Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](Cl)[CH:3]=1.[O:9]1[C:14]2[CH:15]=[CH:16][C:17]([NH2:19])=[CH:18][C:13]=2[O:12][CH2:11][CH2:10]1>[Cu]I>[O:9]1[C:14]2[CH:15]=[CH:16][C:17]([NH:19][C:4]3[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][N:5]=3)=[CH:18][C:13]=2[O:12][CH2:11][CH2:10]1
Reactant: Nc1ccnc(Cl)c1
Reactant: Nc1ccc2c(c1)OCCO2
Agent: [Cu]I
Product: Nc1ccnc(Nc2ccc3c(c2)OCCO3)c1
Temperature: 200 °C

Procedure:
In a 5-mL vial was added 4-amino-2-chloropyridine (Aldrich Chemical Company) (1.1 g, 8.7 mmol), 1,4-benzodioxane-6-amine (Aldrich Chemical Company) (5.3 g, 35 mmol) and copper (I) iodide (Aldrich Chemical Company) (0.17 g, 0.87 mmol). The content was sonicated at room temperature for 5 min and then heated in the Smith Microwave Synthesizer at 200° C. for 10 min. The residue was purified by flash chromatography (95:5 dichloromethane:2N NH3 in MeOH) to give the title compound as a dark solid. MS (ESI, pos. ion) m/z: 244 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[CH:8]/[C:9]1[C:17]2[C:12](=[CH:13][C:14]([CH:18]=O)=[CH:15][CH:16]=2)[N:11]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[N:10]=1.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][C:27]1=[O:35].N1CCCCC1>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[CH:8]/[C:9]1[C:17]2[C:12](=[CH:13][C:14](/[CH:18]=[C:28]3/[C:27](=[O:35])[NH:26][C:34]4[C:29]/3=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:15][CH:16]=2)[N:11]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[N:10]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: O=Cc1ccc2c(/C=C/c3ccccn3)nn(C3CCCCO3)c2c1
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2ccccc2/C1=C\c1ccc2c(/C=C/c3ccccn3)nn(C3CCCCO3)c2c1
Temperature: 60 °C
Yield: 17.9 %

Procedure:
To a solution of (E)-3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-carbaldehyde (25 mg, 0.0749 mmol), oxindole (10 mg, 0.0749 mmol), and MeOH (1 mL) was added piperidine (1 uL) and the reaction heated to 60° C. for 3 hours. The reaction was cooled to room temperature and the product yellow solid was precipitated with MeOH (1 mL) and then filtered to give 11 mg. The filtrate was purified by column chromatography (silica gel, 99:1 to 98:2 CH2Cl2/MeOH) to give an additional 6 mg of product (17 mg total, 50%). 1H NMR (400 MHz, CDCl3) δ 8.69-8.62 (m, 1H), 8.14 (d, J=8.3 Hz, 1H), 8.00-7.91 (m, 3H), 7.77 (d, J=8.1 Hz, 1H), 7.72 (t, J=8.3 Hz, 1H), 7.63 (d, J=16.9 Hz, 1H), 7.53 (m, 2H), 7.44 (b.s., 1H), 7.25-7.17 (m, 2H), 6.92-6.86 (m, 2H), 5.77 (d, J=10.6 Hz, 1H), 4.09 (d, J=9.6 Hz, 1H), 3.84-3.74 (m, 1H), 2.67-2.53 (m, 1H), 2.24-2.13 (m, 2H), 1.85-1.66 (m, 3H); MS ESI 449.2 [M+H]+, calcd for [C28H24N4O2+H]+ 449.20.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[O:5][N:4]=1)[CH3:2].ClCl.[Cl:14]C(Cl)(Cl)Cl.O>C(O)(=O)C>[CH2:1]([C:3]1[C:7]([Cl:14])=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[O:5][N:4]=1)[CH3:2]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCc1cc(NC(C)=O)on1
Agent: ClCl
Solvent: CC(=O)O
Solvent: O
Product: CCc1noc(NC(C)=O)c1Cl
Temperature: 25 °C
Yield: 203.3 %

