Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([O:8]C(OC(C)(C)C)=O)=O)([CH3:4])[CH3:3].[CH3:16][NH2:17]>C(Cl)Cl>[CH3:16][NH:17][C:6](=[O:8])[O:5][C:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CN
Solvent: ClCCl
Product: CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a solution of Boc anhydride (7.5 g, 34.36 mmol) in DCM (40 mL) was added methylamine (173 mL, 2M solution in THF, 345 mmol) and the reaction mixture was stirred at room temperature overnight. The solvent and excess methylamine were removed in vacuo and dilute 2M HCl (10 mL) was added. The aqueous layer was extracted with DCM (×2) and the combined organics were dried and concentrated to give the title compound as a yellow oil (3.791 g). δH (CDCl3, 400 MHz) 4.58 (1H, br.s), 2.73 (3H, d), 1.44 (9H, s).
Reaction SMILES: [F:1][C:2]([F:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH2:5])=O.B>C1COCC1>[F:1][C:2]([F:12])([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH2:3][NH2:5]
Reactant: NC(=O)C(F)(F)c1ccccc1
Agent: B
Solvent: C1CCOC1
Product: NCC(F)(F)c1ccccc1
Reaction time: 20 h
Yield: 83.9 %

Procedure:
To a s solution of 2,2-difluoro-2-phenyl-acetamide (0.76 g, 4.4 mmol) in THF (5 mL) is added Borane in THF (1 M, 20 mL, 20 mmole) at 10° C. After 70° C. for 20 h, the mixture is quenched with water (10 mL), concentrated, and chromatographed on SiO2 eluting with 90% EtOAc in heptane to afford 2,2-difluoro-2-phenyl-ethylamine (0.58 g). LCMS: RT=0.92 minutes; MS: 158 (M+H); 1H NMR (300 MHz, CDCl3) □7.57-7.45 (5H, m), 3.2 (2H, t).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][OH:18].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][CH2:17][OH:18])=[CH:4][CH:3]=1
Reactant: OCCBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCOc1ccc(Br)cc1
Temperature: 90 °C
Reaction time: 6 h
Yield: 50.7 %

Procedure:
In DMF (150 ml) was dissolved 4-bromophenol (25 g). To the mixture was added potassium carbonate (30 g) and then was added dropwise 2-bromoethanol (23.5 g), and the mixture was stirred at 90° C. for 6 hours and cooled to room temperature. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=2/1) to give 2-(4-bromophenoxy)-1-ethanol (15.9 g).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:36]1[CH:41]=[CH:40][C:39]([C:42](=[NH:44])[NH2:43])=[CH:38][C:37]=1[C:45](=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)(=O)=O>N1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([O:13][C:36]2[CH:41]=[CH:40][C:39]([C:42](=[NH:43])[NH2:44])=[CH:38][C:37]=2[C:45](=[O:52])[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C=CC(=O)O)cc1
Reactant: CS(=O)(=O)Oc1ccc(C(=N)N)cc1C(=O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C=CC(=O)Oc2ccc(C(=N)N)cc2C(=O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a mixture of 3.1 g of 4-acetyloxycinnamic acid and 50 ml of dried pyridine, while being cooled in ice, was added 3.7 g of DCC. To the mixture, after having been stirred for 30 minutes, was added 5.0 g of 4-amidino-2-benzoylphenol methanesulfonate. The mixture was stirred overnight at room temperature. The insolubles precipitated from the reaction mixture were collected by filtration and mixed with DMF. Ethyl ether was added to the supernatant to precipitate an insoluble substance which was recrystallized from ethanol, yielding 4.7 g of colorless crystals of 4-amidino-2-benzoylphenyl 4-acetyloxycinnamate methanesulfonate.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:11][CH2:12]O>S(=O)(=O)(O)O>[CH2:11]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[NH2:1])[CH3:12]
Reactant: Nc1ncccc1C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cccnc1N
Yield: 74 %

