Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([F:21])[CH:20]=2)[C:13]2[C:22]([C:27]#[N:28])=[C:23]([F:26])[CH:24]=[CH:25][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.Cl[C:31]1[N:39]=[CH:38][N:37]=[C:36]2[C:32]=1[N:33]=[CH:34][N:35]2C1CCCCO1.CCN(C(C)C)C(C)C>Cl.O1CCOCC1.CO>[F:26][C:23]1[CH:24]=[CH:25][C:12]2[N:11]=[C:10]([C@@H:8]([NH:7][C:31]3[N:39]=[CH:38][N:37]=[C:36]4[C:32]=3[N:33]=[CH:34][NH:35]4)[CH3:9])[N:14]([C:15]3[CH:16]=[N:17][CH:18]=[C:19]([F:21])[CH:20]=3)[C:13]=2[C:22]=1[C:27]#[N:28]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)c(C#N)c2n1-c1cncc(F)c1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c(C#N)c2n1-c1cncc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.3 %

Procedure:
{(S)-1-[7-Cyano-6-fluoro-1-(5-fluoropyridin-3-yl)-1H-benzoimidazol-2-yl]-ethyl}carbamic acid tert-butyl ester (215 mg, 0.54 mmol) was dissolved in HCl in dioxane (4N, 5 mL) and the reaction mixture stirred at RT for 1 hour. The mixture was concentrated in vacuo and the residue dissolved in IPA (5 mL). 6-Chloro-9-(tetrahydropyran-2-yl)-9H-purine (167 mg, 0.70 mmol) and DIPEA (275 μL, 1.61 mmol) were added and the reaction mixture heated at 90° C. for 16 hours. The reaction mixture was concentrated in vacuo and the resultant residue was subjected to flash chromatography (SiO2, eluting with 0-10% methanol in EtOAc) to give an off white solid LCMS (Method C): RT=2.89 min, [M+H]+=502. The solid was dissolved in HCl in methanol (1.25 M, 5 mL) and the reaction mixture stirred at RT for 10 min. The reaction mixture was concentrated in vacuo and the resultant residue subjected to prep. HPLC (C18 phenomenex column, 10-90% MeCN in water 0.1% formic acid, 20 min gradient) to give 346 as a white solid (66 mg, 29%). 1H NMR 300 MHz δ (d6-DMSO): 12.91 (1H, br s), 8.89-8.46 (2H, m), 8.44-7.85 (5H, m), 7.42 (1H, t, J=9.6 Hz), 5.65-5.37 (1H, m), 1.67 (3H, t, J=6.8 Hz), LCMS (Method K): RT=3.03 min, [M+H]+=418
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3](=O)[CH2:4][C:5](=O)[C:6]([F:9])([F:8])[F:7].[NH2:14][C:15]1[N:19]=[C:18]([S:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:17][N:16]=1>C(O)(=O)C>[CH2:21]([S:20][C:18]1[N:19]=[C:15]2[N:14]=[C:5]([C:6]([F:9])([F:8])[F:7])[CH:4]=[C:3]([C:2]([F:13])([F:12])[F:1])[N:16]2[N:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(CC(=O)C(F)(F)F)C(F)(F)F
Reactant: Nc1n[nH]c(SCc2ccccc2)n1
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(C(F)(F)F)n2nc(SCc3ccccc3)nc2n1
Temperature: 25 °C
Yield: 93.8 %

Procedure:
A solution of 20.8 g (0.100 mol) of 1,1,1,5,5,5-hexafluoro-2,4-pentanedione and 20.6 g (0.100 mol) of 3-amino-5-benzylthio-1,2,4-triazole in 150 ml of glacial acetic acid was heated at reflux for 14 hours. The solution was cooled to room temperature and poured over ice. The solid which separated was collected by filtration, washed with water and dried in vacuo to yield 35.5 g (94%) of the desired product as a pale yellow solid, m.p. 78.5°-80.5° C. IR, 1H NMR and 19F NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:7][CH:8]([OH:10])[CH3:9].[CH:11](Cl)(Cl)Cl>>[CH2:7]([C@H:8]1[CH2:9][O:10]1)[CH2:11][C:3]1[CH:2]=[CH:1][CH:6]=[CH:5][CH:4]=1
Reactant: CCCCCC
Reactant: CC(C)O
Reactant: ClC(Cl)Cl
Product: c1ccc(CC[C@H]2CO2)cc1
Yield: 74 %