Procedure:
3-Ethyl-5-acetylaminoisoxazole (1) (1.98 g) was dissolved in acetic acid (15 ml), chlorine-tetrachloromethane (18 ml, containing 1.09 g of chlorine) was added thereto under stirring at room temperature and after addition of water the mixture was extracted with chloroform after 5 minutes. The extract was washed with water, dried over sodium sulfate and evaporated. The resulting crystalline residue was recrystallized from ether/hexane to give 3-ethyl-4-chloro-5-acetylaminoisoxazole (2) (1.86 g), mp. 113°-114° C.
Reaction SMILES: [NH2:1][C:2](=[O:28])[C@@H:3]([NH:20]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:20][C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)[C:2]([NH2:1])=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(S(=O)(=O)c2ccccc2)cc1)C(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)[C@@H](N)Cc1ccc(S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
To a stirred solution of (S)-tert-butyl 1-amino-1-oxo-3-(4-(phenylsulfonyl)phenyl)propan-2-ylcarbamate (440 mg) in DCM (10 mL) at 0° C. was added TFA (2.51 mL). The mixture was allowed to warm to RT and stirred for 1 h. The mixture was concentrated in vacuo and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate, dried over sodium sulfate, filtered and concentrated in vacuo to leave the subtitle compound (175 mg) as a white solid.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[Cl:13][C:14]1[C:15]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:16]([NH:20][NH2:21])[N:17]=[N:18][CH:19]=1.O>C1COCC1>[Cl:13][C:14]1[CH:19]=[N:18][N:17]2[C:1](=[O:2])[NH:21][N:20]=[C:16]2[C:15]=1[C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1
Reactant: NNc1nncc(Cl)c1-c1ccc(Cl)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(Cl)cnn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
To a solution of 1,1′-carbonyldiimidazole (1.78 g, 11 mmol) in THF (10 mL) at RT was added a suspension of 1-(5-chloro-4-(4-chlorophenyl)pyridazin-3-yl)hydrazine (560 mg, 2.19 mmol) in THF (10 mL). After addition, the reaction became a clear solution and was stirred at RT for 1 h. The reaction mixture was then poured into water and extracted with EtOAc (3×50 mL). The combined organic layers were washed with saturated NaCl. The organic layer was dried (Na2SO4), filtered and concentrated. To the obtained residue was added EtOAc (20 mL), and the resulting yellow precipitate was collected by filtration and washed with hexane to give the title compound, 7-chloro-8-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one as a yellow solid (300 mg, 61%). LC/MS (method A): RT=2.86 min, (M+H)+=281.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([N+:22]([O-])=O)[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[C:8]#[N:9])[CH:2]=[CH2:3].O.O.[Sn](Cl)Cl>C(O)C.Cl>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([NH2:22])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[C:8]#[N:9])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(C#N)cc([N+](=O)[O-])c1Oc1ccccc1OC
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: C=CCOc1cc(C#N)cc(N)c1Oc1ccccc1OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3.59 g of 3-allyloxy-4-(2-methoxy-phenoxy)-5-nitro-benzonitrile were dissolved in ethanol (120 ml), a solution of tin dichloride dihydrate (8.55 g) in 37% HCl (25 ml) was added dropwise thereto at room temperature and the mixture was subsequently stirred at room temperature for 12 hours. The mixture was poured on to ice-water, adjusted to pH 7 and the product was extracted with ethyl acetate. After usual processing of the organic phase there was obtained 3-allyloxy-5-amino-4-(2-methoxy-phenoxy)-benzonitrile as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([F:20])=[CH:4][N:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=2)[NH2:31])[CH2:24][CH2:23]1.C(O)C.Cl>O>[F:20][C:5]1[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:7][C:2]([NH:31][C:30]2[CH:32]=[CH:33][CH:34]=[C:28]([N:25]3[CH2:24][CH2:23][N:22]([CH3:21])[CH2:27][CH2:26]3)[CH:29]=2)=[N:3][CH:4]=1
Reactant: CCOC(=O)c1ccccc1Nc1nc(Cl)ncc1F
Reactant: CN1CCN(c2cccc(N)c2)CC1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccccc1Nc1nc(Nc2cccc(N3CCN(C)CC3)c2)ncc1F
Temperature: 95 °C

Procedure:
Ethyl 2-[(2-chloro-5-fluoro-4-pyrimidinyl)amino]benzoate (1.0 g, 3.4 mmol), 3-(4-methyl-1-piperazinyl)aniline (0.65 g, 3.4 mmol), ethanol (45 mL) and 6N HCl (1.5 mL, 8.8 mmol) were heated with stirring in a reaction vessel, which was sealed and heated at 95° C. for 24 h. The reaction mixture was cooled to room temperature, poured into water, extracted with ethyl acetate and neutralized to pH 7 by the slow addition of 6N NaOH. The resulting precipitate was collected on a sintered glass funnel and washed with water and ethyl ether to afford the title compound as a tan solid; yield 1.0 g (65%). MS: M(C24H27FN6O2)=450.52 (M+H)+=451.2.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([O:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][N:28]=1)[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:30]5[CH:29]=[N:28][C:27]([O:26][CH2:24][CH3:25])=[N:32][CH:31]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CCOc1ncc(B(O)O)cn1
Product: CCOc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cn1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.106 mmol) and 2-ethoxypyrimidine-5-boronic acid (Synthonix, Wake Forest, USA, 22 mg, 0.130 mmol) to give the title compound as a white solid. (HPLC: tR 2.51 min (Method A); M+H=416 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.98 (s, 1H), 8.73-8.67 (m, 2H), 8.16-8.09 (m, 2H), 7.98-7.91 (m, 1H), 7.51-7.46 (m, 1H), 4.39 (q, 2H), 3.89 (s, 3H), 3.57 (s, 3H), 1.96 (s, 3H), 1.35 (t, 3H))
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:8][NH:7][C:6]2[N:9]=[CH:10][CH:11]=[CH:12][C:5]=2[CH2:4][NH:3]1.[Br:14]Br>CN(C=O)C>[Br:14][C:11]1[CH:10]=[N:9][C:6]2[NH:7][CH2:8][C:2]([CH3:13])([CH3:1])[N:3]=[CH:4][C:5]=2[CH:12]=1
Reactant: CC1(C)CNc2ncccc2CN1
Reactant: BrBr
Solvent: CN(C)C=O
Product: CC1(C)CNc2ncc(Br)cc2C=N1
Temperature: 0 °C
Yield: 56.8 %

