Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:13]([NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:20]=2)=[N:12]S(=O)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:33]>CO>[ClH:33].[ClH:33].[ClH:33].[CH2:1]([NH:8][C:9](=[NH:10])[C:13](=[NH:12])[NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S1N=C(NCCCOc2cccc(CN3CCCCC3)c2)C(NCc2ccccc2)=N1
Agent: Cl
Solvent: CO
Product: N=C(NCCCOc1cccc(CN2CCCCC2)c1)C(=N)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A suspension of 3-benzylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole 1-oxide (5.14 g; 11.3 mmoles) [prepared according to published United Kingdom Patent Application No. 2,067,987] in 100 ml of methanol was treated with 7.55 ml of concentrated HCl. After stirring at ambient temperature for 3 hours, the solution was concentrated and the residue was triturated with acetone, filtered and dried to give 5.16 g (88%) of the title compound, mp 187°-205° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[O:10]COCC[Si](C)(C)C)[CH3:2].[Li]C(C)(C)C.[C:24](=[O:26])=[O:25]>C1COCC1.CCOCC>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:24]([OH:26])=[O:25])[C:5]=1[OH:10])[CH3:2]
Reactant: CCOc1ccncc1OCOCC[Si](C)(C)C
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOc1ccnc(C(=O)O)c1O
Reaction time: 0.75 h

Procedure:
A stirred solution of 11 (2.9 g) in THF (50 mL) under an argon atmosphere was cooled to ≦−70° C. To this was slowly added t-BuLi (8 mL, 1.5M pentane solution) while keeping the reaction temperature at ≦−66° C. After the addition was complete, the mixture was stirred at ≦−70° C. for 45 minutes and then poured into a slurry of crushed dry ice in ether. The resulting mixture was stirred until it reached room temperature, then the solvents were evaporated. THF (25 mL) and 4N HCl (15 mL) were added to the residue and the resulting mixture was stirred at room temperature for two hours. At the end of this period, the insoluble material was filtered, washed with a small volume of THF and air dried to give the title compound as a white solid (1.05 g). Preparation of 6-Bromo-3-benzyloxy-4-methoxypyridine-2-carboxylic Acid (16) and its Acid Chloride (3) (See Scheme 4). a. Preparation of Methyl 4,6-Dibromo-3-hydroxypyridine-2-carboxylate (14).
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH:15](OCC)(OCC)[O:16][CH2:17][CH3:18].C(OC(=O)C)(=O)C>>[CH2:17]([O:16][CH:15]=[CH:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:6])[CH3:18]
Reactant: CC(=O)CC(=O)OCc1ccccc1
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=CC(=O)CC(=O)OCc1ccccc1

