight. The solvent was removed, the residue was extracted with pentane and filtered. The pentane was removed to give a mixture of isomers. Yield was 3.733 g (86.3%). Mass spectra m/e 208 (41 percent).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([NH:13][CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Cl)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(NC2CCNC2)cc1
Yield: 215.9 %

Procedure:
To a solution of tert.butyl-3-(4-chloroanilino)-1-pyrrolidinecarboxylate (130 mg, 0.438 mmol) in CH2Cl2 (5 mL) was added CF3COOH (1 mL). After 30 min the volatiles were removed in vacuo to give the subtitled product (186 mg) and was used directly in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[CH:13][N:14]=[C:7]3[C:6]=2[CH:15]=1.[F:16][C:17]1[C:22](B(O)O)=[CH:21][CH:20]=[CH:19][N:18]=1.C([O-])(=O)C.[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:16][C:17]1[C:22]([C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[CH:12]=[CH:13][N:14]=[C:7]4[C:6]=3[CH:15]=2)=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: OB(O)c1cccnc1F
Reactant: Brc1ccc2c(c1)-c1nccn1CCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ncccc1-c1ccc2c(c1)-c1nccn1CCO2
Temperature: 100 °C

Procedure:
To 10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (140 mg, 0.53 mmol) in DMF (20 mL) and water (2 mL) was added 2-Fluoropyridine-3-boronic acid (89 mg, 0.632 mml), Potassium acetate (207 mg, 2.11 mmol) and Tetrakis(triphenylphosphine)palladium (30 mg, 0.0264 mmol). The reaction mixture was degassed for 5 minutes, and heated at 100° C. overnight. LCMS showed desired product peak. The reaction was allowed to cool to room temperature, diluted with EtOAc, and filtered through a thin pad of celite. The filtrate was washed with water followed by brine, dried over MgSO4 and concentrated. The crude residue was purified by Prep HPLC to provide 10-(2-fluoropyridin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine. LC/MS (ESI+): m/z 282 (M+H)
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:5]([C:21]([F:24])([F:23])[F:22])=[N:6][N:7]([CH2:9][C:10]2[NH:11][C:12](=[O:20])[C:13]3[CH:18]=[C:17]([CH3:19])[S:16][C:14]=3[N:15]=2)[CH:8]=1.N1C=CC=CC=1.[S:31](Cl)([CH3:34])(=[O:33])=[O:32]>O>[CH3:34][S:31]([O:1][CH2:2][CH2:3][C:4]1[C:5]([C:21]([F:23])([F:22])[F:24])=[N:6][N:7]([CH2:9][C:10]2[NH:11][C:12](=[O:20])[C:13]3[CH:18]=[C:17]([CH3:19])[S:16][C:14]=3[N:15]=2)[CH:8]=1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc2c(=O)[nH]c(Cn3cc(CCO)c(C(F)(F)F)n3)nc2s1
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc2c(=O)[nH]c(Cn3cc(CCOS(C)(=O)=O)c(C(F)(F)F)n3)nc2s1
Temperature: -10 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
2-((4-(2-Hydroxyethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-6-methylthieno[2,3-d]pyrimidin-4(3H)-one (1.99 g, 5.55 mmol) was completely dissolved in pyridine (0.44 g, 20 mL, 5.55 mmol) and cooled in an acetone/sodium chloride/ice bath. Internal temperature was maintained at −10° C. Mesyl chloride (2.07 g, 1.40 mL, 18.1 mmol) was added portionwise and the temperature exothermed to 0° C. The mixture was stirred for 1 h at 0° C. and deionised water was added until solid precipitated out. The reaction was filtered, washed with water, and concentrated in vacuo to give the title compound as a pale yellow solid (2.11 g, 4.83 mmol, 87%).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]2[CH2:10][CH2:9]2)=[O:7])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([OH:29])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C1C=CC=CC=1>CO>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([OH:29])[CH2:24][CH2:25][N:26]([CH2:9][CH2:10][NH:8][C:6](=[O:7])[C:5]3[CH:11]=[CH:12][C:2]([F:1])=[CH:3][C:4]=3[N+:13]([O-:15])=[O:14])[CH2:27][CH2:28]2)=[CH:19][CH:18]=1
Reactant: O=C(c1ccc(F)cc1[N+](=O)[O-])N1CC1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Solvent: c1ccccc1
Solvent: CO
Product: O=C(NCCN1CCC(O)(c2ccc(Cl)cc2)CC1)c1ccc(F)cc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
A mixture of 15 parts of 1-(4-fluoro-2-nitrobenzoyl)-aziridine, 11 parts of 4-(4-chlorophenyl)-4-piperidinol, 55.8 parts of benzene and 8.8 parts of methanol is stirred and refluxed for 1.50 hours. After stirring is continued overnight at room temperature, the reaction mixture is evaporated. The residue is dissolved in trichloromethane. The solution is washed with water and 8 parts of methanol are added. The whole is stirred for 10 minutes with silica gel. The latter is filtered off and the filtrate is evaporated. The residue is triturated with 2,2'-oxybis propane. The precipitated product is filtered off and crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 9.5 parts of N-{2-[4-(4-chlorophenyl)-4- hydroxy-1-piperidinyl]ethyl}-4-fluoro-2-nitrobenzamide; mp. 144.3° C.
Reaction SMILES: CN(C)C=O.[C:6]([C:8]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9]1)#[CH:7].N1C=CN=C1.[CH2:19]([Si:21]([CH2:25][CH3:26])([CH2:23][CH3:24])Cl)[CH3:20]>CCCCCC>[C:6]([C:8]1([O:13][Si:21]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:19][CH3:20])[CH2:12][CH2:11][CH2:10][CH2:9]1)#[CH:7]
Reactant: CC[Si](Cl)(CC)CC
Reactant: C#CC1(O)CCCC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C#CC1(O[Si](CC)(CC)CC)CCCC1
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
To a dimethylformamide solution (49.5 ml) of 1-ethynyl-1-hydroxycyclopentane (5.45 g, 49.5 mmol) were added imidazole (6.74 g, 99.0 mmol) and triethylchlorosilane (9.97 ml, 59.4 mmol) at room temperature, followed by stirring for 30 minutes. The reaction solution was added to a mixture of n-hexane and a saturated aqueous sodium bicarbonate solution, and the organic layer was separated. The aqueous layer was extracted with hexane, and the organic layers were combined, washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. After filtration, the filtrate was evaporated under reduced pressure to give the title compound (9.26 g).
Reaction SMILES: C([Li])CCC.CC(C)=O.C(=O)=O.Br[C:14]1[CH:32]=[CH:31][C:17]([N:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:15]=1.C(O[B:37]1[O:41][C:40]([CH3:43])([CH3:42])[C:39]([CH3:45])([CH3:44])[O:38]1)(C)C>C1COCC1>[C:19]1([N:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]2[CH:31]=[CH:32][C:14]([B:37]3[O:41][C:40]([CH3:43])([CH3:42])[C:39]([CH3:45])([CH3:44])[O:38]3)=[CH:15][CH:16]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC1(C)OB(c2ccc(N(c3ccccc3)c3ccccc3)cc2)OC1(C)C
Temperature: -78 °C
Reaction time: 12 h
Yield: 72.4 %

