Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[Cl:9][CH2:10][CH2:11][C:12](O)=[O:13].FC(F)(F)S(O)(=O)=O.ClCCl>O>[Cl:9][CH2:10][CH2:11][C:12]([C:6]1[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=1[OH:5])=[O:13]
Reactant: O=C(O)CCCl
Reactant: Oc1cccc(O)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=C(CCCl)c1ccc(O)cc1O
Temperature: 80 °C
Yield: 74.6 %

Procedure:
To a stirred mixture of resorcinol (10 g, 91 mmol) and 3-chloropropanoic acid (9.95 g, 92 mmol) was added trifluoromethanesulfonic acid (50 g, 333 mmol) in one portion. The solution was warmed to 80° C. for 30 min, cooled to room temperature over 15 min, and poured into dichloromethane (200 mL). The resulting solution was slowly poured into water (200 mL), and the layers were separated. The aqueous layer was extracted with dichloromethane (2×100 mL), dried over anhydrous sodium sulfate, and filtered. Concentration under reduced pressure afforded 3-chloro-1-(2,4-dihydroxyphenyl)propan-1-one (13.62 g, 67.9 mmol, 74.8% yield) as an orange semi-solid. The compound was used without any further purification. LC/MS M+1=200; 1H NMR (400 MHz, CDCl3) δ ppm 12.39 (1H, s), 7.56 (1H, d, J=8.58 Hz), 7.19 (1H, s), 6.17-6.49 (1H, m), 5.23 (1H, s), 3.78-4.01 (2H, m), and 3.34 (2H, t, J=6.71 Hz).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:11]I>C1COCC1>[Br:1][C:2]1[C:7]([O:8][CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccnc1Br
Reaction time: 18 h

Procedure:
A solution of 2-bromo-3-hydroxy-pyridine (1 equiv., Aldrich Chemical Company) in THF is treated with NaH (1 equiv.) at 0° C. for 30 min. Methyl iodide (1 equiv.) is added and stirred for 18 h. The reaction mixture is evaporated, the residue is taken into ethyl acetate, washed with 5% Na2CO3 (aqueous), dried over MgSO4 and evaporated to give 2-bromo-3-methoxy-pyridine.
Reaction SMILES: [C:1]([C:3]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].[F:9][C:10]1[C:11](I)=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>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.CN(C=O)C.CCN(CC)CC>[F:9][C:10]1[C:11]([C:2]#[C:1][C:3]2([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4]2)=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: C#CC1(O)CCCC1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CC3(O)CCCC3)c21

Procedure:
Using Method C above, 1-ethynyl-1-cyclopentanol (35.8 mg, 0.33 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.13 mmol) (Starting Material 6) using (Ph3P)4Pd (15 mg) and Cul (2.5 mg) as catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 80° C. for 5 h to yield (Z)-1,3-Dihydro-5-fluoro-4-[(1-hydroxycyclopentyl)ethynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 32 mg, 67%).
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: Oc1ccc(Br)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
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: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=1.[CH:9](/B(O)O)=[CH:10]/[CH3:11].ClC1C=CC(CC2C=C(C=O)SC=2)=CC=1>CN(C=O)C>[CH:9](/[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=1)=[CH:10]/[CH3:11]
Reactant: C/C=C\B(O)O
Reactant: O=Cc1cc(Br)co1
Agent: O=Cc1cc(Cc2ccc(Cl)cc2)cs1
Solvent: CN(C)C=O
Product: C/C=C\c1coc(C=O)c1
Yield: 48.2 %