Procedure:
Colorless oily substance, 74% yield, 97% ee (CHIRALPAK IC, hexane/iPrOH 99.9:0.1); [α]D22 −16.3° (c=0.38, CHCl3)): δ7.32-7.28 (m, 2H), 7.22-7.18 (m, 3H), 2.98-2.93 (m, 1H), 2.87-2.72 (m, 3H), 2.49-2.47 (dd, J=2.7, 5.1 Hz, 1H), 1.93-1.79 ppm (m, 2H).
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[CH2:10][C:11]([N:13]1[CH2:34][CH2:33][C:16]2([C:20](=[O:21])[N:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)[CH2:15][CH2:14]1)=[O:12]>C1COCC1.C(Cl)(Cl)Cl>[CH:3]1([O:8][CH2:10][C:11]([N:13]2[CH2:14][CH2:15][C:16]3([C:20](=[O:21])[N:19]([C:22]4[CH:27]=[CH:26][C:25]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)[CH2:33][CH2:34]2)=[O:12])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C(CCl)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Reactant: OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=C(COC1CCCC1)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
To a suspension of NaH (5 mg, 0.13 mmol) in THF (2 mL) at 0° C. was added cyclopentanol (10 uL, 0.11 mmol) and the mixture was stirred for 30 min at 0° C. A solution of 8-(2-chloro-acetyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (example 225, 42 mg, 0.11 mmol) in THF (500 uL) was added drop-wise and the reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was diluted with chloroform and the resultant precipitate was filtered off and the filtrate was concentrated in vacuo to give the crude residue which was purified by flash column chromatography (7:3 AcOEt/heptane) which afforded the desired product as a white solid (16 mg, 34%). MS (ESI): 441.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C1COCC1>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:6]
Reactant: C1CCNC1
Reactant: Cc1cccc(C(=O)O)c1Br
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)N2CCCC2)c1Br
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2-Bromo-3-methylbenzoic acid (5.0 g, 23.3 mmol) was dissolved in THF (100 mL) and added N,N′-carbonyldiimidazole (4.52 g, 27.9 mmol). The reaction mixture was stirred at ambient temperature for 14 h. Pyrrolidine (6.8 mL, 81 mmol) was added in one portion. The mixture was stirred for 8 h and then partitioned between EtOAc and water. The organic layer was washed with water, diluted HCl, saturated bicarbonate, water and brine. The solution was then concentrated in vacuo to afford (2-bromo-3-methylphenyl)(pyrrolidin-1-yl)methanone as a white crystalline solid, upon standing overnight at RT.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:4]#[N:5].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)CC)C.Cl>ClCCl>[C:4]([C:3]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:2][O:1][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24])#[N:5]
Reactant: CCCCCC(C#N)(CO)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCC(C#N)(COS(=O)(=O)c1ccc(C)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 72 %