Procedure:
From benzyl acetoacetate (38.4 g, 0.20 mol), triethyl orthoformate (29.6 g, 0.20 mol) and acetic anhydride (41 g, 0.40 mol): 10.7 g, 21.5%; bp=170°-183° C. at 0.5 mm Hg; NMR (CDCl3) δ 1.0-1.4 (t, 3H), 2.2-2.3 (d, 3H), 4.0-4.4 (q, 2H), 5.2 (d, 2H), 7.4 (s, 5H), 7.8-8.0 (d, 1H).
Reaction SMILES: C([N:3](CC)CC)C.[Cl:8][C:9]1[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=1[C:19](=[O:30])[C:20](=[CH:26]OCC)[C:21]([CH:23]1[CH2:25][CH2:24]1)=[O:22].Cl.NO>C(#N)C>[Cl:8][C:9]1[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=1[C:19]([C:20]1[CH:26]=[N:3][O:22][C:21]=1[CH:23]1[CH2:25][CH2:24]1)=[O:30]
Reactant: CCOC=C(C(=O)c1ccc(S(C)(=O)=O)cc1Cl)C(=O)C1CC1
Reactant: CCN(CC)CC
Agent: Cl
Agent: NO
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(C(=O)c2cnoc2C2CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
Triethylamine (0.9 g) was added to a mixture of 1-[2-chloro-4-(methylsulphonyl)phenyl]-3-cyclopropyl-2-ethoxymethylenepropan-1,3-dione (3.5 g) and hydroxylamine hydrochloride (1.0 g) in acetonitrile and the mixture was stirred at room temperature for 1 hour and left to stand overnight. The mixture was evaporated to dryness and the residue was partitioned between ethyl acetate and water. The organic layer was dried (magnesium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was purified by column chromatography on silica eluted with ethyl acetate and toluene. The product was recrystallized from ethyl acetate and cyclohexane to give 4-[2-chloro-4-(methylsulphonyl)benzoyl]-5-cyclopropylisoxazole (0.98 g) as a white solid, m.p. 116° C.
Reaction SMILES: C[Li:2].[CH2:3]([C:6]1[CH2:10][CH:9]=[CH:8][CH:7]=1)[CH:4]=[CH2:5]>CCOCC>[CH2:3]([C:6]1([Li:2])[CH:10]=[CH:9][CH:8]=[CH:7]1)[CH:4]=[CH2:5]
Reactant: C=CCC1=CC=CC1
Reactant: [Li]C
Solvent: CCOCC
Product: [Li]C1(CC=C)C=CC=C1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 0.105 mol of methyllithium in ether is added slowly to a solution, vigorously stirred at 0° C., of the β-propenylcyclopentadiene prepared in the preceding stage (a) in ether. The mixture is heated to ambient temperature (20° C.) and is kept stirred for 1 hours. A precipitate of β-propenylcyclopentadienyllithium is isolated by filtration, washed with ether 2′ 100 ml) and dried to give a white powder. 47.5 millimoles of zirconium tetrachloride dissolved in 100 ml of THF are added to a vigorously stirred solution of β-propenylcyclopentadienyllithium in 100 ml of THF at 0° C. The mixture is heated to ambient temperature (20° C.) and is stirred for 16 hours. The volatile compounds are removed under vacuum and the residue is extracted with ether (4′ 100 ml) and filtered. The product is obtained in the form of a white solid by slow cooling of the solution to −78° C. and recrystallization from cold ether.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)([O-:16])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a solution of tert-butyl 1-piperazinecarboxylate, 1 (0.74 g, 4 mmol), and 4-nitrobenzyl bromide, 2 (0.86 g, 4 mmol), in N,N-dimethylformamide (DMF, 5 mL) was added potassium carbonate (3 g), and the reaction mixture was stirred at room temperature for 4 h. The product was extracted with ethyl acetate (50 mL), and the organic phase was washed with water (20 mL×3). The solution was dried with sodium sulfate, and solvent was removed in vacuo. The product was purified by column chromatography, eluting with ethyl acetate to afford 3 as a solid (1.22 g, 95% yield), mp 99-100° C. 1H NMR (DMSO-d6): 8.21-8.19 (d, 2H, J=8.8 Hz, Ar-H), 7.61-7.59 (d, 2H, J=8.0 Hz, Ar-H), 3.63 (s, 2H, CH2), 3.34-3.30 (m, 4H, partially obscured, 2×CH2), 2.35-2.3 (m, 4H, 2×CH2), 1.39 (s, 9H, 3×CH3). Anal. (C16H23N3O4) C, H, N.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:18])[CH2:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.Cl[CH2:20][CH2:21][CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24].C(N(CC)CC)C>C(O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[O:18])[CH2:11][N:12]1[CH2:13][CH2:14][N:15]([CH2:20][CH2:21][CH2:22][C:23](=[O:24])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:16][CH2:17]1
Reactant: O=C(CCCCl)c1ccccc1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1NC(=O)CN1CCN(CCCC(=O)c2ccccc2)CC1

Procedure:
A mixture of N-(2,6-dimethylphenyl)-2-piperazinylacetamide (4) (100 mg, 0.4 mmol), 4-chloro-1-phenylbutan-1-one (12) (100 mg, 0.55 mmol), and triethylamine (0.4 mL) in ethanol (3 mL) was heated at reflux for 16 hours. Ethanol was removed under reduced pressure and the residue was purified by preparative TLC using 10% methanol in dichloromethane as mobile phase to afford N-(2,6-dimethylphenyl)-2-[4-(4-oxo-4-phenylbutyl)piperazin-1-yl]acetamide, a compound of formula (16).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[NH:22][CH:21]=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.Cl.[NH:24]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@@H:25](C(O)=O)[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.O1CCOCC1>[C:40]([O:39][C:37](=[O:38])[NH:24][CH:25]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:6](=[O:7])[N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:15]3[NH:22][CH:21]=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:12][CH2:13]1)([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3cc[nH]c23)CC1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3cc[nH]c23)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.2 %

