Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][CH:5]=2.[BH3-]C#N.[Na+].[CH3:19][C:20](OC(C)=O)=[O:21]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:20]([N:3]1[C:4]2[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[CH:7]=[CH:6][CH:5]=2)[CH2:10][CH:2]1[CH3:1])(=[O:21])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc2c(C(F)(F)F)cccc2[nH]1
Agent: CN(C)c1ccncc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)N1c2cccc(C(F)(F)F)c2CC1C
Temperature: 0 °C
Reaction time: 14 h
Yield: 42.6 %

Procedure:
A mixture of 2-methyl-4-(trifluoromethyl)-1H-indole (Example 114D) (0.48 g, 2.41 mmol) was dissolved in HOAC (3.0 mL), cooled to 0° C. and NaBH3CN (0.454 g, 7.23 mmol) was added in one portion. After 5 min the mixture was removed from the cooling bath and stirred at rt for 14 h. The mixture cooled to 0° C. and the pH was adjusted to ca. 13 by addition of 1 N NaOH (20 mL) and further addition of solid NaOH pellets. The mixture was extracted with Et2O (×3), combined organics were washed (H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in dry CH2Cl2 (10 mL) and treated with DMAP (0.884 g, 7.23 mmol). The mixture was cooled to 0° C. and Ac2O (0.455 mL, 4.81 mmol) was added dropwise via syringe. The mixture was stirred overnight, slowly warming to rt, diluted with CH2Cl2, washed (10% HCl, H2O, brine), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 0.25 g of the title compound as a pale yellow oil: MS (ES) m/z 244 (M+1).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:6][CH2:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10]>CC(C)=O>[Br-:6].[O:13]=[C:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:7][S+:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)C(=O)CBr
Reactant: C1CCSC1
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)C[S+]1CCCC1
Product: [Br-]
Reaction time: 24 h
Yield: 85 %

Procedure:
Using the 100-millilitter 3-port flask, 2 grams of tetrahydrothiophene was dissolved in 20 milli-litter of acetone. 4.87 grams of 1-bromo-3,3-dimethyl-2-butanone was dropped into the solution over agitation. After 24 hours, white crystal was precipitated, and was filtrated. The white crystal was pulverized, and was washed in ether. The pulverized white crystal was dried at 30 degrees in centigrade for 6 hours by using a low-pressure drier. 5.15 grams of 2-oxo-3,3-dimethylbutyl-thiacyclopentanium bromide was obtained. The yield was 75.0%.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[OH-].[K+:34]>C(O)(C)C.O>[CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([O-:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[K+:34]
Reactant: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)o1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c([O-])c(=O)n2C)o1
Temperature: 27.5 °C
Reaction time: 17 h
Yield: 88.4 %

Procedure:
Raltegravir (50 gm) was suspended in isopropyl alcohol (500 ml) and then added a solution of potassium hydroxide (8 gm) in water (10 ml) at 25 to 30° C. The reaction mass was stirred for 17 hours at 25 to 30° C. and filtered. The solid obtained was dried under vacuum at 60° C. for 9 hours to obtain 48 gm of raltegravir potassium crystalline form H1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][CH3:16])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[CH2:24]([O:17][C:3]1[CH:4]=[CH:5][C:6]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][CH3:16])[CH2:9]2)=[CH:7][C:2]=1[Br:1])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: CCCN1CCOC(c2ccc(O)c(Br)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCN1CCOC(c2ccc(OCc3ccccc3)c(Br)c2)C1
Temperature: 150 °C
Yield: 100 %

