Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[Br:6][C:7]1[C:16]([F:17])=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][C:11]([CH3:18])=[N:12]2>S(=O)(=O)(O)O.ClCCl>[Br:6][C:7]1[C:16]([F:17])=[CH:15][C:14]([N+:1]([O-:4])=[O:2])=[C:13]2[C:8]=1[CH:9]=[CH:10][C:11]([CH3:18])=[N:12]2
Reactant: Cc1ccc2c(Br)c(F)ccc2n1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccc2c(Br)c(F)cc([N+](=O)[O-])c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.8 %

Procedure:
A solution of 11.5 g of potassium nitrate in 30 ml of concentrated sulfuric acid was added to 21.0 g of 5-bromo-6-fluoroquinaldine in 117 ml of concentrated sulfuric acid dropwise at -5° C. After stirring at room temperature for 5 hours, the reaction mixture was poured into 2 l of ice water to precipitate solids which were then collected by filtration. The filtrate was rendered alkaline to form a small amount of solids, which together with the former solids were dissolved in dichloromethane. After the solution was dried over sodium sulfate the solvent was distilled off. Recrystallization of the residue from isopaopanol gave 22.9 g of 5-bromo-6-fluoro-8-nitroquinaldine. m.p. 135°-137° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:20][C:21]4[NH:26]/[C:25](=[N:27]/[NH2:28])/[CH2:24][O:23][C:22]=4[N:29]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CO[C:39](OC)(OC)[CH3:40]>>[CH3:39][C:40]1[N:26]2[C:21]3[CH:20]=[C:19]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:18]([C:15]4[CH:14]=[CH:13][C:12]([C:8]5([NH:7][C:6](=[O:36])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:11][CH2:10][CH2:9]5)=[CH:17][CH:16]=4)=[N:29][C:22]=3[O:23][CH2:24][C:25]2=[N:27][N:28]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N/C(=N/N)CO4)cc2)CCC1
Reactant: COC(C)(OC)OC
Product: Cc1nnc2n1-c1cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc1OC2
Yield: 47 %

Procedure:
A solution of (E)-tert-butyl(1-(4-(2-hydrazono-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (50 mg, 0.103 mmol) in 1,1,1-trimethoxyethane (1 ml) was heated to 150° C. for 15 minutes under microwave irradiation. The resulting reaction mixture was concentrated to dryness under reduced pressure and purified by Biotage silica gel chromatography (gradient 0% to 100% ethyl acetate in n-hexanes) to give the title compound (24 mg, 47%). LCMS (Method A): RT=6.71 min, M+1=510. 1H NMR (500 MHz, CDCl3): 7.84 (1H, s), 7.37-7.33 (5H, m), 7.30-7.27 (2H, m), 7.24-7.19 (2H, m), 5.59 (2H, s), 2.87 (3H, s), 2.54-2.40 (4H, m), 2.13-2.02 (1H, m), 1.87-1.78 (1H, m), 1.45-1.27 (9H, br s).
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=2[Cl:14])[N:5]=[N:4][N:3]=1.[C:15]1([CH:21]2[CH2:25][CH2:24][CH2:23][NH:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Cl:14][C:8]1[C:9]([Cl:13])=[CH:10][CH:11]=[CH:12][C:7]=1[N:6]1[C:2]([N:22]2[CH2:23][CH2:24][CH2:25][CH:21]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:3][N:4]=[N:5]1
Reactant: Clc1cccc(-n2nnnc2Cl)c1Cl
Reactant: c1ccc(C2CCCN2)cc1
Product: Clc1cccc(-n2nnnc2N2CCCC2c2ccccc2)c1Cl
Yield: 20.1 %