Procedure:
A solution of 3,3-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepine (0.43 g, 1.8 mmol) in DMF (20 mL) was cooled in an ice bath and treated drop-wise with Br2 (0.19 mL, 3.7 mmol). After stirring in the ice bath for 2.5 h, the reaction was quenched with H2O (25 mL) and NaHCO3 (50 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with H2O (2×50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated to an orange oil. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 98:2 to 96:4) gave the title compound (0.26 g, 54%) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 8.15 (d, J=2.3 Hz, 1H), 8.03 (s, 1H), 7.73 (d, J=2.3 Hz, 1H), 5.93 (br s, 1H), 3.09 (d, J=4.9 Hz, 2H), 1.30 (s, 6H); MS (ESI) m/e 254 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][CH2:5][CH2:6][NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][C:34]([F:37])([F:36])[F:35])[N:17]=2)[CH2:10][CH2:9]1.CO.O.[Li+].[OH-]>CO>[N+:22]([C:21]1[C:16]([NH:15][CH2:14][C@H:11]2[CH2:12][CH2:13][C@H:8]([NH:7][CH2:6][CH2:5][CH2:4][C:3]([OH:38])=[O:2])[CH2:9][CH2:10]2)=[N:17][C:18]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][C:34]([F:37])([F:36])[F:35])=[N:19][CH:20]=1)([O-:24])=[O:23]
Reactant: COC(=O)CCCNC1CCC(CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCN[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4-{[5-nitro-2-(2-trifluoromethoxy-benzylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexylamino)-butyric acid methyl ester (39 mg, 0.072 mmol) in 6:1 MeOH/water (0.7 mL) was added LiOH (9 mg, 0.375 mmol) and the mixture stirred at room temperature overnight. The resulting suspension was diluted with MeOH (1 mL) and stirred at room temperature for a further 2 h. The reaction mixture was concentrated in vacuo and the remaining aqueous residue treated with 2 N HCl until the mixture reached pH 5-6. The resulting solid was filtered and washed with water. The material was subjected to semi-preparative to separate the title compound [7 mg, 13%, m/z 527 (M+1)+] and 1-(trans-4-{[(5-nitro-2-{[2-(trifluoromethoxy)benzyl]amino}pyrimidin-4-yl)amino]methyl}cyclohexyl)pyrrolidin-2-one [15 mg, 41%, m/z 509 (M+1)+].
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])/[CH:2]=[CH:3]/[CH2:4][CH3:5].[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[N:9]1([CH:3]([CH2:4][CH3:5])[CH2:2][C:1]([O:7][CH3:8])=[O:6])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C1CCNCC1
Reactant: CC/C=C/C(=O)OC
Product: CCC(CC(=O)OC)N1CCCCC1
Temperature: 65 °C
Reaction time: 24 h