Procedure:
A solution of 2-aminonicotinic acid (2.0 g, 14.4 mmol) in anhydrous EtOH (70 mL) and concentrated sulfuric acid (14 mL) was heated to reflux for 16 h. The solution was concentrated under reduced pressure, neutralized with saturated aqueous Na2CO3 (50 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic phases were dried (MgSO4), filtered and concentrated to give 2-aminonicotinic acid ethyl ester as a yellow solid (1.74 g, 74%). 1H NMR (CDCl3) δ1.40 (t, 3H, J=6.0 Hz), 4.34 (q, 2H, J=7.0 Hz), 6.41 (br s, 2H (NH2)), 6.63 (m, 1H), 8.14 (d, 1H, J=7.8 Hz), 8.22 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[CH2:23]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
A mixture of methyl 4-hydroxybenzoate (3.0 g, 19.7 mmole), potassium carbonate (2.8 g, 20.2 mole) and N,N-dimethylformamide (40 mL) was stirred at 70° C. for 2 hours. Benzyl bromide (2.38 mL, 20 mmole) was added and the reaction was maintained for an additional 18 hours. The mixture was cooled to ambient temperature and dissolved into water (400 mL). The aqueous phase was extracted with ethyl acetate (3×100 mL). The combined organic fractions were dried over magnesium sulfate, filtered and concentrated to provide 4.5 g of methyl 4-benzyloxybenzoate as a white powder, m.p. 96°-97° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[OH-].[Na+].[C:14](OC(=O)C)(=[O:16])[CH3:15].Cl>>[C:14]([O:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(O)cccc1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Oc1cccc(C(=O)O)c1C
Temperature: 5 °C
Yield: 90 %

Procedure:
60.9 g (0.40 mol) of 3-hydroxy-2-methylbenzoic acid are introduced into 500 ml of 2N sodium hydroxide solution (1.00 mol) with stirring and the solution formed in the course of this is cooled to 5° C. 61.3 g (0.60 mol) of acetic anhydride are added to the cooled solution. The reaction mixture is cooled here such that the temperature does not exceed 8° C. The reaction mixture is then acidified with 88 ml of 37% hydrochloric acid. The precipitated product is filtered off, washed three times with 50 ml of water and dried in vacuo. 69.9 g of 3-acetoxy-2-methylbenzoic acid are obtained. This corresponds to a yield of 90.0% of theory.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)(=[O:7])[CH3:6]>O>[C:5]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:1]([O-:4])=[O:2])=[C:11]([Cl:15])[CH:10]=1)(=[O:7])[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1cccc(Cl)c1
Solvent: O
Product: CC(=O)Nc1ccc([N+](=O)[O-])c(Cl)c1
Temperature: 0 °C

Procedure:
To fuming nitric acid (120 mL) at -50° C. was added N-acetyl-3-chloroaniline (30 g) over a period of 45 minutes. The reaction was kept between -50° C. and -30° C. using a dry ice/acetone bath. The reaction mixture was stirred for an additional hour and then poured into 1500 mL of crushed ice and water. The precipitate was filtered and slurried with 1 liter of slightly alkaline water (ammonium hydroxide) twice. The precipitate was then dried and recrystallized from toluene to yield (3.6 g) of N-acetyl-3-chloro-4-nitroaniline; m.p. 134°-136° C.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.C(N(CC)CC)C.[P:16](Cl)([Cl:19])([Cl:18])=[O:17]>CCOCC>[P:16]([Cl:19])([Cl:18])(=[O:17])[O:7][C:6]1[CH:5]=[CH:4][C:3]([Br:8])=[CH:2][CH:1]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccc(Br)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=P(Cl)(Cl)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Following the procedure described by McGuigan et al., 1993, Supra, a solution of p-bromophenol (13.20 g; 76.30 mmol) and distilled triethylamine (10.65 mL) in anhydrous Et2O (165 mL) was added dropwise into a vigorously stirred solution of phosphoryl chloride (8.5 mL; 91.2 mmol) in anhydrous Et2O (83 mL) at 0° C. over a period of three hours under nitrogen atmosphere. Subsequently, the resultant mixture was gradually warmed up to room temperature, stirred efficiently overnight at room temperature and then heated to reflux for two hours. The reaction mixture was cooled to room temperature and filtered under aspirator pressure. The precipitate was washed with anhydrous Et2O (2×50 mL). The combined Et2O layers were evaporated to dryness on rotary evaporator to yield crude 4c as a pale yellow oil which was then subjected to vacuum distillation to give pure 4c (14.05 g; 63.5% yield) as a colorless viscous oil (bp. 110–115° C./2 mm Hg). IR (Neat) 3095, 1481, 1303, 1187, 948, 829 cm−1. 1H NMR (300 MHz, CDCl3) δ 7.50 (2H, d, J=9.0 Hz), 7.15 (2H, d, J=9.0 Hz). GC/MS (m/e) 290 (M+), 254 (M+-Cl), 173 (M+-POCl2, 81Br), 171 (M+-POCl2, 79Br), 156 (M+-PO2Cl2, 81Br), 154 (M+-PO2Cl2, 79Br).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH2:13][CH2:14][C:15]([OH:17])=O>C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:7]=1[CH2:13][CH2:14][C:15]2=[O:17]
Reactant: O=C(O)CCc1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C1CCc2c(Cl)cc(Cl)cc21

