Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](O)=[O:14])=[C:6]([CH2:18][CH2:19][CH3:20])[C:5]=1[OH:21])(=[O:3])[CH3:2].Cl.[NH2:23][OH:24].C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:23][OH:24])=[O:14])=[C:6]([CH2:18][CH2:19][CH3:20])[C:5]=1[OH:21])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCCC(=O)O)ccc(C(C)=O)c1O
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1c(OCCCCC(=O)NO)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Four and six-tenths grams of 5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentanoic acid were converted to the corresponding acid chloride according to the procedure of Example 55. The resulting acid chloride and 1.05 g. of hydroxylamine hydrochloride were dissolved in 50 ml. of methylene chloride, after which were added 4.15 ml. of triethylamine in about 50 ml. of methylene chloride. After stirring overnight at room temperature, the methylene chloride was removed by evaporation and the residue was partitioned between acetate and dilute hydrochloric acid. The layers were separated, and the ethyl acetate solution was evaporated in vacuo. The residue was dissolved in diethyl ether and the solution was extracted with dilute sodium hydroxide solution. The aqueous basic solution was then made acidic with dilute hydrochloric acid and the solution was extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and evaporated to dryness. The residue was crystallized from methylene chloride/hexane to provide 400 mg. of the title product.
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([NH2:21])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([OH:10])=[O:9])(=[O:4])(=[O:3])[NH2:2].[CH2:22]([CH2:26][C:27](=O)[CH3:28])[C:23]([CH3:25])=O>C(O)(=O)C>[S:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N:21]2[C:27]([CH3:28])=[CH:26][CH:22]=[C:23]2[CH3:25])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([OH:10])=[O:9])(=[O:3])(=[O:4])[NH2:2]
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Solvent: CC(=O)O
Product: Cc1ccc(C)n1-c1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
A mixture of 3-sulphamoyl-4-phenoxy-5-aminobenzoic acid (1.54 g=5 mmols; P. W. Feit, J. Med. Chem. 14, 432 (1971)), acetonylacetone (0.57 g=5 mmols) and 10 ml of glacial acetic acid is refluxed under N2 for 30 minutes, the red reaction solution is evaporated in vacuo and freed from residues of glacial acetic acid and water by adding benzene and evaporating azeotropically, the residue is dissolved in acetone, the solution is boiled with silica gel and filtered through a fine filter and the solution is concentrated to 50 ml and, after adding 50 ml of ethyl acetate, freed from acetone residues in vacuo, whereupon crystallisation takes place. After the purification procedure has been repeated, beige-coloured crystals with a melting point of 283°-286° (decomposition) result.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([O:8][C:9]([C:11]1([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]=[CH:13][CH2:12]1)=[O:10])[CH3:7].CN([CH:24]=[O:25])C>>[CH2:6]([O:8][C:9]([C:11]1([C:16]2[S:17][C:18]([CH:24]=[O:25])=[CH:19][CH:20]=2)[CH2:15][CH:14]=[CH:13][CH2:12]1)=[O:10])[CH3:7]
Reactant: CCOC(=O)C1(c2cccs2)CC=CC1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)C1(c2ccc(C=O)s2)CC=CC1
Temperature: 105 °C
Reaction time: 0.5 h

Procedure:
POCl3 (275 mg, 1.8 mmol) was added to 1 ml DMF at ambient temperature and stirred for 30 minutes. The product of Step 1, above (2) (208 mg, 0.93 mmol), was dissolved in 1 ml DMF, added to the reaction mixture and stirred for 1 hour at ambient temperature. The reaction mixture was heated to 105° C. for 3 hours, cooled to ambient temperature, quenched with saturated sodium acetate solution and extracted (2×10 ml, EtOAc). The organics were washed with brine and dried over MgSO4, filtered and concentrated to yield the title compound (3).
Reaction SMILES: C(O[CH:4](OCC)[N:5]([CH3:7])[CH3:6])C.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([CH3:26])[C:20]([NH:22][N+:23]([O-:25])=[O:24])=[NH:21])=[CH:14][N:13]=1.CCCCCC>O1CCOCC1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([CH3:26])[C:20]([N:21]=[CH:4][N:5]([CH3:7])[CH3:6])=[N:22][N+:23]([O-:25])=[O:24])=[CH:14][N:13]=1
Reactant: CCOC(OCC)N(C)C
Reactant: CN(Cc1ccc(Cl)nc1)C(=N)N[N+](=O)[O-]
Solvent: CCCCCC
Solvent: C1COCCO1
Product: CN(C)C=NC(=N[N+](=O)[O-])N(C)Cc1ccc(Cl)nc1
Temperature: 130 °C

