Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:24]=[CH:23][C:7]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:19])[C:17]=2[CH3:18])=[CH:14][CH:13]=[CH:12][C:11]=3[CH:20]=CC)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH2:25].[Mn]([O-])(=O)(=O)=[O:27].[K+].S(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH:1]([C:4]1[CH:24]=[CH:23][C:7]([C:8]2[O:25][C:20]3[C:15]([C:16](=[O:19])[C:17]=2[CH3:18])=[CH:14][CH:13]=[CH:12][C:11]=3[C:10]([OH:9])=[O:27])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O
Reactant: CC=Cc1cccc2c(=O)c(C)c(-c3ccc(C(C)C)cc3)oc12
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1c(-c2ccc(C(C)C)cc2)oc2c(C(=O)O)cccc2c1=O
Reaction time: 8 h

Procedure:
4'-Isopropyl-3-methyl-8-propenylflavone (3.4 grams) is dissolved in 40 ml of glacial acetic acid, small amount of water is added thereto, 6.6 grams of potassium permanganate is added thereto during eight hours with stirring keeping the inner temperature at 20° to 30° C., then aqueous solution of sodium bisulfite is added thereto keeping the inner temperature at 30° to 40° C., and the mixture is stirred for one hour. Crystals separated out therefrom are collected by filtration, washed with water, dissolved in 10% sodium hydroxide solution, the solution is treated with activated charcoal, filtered, and the filtrate is adjusted to pH 3 with concentrated hydrochloric acid, crystals separated out are collected by filtration, washed with water and recrystallized from methanol to give 1.9 grams of 4'-isopropyl-3-methylflavone-8-carboxylic acid, colorless prisms, melting point 216° to 220° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([CH2:15][CH2:16][C:17]([OH:19])=O)(=[O:14])=[O:13])[CH:6]=[CH:5]2.S(Cl)([Cl:22])=O>CN(C=O)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([CH2:15][CH2:16][C:17]([Cl:22])=[O:19])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)CCS(=O)(=O)c1ccc2cc(Cl)ccc2c1

Procedure:
3-((6-Chloro-2-naphthyl)sulfonyl)propionic acid (14.9 g), thionyl chloride (4.4 mL) and DMF (2 drops) were added to toluene (100 mL), and the mixture was refluxed for 1.5 hours. The solvent was distilled off under reduced pressure, and the residue was washed with ether and hexane to give the title compound (15.5 g) as a brown solid.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][CH2:4][C:5]1([C:9]([O:11]CC)=[O:10])[CH2:8][CH2:7][CH2:6]1.O.[OH-].[Na+]>C(O)C.C1COCC1>[F:1][CH:2]([F:14])[O:3][CH2:4][C:5]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][CH2:6]1
Reactant: CCOC(=O)C1(COC(F)F)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C1(COC(F)F)CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.2 %

Procedure:
To a stirred solution of Intermediate 223A (0.263 g, 1.263 mmol) in ethanol (3.5 mL), THF (3.5 mL), and water (3 mL) was added NaOH (0.152 g, 3.79 mmol) and the reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated and the residue dissolved in water and extracted with ethyl acetate (3×15 mL) The aqueous layer was then acidified to pH 2-3 using a 1.5 N aqueous solution of HCl and extracted with EtOAc (3×15 mL). The combined organic layer was washed with water, dried over Na2SO4 and concentrated to afford Intermediate 223B as a brown oil (0.08 g, 35% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.41 (s, 1H), 6.97-6.40 (m, 1H), 4.15-3.90 (m, 2H), 2.38-2.09 (m, 2H), 2.01-1.51 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[C@H:10]([CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[NH:11][C:12](=[O:15])[CH2:13]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:28].[Na+]>CC(=O)CC>[CH2:1]([O:8][C:9](=[O:27])[C@H:10]([CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[NH:11][C:12](=[O:15])[CH2:13][I:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)N[C@@H](CC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: O=C(CI)N[C@@H](CC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Yield: 99.3 %