Procedure:
Following the general procedure of arylboronic ester synthesis as reported in Ranger et al., Chem. Commun. 1597-1598 (1997), incorporated herein by reference, n-butyllithium was added dropwise via syringe to a −78° C. (acetone-dry ice cooling bath) solution of 4-bromo-N,N-diphenylaniline (24 g, 0.074 mole) in 175 ml dry THF. Stirring was continued at −78° C. for an hour and then at −50° C. for an hour. The mixture was cooled to −78° C. and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (17.22 g, 0.0925 mole) added via syringe in one portion. The temperature was maintained at −78° C. for three hours. The cooling bath was removed and the reaction left to warm to room temperature while standing for 12 hours. The reaction mixture was poured into saturated ammonium acetate and extracted with ether. The ether layer was dried over magnesium sulfate and concentrated to give a viscous oil. Purification by column chromatography (silica gel eluting with hexane:toluene mixtures of increasing gradient from 100% hexane to 40% hexane) gave N,N-diphenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline as an oil (19.9 g, 72.8% yield), which slowly crystallized to a solid on standing.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@H]1CCN(Cc2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CS(=O)(=O)O[C@H]1CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
(S)-1-Benzyl-3-hydroxypyrrolidine (20.2 g, 114 mmol) was dissolved in toluene (200 mL). To this stirred solution, triethylamine (20 mL, 142 mmol) was added followed by methanesulfonyl chloride (10.5 mL, 136 mmol) during a period of 40 min at 0° C. The resultant slurry was allowed to stir for two hours at 0° C. and 7% sodium bicarbonate (200 mL) was added to the reaction mixture. Organic layer was separated, and the aqueous layer was extracted with toluene (3×100 mL). The combined organic layers were washed with saturated sodium bicarbonate (3×200 mL), dried over Na2SO4 and concentrated under reduced pressure to give (S)-methanesulfonic acid 1-benzyl-pyrrolidin-3-yl ester as a yellow oil (28 g, 96%). The material was used directly for next step without purification. 1H NMR (400 MHz, CDCl3) δ 7.34-7.17 (m, 5H), 5.24-5.18 (m, 1H), 3.71 (d, JAB=13.0 Hz, 1H), 3.64 (d, JAB=13.0 Hz, 1H), 3.01 (s, 3H), 2.89-2.80 (m, 3H), 2.56-2.50 (m, 1H), 2.38-2.31 (m, 1H), 2.14-2.07 (m, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[O:17][CH3:18]>>[CH3:18][O:17][C:9]1[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: COc1ccc([N+](=O)[O-])cc1Br
Product: COc1ccc([N+](=O)[O-])cc1N1CCNCC1