Procedure:
Variant a): 1.5 g of N,N-dimethylformamide-diethyl-acetal are added to 2.43 g of N-(2-chloropyrid-5-ylmethyl)-N-methyl-N'-nitroguanidine in 75 ml of dioxane. The mixture is heated at 130° C. for 45 minutes and is then freed of solvent using a rotary evaporator. The crude product is chromatographed over silica gel using first ethyl acetate and then ethyl acetate/ethanol (5:1). A viscous oil is formed which, after the addition of hexane, yields crystals of the desired product (m.p.: 85°-89° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.C(O[CH:18]=[C:19]([C:23](=[O:25])[CH3:24])[C:20](=[O:22])[CH3:21])C>C(O)C>[C:20]([C:19]([C:23](=[O:25])[CH3:24])=[CH:18][NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)(=[O:22])[CH3:21]
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Reactant: CCOC=C(C(C)=O)C(C)=O
Solvent: CCO
Product: CC(=O)C(=CNc1ccc(C2=NNC(=O)CC2)cc1)C(C)=O

Procedure:
A solution containing 0.38 g of 6-(4-aminophenyl)-4,5-dihydropyridazin-3(2H)one and 0.4 g of 3-ethoxymethylene-2,4-pentanedione in 5 ml of ethanol was refluxed for 1 h. Yield 0.3 g, mp 218°-222° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.O[CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>CO.CN1C(=O)CCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]([CH2:13][CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]3)[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: O=c1[nH]c2ccc(Br)cc2s1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Cn2c(=O)sc3cc(Br)ccc32)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a round bottom flask was added 6-bromo-1,3-benzothiazol-2(3H)-one (0.300 g, 1.304 mmol), tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (0.365 g, 1.695 mmol), triphenylphosphine (0.455 g, 1.695 mmol), diisopropyl (E)-diazene-1,2-dicarboxylate (DIAD) (0.330 mL, 1.695 mmol), and NMP (5 mL). The reaction mixture was then permitted to stir at room temperature for two hours. The crude reaction mixture was then diluted with methanol, filtered and concentrated. Purification of crude reaction mixture by reverse phase chromatography (Waters Sunfire MSC18, 30% acetonitrile/0.1% trifluoroacetic acid/water→100% acetonitrile/0.1% trifluoroacetic acid/water) tert-butyl 4-[(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)methyl]piperidine-1-carboxylate (11-1) as a tan solid. HRMS (M+H)+: observed=427.0691, calculated=427.0686.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=1.[Cl-].[NH4+]>C(OCC)C.C([Li])CCC>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([OH:21])([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(=O)c1ccc(Cl)cc1
Reactant: Brc1cccnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CCOC(=O)C(O)(c1ccc(Cl)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48.3 %