Procedure:
To the phenol from example 30 (117.5 mg, 0.39 mmol) in dry DMF (10 ml), under an atmosphere of nitrogen, was added potassium carbonate (75 mg, 0.54 mmol) and benzyl bromide (0.07 ml, 0.54 mmol). The reaction mixture was heated to 150° C. for 48 hours. After cooing, the reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (50 ml) and water (50 ml). The aqueous layer was then re-extracted with ethyl acetate (2×20 ml). The combined organic extracts were then dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the crude product as a brown oil. This was purified by column chromatography on silica eluting with dichloromethane:methanol (98:2) to give the title compound as a colourless oil (153 mg, 0.39 mmol, 100%). 1H NMR (CDCl3, 400 MHz) δ: 0.93 (t, 3H), 1.56 (q, 2H), 2.05 (t, 1H), 2.25 (t, 1H), 2.37 (t, 2H), 2.82 (d, 1H), 2.92 (d, 1H), 3.85 (t, 1H), 4.02 (d, 1H), 4.52 (d, 1H), 5.15 (s, 2H), 6.87 (d, 1H), 7.20 (d, 1H), 7.30 (d, 1H), 7.37 (t, 2H), 7.45 (d, 2H), 7.58 (s, 1H). LRMS: m/z 392 (M-H+).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]([O:11][C:12]([N:14]1[CH2:18][C:17](=O)[CH2:16][C@H:15]1[C:20]([OH:22])=[O:21])=[O:13])([CH3:10])([CH3:9])[CH3:8]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:7]([O:11][C:12]([N:14]1[CH2:18][C:17](=[CH2:1])[CH2:16][C@H:15]1[C:20]([OH:22])=[O:21])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 46.7 %

Procedure:
To a mixture of methyltriphenylphosphonium bromide (236.4 g, 2.7 eq) in THF (1 L) was rapidly added potassium tert-butoxide (75.6 g, 2.75 eq) while maintaining the temperature around 0° C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 2 hours, and re-cooled to 0° C. (S)-1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylic acid (56.2 g, 0.245 mol) was added portionwise to the reaction mixture while maintaining the temperature below 5° C. Then, the reaction was allowed to warm to room temperature and stirred at room temperature overnight before being re-cooled to 0° C. and quenched by addition of saturated NaHCO3 solution (500 mL) and water (200 mL). The mixture was evaporated. The aqueous layer was extracted with tert-butyl methyl ether (2×400 mL). The aqueous layer was filtered through a pad of celite and the filtrate was acidified with 6N HCl (200 mL) and extracted with ethyl acetate (2×1 L). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated to dryness. The residue was dissolved in ethyl acetate (0.7 L), extracted with 0.5 N NaOH (0.7 and 0.3 L). The aqueous layer was acidified with 6N HCl (100 mL), extracted with ethyl acetate (1 L and 0.8 L). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated to dryness. The residue was dissolved in 50% ethyl acetate in cyclohexane (150 mL), slowly evaporated to give a yellowish solid. It was filtered and dried to give the title compound (26 g). The filtrate was evaporated to give a yellowish solid, filtered and dried to provide the title compound (10 g). Total 36 g (65%) as a white solid. Also, the residue contained 18 g of the product as 80% purity. 1H NMR (500 MHz, CDCl3): 5.04-5.02 (m, 2H), 4.53 (dd, J=8.4, 3.2 Hz, 0.5H), 4.42 (d, J=9.3 Hz, 0.5H), 4.09-3.98 (m, 2H), 3.05-2.69 (m, 2H), 1.49 and 1.43 (2 s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[CH3:17]O>>[Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([O:8][CH3:17])=[O:7]
Reactant: CO
Reactant: O=C(O)c1ccc(Cl)cc1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Cl)cc1O
Temperature: 25 °C

Procedure:
4-Chlorosalicylic acid (34.51 g, 0.2 mol) (Aldrich) was suspended in a solution of methanol (100 mL) and concentrated sulfuric acid (8 mL). The mixture was heated at reflux for 17 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The resulting residue was dissolved in ether (400 mL) and washed successively with water (400 mL), saturated aqueous sodium bicarbonate (400 mL), and saturated aqueous sodium chloride (400 mL). The ether solution was then dried (MgSO4), filtered, and concentrated. The resulting yellow oil was distilled to give methyl 4-chlorosalicylate. (Yield 32.89 g, 88%; b.p. 86-90° C., 0.15 mm Hg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[Cl:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C(OCCCCC)(=O)C>[ClH:19].[N:22]1([CH2:21][CH2:20][O:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: ClCCN1CCCCC1
Reactant: COC(=O)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCOC(C)=O
Product: O=C(O)c1ccc(OCCN2CCCCC2)cc1
Reaction time: 1 h
Yield: 91 %