Procedure:
A mixture of 500 g of methyl 2-trans-pentenoate and 372 g of piperidine was heated at 65° C. for 17 hours and then at 100° C. for 24 hours. After distillation over a Vigreux column, 562 g (64% of theory) of methyl 3 -piperidinovalerate of boiling point 64° C./2 mbar, nD20 =1.4592, were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[C:12]([CH:14]=[O:15])[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-:24])=[O:23])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.O.[Mn]([O-])(=O)(=O)=[O:27].[K+]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[C:12]([C:14]([OH:27])=[O:15])[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-:24])=[O:23])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-n2cc(C=O)c(-c3ccccc3[N+](=O)[O-])n2)c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: COc1cccc(-n2cc(C(=O)O)c(-c3ccccc3[N+](=O)[O-])n2)c1
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a mixture of 1-(3-methoxyphenyl)-3-(2-nitrophenyl)-1H-pyrazole-4-carbaldehyde (1.00 g), water (2 ml) and pyridine (2 ml) was added portionwise potassium permanganate (538 mg). After stirring for 1 hour, the precipitated manganese oxide was filtered off through Celite, the Celite layer was washed with 1N aqueous sodium hydroxide solution. The filtrate and washings were combined, washed with ethyl acetate. The aqueous layer was acidified with 6N hydrochloric acid, extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was solidified by adding hexane. The solid was collected by filtration and washed with hexane to obtain the target compound (676 mg).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4]1[CH:5]=[C:6]([Cl:11])[C:7](I)=[N:8][CH:9]=1.C([Mg]Cl)(C)C.[CH:19](=[O:21])[CH3:20]>C1COCC1>[CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4]1[CH:5]=[C:6]([Cl:11])[C:7]([CH:19]([OH:21])[CH3:20])=[N:8][CH:9]=1
Reactant: COC(OC)c1cnc(I)c(Cl)c1
Reactant: CC=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COC(OC)c1cnc(C(C)O)c(Cl)c1
Reaction time: 0.5 h
Yield: 38 %

Procedure:
A solution of 5-[bis(methyloxy)methyl]-3-chloro-2-iodopyridine (239 mg, 0.762 mmol) in THF (1.5 ml) was slowly added to a solution of i-PrMgCl (400 μl, 0.800 mmol) in THF (1.5 ml) at −20° C. under N2 and the mixture was stirred at that temperature. After 30 min a small amount of starting material was still observed by LCMS. After 2 h, LCMS still showed some starting material. More i-PrMgCl (60 μl) was added and after 40 min disappearance of the starting material was observed by LCMS. Acetaldehyde (47 μl, 0.841 mmol) was added and the mixture stirred at −20° C. for 10 min. Partial conversion was observed by LCMS and no evolution was observed after 1 h. Excess acetaldehyde was added but no changes were observed after 30 min by LCMS. Then, it was quenched with saturated NH4Cl, extracted with EtOAc, dried (MgSO4), filtered, and concentrated to afford 177.4 mg of crude material as a brown oil. The mixture was purified by flash chromatography using Flashmaster II, a 10 g Merck silica gel cartridge, and mixtures of hexane and EtOAc as eluent. 1-{5-[bis(methyloxy)methyl]-3-chloro-2-pyridinyl}ethanol (67 mg, 38%) was isolated as a yellow oil.
Reaction SMILES: C(O)(C)C.[CH3:5][C:6]1([CH3:14])[CH:12]2[CH2:13][CH:7]1[CH2:8][CH2:9][C:10]2=[CH2:11].[S:15](=[O:18])([OH:17])[O-:16].[NH4+:19]>O>[C:10]1([CH2:11][S:15]([O-:18])(=[O:17])=[O:16])[CH2:12][CH2:13][C@H:7]([CH:6]([CH3:14])[CH3:5])[CH2:8][CH:9]=1.[NH4+:19]
Reactant: C=C1CCC2CC1C2(C)C
Reactant: O=S([O-])O
Agent: [NH4+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)[C@@H]1CC=C(CS(=O)(=O)[O-])CC1
Reaction time: 22 h

Procedure:
Into a 1 liter flask equipped with magnetic stirrer were placed 450 ml isopropanol, 240 ml water and 54.4 grams (0.4 mole) β-pinene. Ammonium bisulfite, 105 grams (45%) was then added thereto. The mixture was stirred at 40°-45° C. for 22 hours. Thereafter, the solution was evaporated to dryness. Residue was extracted with methanol. The methanolic solution was filtered, and the resultant filtrate evaporated to dryness. Obtained were 84 grams product (85.8% purity; 77% yield).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([OH:11])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.O>[CH2:14]([O:11][C:5]1[C:6]([N+:8]([O-:10])=[O:9])=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1nc(Br)ccc1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1nc(Br)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 67.2 %

Procedure:
To a solution of 6-bromo-2-nitropyridin-3-ol (1.0 g, 4.6 mmol), in anhydrous DMF (15 mL) at 0° C. was added 60% sodium hydride in mineral oil (200 mg, 5.0 mmol). The reaction mixture was stirred at 0° C. for 5 min and at room temperature for 15 min. Benzyl bromide (0.6 mL, 5.0 mmol) was added dropwise and the resulting mixture was stirred at 60° C. for 1 hour, cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was separated and washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (Si—PPC, Et2O:pentane, gradient 0:100 to 100:0) to give 3-Benzyloxy-6-bromo-2-nitropyridine as a yellow solid (956 mg, 67%). 1H NMR (400 MHz, CHCl3-d): δ 7.60 (d, J=8.6 Hz, 1 H); 7.41-7.35 (m, 6 H); 5.25 (s, 2 H).