Procedure:
To a solution of 3-bromopyridine (640 mg) in diethyl ether (10 ml), n-butyl lithium (2.5M-hexane solution, 1.80 ml) was added at −74° C. After 15 minutes' stirring at the same temperature, a solution of ethyl 2-(4-chlorophenyl)-2-oxoacetate (960 mg) in diethyl ether (100 ml) was added. The temperature of the system was raised to room temperature over 30 minutes, and to the reaction solution saturated aqueous ammonium chloride solution was added and extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was condensed under reduced pressure, and the resulting residue was purified on silica gel column chromatography (hexane/ethyl acetate=3/2) to provide ethyl 2-(4-chlorophenyl)-2-hydroxy-2-(3-pyridinyl)acetate (571 mg) as a yellow oily substance.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:17][C:6]2=[CH:7][C:8]3[C:9]([CH3:16])=[CH:10][C:11]([CH3:15])=[N:12][C:13]=3[CH:14]=[C:5]2[CH:4]=[CH:3]1.ClC1C=CC=[C:22]([C:26]([O:28]O)=[O:27])C=1.CO.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[C:26]([O:28][CH2:15][C:11]1[CH:10]=[C:9]([CH3:16])[C:8]2[CH:7]=[C:6]3[O:17][C:2]([CH3:18])([CH3:1])[CH:3]=[CH:4][C:5]3=[CH:14][C:13]=2[N:12]=1)(=[O:27])[CH3:22]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(C)c2cc3c(cc2n1)C=CC(C)(C)O3
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(=O)OCc1cc(C)c2cc3c(cc2n1)C=CC(C)(C)O3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a solution of 2,2,7,9-tetramethyl-2H-pyrano[2,3-g]quinoline (3.0 g, 12.5 mmol) in chloroform (30.0 mL), a solution of m-chloroperbenzoic acid (4.76 g, 27.6 mmol) in chloroform (12 mL)-methanol (3 mL) was added dropwise at room temperature, and the resulting mixture was stirred at room temperature for 30 minutes. Upon the completion of the reaction, sodium thiosulfate aqueous solution was added to the reaction solution, and it was extracted. The resulting organic phase was washed with sodium hydrogencarbonate and then with sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. After distilling off the solvent, acetic anhydride (12 mL) was added to the residue, and the resulting mixture was stirred at 150° C. for 1 hour. Upon the completion of the reaction, acetic anhydride was distilled off, the residue was neutralized with sodium carbonate aqueous solution, extracted with chloroform, and the resulting organic phase was washed with sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by medium pressure column chromatography (hexane/ethyl acetate=2/1) and the aimed product was obtained (yield: 64%).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C:22](=O)[CH3:23])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:25]1[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH2:26]1.[BH3-]C#N.[Na+]>CCO>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]([N:25]2[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH2:26]2)[CH3:23])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC(=O)c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1CCN(C(C)c2ccc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 1-(6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)ethanone (200 mg, 0.62 mmol) and ethyl 4-piperidinecarboxylate (146 mg, 0.93 mmol, 1.5 eq) in anhydrous EtOH (5 mL) was stirred at room temperature for 15 min, then Ti(OEt)4 (356 mg, 1.23 mmol, 2 eq) was added. The reaction mixture was stirred at reflux for 16 h under N2. After cooling to room temperature, the mixture was concentrated and the residue was dissolved in EtOH (3 mL) and NaBH3CN (125 mg, 1.85 mmol, 3 eq) was added. The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated and purified by silica gel (PE/EA=4/1) to give ethyl 1-(1-(6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)piperidine-4-carboxylate as yellow oil (140 mg, yield: 53%). ESI-MS (M+H+): 466.4. 1H NMR (400 MHz, CDCl3) δ: 7.71-7.65 (m, 2H), 7.60 (s, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.14-7.11 (m, 2H), 4.29-4.24 (m, 1H), 4.11 (q, J=7.2 Hz, 2H), 3.56 (br, 1H), 3.07 (br, 1H), 2.84 (br, 1H), 2.29-2.20 (m, 3H), 2.08-2.01 (m, 4H), 1.90-1.81 (m, 5H), 1.45-1.38 (m, 5H), 1.26-1.09 (m, 6H), 0.89 (s, 9H).
Reaction SMILES: Cl.[C:2]1([NH:12][NH2:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C([O:22][CH:23]=[C:24]([C:30](OCC)=O)[C:25]([O:27][CH2:28][CH3:29])=[O:26])C>O>[OH:22][C:23]1[N:12]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][CH:3]=2)[N:13]=[CH:30][C:24]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: NNc1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cnn(-c2cccc3ccccc23)c1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of naphthalen-1-ylhydrazine hydrochloride (1 g, 5.1 mmol) and potassium carbonate (1.4 g, 10.3 mmol) in water (30 mL) was added diethyl ethoxymethylenemalonate (1.1 g, 5.1 mmol) at room temperature. The reaction mixture was stirred for 3 hours at room temperature and then extracted with ethyl acetate. The aqueous layer was acidified with 1N HCl to pH 2 and then extracted with ethyl acetate again. This organic layer was dried over sodium sulfate and concentrated to give ethyl 5-hydroxy-1-(naphthalen-1-yl)-1H-pyrazole-4-carboxylate as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[C:12]([NH2:16])(=[O:15])[CH:13]=[CH2:14].C1(C=CC(O)=CC=1)O>S(=O)(=O)(O)O>[OH:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:1][CH2:14][CH2:13][C:12]([NH2:16])=[O:15]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: C=CC(N)=O
Agent: O=S(=O)(O)O
Agent: Oc1ccc(O)cc1
Product: NC(=O)CCNc1ccc([N+](=O)[O-])cc1O