Procedure:
A solution of N-α-chloroacetyl-L-aspartic acid dibenzyl ester (111 g, 0.285 mol) and sodium iodide (59.5 g, 0.40 mol) in 2-butanone was heated at reflux for a period of 1.5 hours. The reaction mixture was concentrated to dryness and the residue was added to a separatory funnel containing ethyl acetate (about 500 mL). The aqueous phase was removed and the organic phase was first extracted with brine (about 250 mL) and then dried over sodium sulfate. The resulting solution was then concentrated in vacuo to provide product 12 (136 g, 0.283 mol, 99%) as a viscous brown oil which slowly crystallized over a period of several days at room temperature. Satisfactory 1H NMR data were obtained for this material. This material was not further purified but was instead used directly in the preparation of 9.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([C@H:13]1[C@@H:17]([CH2:18][OH:19])[O:16][C:15](=[O:20])[NH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])(O)=O.[Na+].C(OCC)(=O)C>CC(C)=O.CN1CCOCC1>[CH2:6]([C@H:13]1[C@@H:17]([CH2:18][O:19][S:2]([CH3:1])(=[O:4])=[O:3])[O:16][C:15](=[O:20])[NH:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)[C@@H](CO)O1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OC[C@H]1OC(=O)N[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A solution of 4.7 ml of methanesulphonyl chloride in 10 ml of acetone is added at 25° C. to a suspension of 10.4 g of the alcohol from Example 8 in 20 ml of acetone and 6.1 ml of N-methylmorpholine and the suspension is stirred at 25° C. for 3 hours. A further 1.1 ml of N-methylmorpholine are added and the mixture is stirred for 1 hour. The suspension is shaken with 80 ml of semi-saturated NaHCO3 solution and ethyl acetate and the separated aqueous phase is extracted with ethyl acetate. The ethyl acetate extracts are washed with water, dried and filtered. The filtrate is concentrated to give 14.3 g (100%) of crude methanesulphonic acid (4S,5S)-4-benzyl-2-oxo-oxazolidin-5-ylmethyl ester, TLC (SiO2 ethyl acetate): Rf =0.4; MS (EI): 286 (M+H+).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:18])=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:7]=1.[NH2:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([N:26]([CH3:28])[CH3:27])=[O:25])=[CH:22][CH:21]=1.CC1C=CC(S(O)(=O)=O)=CC=1>CN1C(=O)CCC1>[Cl:18][C:5]1[N:4]=[N:3][C:2]([NH:19][C:20]2[CH:30]=[CH:29][C:23]([C:24]([N:26]([CH3:28])[CH3:27])=[O:25])=[CH:22][CH:21]=2)=[N:7][C:6]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[F:17]
Reactant: Fc1cccc(CNc2nc(Cl)nnc2Cl)c1F
Reactant: CN(C)C(=O)c1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCCC1=O
Product: CN(C)C(=O)c1ccc(Nc2nnc(Cl)c(NCc3cccc(F)c3F)n2)cc1
Temperature: 105 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
3,6-Dichloro-N-(2,3-difluorobenzyl)-1,2,4-triazin-5-amine (75 mg, 0.26 mmol) was dissolved in 5 mL NMP. To it was added 4-amino-N,N-dimethylbenzamide (86 mg, 0.52 mmol) and pTSA (49 mg, 0.26 mmol). The mixture was stirred at 105° C. for overnight and subjected to reverse phase preparative HPLC to isolate 4-(6-chloro-5-(2,3-difluorobenzylamino)-1,2,4-triazin-3-ylamino)-N,N-dimethylbenzamide (58 mg). MS found for C19H17ClF2N6O as (M+H)+ 419.3. UV: λ=273 nm.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[O:21]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[N:22]1.[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH2:26][C:23]3[CH:24]=[CH:25][O:21][N:22]=3)[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Reactant: O=Cc1ccon1
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NCc3ccon3)ccc2F)N=C1N