Procedure:
Thionyl chloride (36.9 g) was added dropwise at 40° C. to a solution of 3-(2,4-di-chlorophenyl)propionic acid (43.8 g) in methylene chloride (200 ml).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]1(=[O:42])[NH:36][C:35](=[O:37])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:32]1(=[O:42])[N:36]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])[C:35](=[O:37])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=CCCCCCCCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCCCCCCCCCN1C(=O)c2ccccc2C1=O

Procedure:
A mixture of 10-undecene-1-ol (5.00 g, 29.36 mmol, 1 equiv), triphenylphosphine (7.70 g, 29.36 mmol, 1 equiv) and phthalimide (4.32 g, 29.36 mmol, 1 equiv) in dry tetrahydrofuran (THF, 30 mL) was stirred vigorously under argon. Diethyl azodicarboxylate (DEAD, 5.11 g, 29.36 mmol, 1 equiv) was diluted with THF (12 mL) and added dropwise by syringe. After the addition, the reaction was stirred at room temperature for 4 hours. The solvent was evaporated under vacuum and ether (30 mL) was added to precipitate the triphenylphosphine oxide and hydrazine dicarboxylate which were removed by filtration. The precipitate was rinsed with ether (2×30 mL) and the combined filtrates were evaporated to afford a yellow solid. The yellow solid was triturated with warm hexanes (3×50 mL) and filtered. The combined hexanes were evaporated to give 1-phthalimidylundec-10-ene as a yellow wax.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(O)(=O)C.O>[CH3:11][O:10][C:8]1[CH:7]=[C:5]([NH:6][C:12](=[O:14])[CH3:13])[CH:4]=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(N)cc(OC)c1
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(NC(C)=O)cc(OC)c1
Temperature: 25 °C

Procedure:
To a solution of 3,5-dimethoxyaniline (7.13 g, 46.5 mmol) in acetic acid (30 mL) and water (10 mL) was added acetic anhydride (4.61 mL, 48.9 mmol) at room temperature. The reaction was heated gently on a steam bath then cooled to room temperature. Excess water was added and the title compound 464A was collected by filtration.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[N-:12]=[N+]=[N-].[Na+].[OH-].[Na+]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:12][CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C1NCCc2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 24 h
Yield: 6.9 %

Procedure:
A suspension of 5-bromo-1-indanone (15 g, 71 mmol) in concentrated sulfuric acid (75 mL) was cooled to 0° C. Sodium azide (6.5 g, 100 mmol) was added portionwise over 1 hour. The reaction was allowed to warm to room temperature and stirred for 24 hours. The mixture was poured onto ice, neutralised with 4N sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by dry flash chromatography using 50–100% ethyl acetate/isohexane to give 6-bromo-3,4-dihydroisoquinolin-1(2H)-one (1.1 g, 7%). δH (500 MHz, CDCl3): 7.92 (1H, d, J=8.3 Hz), 7.49 (1H, dd, J=1.4, 8.3 Hz), 7.39 (1H, d, J=0.9 Hz), 6.46 (1H, s), 3.57–3.55 (2H, m), 2.98 (2H, t, J=6.6 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([OH:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH:19]([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([O:17][CH:19]([CH3:21])[CH3:20])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)I
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Oc1cc(OCc2ccccc2)ccc1C=O
Temperature: 25 °C