Procedure:
The product of Example 75B (0.1 g) was reacted with 2-phenylpyrrolidine (0.1 g) according to the method of Example 75C to provide 0.029 g of the title compound as a white solid. MS (ESI/NH3) m/z 359 (M+H)+. 1H NMR (DMSO-d6) δ 1.78-1.9 (m, 4H), 3.3-3.6 (m, 2H), 4.8-5.0 (m, 1H) 6.8-6.9 (m, 1H), 7.0-7.2 (m, 5H), 7.59-7.65 (t, 1H), 7.79-7.85 (d, 1H), 7.95-7.99 (d, 1H).
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([CH2:6][NH2:7])[CH2:4][NH2:5].C[O-].[Na+].Cl.[NH2:12][C:13](N)=N>CO>[ClH:1].[CH3:2][CH:3]1[CH2:6][NH:7][C:13]([NH2:12])=[N:5][CH2:4]1
Reactant: N=C(N)N
Reactant: CC(CN)CN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC1CN=C(N)NC1

Procedure:
To a solution containing 6.7 g (41.6 mmol) of 2-methyl-1,3-propandiamine hydrochloride (Tetrahedron (1994) 50(29), 8617-8632) in 50 ml of methanol was added 83 ml of a solution of sodium methylate in methanol (1 mmol/ml) and the resulting mixture treated with 3.97 g (41.6 mmol) of guanidine hydrochloride.
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[CH3:23][O:24][C:25]1[N:30]=[CH:29][C:28](/[CH:31]=[CH:32]\[C:33]#[N:34])=[CH:27][CH:26]=1>>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:11]2[CH:10]=[C:31]([C:28]3[CH:29]=[N:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)[CH:32]=[C:33]([NH2:34])[N:12]2[N:13]=1
Reactant: COc1ccc(/C=C\C#N)cn1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccccc2F)n1)c1ccccc1
Product: COc1ccc(-c2cc(N)n3nc(-c4ccccc4F)nc3c2)cn1

Procedure:
The title compound, MS m/e (%):336(M+H+,100), was prepared in accordance with the general method of example 1 from 3-benzenesulfonylmethyl-5-(2-fluoro-phenyl)-1H-[1,2,4]triazole and (E)/(Z)-3-(6-methoxy-pyridin-3-yl)-acrylonitrile.
Reaction SMILES: [Na].[CH2:2]([OH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:10][C:11]1[N:19]=[C:18]2[C:14]([N-:15][CH:16]=[N:17]2)=[C:13]([N+](C)(C)C)[N:12]=1.Cl>CS(C)=O>[Cl:10][C:11]1[N:19]=[C:18]2[C:14]([NH:15][CH:16]=[N:17]2)=[C:13]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:12]=1
Reactant: C[N+](C)(C)c1nc(Cl)nc2nc[n-]c12
Reactant: OCc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CS(C)=O
Product: Clc1nc(OCc2ccccc2)c2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 0 %

Procedure:
Sodium spheres (250 mg, 10.87 mmol) and benzyl alcohol (2 ml, 19.33 mmol) were mixed and vigorously stirred under N2 at 60°-100° (oil-bath) until all the sodium had dissolved (30 minutes) The mixture was cooled to room temperature and a suspension of 2-chloro-6-trimethylammoniopurinide (100 g, .73 mmol) in sieve-dried DMSO (10 ml) was added. This was stirred at room temperature under N2 for 13/4 hours and the reaction mixture was then added dropwise to ice-H2O (100 ml). The pH of the solution was adjusted to 7.0 using lM HCl and the white solid which formed was filtered off, washing well on the pad with H2O. This material was dried in vacuo over P2O5 at room temperature to give 0 mg (79.5% yield) of product. An analytical sample was obtained by recrystallizing from ethanol-H2O and drying the product in vacuo. Analysis Calculated for:
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14](=[O:16])[NH:13][C:12]=2[CH:17]=1)[C:4]([OH:6])=[O:5].Cl.[CH3:19]O>>[CH3:19][O:5][C:4](=[O:6])[CH:3]([NH2:2])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14](=[O:16])[NH:13][C:12]=2[CH:17]=1
Reactant: NC(Cc1ccc2oc(=O)[nH]c2c1)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)C(N)Cc1ccc2oc(=O)[nH]c2c1