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and isoxazole-3-carbaldehyde using decaborane yielded the title compound as a light yellow waxy solid. MS (ESI): m/z=360.4 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:4]=2[N:3]=[C:2]1[C:18]1[C:25]([C:26]#[N:27])=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21])=[CH:10][CH:9]=[CH:8][CH:7]=3.C(=O)([O-])[O-].[Cs+].[Cs+].O.C(OCC)(=O)C.[Cl:41][CH2:42]I>>[Cl:41][CH2:42][N:1]1[C:5]2[C:6]3[C:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:4]=2[N:3]=[C:2]1[C:18]1[C:25]([C:26]#[N:27])=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21])=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: ClCI
Reactant: N#Cc1cccc(C#N)c1-c1nc2c3ccccc3c3ccccc3c2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cccc(C#N)c1-c1nc2c3ccccc3c3ccccc3c2n1CCl
Temperature: 80 °C
Yield: 31 %

Procedure:
2-(1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile from Step 2 (1 g, 2.91 mmol) was mixed with cesium carbonate (1.14 g, 3.49 mmol) in chloroiodomethane (10 mL). The mixture was heated to 80° C. overnight. The reaction was cooled to room temperature and poured into 200 mL water and 500 mL ethyl acetate. The layers were separated, and the organic layer was washed with 200 mL water, 200 mL saturated aqueous sodium bicarbonate solution, 100 mL brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The crude solid was purified by flash column chromatography using 40% ethyl acetate in hexane to give 357 mg of 2-[1-(chloromethyl)-1H-phenanthro[9,10-d]imidazol-2-yl]isophthalonitrile (31%) plus 650 mg of a mixture of product and starting material.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6]=1[CH3:19])=O.[NH2:20][C:21]([NH2:23])=[S:22]>CCO>[CH3:19][C:6]1[CH:7]=[C:8]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[C:3]1[N:20]=[C:21]([NH2:23])[S:22][CH:2]=1
Reactant: NC(N)=S
Reactant: Cc1cc(Sc2ccccc2)cc(C)c1C(=O)CBr
Solvent: CCO
Product: Cc1cc(Sc2ccccc2)cc(C)c1-c1csc(N)n1
Yield: 88.9 %

Procedure:
A reaction mixture containing 2-bromo-1-(2,6-dimethyl-4-(phenylthio)phenyl)ethanone (591.7 mg, 1.8 mmol, 1.0 equiv) and thiourea (134.3 mg, 1.8 mmol, 1.0 equiv) in EtOH (15.0 mL) was heated at reflux for 16 h. The solution was concentrated under reduced pressure, and the residue was re-dissolved in EtOAc (50 mL). The solution was washed with saturated aqueous NaHCO3 (30 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (5.0% EtOAc in hexanes as eluant) to provide 4-(2,6-dimethyl-4-(phenylthio)phenyl)thiazol-2-amine (483.7 mg, 1.6 mmol) as yellow solids in 88% yield: 1H NMR (DMSO-d6, 500 MHz) δ 7.33-7.38 (m, 2H), 7.29-7.33 (m, 3H), 7.06 (brs, 2H), 6.89 (s, 2H), 6.38 (s, 1H), 2.07 (s, 6H); ESI-MS: m/z 313.8 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][N:12]=3)[N:9]=[CH:10][C:3]=12.CS([O-])=O.[Na+].[H-].[Na+].[OH:25][C@@H:26]([CH2:37][CH2:38][O:39][CH3:40])[C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][N:31]=1)=[O:28]>C1COCC1.CCOC(C)=O>[Cl:17][C:16]1[C:11]([N:8]2[C:4]3=[N:5][CH:6]=[N:7][C:2]([O:25][C@@H:26]([CH2:37][CH2:38][O:39][CH3:40])[C:27]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][N:31]=4)=[O:28])=[C:3]3[CH:10]=[N:9]2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: Clc1cccnc1-n1ncc2c(Cl)ncnc21
Reactant: COCC[C@H](O)C(=O)Nc1ccc(C)cn1
Agent: CS(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(C)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 87.4 %