Procedure:
1-(2-Methoxy-5-nitro-phenyl]piperazine was prepared in a manner similar to Preparation 1A except that piperazine was coupled to 2-bromo-1-methoxy-4-nitro-benzene. LRMS (ESI+): 238.4 (M+1)
Reaction SMILES: [Na].Cl[C:3]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[CH3:16][OH:17]>>[CH3:16][O:17][C:3]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CO
Reactant: O=[N+]([O-])c1c(Cl)ccc2cccnc12
Agent: [Na]
Product: COc1ccc2cccnc2c1[N+](=O)[O-]

Procedure:
To a freshly prepared solution of sodium (16.5 g, 0.720 mol) in methanol (750 mL) was added 7-chloro-8-nitroquinoline (18.72 g, 0.090 mol) [E. Fourneau, M. and Mme. Trefouel, and A. Wancolle, Bull. Soc. Chim. Fr., 47, 738(1930); A. K. Sen, N. K. Ray, V. P. Basu, J. Sci. Ind. Res., 11B, 322(1952) (C.A. 47, 4339e)]. This mixture was refluxed for 3 hr, cooled, then filtered to collect the precipitated solid. This solid was slurried in water, collected on a filter and dried; yield, after recrystallization from toluene, 16.12 g (88%); mp 178°-178.5°: Anal. Calcd for C10H8N2O3 : C, 58.82; H, 3.95; N, 13.72. Found: C, 58.66; H, 3.78; N, 13.69.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[CH:22][C:6]2[C:7]([OH:21])=[CH:8][C:9]3[C:10]([CH3:20])([CH3:19])[C:11]4[CH:12]=[C:13](Br)[CH:14]=[CH:15][C:16]=4[C:17]=3[C:5]=2[CH:4]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].COC>O>[CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[CH:22][C:6]2[C:7]([OH:21])=[CH:8][C:9]3[C:10]([CH3:20])([CH3:19])[C:11]4[CH:12]=[C:13]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[O:27][CH3:26])[CH:14]=[CH:15][C:16]=4[C:17]=3[C:5]=2[CH:4]=1
Reactant: COc1ccccc1B(O)O
Reactant: COc1cc2c(O)cc3c(c2cc1OC)-c1ccc(Br)cc1C3(C)C
Agent: COC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc2c(O)cc3c(c2cc1OC)-c1ccc(-c2ccccc2OC)cc1C3(C)C
Temperature: 25 °C
Yield: 93.6 %