Procedure:
A mixture of 4-(benzyloxy)-2-hydroxybenzaldehyde (1 g, 4.38 mol), 2-iodopropane (1.2 eq.) and potassium carbonate (2.5 eq.) in acetone (40 mL) was refluxed overnight. The reaction was cooled to room temperature and filtered through a celite plug, and concentrated to dryness. The crude material was purified by flash column chromatography with ethyl acetate and hexanes to provide 4-(benzyloxy)-2-isopropoxybenzaldehyde (698).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](N)=[O:8])=[CH:5][CH:4]=1)#[N:2].N([O-])=[O:13].[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:13])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(N)=O)cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: N#Cc1ccc(C(=O)O)cc1
Temperature: 5 °C
Yield: 91.2 %

Procedure:
p-Cyanobenzamide (14.6 g), sodium nitrite (20.7 g), acetic acid (200 ml), and acetic anhydride (20 ml) were mixed and stirred vigorously at 5° C. To the mixture, trifuloroacetic acid (35 g) was added dropwise over three hours, and further stirred vigorously for five hours. The solvent was removed under reduced pressure, and water (300 ml) was added to the residue. The precipitated crystals were collected through filtration, washed with water, and dried, to thereby obtain 13.4 g of p-cyanobenzoic acid (yield 92%). The p-cyanobenzoic acid obtained had a purity of 98%.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]1[CH2:12][CH2:13][CH2:14][N:15]=1>C(O)C>[F:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[CH:11]1[CH2:12][CH2:13][CH2:14][NH:15]1
Reactant: Fc1ccc(F)c(C2=NCCC2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Fc1ccc(F)c(C2CCCN2)c1
Temperature: 25 °C

Procedure:
In step 6A-3, sodium borohydride (2.1 g, 55.2 mmol) was added at room temperature to a solution of 5-(2,5-difluorophenyl)-3,4-dihydro-2H-pyrrole (6-4) (5.0 g, 28 mmol) in anhydrous ethanol (150 mL). The reaction mixture was stirred over-night at room temperature. The ethanol was removed using a rotary evaporator and the resulting orange solid was reconstituted with ethyl acetate. The organic layer was washed with brine (3×150 mL), dried with sodium sulfate and the. ethyl acetate was removed to yield 2-(2,5-difluorophenyl)pyrrolidine (6-5) as a light yellow oil. m/z=184.2 [M+1].
Reaction SMILES: B.[CH3:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:6]#[N:7].[ClH:13]>O1CCCC1.CO>[ClH:13].[NH2:7][CH2:6][C:5]1[CH:4]=[C:3]([CH3:2])[C:10]([OH:11])=[C:9]([CH3:12])[CH:8]=1
Reactant: Cc1cc(C#N)cc(C)c1O
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(CN)cc(C)c1O
Temperature: 25 °C

Procedure:
A solution of borane in tetrahydrofuran (1M in tetrahydrofuran, 27.1 mL, 27.1 mmol) was added dropwise to a solution of 3,5-dimethyl-4-hydroxybenzonitrile (1.0 g, 6.79 mmol) in tetrahydrofuran (70 mL) and the resulting solution was heated under reflux for 16 hours. The reaction mixture was cooled to room temperature, treated with 6N hydrochloric acid (20 mL) and heated under reflux for a further 30 minutes. The reaction mixture was then cooled to room temperature and the solvent was removed in vacuo. The residue was purified using a strong cation exchange resin eluting with methanol followed by 2M ammonia in methanol, to give an orange oil. This oil was then treated with 1M hydrogen chloride in methanol (20 mL) and the reaction mixture was concentrated in vacuo to afford the title compound as a pale yellow solid in quantitative yield, 1.12 g. 1HNMR (400 MHz, CDCl3) δ: 2.22 (6H, s), 3.75 (2H, s), 6.90 (2H, s).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][F:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:15][CH2:14][CH2:13][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: FCCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OCCF)cc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 4-hydroxybenzoate (4.03 g), 1-bromo-2-fluoroethane (5.05 g) and potassium carbonate (10.98 g) in N,N-dimethylformamide (68 ml) was stirred at 70° C. for 1 hour. The reaction mixture was cooled to room temperature, and thereto was added water. The mixture was extracted with ethyl acetate, and the organic layer was washed successively with water and brine, and then dried over magnesium sulfate. The insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure to give methyl 4-(2-fluoroethyloxy)benzoate, which was used in the subsequent step without further purification.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:20]([C:23]1[CH:45]=[CH:44][C:26]([CH2:27][O:28][C:29](=[O:43])[CH:30]([N:32]2[C@H:35]([S:36][C:37](=[O:39])[CH3:38])[C@@H:34]([O:40][CH3:41])[C:33]2=[O:42])Cl)=[CH:25][CH:24]=1)([O-:22])=[O:21]>O1CCOCC1>[N+:20]([C:23]1[CH:45]=[CH:44][C:26]([CH2:27][O:28][C:29](=[O:43])[C:30]([N:32]2[C@H:35]([S:36][C:37](=[O:39])[CH3:38])[C@@H:34]([O:40][CH3:41])[C:33]2=[O:42])=[P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CO[C@H]1C(=O)N(C(Cl)C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1SC(C)=O
Solvent: C1COCCO1
Product: CO[C@H]1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1SC(C)=O
Reaction time: 8 h