Procedure:
The title compound was synthesized from 4-bromo-furan-2-carboxaldehyde (1.1 g, 6.3 mmol, 1 equiv) and cis-propene boronic acid (0.65 g, 7.5 mmol, 1.2 equiv) using the conditions to synthesize 4-(4-chlorobenzyl)thiophene-2-carbaldehyde, with the exception that the reaction was run in DMF (20 mL). The resulting residue was purified via ISCO Companion (0-25% EtOAc/heptane over 30 min, retention time of product: 23-26 min) to give (Z)-4-(prop-1-enyl)furan-2-carbaldehyde (0.4130 g, 48% yield). LC/MS m/e 136.8 (M+H). 1H NMR (400 MHz, CD3CN) δ (ppm): 9.59 (d, J=0.63 Hz, 1H), 7.83 (s, 1H), 7.42 (s, 1H), 6.23 (dd, J=11.40, 1.68 Hz, 1H), 5.79-5.89 (m, 1H), 1.87 (dd, J=7.10, 1.78 Hz, 3H).
Reaction SMILES: C1CC1.[CH2:4]([O:6][C:7]([CH:9]1[CH2:11][C:10]1([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])[CH3:5].OS(O)(=O)=O.[N:29]([O-])=[O:30].[Na+]>CC(O)=O.O>[CH2:4]([O:6][C:7]([C:9]1[CH2:11][C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:30][N:29]=1)=[O:8])[CH3:5]
Reactant: O=N[O-]
Reactant: CCOC(=O)C1CC1(c1ccccc1)c1ccccc1
Agent: C1CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C1=NOC(c2ccccc2)(c2ccccc2)C1
Temperature: 18 °C
Yield: 95.3 %

Procedure:
The cyclopropane derivative, 2,2-diphenylcyclopropanyl carboxylate ethyl ester (1.0 g, 3.8 mmol) was dissolved in 4.0 mL AcOH at room temperature (18° C.). Into the solution was carefully added 2.0 mL concentrated H2SO4, followed by adding NaNO2 (0.29 g, 4.1 mmol, 1.1 eq) in several portions so that the reaction temperature did not excess 40° C. After addition, the reactants were stirred at room temperature (about 18° C.) for half an hour before the reactants were poured into iced water and extracted with diethyl ether (2×20 mL), the ethereal solutions were combined and washed with sat. NaHCO3 (2×20 mL), then water (20 mL) and brine (20 mL). The washed ethereal solution was then dried over Na2SO4. After removing the desiccant, the ethereal solution was concentrated to furnish a thick oily product. The 1H NMR of the crude product showed that the reaction was clean and the yield was virtually 100%. The thick oily crude product was stirred with 10 mL petrol to give a pale yellow solid 1.07 g, 97% yield.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]([C:9]1[CH:10]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:11]([C:17](O)=[O:18])=[C:12]([CH3:16])[NH:13][C:14]=1[CH3:15])=[O:8]>ClCCl>[Cl:3][C:17]([C:11]1[CH:10]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:9]([C:7]([O:6][CH3:5])=[O:8])=[C:14]([CH3:15])[NH:13][C:12]=1[CH3:16])=[O:18]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)Cl)C1c1cccc([N+](=O)[O-])c1

Procedure:
Thionyl chloride (0.4 g, 3.4 mmol) was slowly added to a solution of 5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (1.0 g, 3 mmol) in dichloromethane dropwisely at −25° C. After the completion of the dropwise addition, the reaction was continued under cooling in an ice bath until the solution became clear. After the completion of reaction, the reaction solution was rotary evaporated to dryness to produce a crude product, which was directly used in the next step.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:14])=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])(=[O:3])[CH3:2].S(Cl)([Cl:17])=O>>[C:1]([O:4][C:5]1[C:6]([CH3:14])=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([Cl:17])=[O:9])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1cccc(C(=O)O)c1C
Product: CC(=O)Oc1cccc(C(=O)Cl)c1C

Procedure:
The 3-acetoxy-2-methylbenzoic acid (3) is then reacted, for example with thionyl chloride, to give 3-acetoxy-2-methylbenzoyl chloride (4) ##STR4##
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[C:11]1(=[O:16])[NH:15][CH2:14][CH2:13][CH2:12]1>>[C:5]1([O:4][C:2]([N:15]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:16])=[O:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: O=C1CCCN1
Product: O=C1CCCN1C(=O)Oc1ccccc1

Procedure:
The title compound was prepared by customary methods from phenyl chloroformate and γ-butyrolactam (2-pyrrolidone).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10]C)[CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].O>ClC(Cl)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([OH:10])[CH:3]=1
Reactant: COc1cc(F)ccc1C#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: O
Product: N#Cc1ccc(F)cc1O
Yield: 86 %