Procedure:
15 g (0.1 mol) of 2-amino-5-nitrophenol, 7.8 g (0.11 mol) of acrylamide, 3 drops of 96% sulfuric acid and 20 mg of hydroquinone were maintained at 100° C. for 45 minutes. The mixture dissolved and an insoluble material was then formed, which was filtered off. This precipitate was taken up in 100 ml of refluxing toluene; after filtering while hot, 18 g of powder were obtained after re-slurrying in hot ethyl acetate (m.p.=194° C.).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[F:22].Cl>O1CCOCC1>[F:22][C:16]1[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=1[CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: Cc1ccc(Br)c(F)c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1ccc(C)cc1F
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 59.6 %

Procedure:
0.49 mol of diethyl malonate was added at 60° C. inside 2 hours to a mixture of 0.51 mol of NaH and 140 ml of 1,4-dioxane. The mixture was stirred for approximately 10 min at 60° C. and then 0.05 mol of Cu(I)Br was added. After 15 min, a mixture of 0.25 mol of 4-bromo-3-fluorotoluene and 10 ml of 1,4-dioxane was added. The reaction mixture was heated at 100° C. for approximately 15 hours and was then cooled to 15° C. After acidifying with 35 ml of 12N HCl at 15 to 20° C., the precipitate produced was filtered off. The filtrate was extracted and the organic phases, after separation, were dried and then freed from the solvent. 40 g of the title compound were obtained.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13](Cl)[N:12]=[C:11]3[N:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)[N:17]=[CH:18][C:10]=13)[CH2:2]2.[N+:32]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)([O-:34])=[O:33]>C1(C)C=CC=CC=1.C(O)C.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>[CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:38]3[CH:39]=[CH:40][C:35]([N+:32]([O-:34])=[O:33])=[CH:36][CH:37]=3)[N:12]=[C:11]3[N:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)[N:17]=[CH:18][C:10]=13)[CH2:2]2
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(Cl)nc32)CC1
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: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(-c4ccc([N+](=O)[O-])cc4)nc32)CC1
Temperature: 120 °C

Procedure:
A mixture of tert-butyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (2.9 mmol), 4-nitrophenylboronic acid (0.73 g, 4.4 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.34 g, 10 mol %) in toluene/ethanol (1:1, 12 mL) and 2 M aqueous sodium carbonate solution (3 mL) was heated in a 10-20 mL Smith process vial in the microwave reactor for one hour at 120° C. The cooled mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed twice with 1 M aqueous sodium hydroxide solution, once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude residue was further purified by automated flash chromatography (methanol/dichloromethane) to provide tert-butyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate. MS (ES+): 536.3 (M+H)+
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([CH2:11][NH:12]C(=O)OC(C)(C)C)[CH:9]=[CH:10][C:5]=2[C:4]([CH3:21])([CH3:20])[O:3]1.[ClH:22]>CO>[ClH:22].[NH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]2[C:4]([CH3:21])([CH3:20])[O:3][B:2]([OH:1])[C:6]=2[CH:7]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc2c(c1)B(O)OC2(C)C
Agent: Cl
Solvent: CO
Product: CC1(C)OB(O)c2cc(CN)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.7 %