Procedure:
To a 2000 gallon tank were added: 1320 L of amyl acetate, 167.42 kg of methyl 4-hydroxybenzoate, 408.6 kg of potassium carbonate, and 283.5 kg of β-chloroethylpiperidine hydrochloride. The mixture was heated to 120° C.-125° C. for 5 hours, at which time HPLC analysis indicated complete consumption of the methyl 4-hydroxybenzoate. The tank was cooled to less than 50° C. 880 L of deionized water were added to the tank. The layers were separated and the aqueous layer was discarded. In a glass lined tank was mixed 367 L of food grade hydrochloric acid and 184 L of deionized water. The acid mixture was combined with the organic layer. The layers were separated and the organic layer was discarded. The mixture of the intermediate ester in aqueous acid heated to reflux until HPLC suggested no further consumption of the ester (13 hours). The mixture was cooled to less than 40° C. 550 L of acetone was added to the mixture and the mixture was cooled to 0° C.-5° C. and stirred for 1 hour. The product was collected by filtration on a centrifuge. The wet cake was rinsed on the centrifuge with 400 L of acetone. The product was dried in a rotary vacuum (double cone) dryer at less than 50° C. and 25-27 inches in mercury. Yield was 91% of theoretical.
Reaction SMILES: [OH:1][CH:2]([CH2:26]O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:22](=[O:23])[C:21]2[N:20]([CH3:24])[CH:19]=[N:18][C:17]=2[N:16]([CH3:25])[C:14]1=[O:15].[BrH:28].O.[C:30]([OH:33])(=O)[CH3:31]>>[C:30]([O:1][CH:2]([CH2:26][Br:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:22](=[O:23])[C:21]2[N:20]([CH3:24])[CH:19]=[N:18][C:17]=2[N:16]([CH3:25])[C:14]1=[O:15])(=[O:33])[CH3:31]
Reactant: Cn1cnc2c1c(=O)n(CCCCCCCCCCC(O)CO)c(=O)n2C
Reactant: CC(=O)O
Reactant: Br
Solvent: O
Product: CC(=O)OC(CBr)CCCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
1-(11,12-Dihydroxydodecyl)-3,7-dimethylxanthine (2.50 g, 6.58 mmol) was stirred with hydrogen bromide (6.39 mL of a 30% solution in acetic acid, 19.73 mmol) for 2 hours. The mixture was then added over 10 minutes to water (25 mL), ice (30 g) and sodium hydride CO3 (15 g) and stirred for 30 minutes. The reaction mixture was extracted with dichloromethane (3×50 mL), and the combined organic phases were dried using magnesium sulfate and evaporated to obtain 3.18 g (99% yield) of 1-(11-acetoxy-12-bromododecyl)-3,7-dimethylxanthine. Without further purification, this crude product was taken up in methanol (10 mL) and treated with a solution of sodium methoxide (prepared from sodium, 0.160 g, 6.90 mmol, and 20 mL methanol). After 60 minutes, the reaction was added to water (30 mL) and extracted with dichloromethane (3×50 mL). The organic portions were combined, dried and evaporated to yield 2.20 g (93% yield) 1-(11,12-oxidododecyl)-3,7-dimethylxanthine as a white solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[OH:12])[CH:2]=[CH2:3].[H][H]>[C].[Pd].CO>[CH2:1]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[OH:12])[CH2:2][CH3:3]
Reactant: [H][H]
Reactant: C=CCc1cc(C#N)ccc1O
Agent: [Pd]
Solvent: CO
Product: CCCc1cc(C#N)ccc1O

Procedure:
A mixture of 8.15 g of 2-allyl-4-cyanophenol prepared in Reference Example 1-(ii), 1.5 g of 5% palladium-carbon and 100 ml of methanol, was stirred in a hydrogen stream for 2.5 hours. The catalyst was removed by filtration, and the solvent was distilled off from the filtrate to obtain 7.30 g of the above identified compound as a colorless oily substance.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[CH3:13]/[C:14](/[C:17]([CH3:19])=O)=[N:15]\[OH:16].[ClH:20].C(OCC)C>C(O)(=O)C>[ClH:20].[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][C:6]([C:7]2[O:8][C:17]([CH3:19])=[C:14]([CH3:13])[N+:15]=2[O-:16])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CC(=O)/C(C)=N/O
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)[n+]([O-])c1C
Temperature: 25 °C
Yield: 86 %