Procedure:
To a solution of 1 g of 4-fluoro-2-methoxy-benzonitrile in 15 mL of dichloroethane was added 1.1 g of aluminum trichloride. The resulting mixture was refluxed for 1 day then poured slowly into water and extracted with ethyl acetate. The organic extracts were washed twice with 10% aqueous solution of sodium hydroxide. The combined basic layers were washed twice with ethyl acetate, acidified with concentrated aqueous solution of hydrochloric acid and extracted three times with ethyl acetate. The combined organic extracts were washed with water, with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 0.78 g of 4-fluoro-2-hydroxy-benzonitrile as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([OH:15])=[C:8]([CH2:12][CH2:13][CH3:14])[CH:9]=[C:10]([F:11])[C:5]=2[O:4][C:3]=1C(O)=O>[Cu]>[CH3:1][C:2]1[C:6]2[C:7]([OH:15])=[C:8]([CH2:12][CH2:13][CH3:14])[CH:9]=[C:10]([F:11])[C:5]=2[O:4][CH:3]=1
Reactant: CCCc1cc(F)c2oc(C(=O)O)c(C)c2c1O
Agent: [Cu]
Product: CCCc1cc(F)c2occ(C)c2c1O
Yield: 74.4 %

Procedure:
A mixture of 3-methyl-4-hydroxy-5-propyl-7-fluorobenzofurancarboxylic acid (0.10 gm; 0.4mmoles) and copper(20 mg) in guinoline (50 mL) was refluxed for a period of 2.5 hours. The two phases were separated and the organic phase was dried (Na2SO4), and concentrated in vacuo. The residue was purified by preparative TLC and eluted with 5% ethylacetate in hexane to yield 3-methyl-4-hydroxy-5-propyl-7-fluorobenzofuran (62 mg ; 75%), identical to the product obtained from the cyclisation reaction described above in step f.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:6]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)#[CH:5]
Reactant: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.9 %

Procedure:
To a solution of methyl 4-((trimethylsilyl)ethynyl)benzoate (1.35 g, 5.35 mmol) in THF (10 mL) was added TBAF (1 M solution in THF, 10.7 mL, 10.70 mmol). The resulting brown reaction mixture was stirred at rt for 3 h and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 5% EtOAc/hexane) to afford the title compound as a white solid (0.65 g, 76%). 1H NMR (CDCl3) δ 8.00 (d, J=8.6 Hz, 2H), 7.56 (d, J=8.6 Hz, 2H), 3.93 (s, 3H), 3.23 (s, 1H).
Reaction SMILES: C([N:8]1[CH2:14][CH:13]2[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)C1C=CC=CC=1>CO>[CH:10]12[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:13]([CH2:12][CH2:11]1)[CH2:14][NH:8][CH2:9]2
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(Cc1ccccc1)C2
Solvent: CO
Product: CC(C)(C)OC(=O)N1C2CCC1CNC2
Temperature: 25 °C
Reaction time: 10 h
Yield: 94 %

Procedure:
A mixture of tert-butyl 3-benzyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, Pd(OH)2-C (1.1 g) in MeOH (22 mL) was stirred under hydrogen atmosphere (4 atm) for 10 h at room temperature. The mixture was filtered through celite and the filtrate was concentrated in vacuo to give a product (1.45 g, 94%) as a white solid. This product was used for next step without purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11]1[O:12][CH:13]=[C:14]([C:16](OC)=[O:17])[N:15]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[BH4-].C(OCC)(=O)C.Cl>C1COCC1.O>[OH:17][CH2:16][C:14]1[N:15]=[C:11]([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:10])[O:12][CH:13]=1
Reactant: COC(=O)c1coc([C@@H](C)NC(=O)OC(C)(C)C)n1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)OC(C)(C)C)c1nc(CO)co1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a solution of (R)-methyl 2-(1-(tert-butoxycarbonylamino)ethyl)oxazole-4-carboxylate (3.07 g, 11.37 mmol) in THF (25 mL) at 0° C., was added LiBH4 (17.0 mL, 2.0M in THF, 34.0 mmol). The reaction was allowed to warm to room temperature and stirred for 3 h. Ethyl acetate (11 mL) was added drop-wise and stirred for 30 min. The reaction was cooled to 0° C. and 17 mL of 1N HCl was added drop-wise and diluted with 30 mL of water. The mixture was then extracted with ethyl acetate, dried on Na2SO4, concentrated, and chromatographed on silica gel (3% MeOH/97% chloroform) to yield 84% of (R)-tert-butyl 1-(4-(hydroxymethyl)oxazol-2-yl)ethylcarbamate.
Reaction SMILES: [Br:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CS(C)=O.I[C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1>CCOC(C)=O.[Cu]I>[Br:1][C:2]1[N:6]=[CH:5][N:4]([C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:22][CH:23]=2)[N:3]=1
Reactant: Brc1nc[nH]n1
Reactant: FC(F)(F)Oc1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: FC(F)(F)Oc1ccc(-n2cnc(Br)n2)cc1
Temperature: 100 °C
Yield: 72.6 %