Procedure:
To a 500 mL single-neck flask was added 2,3-dimethoxy-7,7-dimethyl-9-bromo-7H-benzo[C]fluoren-5-ol (10 g) prepared according to the first five steps of example 1 in US 2006/0226402 which is included herein as reference, 2-methoxyphenylboronic acid (4.3 g), sodium carbonate (5.9 g), dimethyl ether (120 mL) and water (24 mL). The mixture was purged with N2 for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.6 g) was added to the mixture. The reaction mixture was heated to reflux for 18 hours. The mixture was cooled to room temperature and poured into water (180 mL). The resulting mixture was extracted with ethyl acetate (100 mL). The top layer was dried over sodium sulfate and then condensed to lesser volume. Solid 2,3-dimethoxy-7,7-dimethyl-9-(2-methoxyphenyl)-7H-benzo[C]fluoren-5-ol (10 g) was obtained by recrystallization from solution in t-butyl methyl ether/hexanes.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:5](N(OC)C)=[O:6].[CH3:17][CH:18](C[AlH]CC(C)C)C>C1COCC1.Cl.CCOC(C)=O>[CH2:17]([C:3]1[C:2]([F:1])=[C:13]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:11][C:4]=1[CH:5]=[O:6])[CH3:18]
Reactant: CC(C)C[AlH]CC(C)C
Reactant: CON(C)C(=O)c1ccc([N+](=O)[O-])c(F)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1c(C=O)ccc([N+](=O)[O-])c1F
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of THF (800 mL) cooled in an ice-salt/water bath was added 3-fluoro-N-methoxy-N-methyl-4-nitrobenzamide followed by addition of 1 M DIBAL in THF by addition funnel over 30 min. The solution was allowed to stir under N2 for 1 h. The reaction mixture was then carefully diluted with 1N HCl (500 mL) and EtOAc (500 mL), transferred to separatory funnel, and separated. The organic phase was washed with 1N HCl (3×250 mL), 1N NaOH (2×250 mL), and water (250 mL). All aqueous layers were back extracted with EtOAc (2×250 mL). The organic layers were combined, dried (MgSO4), filtered, and concentrated in vacuo to afford 67 g of the above compound (396 mmol, yield 88%). 1H-NMR (DMSO-d6) δ 10.06 (s, 1H), 8.36 to 8.32 (t, J=7.8 Hz, 1H), 8.06 to 8.03(d, J=11.2 Hz, 1H), 7.95 to 7.93 (d, J=9.1 Hz, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]#[C:8][C:9]1[C:10]([CH:23]=[O:24])=[CH:11][C:12]2[C:13]([CH3:22])([CH3:21])[CH2:14][CH2:15][C:16]([CH3:20])([CH3:19])[C:17]=2[CH:18]=1.[H][H]>C(O)C.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][CH2:8][C:9]1[C:10]([CH:23]=[O:24])=[CH:11][C:12]2[C:13]([CH3:22])([CH3:21])[CH2:14][CH2:15][C:16]([CH3:19])([CH3:20])[C:17]=2[CH:18]=1
Reactant: CC1(C)CCC(C)(C)c2cc(C=O)c(C#Cc3ncccn3)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1(C)CCC(C)(C)c2cc(CCc3ncccn3)c(C=O)cc21
Yield: 68.3 %

Procedure:
To a solution of 0.362 g (1.14 mmol) of 3-(2-(2-pyrimidyl)ethynyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaldehyde in 20 mL of ethanol was added 0.060 g of 10% palladium on carbon and the suspension was shaken under 40 psi hydrogen gas for 3 hours. The resulting solution was filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel (30% ethyl acetate/hexane) to afford 0.251 g (68%) of 3-(2-(2-pyrimidyl)ethyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaldehyde (m.p.=78.0-84.5° C.).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH:6]([S:9]([CH2:12][C:13](=[O:15])[CH3:14])(=[O:11])=[O:10])([CH3:8])[CH3:7]>CC(O)=O.C(Cl)Cl>[Cl:4][CH:12]([S:9]([CH:6]([CH3:8])[CH3:7])(=[O:11])=[O:10])[C:13](=[O:15])[CH3:14]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(=O)CS(=O)(=O)C(C)C
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)C(Cl)S(=O)(=O)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 157.9 %

Procedure:
Sulfuryl chloride (0.248 mL, 3.05 mmol) was added dropwise to a solution of 1-(isopropylsulfonyl)propan-2-one (418 mg, 2.55 mmol) in 1:1 AcOH/DCM (16 ml) at 0° C. The reaction was stirred at rt for 4 h. The solvent was removed in vacuo, then diluted with dichloromethane. The organic layer was washed (2×) with saturated NaHCO3 solution, dried over Na2SO4, filtered, and concentrated to leave 800 mg of a colorless oil. The material was used without further purification.