Procedure:
The product from Example 17 is held for 6 hours at reflux in 1500 ml of methanol saturated with HCl gas. The alcoholic solution is evaporated to yield a product which is recrystallized from water or methanol: ether to yield the Example 21 title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.[ClH:20]>CO>[ClH:20].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(Br)cc1
Agent: Cl
Solvent: CO
Product: Brc1ccc(C2CCCN2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The suspension of tert-butyl 2-(4-bromophenyl)pyrrolidine-1-carboxylate (1.2 g, 3.7 mmol) in anhydrous methanol (10 mL) was added hydrogen chloride in methanol (20 mL, 4.0 M in MeOH) under nitrogen. The reaction was stirred at room temperature for 1.5 hours. The mixture was concentrated to afford the title compound (0.99 g, quantitative yield) which was used without purification in the next step.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Cl:13])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=O)C.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[Cl-].[Zn+2].[Cl-]>[C:14]([C:11]1[CH:10]=[C:9]([Cl:13])[CH:8]=[C:7]2[C:12]=1[NH:4][CH2:5][CH2:6]2)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)N1CCc2cc(Cl)ccc21
Reactant: O=C(Cl)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Product: O=C(c1ccccc1)c1cc(Cl)cc2c1NCC2

Procedure:
7-Benzoly-5-chloroindoline was prepared by treating 1-acetyl-5-chloroindoline with benzoyl chloride at 120°-175°C. using zinc chloride as a catalyst. The acetyl group was removed by acid hydrolysis to give the yellow colored 7-benzoyl-5-chloroindoline. The yellow solid melted at 112°-115°C. A mixture melting point with material prepared in Example 2 showed no depression.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:8]2[CH2:20][CH2:21][C:22](=[O:23])[C:7]=2[C@@H:6]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=2[S:32]([CH3:35])(=[O:34])=[O:33])[NH:5]1.I[CH2:37][C:38]#[N:39].C(#N)C>O1CCCC1>[C:38]([CH2:37][N:5]1[C@H:6]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=2[S:32]([CH3:35])(=[O:33])=[O:34])[C:7]2[C:22](=[O:23])[CH2:21][CH2:20][C:8]=2[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=2)[C:4]1=[O:3])#[N:39]
Reactant: N#CCI
Reactant: CS(=O)(=O)c1cc(C#N)ccc1[C@H]1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CS(=O)(=O)c1cc(C#N)ccc1[C@@H]1C2=C(CCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1CC#N
Reaction time: 0.33 h

Procedure:
Sodium hydride (60% in mineral oil, 12 mg, 0.30 mmol) is added to a solution of (S)-4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]-pyrimidin-4-yl)-3-(methylsulfonyl)benzonitrile (example 10A, 50 mg, 105 μmol) in tetrahydrofuran (3.0 mL). After 20 min, 2-iodoacetonitrile (8 μL, 0.11 mmol) is added. After 2 h, a second portion of 2-iodoacetonitrile (8 μL, 0.11 mmol) is added. After 2 h, a third portion of 2-iodoacetonitrile (8 μL, 0.11 mmol) is added. The mixture is stirred over night, treated with acetonitrile and purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 8 mg; ESI mass spectrum [M+H]+=515; Retention time HPLC: 1.01 min (Z018_504).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][N:4]=1.Br[C:20]1[C:21]([CH3:39])=[C:22]([NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=2)[CH:23]=[CH:24][CH:25]=1>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].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>[NH2:9][C:8]1[CH:7]=[C:6]([C:20]2[C:21]([CH3:39])=[C:22]([NH:26][C:27](=[O:38])[C:28]3[CH:29]=[CH:30][C:31]([C:34]([CH3:35])([CH3:36])[CH3:37])=[CH:32][CH:33]=3)[CH:23]=[CH:24][CH:25]=2)[CH:5]=[N:4][C:3]=1[O:2][CH3:1]
Reactant: Cc1c(Br)cccc1NC(=O)c1ccc(C(C)(C)C)cc1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ncc(-c2cccc(NC(=O)c3ccc(C(C)(C)C)cc3)c2C)cc1N
Temperature: 95 °C
Yield: 64.2 %