Procedure:
To a 250 mL reaction flask was added 3-bromo-1H-1,2,4-triazole (5 g, 33.8 mmol), CuI (0.644 g, 3.38 mmol) and Cs2CO3 (11.01 g, 33.8 mmol). The flask was evacuated/backfilled with nitrogen gas, and then DMSO (33.8 ml) and 1-iodo-4-(trifluoromethoxy)benzene (4.87 g, 16.90 mmol) were added. The reaction mixture was heated to 100° C. for 20 hours (h). The reaction wascooled to room temperature (RT), diluted with EtOAc and filtered through a plug of Celite®. The Celite® was further washed with EtOAc. Water was added to the combined organics, and the layers were separated. The aqueous phase was neutralized to pH 7, and further extracted with EtOAc. The combined organics were concentrated in vacuo. Purification via flash column chromatography using EtOAc/hexanes as eluent provided the title compound as an off-white solid (3.78 g, 73%): mp 69-70° C.; 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.70 (d, J=8.9 Hz, 2H), 7.38 (d, J=8.5 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ-58.04; EIMS m/z 307 ([M]+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[OH-].[Na+]>C(O)C>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(-n2ccnc2)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(-n2ccnc2)ccc1N

Procedure:
Stannous chloride dihydrate (55.0 g) was added portionwise to a stirred suspension of 1-(3-methyl-4-nitrophenyl)imidazole (10.0 g) in absolute ethanol (100 cm3). After heating under reflux for 4 hours, the cooled mixture was basified to pH8 with aqueous 2.5M sodium hydroxide solution and filtered. The filtrate was evaporated in vacuo, partitioned between chloroform (100 cm3) and water (50 cm3), and the aqueous phase was further extracted with chloroform (3×50 cm3). The combined and dried (MgSO4) extracts were concentrated in vacuo to give a solid which was recrystallised from ethyl acetate to afford 1-(4-amino-3-methylphenyl)imidazole, m.p. 131°-134°, (4.7 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])=[O:4].B.CO.Cl>O1CCCC1>[OH:10][CH2:9][C:8]1[CH:12]=[CH:13][C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:6]([N+:14]([O-:16])=[O:15])[CH:7]=1
Reactant: COC(=O)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(CO)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.7 %

Procedure:
A mixture of 4-methoxycarbonyl-3-nitrobenzoic acid (2.25 g), 1M borane in tetrahydrofuran solution (50 ml) and dry tetrahydrofuran (45 ml) was stirred at room temperature for 48 hours. To this mixture, methanol (2 ml) and 1N hydrochloric acid (10 ml) were added and then the solvents were evaporated off. The crude residue was taken up with ethyl acetate, washed in turn with water and sat. sodium bicarbonate solution, dried over magnesium sulfate and evaporated to give an oil which was chromatographed on silica gel. Elution with toluene-chloroform (1:1) gave methyl 4-hydroxymethyl-2-nitrobenzoate (1.85 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Br)[CH:5]=1.[C-:13]#[N:14].[Na+].O>CN(C=O)C>[C:13]([CH2:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([O:2][CH3:1])=[O:12])#[N:14]
Reactant: [C-]#N
Reactant: COC(=O)c1cccc(CBr)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(CC#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of 3-(bromomethyl)benzoic acid methyl ester (25 g, 109 mmol) in DMF (250 mL) was added NaCN (5.4 g, 109 mmol). The reaction mixture was stirred overnight at rt. The mixture was poured into water (1.5 L), followed by the extraction with TBME (2×500 mL). The combined organic layers were washed with water, brine, dried (Na2SO4), filtered and evaporated under reduced pressure to yield methyl 3-(cyanomethyl)benzoate 1 (17 g, 89%). 1H-NMR (400 MHz, CDCl3) 3.82 (s, 2H), 3.94 (s, 3H), 7.48 (m, 1H), 7.57 (m, 1H), 8.03 (m, 2H).
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10].C(OCC)(=O)C.O>CS(C)=O>[C:1]([CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])#[N:2]
Reactant: [C-]#N
Reactant: COC(=O)c1cccc(CBr)c1
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1cccc(CC#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
0.924 g of sodium cyanide was dissolved in 15 mL of dimethylsulfoxide, to which a solution of 4.00 g of methyl 3-(bromomethyl)benzoate in 5 mL of dimethylsulfoxide was added in an ice bath, and this solution was stirred for 2 hours at room temperature. The reaction mixture was added to a mixture of ethyl acetate and water, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to yield 3.00 g of methyl 3-(cyanomethyl)benzoate as orange oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[C-:13]#[N:14].[K+]>CO>[C:13]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:14]
Reactant: [C-]#N
Reactant: COC(=O)c1cccc(CBr)c1
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cccc(CC#N)c1
Temperature: 22 °C