Procedure:
To a solution containing 4.24 g (19.5 mmol) of 2-hydroxymethyl-2-phenyl-heptanenitrile in 25 mL of dichloromethane are added 4.1 g (21.5 mmol) of p-toluenesulfonyl chloride and 6 mL of triethylamine. The reaction medium is stirred for 15 hours at room temperature and then treated with 1N hydrochloric acid solution and extracted with dichloromethane. The organic phase is dried over sodium sulfate, filtered and evaporated under pressure. A yellow oil is obtained and precipitated from a 9/1 heptane/diisopropyl ether mixture. The precipitate formed is filtered off and rinsed with diisopropyl ether. 5.26 g in the form of a beige-coloured powder are obtained in a yield of 72%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])C(=O)[NH:8]2)=[CH:4][C:3]=1[F:13].[OH-:14].[Na+].OO.Cl>>[NH2:8][C:9]1[CH:10]=[C:2]([Br:1])[C:3]([F:13])=[CH:4][C:5]=1[C:6]([OH:12])=[O:14]
Reactant: O=C1Nc2cc(Br)c(F)cc2C1=O
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Product: Nc1cc(Br)c(F)cc1C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
To a 100 mL round bottom flask, 6-bromo-5-fluoro-1H-indole-2,3-dione (3 g, 0.0121 mol) and 2N NaOH (15 mL) were added and cooled the reaction vessel to 0° C. To this reaction mixture 30% hydrogen peroxide (10.5 mL) was slowly added. The reaction mixture was stirred at 0° C. for 3 h. Subsequently, the reaction mixture was acidified with 2 N HCl at 0° C. [pH-5] to afford the solid compound. The solid material was collected by filtration and dried to obtain the title compound (700 mg, 25%). 1H NMR (300 MHz, DMSO-d6): δ 7.52 (d, J=9.6 Hz, 1H), 7.09 (d, J=6.0 Hz, 1H); LC-MS (ESI): Calculated mass: 232.9; Observed mass: 231.9 [M−H]+ (RT: 0.23 min).
Reaction SMILES: [NH2-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:10]#[N:11].Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:23][CH2:22]1>COCCOC.O>[C:10]([C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1)[CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:25][CH2:26]1)#[N:11]
Reactant: COc1ccccc1N1CCN(CCCl)CC1
Reactant: N#CC(c1ccccn1)c1ccccn1
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccccc1N1CCN(CCC(C#N)(c2ccccn2)c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
To a suspension of 0.21 g of 95% sodium amide in 2 mL of 1,2-dimethoxyethane was added dropwise a solution of 0.78 g of 2,2-bis-(2-pyridyl)acetonitrile (prepared as described in Heterocycles 1995, 40, 757) in 8 mL of 1,2-dimethoxyethane, with stirring under a nitrogen atmosphere at room temperature. After 1 h, there were added dropwise, 1.02 g of 1-(2-chloroethyl)-4-(2-methoxy-phenyl)piperazine dissolved in 4 mL of 1,2-dimethoxyethane. The resultant reaction mixture was then refluxed for 20 h, followed by cooling to room temperature, and was then poured cautiously into 40 g of ice, diluted with water, and extracted with ethyl acetate. The combined organic phases were then washed with water, dried on sodium sulphate, and then evaporated thoroughly under vacuum. The obtained crude was then purified by flash chromatography (ethyl acetate-methanol gradient from 10:0 to 9:1). The recovered fractions were then evaporated to complete dryness, affording 1.13 g of the title product (68.4%).
Reaction SMILES: [NH2:1][NH2:2].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][CH2:15][C:16]([C:18]2[CH:27]=[CH:26][C:25]3[C:24]([CH3:29])([CH3:28])[CH2:23][CH2:22][C:21]([CH3:31])([CH3:30])[C:20]=3[CH:19]=2)=O)=[CH:9][CH:8]=1)([O:5][CH3:6])=[O:4].[OH-].[Na+]>C(O)C.O>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:1]=[N:2][C:16]([C:18]3[CH:27]=[CH:26][C:25]4[C:24]([CH3:29])([CH3:28])[CH2:23][CH2:22][C:21]([CH3:31])([CH3:30])[C:20]=4[CH:19]=3)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)([O:5][CH3:6])=[O:4]
Reactant: NN
Reactant: COC(=O)c1ccc(C(=O)CCC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(-c2ccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)nn2)cc1

Procedure:
0.3 g (10 millimoles) of 100% pure hydrazine were added dropwise at room temperature to a solution of 4.0 g (10 millimoles) of 1-(4-carbomethoxyphenyl)-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-butane-1,4-dione (for preparation see Example 9) in 50 ml of ethanol. The reaction mixture was then refluxed for 20 minutes, cooled and then stirred into water, and the yellow crystals were filtered off under suction and dried in a stream of nitrogen. For aromatization of unoxidized dihydropyridazine, the crude product was stirred with periodic acid in ethanol until checking by thin layer chromatography showed that mainly a pure product was obtained. The product was then diluted with water, rendered basic with 2N sodium hydroxide solution and extracted with methylene chloride. The organic phase was washed with water, dried over magnesium sulfate and evaporated down. 3.1 g of the title compound remained as an oil; H-NMR (CF3COOH):=8.82 and 8.88 ppm (in each case d, 2H, pyridazine-H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:14])[N:3]=1.[CH3:22][C:23]1[NH:27][N:26]=[C:25]([NH2:28])[CH:24]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:28][C:25]3[CH:24]=[C:23]([CH3:22])[NH:27][N:26]=3)=[N:3][C:4]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[O:14])=[N:5]2)=[CH:10][CH:9]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: O=C(c1ccc(F)cc1)c1nc(Cl)c2ccc(F)cc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3cc(F)ccc23)n[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 45 %