Procedure:
34.8 g (0.20 mol) of 4-trifluoromethylbenzaldehyde and 20.2 g (0.20 mol) of 2,3-butanedione monoxime were dissolved in 100 ml of glacial acetic acid and the mixture was stirred at room temperature while passing gaseous hydrogen chloride through the mixture until a saturated solution was obtained. The mixture was stirred at room temperature overnight and then treated with an excess of anhydrous diethyl ether. The colourless crystalline precipitate was filtered off, washed free of mother liquors using fresh anhydrous diethyl ether and dried in vacuo to give 50 g (86%) of 2-(4-trifluoromethylphenyl)-4,5-dimethyloxazole N-oxide hydrochloride of melting point 175°-177° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH2:12]([NH2:18])[CH:13]1[O:17][CH2:16][CH2:15][CH2:14]1>O>[CH3:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH:18][CH2:12][CH:13]1[O:17][CH2:16][CH2:15][CH2:14]1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: NCC1CCCO1
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1NCC1CCCO1
Temperature: 140 °C

Procedure:
A mixture of 0.2 mol (31.0 g) of 3-methyl-4-fluoronitrobenzene and 0.7 mol (70.7 g) of tetrahydrofurfurylamine is heated for one hour in an oil bath at 140° C. The reaction mixture is then poured into 400 g of ice-cooled water. The expected product rapidly crystallises; after it has been filtered off, washed with water, recrystallised from ethanol and dried in vacuo, it melts at 60° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>>[F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH:4][S:13]([CH3:12])(=[O:15])=[O:14]
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1F

Procedure:
First, the amino group of 2-fluoro-5-nitroaniline is sulfonylated by using methanesulfonyl chloride to give N-(2-fluoro-5-nitrophenyl)methanesulfonamide.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH2:9]([N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCCCCCC.CS(C)=O>[CH2:9]([N:16]1[CH2:21][CH2:20][C:19]2([O:22][CH2:4]2)[CH2:18][CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CS(C)=O
Product: c1ccc(CN2CCC3(CC2)CO3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (55% suspension in mineral oil, 1.57 g, 35 mmol) was washed with heptane, dried in the stream of nitrogen and suspended in dry DMSO (10 ml). A solution of trimethylsulfoxonium iodide (4.8 g, 22 mmol) in DMSO (45 ml) was added dropwise under nitrogen. After stirring for 20 min a solution of 1-benzylpiperidin-4-one (3.78 g, 20 mmol) was added dropwise. The mixture was stirred overnight at room temperature, then poured over ice (200 g), and extracted with dichloromethane (2×200 ml). The combined extracts were washed with water (3×100 ml) and dried over Na2SO4. The solvent was removed i. vacuo. The residue was dissolved in diethyl ether, and the insoluble material was removed by filtration. Evaporation of solven afforded pale-yellow oil (2.95 g, 73%).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.B.[Na]>C(O)C.CO.O1CCCC1>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([OH:11])[CH2:3][CH2:2]1
Reactant: O=C1CCOc2ccccc21
Agent: B
Agent: [Na]
Solvent: CCO
Solvent: CO
Solvent: C1CCOC1
Product: OC1CCOc2ccccc21

Procedure:
The compound 3 is reduced using a reducing agent such as sodium boron hydride in a solvent such as methanol, ethanol and tetrahydrofuran, preferably in an alcohol solvent such as methanol and ethanol, under cooling to room temperature to give 4-chromanol (compound 4 wherein R1, R2 and R3 are as defined above).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:12]1[N:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15].O>CCCCCC.C1COCC1>[CH2:3]([O:10][C:12]1[C:13]([C:14]#[N:15])=[CH:16][CH:17]=[CH:18][N:19]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: N#Cc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: N#Cc1cccnc1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
Sodium hydride (60%, 2.89 g, 72.3 mmol) was washed with hexane (1×) and suspended in THF (50 ml). Anhydrous benzyl alcohol (8.57 g, 79.3 mmol) was added dropwise and the reaction mixture was stirred for 30 minutes. A solution of 2-chloronicotinonitrile (10.0 g, 72.2 mmol) in THF (50 ml) was added via a syringe (exotherm). The reaction was stirred at ambient temperature for 18 hours then water was added to quench the reaction. The reaction mixture was partitioned between EtOAc/water and the organic phase dried (MgSO4) and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2) to give 2-benzyloxy-3-cyanopyridine as a pale yellow oil which crystallised on standing (11.4 g, 75%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[C:16]1(=[O:26])[O:21][C:19](=[O:20])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.ClCCl.[Cl-].[Al+3].[Cl-].[Cl-]>O>[CH3:1][C:2]1([CH3:15])[C:3]2[CH:4]=[C:5]([C:16]([C:17]3[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=3[C:19]([OH:21])=[O:20])=[O:26])[CH:6]=[CH:7][C:8]=2[C:9]2[C:14]1=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC1(C)c2ccccc2-c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC1(C)c2ccccc2-c2ccc(C(=O)c3ccccc3C(=O)O)cc21
Temperature: 25 °C
Yield: 80 %