Procedure:
To a solution of 4-(5H-Pyrrolo[3,2-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (43 mg, 0.14 mmol) in DCM (4 mL) was added HCl in Dioxane (4M, 1 mL). The mixture was stirred at room temperature for 4 hours. The solvent was removed and the residue was treated with TEA (2 mL), Boc-D-Phe(4-Cl)—OH (43 mg, 0.14 mmol), HOBT (30 mg, 0.222 mmol) and EDCI (41 mg, 0.214 mmol) in DCM (5 mL). The mixture was stirred at room temperature for 12 hours. The solvent was removed and the residue was subject to chromatography on silica gel to give product {1-(4-chlorobenzyl)-2-oxo-2-[4-(5H-pyrrolo[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-ethyl}-carbamic acid tert-butyl ester (30 mg, 44%). 1H NMR (CDCl3, 400 Hz) δ 9.85 (s, 1H), 8.48 (s, 1H), 7.37 (s, 1H), 7.25-7.23 (d, J=8.4 Hz, 2H), 7.13-7.11 (d, J=8.4 Hz, 2H), 6.60 (s, 1H), 5.39-5.37 (d, J=8.8 Hz, 1H), 4.83-4.78 (m, 1H), 3.81-3.43 (m, 7H), 3.31-3.27 (m, 1H), 3.00-2.91 (m, 2H), 1.41 (s, 9H). MS (ESI+) [M+H]+ 485.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH3:17][Mg]Cl.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1.O>[CH3:17][C:5]1[C:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:8][C:7]=2[CH:15]=[CH:16][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: C[Mg]Cl
Reactant: O=[N+]([O-])c1ccc2sc3ccccc3c2c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1c([N+](=O)[O-])ccc2sc3ccccc3c12
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a stirred suspension of 2-nitrodibenzothiophene (2.20 g, 9.61 mmol) in dry THF (100 ml) at −15° C. was slowly added methyl magnesium chloride (3 M solution in THF; 9.6 ml, 29 mmol). After stirring at this temperature for 5.5 h, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (6.98 g, 30.75 mmol) was added portion wise, keeping the temperature below −10° C. The mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was diluted with water and extracted into DCM. The organic layers were further washed with water, dried and purified by chromatography (eluent-50% DCM /isohexane) to give the title compound as a yellow solid. NMR 8.52 (m, 1H), 8.12 (m, 2H), 7.94 (d, 1H), 7.61 (m, 2H), 2.92 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[N:4][S:5][C:6]=1[C:7]([NH2:9])=[O:8].[N:18]([O-])=O.[Na+]>C(O)(=O)C.Cl.O>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:3]2[C:2]3[N:1]=[N:18][NH:9][C:7](=[O:8])[C:6]=3[S:5][N:4]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(-c2nsc(C(N)=O)c2N)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(-c2nsc3c(=O)[nH]nnc23)cc1
Reaction time: 1 h
Yield: 78.5 %

Procedure:
1 g of 4-amino-3-(4-methoxyphenyl)-5-isothiazolecarboxamide in 10 ml of glacial acetic acid and 3 ml of concentrated hydrochloric acid was stirred at 0° C. during the addition of a solution of 416 mg of sodium nitrite in 5 ml of water. The cooling bath was removed, the mixture was stirred for 1 hour and the precipitated product was removed by filtration. Recrystallization from aqueous dimethylformamide gave 820 mg of 7-(4-methoxyphenyl)-isothiazolo[4,5-d]-1,2,3-triazin-4(3H)-one as an off-white solid of melting point 213° C. (dec.).
Reaction SMILES: [CH:1](NC(C)C)(C)C.[CH3:8][O:9][C:10]([CH:12]1[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]1)=[O:11].IC>C1COCC1>[CH3:8][O:9][C:10]([C:12]1([CH3:1])[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]1)=[O:11]
Reactant: COC(=O)C1CCC(C(=O)O)CC1
Reactant: CC(C)NC(C)C
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCC(C(=O)O)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
N,N-Diisopropylamine (1.18 mL, 8.35 mmol) was added dropwise to a 2M solution of nbutyllithium (4.18 mL, 8.4 mmol) at −78° C. under nitrogen. After 15 min at this temperature the solution was raised to and held at 0° C. for 15 min prior to re-cooling to −78° C. and treatment with a solution of 4-(methoxycarbonyl)cyclohexanecarboxylic acid (0.62 g, 3.34 mmol) in THF (8 mL). After 30 min., iodomethane (0.31 mL, 5 mmol) was added dropwise and the mixture was allowed to warm to rt over 2 hr. The mixture was cooled to at 0° C., quenched with 2 N HCl (10 mL) then was extracted with EtOAc (2×10 mL), washed with brine (3×15 mL), and dried over anhydrous magnesium sulfate. Concentration of the combined organic extracts afforded a yellow solid. NMR(CDCl3) consistent with crude, desired product.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:9](Br)[N:8]([C@@H:25]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:37][C:38]1(C)[C:42](C)(C)OB(C(C)=C)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:9]([C:38]([CH3:42])=[CH2:37])[N:8]([C@@H:25]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](n2c(Br)c(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
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: C1COCCO1
Product: C=C(C)c1c(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc2n1[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Yield: 85.4 %