Procedure:
A 48-mL seal tube equipped with a magnetic stirring bar was charged with 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (5) (1.0 g, 4.0 mmol), N-(3-bromo-2-methylphenyl)-4-tert-butylbenzamide (1.8 g, 5.0 mmol), and tetrakis(triphenylphosphine)palladium (0.20 g, 0.20 mmol) in DME (10 mL) and 1 N sodium carbonate (10 mL). After the mixture was degassed for 15 min., it was heated at 95° C. for 16 h. Then, the reaction mixture was cooled to room temperature and poured into H2O (10 mL). To this was added dichloromethane (20 mL) and the layers were separated. The aqueous phase was extracted with dichloromethane (3×10 mL), and the combined organic extracts were washed with H2O (5 mL) and brine (5 mL), dried (Na2SO4), and concentrated. The crude mixture was purified by column chromatography, gradient 0-10%, MeOH in dichloromethane, to afford 1.0 g (64%) of N-(3-(5-amino-6-methoxypyridin-3-yl)-2-methylphenyl)-4-tert-butylbenzamide (6) as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[C:11]([F:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][N:18]1CCCC1=O>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:17]#[N:18])=[C:11]([F:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cc(OCc2ccccc2)ccc1Br
Reactant: CN1CCCC1=O
Product: N#Cc1ccc(OCc2ccccc2)cc1F
Temperature: 25 °C

Procedure:
Compound 20 (10.00 g, 35.7 mmol) and cuprous cyanide (13.00 , 71.4 mmol) were suspended in 1-methyl-2-pyrollidinone (250 ml) and heated under reflux for 24 h. The reaction mixture was cooled to room temperature and filtered through ‘hyflo’ to remove the excess cuprous cyanide. Water (200 ml) was added to the solution which was subsequently washed with ether (2×400 ml). The combined ether extracts were then washed with water (2×500 ml) and brine (500 ml) and then dried (MgSO4). The drying agent was filtered off and the solvent removed in vacuo to yield an off-white solid which was purified by column chromatography (dichloromethane) on silica to yield colourless crystals. Yield 5.79 g (71%).
Reaction SMILES: ClC(Cl)(Cl)C([C:5]1[N:9]2[C:10]([CH2:14][N:15]([C:27](OC(C)(C)C)=[O:28])[CH2:16][CH2:17][CH2:18][NH:19][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])=[CH:11][CH:12]=[CH:13][C:8]2=[N:7][CH:6]=1)=O.I[Si](C)(C)C.C(=O)([O-])O.[Na+].C(OCC)(=O)C>C(Cl)(Cl)Cl>[F:25][C:23]([F:24])([F:26])[S:20]([NH:19][CH2:18][CH2:17][CH2:16][N:15]1[CH2:14][C:10]2[N:9]3[C:5](=[CH:6][N:7]=[C:8]3[CH:13]=[CH:12][CH:11]=2)[C:27]1=[O:28])(=[O:21])=[O:22]
Reactant: CC(C)(C)OC(=O)N(CCCNS(=O)(=O)C(F)(F)F)Cc1cccc2ncc(C(=O)C(Cl)(Cl)Cl)n12
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C1c2cnc3cccc(n23)CN1CCCNS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54.8 %

Procedure:
To a solution of 1.16 g (2.00 mmol) of 3-trichloroacetyl-5-[N-tert-butoxycarbonyl-N-[3-(trifluoromethanesulfonamido)propan-1-yl]aminomethyl]imidazo[1,2-a]pyridine in 25 ml of chloroform was added dropwise 0.57 ml (4.00 mmol) of iodotrimethylsilane at room temperature. The reaction mixture was stirred for 15 minutes, which was then poured into ice-water, followed by neutralization with a saturated aqueous solution of sodium hydrogencarbonate. This solution was extractedith 150 ml of ethyl acetate. The organic layer was washed with 100 ml of a 1.0N aqueous solution of sodium thiosulfate, then with 100 ml of a saturated aqueous saline solution. The organic layer was dried over magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by silicagel column chromatography (eluent: chloroform/methanol=20:1) to give 397 mg of the desired compound (54.8%, pale yellow solid).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:13]=[C:14]([CH3:15])[C:3]=12.CO.[CH3:24][NH2:25]>>[CH3:24][NH:25][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:13]=[C:14]([CH3:15])[C:3]=12
Reactant: Cc1nn(-c2ccccn2)c2nc3ccccc3c(Cl)c12
Reactant: CN
Solvent: CO
Product: CNc1c2ccccc2nc2c1c(C)nn2-c1ccccn1
Temperature: 100 °C