Procedure:
To a solution of 5.71 g (24.9 mmol) of methyl 3-bromomethylbenzoate in 36 mL of methanol was added 2.11 g (32.4 mmol) of potassium cyanide. The mixture was refluxed for about 16 h, cooled to 22° C. and filtered. The filtrate was evaporated and the residue was purified by flash chromatography on silica gel, eluting first with hexane and then gradually increasing to 15% ethyl acetate/hexane to give methyl 3-(cyanomethyl)benzoate.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12])=[O:4].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(OCC)(=O)C>ClCCl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1)=[O:12])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
To a solution of (2S,4R)-1-p-nitrobenzyloxycarbonyl-4-hydroxypyrrolidine-2-carboxylic acid methyl ester (59.44 g: 0.183 mole) in dichloromethane (150 ml) stirring at -20° C., triethylamine (30.5 ml: 1.2 eq.) and methanesulfonyl chloride (17 ml: 1 eq.) are added. The mixture is stirred at the same temperature for 35 minutes. To the mixture is added ice water and ethyl acetate. The organic layer is taken, washed with water, dried over magnesium sulfate, and concentrated in vacuo to give (2S,4R)-1-p-nitrobenzyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-carboxylic acid methyl ester (74.05 g). Yield: Quantitative. NMR δ(CDCl3) ppm: 2.20 to 2.42(m, 1H), 2.55 to 2.85(m, 1H), 3.07(s, 3H), 3.67(s, 1.5H), 3.78(s, 1.5H), 3.80 to 4.05(m, 2H), 4.53(t, J=7 Hz, 1H), 5.06 to 5.40(m, 3H), 7.47(d, J=9 Hz, 1H), 7.51(d, J=9 Hz, 1H), 8.23(d, J=9 Hz, 2H). IR ν (CHCl3) cm-1 : 1748, 1712, 1608.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].[H-].[Na+].Cl[CH2:16][CH2:17][O:18]C1CCCCO1.[I-].[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O.O>[CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:16][CH2:17][OH:18])[C:3]1=[O:11]
Reactant: ClCCOC1CCCCO1
Reactant: CC1(C)C(=O)Nc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)C(=O)N(CCO)c2ccccc21
Temperature: 75 °C

Procedure:
3,3-Dimethyl-1,3-dihydro-2H-indol-2-one (6.3 g, 40 mmol) was dissolved in dry dimethylformamide under nitrogen at room temperature. Sodium hydride (60% dispersion in mineral oil, 1.8 g, 45 mmol) was added and the mixture was stirred until gas evolution ceased. 2-(2-Chloroethoxy)tetrahydro-2H-pyran (7.5 g, 42 mmol) and sodium iodide (0.6 g, 4 mmol) was added and the mixture was warmed to 75° C. for 15 hours. Water was added and the mixture was concentrated under reduced pressure. The residue was taken up in ethyl acetate, washed (×3) with water, dried (MgSO4), filtered and concentrated under reduced pressure. The resulting oil was taken up in methanol, para toluenesulphonic acid (0.75 g, 4 mmol) was added and the mixture was stirred at room temperature for 12 hours. The mixture was concentrated under reduced pressure, taken up in ethyl acetate, washed (×3) with aqueous sodium hydrogen carbonate solution dried (MgSO4), filtered and concentrated under reduced pressure. The resulting oil was purified by chromatography on silica gel, eluent hexane/ethyl acetate, to give 3,3-dimethyl-1-(2-hydroxy-1-ethyl)-1,3-dihydro-2H-indol-2-one which was characterised by 1H nmr and MS.