Procedure:
To a solution of ethyl 4-chloro-7-fluoroquinazoline-2-carboxylate (122 mg, 0.479 mmol) in 5 mL THF at −40° C. was added 1M 4-fluorophenylmagnesium bromide/THF (0.58 mL, 0.58 mmol) and the mixture was stirred at −40° C. for 2 h. Saturated aq NH4Cl was added and the mixture was concentrated under reduced pressure. The residue was partitioned between H2O (100 mL) and DCM (50 mL). The separated aqueous phase was extracted with DCM (2×50 mL) and the combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to afford a solid (130 mg) containing (4-chloro-7-fluoroquinazolin-2-yl)(4-fluorophenyl)methanone. A solution of the solid (130 mg, ca. 0.43 mmol) and KI (78 mg, 0.47 mmol) in DMF (6 mL) was stirred at rt for 30 min, and then 5-methyl-1H-pyrazol-3-amine (88 mg, 0.88 mmol) and DIEA (96 uL, 0.56 mmol) were added. The mixture was stirred at rt for 24 h, and then water was added. The precipitated solid was collected by filtration washing with water. The solid was purified by preparative reverse-phase HPLC eluting with 10-80% ACN/H2O containing 0.05% HOAC to afford (7-fluoro-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)(4-fluorophenyl)methanone as a solid (96 mg, 45%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.18 (s, 3H), 6.48 (s, 1H), 7.39 (m, 2H), 7.63 (m, 2H), 8.13 (m, 2H), 8.84 (m, 1H), 10.80 (s, 1H), 12.08 (br s, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[CH2:4][CH2:5][O:6][C:7]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:8]=1[C:9]1[C:10]([O:26][CH3:27])=[CH:11][C:12]([O:24][CH3:25])=[C:13]([N+:21]([O-])=O)[C:14]=1[C:15]2=[O:20])[CH3:2].C(=O)(O)[O-].[Na+].CO.C(Cl)[Cl:38]>C(O)C.O>[ClH:38].[NH2:21][C:13]1[C:14]2[C:15](=[O:20])[C:16]3[C:8](=[C:7]([O:6][CH2:5][CH2:4][N:3]([CH2:28][CH3:29])[CH2:1][CH3:2])[CH:19]=[CH:18][CH:17]=3)[C:9]=2[C:10]([O:26][CH3:27])=[CH:11][C:12]=1[O:24][CH3:25]
Reactant: ClCCl
Reactant: CCN(CC)CCOc1cccc2c1-c1c(OC)cc(OC)c([N+](=O)[O-])c1C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CO
Product: CCN(CC)CCOc1cccc2c1-c1c(OC)cc(OC)c(N)c1C2=O
Product: Cl
Temperature: 70 °C