Procedure:
A solution of 4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (0.8 g, 2.71 mmol) in 40% methylamine in methanol (21 mL, 0.27 mol) was heated under reflux at 100° C. for 4 hours in a sealed stainless tube. The solution was allowed to cool to room temperature, and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (chloroform:methanol=98:2) to give an oil of N-methyl-N-[3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-yl]amine. To a solution of the oil in ethanol (10 mL), was added a saturated hydrochloric acid/ethanol solution (10 mL), and the solvent was evaporated under reduced pressure. The residue thus obtained was recrystallized from methanol/ethyl acetate to give the title compound (0.63 g, 64% yield).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH:10]=2)O1.Br[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=1.C(Cl)Cl>COCCOC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[O:13]1[C:12]2([CH2:17][CH2:18][C:9]([C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=3)=[CH:10][CH2:11]2)[O:16][CH2:15][CH2:14]1
Reactant: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc(C2=CCC3(CC2)OCCO3)nc1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
A stirred solution of 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dioxaspiro[4.5]dec-7-ene prepared as above (8.40 g, 31.56 mmol), 2-bromo-5-nitropyridine (6.0 g, 29.55 mmol) in DME (200 mL), degassed 2M potassium carbonate (40 mL) was added palladium tetrakis(triphenylphosphine) (Pd(PPh3)4; 1.8 g, 1.58 mmol). The reaction mixture was evacuated with nitrogen (3 cycles) and allowed to stir under vacuum for 5 minutes, then heated to 80° C. overnight. The reaction mixture was allowed to cool to ambient temperature, EtOAc (200 mL) was added followed by water (200 mL), the suspension was filtered and the organic phase was separated and the aqueous layer re-extracted into EtOAc (200 mL). The organic extracts were combined, washed with brine (200 mL), dried (MgSO4) and concentrated to leave crude product. DCM was added and the suspension was filtered and dried to leave the title compound (1.64 g). The filtrate was concentrated after the addition of DCM a further 1.51 g of product was obtained, the filtrate was purified on a 120 g SiliCycle cartridge eluting 20-50-70% EtOAc in isohexane to provide 1.72 g of product. Total yield is 4.85 g (18.51 mmol, 58%);
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[C:11]1[CH:18]3[CH2:19][CH:14]4[CH2:15][CH:16]([CH2:20][CH:12]1[CH2:13]4)[CH2:17]3)[CH2:8]2.[Br:21]N1C(=O)CCC1=O.O.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[Br:21][CH:10]1[CH:5]2[CH2:4][CH:3]3[CH2:9][CH:7]([CH2:8][CH:1]1[C:2]3=[C:11]1[CH:12]3[CH2:20][CH:16]4[CH2:15][CH:14]([CH2:19][CH:18]1[CH2:17]4)[CH2:13]3)[CH2:6]2
Reactant: O=C1CCC(=O)N1Br
Reactant: C1C2CC3CC1CC(C2)C3=C1C2CC3CC(C2)CC1C3
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: BrC1C2CC3CC(C2)C(=C2C4CC5CC(C4)CC2C5)C1C3
Reaction time: 12 h