Procedure:
4-Chloro-1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B15) (219 mg, 0.82 mmol) was added to sodium methanesulfinate (75 mg, 0.73 mmol) and sodium hydride (38.0 mg, 0.95 mmol) in THF (5 mL) at 23° C. under nitrogen. The resulting suspension was stirred at ambient temperature for 5 minutes. (S)-2-Hydroxy-4-methoxy-N-(5-methylpyridin-2-yl)butanamide (Intermediate F1) (142 mg, 0.63 mmol) was added dropwise and the suspension was stirred at ambient temperature for a further 30 minutes. The mixture was diluted with EtOAc (50 mL), and washed sequentially with water (2×25 mL) and saturated brine (25 mL). The organic layer was dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography, elution gradient 40 to 100% EtOAc in isohexane to afford (2S)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-4-methoxy-N-(5-methylpyridin-2-yl)butanamide (250 mg, 87%).
Reaction SMILES: C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.CN(CCCN1CN(CCCN(C)C)CN(CCCN(C)C)C1)C.[CH3:41][S:42][C:43]1[CH:48]=[CH:47][C:46]([N:49]=[C:50]=[O:51])=[CH:45][CH:44]=1.[C:52]([O:56][CH2:57][CH2:58][OH:59])(=[O:55])[CH:53]=[CH2:54].[N-]=C=O>C(OCC)(=O)C>[C:52]([O:56][CH2:57][CH2:58][O:59][C:50](=[O:51])[NH:49][C:46]1[CH:47]=[CH:48][C:43]([S:42][CH3:41])=[CH:44][CH:45]=1)(=[O:55])[CH:53]=[CH2:54]
Reactant: C=CC(=O)OCCO
Reactant: CSc1ccc(N=C=O)cc1
Agent: CN(C)CCCN1CN(CCCN(C)C)CN(CCCN(C)C)C1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [N-]=C=O
Solvent: CCOC(C)=O
Product: C=CC(=O)OCCOC(=O)Nc1ccc(SC)cc1
Temperature: 60 °C