Procedure:
Prepare a mixture of 5-(2-diethylamino-ethoxy)-2,4-dimethoxy-1-nitro-fluoren-9-one (0.08 g, 0.18 mmole) and stannous chloride dihydrate (SnCl2.2H2O, 0.80 g, 3.5 mmole) in 20 mL ethanol. Heat at 70° C. under argon overnight. Dilute with about 60 mL water and make slightly basic by addition of 5% sodium bicarbonate. Extract the precipitate with ethyl acetate and dry over magnesium sulfate. Filter and evaporate the solvent. Make acidic (to pH=2) with 5% hydrochloric acid and extract the organics. Make the aqueous phase basic (to pH=8) and extract with methylene chloride. Dry over magnesium sulfate. Filter and evaporate the solvent to obtain a red oil. Chromatron with 7% methanol in methylene choride and condense under high vacuum to obtain the free base of the title compound (0.48 g). m.p. 208°-210° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-:16].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][F:25]>C(#N)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:16])[CH2:14][CH2:13][N:12]([CH2:22][CH2:23][CH2:24][F:25])[CH2:11][CH2:10]1
Reactant: O=C([O-])[O-]
Reactant: Clc1cccc(C2CCNCC2)c1Cl
Reactant: FCCCBr
Agent: [K+]
Solvent: CC#N
Product: OC1(c2cccc(Cl)c2Cl)CCN(CCCF)CC1

Procedure:
Preparation according to Example 2: 4-(2,3-dichlorophenyl)piperidine (0.02 g, 0.081 mmol), acetonitrile (2 ml), potassium carbonate (0.02 g, 0.14 mmol), 1-bromo-3-fluoropropane (0.010 ml, 0.082 mmol). MS m/z (relative intensity, 70 eV) 307 (M+, 4), 305 (M+, 8), 260 (63), 258 (bp), 242 (20), 240 (29).
Reaction SMILES: I[CH3:2].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:9](=[C:14]([C:17]4[O:21][N:20]=[C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:18]=4[C:28]([F:31])([F:30])[F:29])[O:15][N:16]=3)[CH2:10][NH:11][C:12]=2[CH:13]=1.[H-].[Na+]>C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:9](=[C:14]([C:17]4[O:21][N:20]=[C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:18]=4[C:28]([F:31])([F:29])[F:30])[O:15][N:16]=3)[CH2:10][N:11]([CH3:2])[C:12]=2[CH:13]=1
Reactant: FC(F)(F)c1c(-c2ccccc2)noc1-c1onc2c1CNc1cc(Br)ccc1-2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1Cc2c(noc2-c2onc(-c3ccccc3)c2C(F)(F)F)-c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
Iodomethane (0.020 mL, 0.325 mmol) was slowly added to a stirred mixture of 7-bromo-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydroisoxazolo[4,3-c]quinoline (Preparation 77D, 0.050 g, 0.108 mmol) and sodium hydride (2.60 mg, 0.108 mmol) in THF (5.0 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with 1 N aqueous hydrochloric acid (10 mL) and extracted with ethyl acetate (3×25 mL). The ethyl acetate extract was dried over sodium sulfate and concentrated to give 7-bromo-5-methyl-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydroisoxazolo[4,3-c]quinoline (0.041 g, 0.084 mmol, 78%) as an orange solid. The product had an HPLC ret. time=4.45 min. (condition B). LC/MS M+1 478.0.
Reaction SMILES: C(O[CH2:8][N:9]1[C:13](=[O:14])[C:12]2[C:15]([CH:21]([CH3:23])[CH3:22])=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:11]=2[S:10]1(=[O:25])=[O:24])(=O)C(C)(C)C.[BrH:26]>C(O)(=O)C.O>[Br:26][CH2:8][N:9]1[C:13](=[O:14])[C:12]2[C:15]([CH:21]([CH3:23])[CH3:22])=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:11]=2[S:10]1(=[O:25])=[O:24]
Reactant: Br
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COC(=O)C(C)(C)C)C2=O
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A solution of 2-(pivaloyloxymethyl)-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (1.33 kg, 3.62 mol), 48% HBr in acetic acid (1 L) and 3 L of acetic acid was stirred on a steam bath (90°-95° C.) for 1.5 hours. The solvent (acetic acid) was removed under vacuum to give a thick slurry of an off-white residue which was diluted with 10 L of cold water and stirred for 30 minutes. The crude product was collected by filtration, washed first with 6 L of water and then with 3 L of saturated sodium bicarbonate solution. The crude solid was dried at 60°-70° C. for 20 hours and then was recrystallized from a mixture of 5 L of ethyl acetate and 6 L of hexane. Two crops were collected to give 1.16 kg (92%) of 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide, as an off-white solid, m.p. 157°-159° C.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([OH:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1)N.[C:13]([CH:16]([CH3:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])(=O)[CH3:14]>C(O)(=O)C.O.CO>[CH3:14][C:13]1[C:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])([CH3:25])[C:8]2[C:3](=[CH:4][CH:5]=[C:6]([S:9]([OH:12])(=[O:11])=[O:10])[CH:7]=2)[N:1]=1
Reactant: CC(=O)C(C)CCCCCC(=O)O
Reactant: NNc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CC1=Nc2ccc(S(=O)(=O)O)cc2C1(C)CCCCCC(=O)O