Procedure:
To a solution of crude compound tert-butyl (1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)methylcarbamate (47.4 mmol) in methanol (150 mL) was added HCl (50 mL, 94.8 mmol). The reaction mixture was stirred for 16 h at rt. The solvent was removed to give compound 6-(aminomethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (7.3 g; yield 67% over 4 steps). MS: m/z=192.1 (M+1, ESI+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14]([N:22]3[CH:26]=[C:25]([Sn](CCCC)(CCCC)CCCC)[N:24]=[CH:23]3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[CH3:40][C:41]([NH:44][S:45]([C:48]1[S:52][C:51](Br)=[CH:50][CH:49]=1)(=[O:47])=[O:46])([CH3:43])[CH3:42].CCCCCCC>C1(C)C=CC=CC=1.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>[C:41]([NH:44][S:45]([C:48]1[S:52][C:51]([C:25]2[N:24]=[CH:23][N:22]([C:14]3[N:13]=[C:12]([C:4]4[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:9])[F:10])=[C:2]([CH3:1])[CH:3]=4)[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=3)[CH:26]=2)=[CH:50][CH:49]=1)(=[O:46])=[O:47])([CH3:43])([CH3:40])[CH3:42]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(-c3ccc(C(F)(F)F)c(C)c3)cc(C(F)(F)F)n2)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4ccc(S(=O)(=O)NC(C)(C)C)s4)c3)n2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
A stirred mixture of 4-(3-methyl-4-trifluoromethyl-phenyl)-2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (Example G.7) (0.33 g, 0.5 mmol), commercially available 5-bromothiophene-2-N-tert-butylsulfonamide (0.16 g, 0.55 mmol), tetrakis(triphenylphosphine)palladium (0.035 g, 0.03 mmol) in toluene (6 mL) was heated under reflux conditions for 15 h, heptane (10 mL) was added and the mixture was stirred at RT for 1 h. The precipitate was collected by filtration and dried to yield 5-{1-[4-(3-methyl-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.24 g) as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:34]=[CH:33][C:15]([O:16][C:17]3[CH:26]=[C:25]4[C:20]([CH:21]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:22][CH2:23][O:24]4)=[CH:19][C:18]=3[Cl:32])=[CH:14][CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[Cl:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1.C([O-])([O-])=O.[Na+].[Na+].O>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.C1(C)C=CC=CC=1>[Cl:32][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:17]=1[O:16][C:15]1[CH:33]=[CH:34][C:12]([C:10](=[O:11])[NH:9][C:4]3[CH:3]=[C:2]([C:39]4[CH:40]=[CH:41][C:36]([Cl:35])=[CH:37][CH:38]=4)[C:7]([F:8])=[CH:6][CH:5]=3)=[CH:13][CH:14]=1)[O:24][CH2:23][CH2:22][CH:21]2[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(F)c(Br)c4)cc3)c(Cl)cc21
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: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(F)c(-c5ccc(Cl)cc5)c4)cc3)c(Cl)cc21
Temperature: 125 °C
Yield: 71.5 %

Procedure:
A mixture of ethyl 7-(4-(3-bromo-4-fluorophenylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (54.8 mg, 0.0998 mmol), 4-chlorophenylboronic acid (20.299 mg, 0.129 mmol), Na2CO3 (31.75 mg, 0.299 mmol), tetrakis(triphenylphosphine)palladium(0) (5.769 mg, 0.0049 mmol), water (0.1 ml), and toluene (1 ml) in a vial was purged with Argon for few minutes and heated for 17 hours at 125° C. The crude mixture was purified on silica gel (EtOAc in hexanes gradient) to provide 41.4 mg of the title compound as a foamy solid (71%).