Procedure:
9,9-dimethyl-9H-fluorene (40 g, 1 eq, 0.206 mol) and Phthalic anhydride (33.6 g, 1.1 eq, 0.227 mol) were placed in a reaction vessel, and added with Dichloromethane (1.5 l). At 0° C., aluminum chloride (40.8 g, 1.5 eq, 0.309 mol) was gradually added thereto, and the temperature was raised up to room temperature. Then, the resultant mixture was stirred for 12 hours. After the reaction was completed, the resultant product was gradually added with distilled water at 0° C. The resultant product was extracted with an excess of dichloromethane, and washed several times with distilled water. After solvent removal, the produced solid was placed in a Hexane 2 l-containing vessel, washed, filtered, and dried, 2-(9,9-dimethyl-9H-fluorene-2-carbonyl)benzoic acid (56.4 g, yield 82%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[CH2:20]([OH:23])[C:21]#[CH:22].Cl>O1CCCC1.[Cu]I.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.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:22]#[C:21][CH2:20][OH:23])=[CH:4][CH:3]=1
Reactant: Clc1ccc(I)cc1
Reactant: C#CCO
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: C1CCOC1
Product: OCC#Cc1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
A solution of 1-chloro-4-iodobenzene (23.9 g, 100.0 mmol) in dry tetrahydrofuran (100 mL) was degassed and copper(I) iodide (570 mg, 3.0 mmol), tetrakis(triphenylphosphine)palladium (3.4 g, 3.0 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (18.2 g, 120.0 mmol) were added. The reaction solution was degassed again and propargyl alcohol (6.7 g, 120.0 mmol) was added under inert atmosphere at ambient temperature. The reaction mixture was stirred (initially under cooling with ice water) for 24 h, then treated with water (20 mL) and acidified with 2 M hydrochloric acid (20 mL). The organic phase was separated and the aqueous phase was extracted with ether (4×30 mL). The combined organic phases were dried with anhydrous magnesium sulfate and concentrated in vacuo yielding brown solid. The residue was purified by column chromatography (silica gel Fluka 60, chloroform) yielding 3-(4-chlorophenyl)prop-2-yn-1-ol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9][CH:10]=[O:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24].[Cl-]>CN(C)C(=O)C.C(#N)C.N1C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][NH:9][CH:10]=[O:11])=[CH:6][CH:7]=2)(=[O:21])=[O:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24]
Reactant: Nc1ccc(NNC=O)cc1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Agent: [Cl-]
Solvent: CC(=O)N(C)C
Solvent: CC#N
Solvent: c1ccncc1
Product: O=CNNc1ccc(NS(=O)(=O)c2ccc(Cl)c([N+](=O)[O-])c2)cc1
Temperature: -5 °C
Yield: 77.8 %

Procedure:
In 90 ml of N,N-dimethylacetamide, 76 ml of acetonitrile, and 17 ml cf pyridine were dissolved 35.4 g of 2-(4-aminophenyl)-1-formylhydrazine in a nitrogen gas atmosphere and after cooling the solution to -5° C., 59.9 g of 4-chloro-3-nitrobenzenesulfonyl chloride were gradually added to the solution while cooling with stirring so that the liquid temperature was not over -5° C. After further stirring the mixture for 1.5 hours at temperature below -5° C., the temperature was raised to room temperature and the reaciton mixture was poured into 1 liter cf a saturated aqueous solid chloride solution. Crystals formed were collected by filtration and washed with water to provide 67.5 g of the desired product.