Procedure:
To a stirred solution of 4-hydrazinobenzenesulfonic acid (Aldrich, 11.25 g, 0.06 mol) in acetic acid (50 ml) was added 7-acetyloctanoic acid (16.7 g, 0.09 mol). The reaction mixture was heated under reflux for 12 hrs. Acetic acid was removed under reduced pressure. The resulting solid was dissolved in methanol and reprecipitated with a saturated solution of potassium hydroxide in isopropanol. The solid was filtered, washed with isopropanol and dried, (8 g, 40%). The analytical sample was obtained by C18 reversed phase column chromatography using water/methanol mixture as solvent., m.p. 250° C. dec; IR νcm−1=2930, 2597, and 1719. 1H NMR, D2O, δ, 7.8-7.9 (m, 2H, 4-H and 6-H of aromatic protons); 7.6 (d, J=7 Hz, 1H, 7-H of aromatic); 2.2 (t, J=7 Hz, 2H, —CH2—COOH); 1.9-2.1 (m, 2H, alkyl); 1.2-1.6 (a singlet merged in a multiplet, 7H, —CH3 & (—CH2)2); 0.6-0.9 (m, 2H, alkyl).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[N:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(#N)C.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH3:20])=[N:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc(Br)cnc21
Reactant: COc1ccccc1B(O)O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(Br)cc12
Yield: 65.2 %

Procedure:
A mixture of 5-bromo-3-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (1.606 g, 3.537 mmol), 2-methoxy-phenyl-boronic acid (575 mg, 3.78 mmol) and of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichlorrnethane adduct (145 mg, 0.178 mmol) in acetonitrile (8 mL) and aqueous solution of sodium carbonate (2M, 8 mL) was stirred in a closed vial at 85° C. for 100 min. The resulting mixture was then distributed between a saturated aqueous solution of sodium bicarbonate and dichloromethane and the aqueous phase extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash silica gel chromatography using a gradient of ethyl acetate in hexanes to afford 5-bromo-3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (1.002 g, 65% yield) as an off-white oil. 1H-NMR (500 MHz, d6-DMSO) δ8.70 (d, 1H), 8.40 (d, 1H), 7.61 (d, 1H), 7.50 (ddd, 1H), 7.23 (dd, 1H), 7.10 (ddd, 1H), 5.81 (s, 2H), 3.85 (s, 3H), 3.66 (t, 2H), 0.84 (t, 2H), −0.10 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:22])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:19]([CH3:21])[CH3:20])[CH:12]=1)[CH2:5]O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.OP(O)(O)=O.[I-:42].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:22])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:19]([CH3:21])[CH3:20])[CH:12]=1)[CH2:5][I:42]
Reactant: [I-]
Reactant: COc1ccc(Oc2c(Cl)cc(CO)cc2Cl)cc1C(C)C
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Product: COc1ccc(Oc2c(Cl)cc(CI)cc2Cl)cc1C(C)C
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 68.3 %

Procedure:
3,5-Dichloro-4-(4-methoxy-3-isopropylphenoxy)-benzylalcohol (3.21 g) (Example 6a) was added into a mixture of P2O5 (576 mg) and H3PO4 (5.5 ml) followed by addition of sodium iodide (2.43 g). The mixture was stirred at 120° C. for 15 min and then partitioned between water and ethyl acetate. The organic layer was washed with an aqueous solution of Na2S2O3 and brine, dried, filtered and concentrated. The residue was crystallized from petroleum ether to give 2.9 g (79%) of 3,5-dichloro-4-(4-methoxy-3-isopropylphenoxy)benzyliodide.