Procedure:
A mixture of (R)-tert-butyl 3-(4-amino-6-bromo-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (9) (150 mg, 0.27 mmol), 4,4,5,5-tetra methyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (136 mg, 0.81 mmol), tetrakis (31 mg, 0.027 mmol) and Na2CO3 (0.40 mL, 2M solution in water) in dioxane (3.0 mL) was purged with N2 before heated at 80° C. overnight. After cooled down to r. t., the reaction mixture was concentrated under reduced pressure to give the crude product which was purified by column chromatographic (silica gel, 0 to 70% ethyl acetate in petroleum ether) to afford (R)-tert-butyl 3-(4-amino-5-(4-phenoxyphenyl)-6-(prop-1-en-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (116) (118 mg, 85% yield) as a brown solid. LC-MS (ESI): m/z (M+1) 512.1.
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[C:9]([S:10]([O:13][C:14]3[CH:15]=[C:16]([OH:21])[CH:17]=[C:18]([CH3:20])[CH:19]=3)(=[O:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=12.C(P(CCCC)CCCC)CCC.[CH2:35](O)[CH2:36][CH2:37][OH:38].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[N:1]1[S:2][N:3]=[C:4]2[C:9]([S:10]([O:13][C:14]3[CH:15]=[C:16]([CH:17]=[C:18]([CH3:20])[CH:19]=3)[O:21][CH2:35][CH2:36][CH2:37][OH:38])(=[O:11])=[O:12])=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cccc3nsnc23)c1
Reactant: OCCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc3nsnc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
To a solution of 3-(benzo-2,1,3-thiadiazole-4-sulfonyloxy)-5-methylphenol (645 mg, 2.0 mmol), as prepared in the preceding step, tri-n-butylphosphine (607 mg, 3.0 mmol) and 1,3-propanediol (760 mg, 10 mmol) in anhydrous tetrahydrofuran (20 mL) was added 1,1'-(azodicarbonyl)dipiperidine (757 mg, 3.0 mmol). The mixture was stirred at ambient temperature overnight. Hexane (30 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (1:1 hexane/ethyl acetate) to give the title compound as a pale yellow oil (615 mg, 82%). 1H-NMR (300 MHz, CDCl3) δ 8.35 (d, J=8.7 Hz, 1H), 8.26 (d, J=7.1 Hz, 1H), 7.72 (t, J=8.8 Hz, 1H), 6.59 (s, 1H), 6.46 (s, 1H), 6.43 (s, 1H), 3.97 (t, J=6.0 Hz, 2H), 3.80 (t, J=6.0 Hz, 2H), 2.21 (s, 3H), 1,96 (m, 2H), 1.65 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:30][CH2:31][CH3:32])[N:4]=[C:5]2[C:14]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:7]=[C:6]2[N:15](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.C([Li])(C)(C)C.[C:38]1(=[O:42])[CH2:41][CH2:40][CH2:39]1.[Cl-].[NH4+]>O1CCCC1.CCCCC>[NH2:15][C:6]1[C:5]2=[N:4][N:3]([CH2:30][CH2:31][CH3:32])[C:2]([CH2:1][C:38]3([OH:42])[CH2:41][CH2:40][CH2:39]3)=[C:14]2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: CCCn1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3ccccc3c2c1C
Reactant: O=C1CCC1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCn1nc2c(N)nc3ccccc3c2c1CC1(O)CCC1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 31.9 %