Procedure:
0.02 g of 2,6-di-tert-butyl-4-methylphenol, 0.01 g of Desmorapid Z, 4.7 g of 4-(methylthio)phenyl isocyanate in 25 g of ethyl acetate were initially introduced into a 100 ml round-bottomed flask and heated to 60° C. Thereafter, 4.1 g of 2-hydroxyethyl acrylate were added dropwise and the mixture was kept further at 60° C. until the isocyanate content had fallen below 0.1%. Thereafter, the ethyl acetate was distilled off at 5 mbar and cooling was effected. The product was obtained as a crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[C:8]([CH3:17])[C:7]=2[CH:18]=1.[Li+].CC([N-]C(C)C)C.C(C1C=CC=CC=1)C.[CH3:35][C:36]([CH3:41])([CH2:39][CH3:40])[CH:37]=[O:38]>C1COCC1.CCCCCCC>[OH:38][CH:37]([C:36]([CH3:41])([CH3:35])[CH2:39][CH3:40])[CH2:17][C:8]1[C:7]2[CH:18]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[O:10][C:9]=1[C:11](=[O:16])[C:12]([CH3:13])([CH3:14])[CH3:15]
Reactant: COc1ccc2oc(C(=O)C(C)(C)C)c(C)c2c1
Reactant: CCC(C)(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CCC(C)(C)C(O)Cc1c(C(=O)C(C)(C)C)oc2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of 0.493 g 1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-2,2-dimethylpropan-1-one from Step A Example 1 in 20 mL anhydrous THF at −78° C. under nitrogen was added 2.0 mL 2 M LDA in heptane, THF, and ethylbenzene. After 50 minutes, 0.40 g 2,2-dimethylbutanal was added. Remove the cooling bath and let the reaction mixture warm up to room temperature. After 70 minutes, the reaction was quenched by adding 2 mL saturated ammonium chloride and the reaction mixture was evaporated under reduced pressure to remove solvents. Dilute the residue with ether, wash with 1 M HCl (2×) and saturated brine, dry over anhydrous Na2SO4, and evaporate to give a crude product. It was purified on RP-HPLC using 65˜100% MeCN in water without TFA to give the title compound as colorless solid after lyophilization. 1H NMR (CDCl3, 500 MHz) 7.44 (d, 9.1 Hz, 1H), 7.20 (d, 2.0 Hz, 1H), 7.10 (dd, 2.5 & 9.1 Hz, 1H), 3.86 (s, 3H), 3.58 (dd, 1.6 & 10.6 Hz, 1H), 3.29˜3.34 (m, 1H), 2.90˜2.95 (m, 1H), 1.51˜1.59 (m, 1H), 1.39˜1.46 (m, 1H), 1.40 (s, 9H), 1.02 (s, 3H), 1.01 (s, 3H), 0.92 (t, 7.6 Hz, 3H). LC-MS: 4.47 min. (m/Z=329.3, 369.2, 347). A faster-eluting isomeric side-product was also isolated during purification and was identified as 1-[2-(1-hydroxy-2,2-dimethylpropyl)-5-methoxy-1-benzofuran-3-yl]-3,3-dimethylpentan-2-one. 1H NMR (CDCl3, 500 MHz) 7.30 (d, 9.0 Hz, 1H), 6.84 (dd, 2.5 & 8.9 Hz, 1H), 6.75 (d, 2.5 Hz, 1H), 4.44 (s, 1H), 4.07 (AB d, 18.5 Hz, 1H), 4.04 (AB d, 18.5 Hz, 1H), 3.78 (s, 3H). 1.74 (q, 7.6 Hz, 2H), 1.263 (s, 3H), 1.260 (s, 3H), 0.99 (s, 9H), 0.91 (t, 7.4 Hz, 3H). LC-MS: 3.95 min. (m/Z=369.3=M+Na, 329.3,).
Reaction SMILES: [Bi](Br)(Br)[Br:2].[Br:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[F:14].[CH2:15]([CH:17]([CH:20]=[CH2:21])[CH2:18]O)[CH3:16].Cl>C1(C)C=CC=CC=1>[Br:2][CH:15]1[CH:17]([CH2:20][CH3:21])[CH2:18][O:11][CH:10]([C:9]2[CH:12]=[CH:13][C:6]([Br:5])=[C:7]([F:14])[CH:8]=2)[CH2:16]1
Reactant: C=CC(CC)CO
Reactant: O=Cc1ccc(Br)c(F)c1
Reactant: Br[Bi](Br)Br
Agent: Cl
Solvent: Cc1ccccc1
Product: CCC1COC(c2ccc(Br)c(F)c2)CC1Br
Temperature: 10 °C
Reaction time: 2 h

Procedure:
72.9 g (0.16 mol) of bismuth(III) bromide are initially introduced in 50 ml of toluene at −10° C., and a solution of 50.0 g (0.25 mol) of 4-bromo-3-fluorobenzaldehyde in 250 ml of toluene is added dropwise. A solution of 27.0 g (0.27 mol) of 2-ethylbut-3-en-1-ol in 50 ml of toluene is metered in at this temperature, and the mixture is stirred at 10° C. for 2 h. Dilute hydrochloric acid is added to the batch, and the organic phase is separated off. The aqueous phase is extracted with toluene, and the combined organic phases are washed successively with water, saturated sodium hydrogen-carbonate solution and saturated sodium chloride solution. The solution is dried using sodium sulfate and concentrated to dryness. The crude product is purified by column chromatography (SiO2, n-heptane:toluene=2:1), giving 4-bromo-2-(4-bromo-3-fluorophenyl)-5-ethyltetrahydropyran as a colourless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([NH:18][C:19](=[O:25])[C:20]([O:23][CH3:24])([CH3:22])[CH3:21])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH2:26]([N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1)[CH:27]=[CH2:28].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[CH2:26]([N:29]1[CH:33]=[C:32]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16]([NH:18][C:19](=[O:25])[C:20]([O:23][CH3:24])([CH3:22])[CH3:21])=[O:17])=[N:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)[CH:31]=[N:30]1)[CH:27]=[CH2:28]
Reactant: COC(C)(C)C(=O)NC(=O)Nc1ccc(Oc2ccnc(Cl)c2)cn1
Reactant: C=CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C=CCn1cc(-c2cc(Oc3ccc(NC(=O)NC(=O)C(C)(C)OC)nc3)ccn2)cn1
Temperature: 90 °C
Yield: 15.3 %