Procedure:
High selectivity for ketone introduction adjacent to double bonds can also be accomplished by selective bromination as shown in this example. 4-Bromoadamantylideneadamantane is prepared as follows. To a solution of 3 mmol (804 mg) of adamantylideneadamantane (X) in 40 ml of CH2Cl2 is added 6.6 mmol (1.175 g) of N-bromosuccinimide. The reaction mixture is refluxed and stirred for 12 hr. The reaction mixture is diluted with CH2Cl2 and ished twice with water and a saturated Na2S2O3 solution. The organic layer is dried over MgSO4 and evaporated. The yield of 4-bromoadamantylideneadamantane (XI) is over 95%). An analytically pure sample is obtained by crystallization from acetone and sublimation [115° C. (0.002 mm)]. Conversion of this intermediate to 4-ketoadamantilideneadamanatne (XII) is accomplished using the same procedure as in Example 4.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20](I)[CH3:21]>>[CH2:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:9][CH:10]=2)[CH2:15][CH2:16]1)[CH3:21]
Reactant: CCI
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Product: CCN1CCC(c2ccc(Oc3ccccc3)cc2)CC1

Procedure:
The same procedure was followed as in Example 11 using the compound (9) synthesized in Example 2 and ethyl iodide to produce the above.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:15][C:14](=[O:16])[O:13][C:11](=[O:12])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][NH:18]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][C:11](=[O:12])[CH:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][NH:18]2)[CH2:15][C:14]([OH:13])=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=C1CC(c2ccc(Cl)c(Cl)c2)CC(=O)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)CC(CC(=O)C1NCCc2ccccc21)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-(3,4-Dichlorophenyl)glutaric anhydride (10 g, Example 1, Step C) in CH2Cl2 (300 mL) at 0° C. was treated sequentially with 1,2,3,4-tetrahydroisoquinoline (6.0 mL), triethylamine (6.7 mL) and N,N-dimethylaminopyridine (472 mg). The mixture was stirred at 0° C. for two hours then allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was diluted with CH2Cl2 (500 mL) and washed with 1N HCl (1×200 mL) and water (1×200 mL). The organic layers were dried over MgSO4, filtered and concentrated to afford the title compound (14 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5]([CH2:10][CH:11]=[CH2:12])[CH2:6][C:7](C)=C)[CH3:2]>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:5]1[CH2:6][CH:7]=[C:11]([CH3:12])[CH2:10]1)=[O:13])[CH3:2]
Reactant: C=CCC(CC(=C)C)C(=O)OCC
Solvent: ClCCl
Product: CCOC(=O)C1CC=C(C)C1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 92.7 %

Procedure:
To a refluxing stirred solution of the 2-Allyl-4-methyl-pent-4-enoic acid ethyl ester (364 mg, 2.0 mmol) in CH2Cl2 (100 mL, 0.02 M solution) was added drop wise a solution of the tricyclohexylphosphine (1,3-Bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(benzylidine)ruthenium(IV)dichloride (85 mg, 0.1 mmol) in CH2Cl2 (3.0 mL). After 50 min, the reaction mixture was cooled to room temperature, concentrated and purified on silica gel bond elute using EtOAc/hexane (1:20) as an eluent furnished the 3-Methyl-cyclopent-3-enecarboxylic acid ethyl ester (286 mg, 93% yield) as an oil. 1H NMR (CDCl3, 400 MHz), 5.25 (brs, 1H), 4.17 (q, J=7.1 Hz, 2H), 3.2-3.1 (m, 1H), 2.65-2.46 (m, 4H), 1.74 (s, 3H), 1.28 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[N:3]=1
Reactant: COc1cccnc1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COc1ccc([N+](=O)[O-])nc1Br
Temperature: 60 °C
Yield: 65 %

Procedure:
2-Bromo-3-methoxypyridine (Desc. 4; 12.4 g, 66 mmol) in concentrated sulphuric acid (30 ml) was treated dropwise with fuming nitric acid (5.5 ml), and the solution heated at 60° C. for 2 hours. After cooling the solution was poured onto ice (500 ml). The solid formed was recovered by filtration, washed with water (500 ml) and sodium bicarbonate solution (500 ml) to give the title product as a yellow solid (10.0 g, 43 mmol, 65% yield).