Procedure:
812 mg of triphenylphosphine and 3 g of poly-Hunig base are added to a solution of 833 mg of 2-[(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl]-2-chloroacetic acid p-nitrobenzyl ester in 50 ml of dioxan and the mixture is stirred overnight at 50°. The poly-Hunig base is removed by filtration and the filtrate is concentrated by evaporation in vacuo. The residue is chromatographed over silica gel with toluene/ethyl acetate (9:1, 4:1 and 1:1) and yields the title comcound.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][C:10]1[N:11]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][N:13]=2.O>CN(C=O)C>[Br:8][C:18]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[N:11]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:20])=[O:21])[C:10]=1[CH3:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2cccnc2n1S(=O)(=O)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Br)c2cccnc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
25 g of NBS in 75 ml of DMF are added to a solution of 34.8 g of 2-methyl-1-(benzenesulfonyl)-7-azaindole in 75 ml of DMF. The mixture is stirred at room temperature for 1 h, poured into water, the precipitate which has precipitated out is separated off, washed with water and dried, giving 42 g of 3-bromo-2-methyl-1-(benzenesulfonyl)-7-azaindole, M˜351.22 g/mol, M+H found 351.
Reaction SMILES: [C:1]1([S:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH:16]([S:18](Cl)(=[O:20])=[O:19])=[CH2:17]>O>[CH:16]([S:18](=[O:20])(=[O:19])[S:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:13])=[O:12])=[CH2:17]
Reactant: O=S(O)c1cccc2ccccc12
Reactant: C=CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CS(=O)(=O)S(=O)(=O)c1cccc2ccccc12
Yield: 24.9 %

Procedure:
15 ml of water was added to 9.6 g of 1-naphthalene sulfinic acid and a solution of 2 g of sodium hydroxide in 5 ml of water was added to the mixture. To the solution there was added a solution of 6.3 g of vinylsulfonyl chloride in 20 ml of acetronitrile at room temperature with stirring and the mixture was stirred at room temperature for additional 24 hours. The reaction solution was poured into 300 ml of water, the resulting precipitates were recovered through filtration and recrystallized from a mixed solvent of benzene and ethanol to give 3.5 g of vinyl-1-naphthyldisulfone.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[C:2]#[CH:3].[CH2:6](Br)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[C:2]#[CH:3]
Reactant: C#CC(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C#CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 37 %

Procedure:
To a solution of 17.0 g (233 mmol) of propiolic acid in 600 mL of anhydrous DMF was added 39.9 g (233 mmol) of benzyl bromide followed by portionwise addition of 76.0 g (233 mmol) of Cs2CO3. After stirring at room temperature for 24 h, the reaction was quenched with a saturated aqueous ammonium chloride solution and extracted with EtOAc (3×200 mL). The combined extracts were washed with water then brine and dried over anhydrous sodium sulfate. The mixture was then filtered through a silica gel pad washing with hexanes, and the filtrate was evaporated under reduced pressure to afford a crude product. The crude product was purified by silica gel chromatography eluting with a 0-20% ethyl acetate in hexane gradient to afford the title compound as a colorless oil (13.8 g, 35%). 1H NMR (CDCl3, 500 MHz) δ 7.41 (m, 5H), 5.25 (s, 2H), 2.92 (s, 1H).