Procedure:
A mixture of Example C5 (0.12 g, 0.33 mmol), 1-allyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.085 g, 0.36 mmol) and K2CO3 (0.14 g, 0.99 mmol) in dioxane (4 mL) and H2O (1 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.040 g, 0.034 mmol), sparged again with Ar and heated at 90° C. overnight. The mixture was cooled to RT, treated with satd. NaHCO3, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via reverse phase silica gel chromatography (MeCN/H2O (0.1% TFA)) to obtain N-((5-((2-(1-allyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-2-methoxy-2-methylpropanamide (22 mg, 14.6%). 1H NMR (400 MHz, DMSO-d6): δ 10.83 (s, 1H), 10.21 (br s, 1H), 8.41 (d, J=5.8 Hz, 1H), 8.33 (s, 1H), 8.28 (d, J=2.9 Hz, 1H), 8.05 (s, 1H), 8.03 (br s, 1H), 7.76 (dd, J=9.0, 2.9 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 6.77 (d, J=5.7 Hz, 1H), 6.02 (m, 1H), 5.21 (m, 1H), 5.13 (m, 1H), 4.77 (d, J=5.8 Hz, 2H), 3.21 (s, 3H), 1.36 (s, 6H); MS (ESI) m/z: 437.2 (M+H+).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:22]1(=[O:28])[O:27][C:25](=O)[CH2:24][CH2:23]1.C(N(CC)CC)C.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[O:27]=[C:25]([N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)[CH2:24][CH2:23][C:22]([N:19]1[CH2:18][CH2:17][C:16](=[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)[CH2:21][CH2:20]1)=[O:28]
Reactant: C1COCCN1
Reactant: C1=Cc2ccccc2C(=C2CCNCC2)c2ccccc21
Reactant: O=C1CCC(=O)O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
In 50 ml of dichloromethane, 4-(5H-dibenzo [a,d]cyclohepten-5-ylidene)piperidine (0.27 g, 1.0 mmol), succinic anhydride (0.12 g, 1.2 mmol), and triethylamine (0.17 ml, 1.2 mmol) were stirred at room temperature overnight. Morpholine (0.14 ml, 1.6 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.27 g, 1.4 mmol) were added and the mixture was further stirred at room temperature for 8 hours. The reaction mixture was washed with 30 ml of 1 N hydrochloric acid, 30 ml of a 1 N aqueous sodium hydroxide solution, and 30 ml of a saturated aqueous sodium chloride solution, dried over magnesium sulfate powder, and purified by silica gel chromatography to obtain the titled compound. Amount obtained: 0.44 g (1.0 mol); Yield: 100%
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[S:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:27][CH2:28][N:29]([CH2:39][C:35]5[S:34][CH:38]=[CH:37][N:36]=5)[CH2:30][CH2:31]4)[N:24]=[CH:25][C:18]=23)=[CH:32][CH:33]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Reactant: O=Cc1nccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(Cc3nccs3)CC2)cc1

Procedure:
4-(4-Methanesulfonyl-phenoxy)-1-(1-thiazol-2-ylmethyl-piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine was prepared according to General Procedure H by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 25) with 2-thiazolecarboxaldehyde (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA), triethylamine, and sodium triacetoxyborohydride in 1,2-dichloroethane. 1H NMR (400 MHz, DMSO-d6) δ 1.95-2.00 (m, 2H), 2.21-2.33 (m, 2H), 2.39-2.45 (m, 3H), 3.04-3.08 (m, 2H), 3.30 (methyl sulfonyl and water peak), 3.92 (s, 2H), 4.79-4.85 (m, 1H), 7.63-7.74 (m, 4H), 8.05-8.07 (m, 2H), 8.39 (s, 1H), 8.56 (s, 1H). Mass spectrum MH+=471.