Procedure:
A solution of di(tert-butyl) 1-methyl-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate (1.32 g, 3.00 mmol) in anhydrous tetrahydrofuran (THF) (30 mL) was cooled to −78° C. under an argon atmosphere. tert-Butyllithium (7.06 mL of a 1.7 M solution in pentane) was added over a period of eight minutes, and the resulting dark-colored solution was stirred at −78° C. for 40 minutes. Cyclobutanone (1.05 g, 15 mmol) was added over a period of two minutes, and the −78° C. bath was replaced with a 0° C. bath. The reaction mixture was stirred for 10 minutes, and then saturated aqueous ammonium chloride (30 mL) was added. The aqueous layer was separated and extracted three times with tert-butyl methyl ether, and the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue (1.3 g) was purified by automated flash chromatography and then boiled in 2 M hydrochloric acid for 30 minutes. The solution was allowed to cool to room temperature overnight and then made basic with the addition of 2 M aqueous sodium carbonate. The resulting solution was extracted four times with chloroform, and the combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue (1.2 g) was purified twice by automated flash chromatography and recrystallized from acetonitrile to provide 297 mg of 1-[(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)methyl]cyclobutanol as a white solid, mp 191-193° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compound was prepared by a procedure similar to that described for D83 starting from [4-(trifluoromethyl)phenyl]boronic acid and 4-bromobenzaldehyde. LC-MS (ESI): m/z 251 [M+H]+; 3.63 min (ret time).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:18][NH:19][NH2:20]>C1(C)C=CC=CC=1>[CH3:18][N:19]1[N:20]=[C:1]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11]1=[O:12]
Reactant: O=C(O)c1ccccc1C(=O)c1ccncc1
Reactant: CNN
Solvent: Cc1ccccc1
Product: Cn1nc(-c2ccncc2)c2ccccc2c1=O
Temperature: 25 °C
Yield: 81.2 %

Procedure:
To a suspension of 2-(isonicotinoyl)benzoic acid (10.0 g, 44.1 mmol) in toluene (50 mL) was added methyl hydrazine (2.59 mL, 48.6 mmol). The mixture was heated to reflux while collecting water in a Dean-Stark trap for 6 hours. Additional methylhydrazine (2.59 mL) was added and the mixture was heated to reflux for another 5 hours. The reaction mixture was cooled to room temperature and the product was collected by filtration. The product was recrystallized from hot methanol to afford 8.5 g (81%) of 2-methyl-4-(4-pyridyl)-1-(2H)-phthalazinone, m.p. 173°-174° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[CH3:11])([O-:3])=[O:2].[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[CH2:11][Br:12])([O-:3])=[O:2]
Reactant: Cc1ccc(F)cc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cc(F)ccc1CBr

Procedure:
A mixture of 2-nitro-4-fluorotoluene (1.65 g), N-bromo-succinimide (1.78 g), carbon tetrachloride 10.0 ml) and benzoyl peroxide (0.1 g) was heated at the reflux temperature until the solid residue was observed to be floating at the surface (ca. 3 hours). After removing the solid by filtration, the filtrate was diluted with diethyl ether, washed with water, dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvents under reduced pressure. The residue (estimated to contain ca. 35% w/w of the benzyl bromide in admixture with unchanged starting material) was subjected to column chromatography using a silica column and diethyl ether/petroleum ether (ratio 1:9 v/v) as eluent to yield pure 2-nitro-4-fluorobenzyl bromide.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[C:8]([CH3:23])=[C:9]([N:13]2[C:17]3=[N:18][CH:19]=[N:20][C:21](O)=[C:16]3[CH:15]=[N:14]2)[CH:10]=[CH:11][CH:12]=1>>[Cl:3][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[C:8]=3[CH3:23])[N:14]=[CH:15][C:16]=12
Reactant: Cc1c(Cl)cccc1-n1ncc2c(O)ncnc21
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1c(Cl)cccc1-n1ncc2c(Cl)ncnc21
Temperature: 100 °C
Reaction time: 4 h
Yield: 87.2 %

Procedure:
Phosphoryl trichloride (16.09 mL, 172.63 mmol) was added in one portion to 1-(3-chloro-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (Intermediate AE6) (3.0 g, 11.51 mmol) and the resulting suspension was heated to 100° C. to give a solution and stirred for 4 hours. Evaporated, the residue poured into ice/water and stirred for 30 minutes. The solids were filtered, washed with water (4×20 mL), dissolved in ethyl acetate (100 mL), dried (MgSO4), filtered and evaporated to afford the product (2.8 g) which was used without further purification. 1H NMR (400 MHz, DMSO) δ 2.06 (3H, s), 7.41-7.54 (2H, m), 7.71-7.73 (1H, m), 8.79 (1H, s), 8.89 (1H, s); m/z (ESI+) (M+H)+=279; HPLC tR=2.59 min.