Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[C:23](=[O:28])N(OC)C)=[O:16])([CH3:13])([CH3:12])[CH3:11].[Cl-].[NH4+]>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:23]([CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][N:17]1[C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])=[O:28]
Reactant: c1ccc2occc2c1
Reactant: CON(C)C(=O)C1CCCCN1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)c1cc2ccccc2o1
Yield: 28.9 %

Procedure:
To a solution of benzofuran (0.37 ml, 3.36 mmol) in THF (40 ml) at −35° C. was added nbutyllithium (1M in THF) (3.34 ml, 3.34 mmol) over 3 min. The resultant mixture was stirred for 10 min. at −35° C. then (RS)-1-(tert-butyloxycarbonyl)-2-(N-methoxy-N-methylcarbamoyl)-piperidine (1.0 g, 3.68 mmol) in THF (5 ml) was added over 1 min. and the resultant solution stirred for 15 min. at −35° C. The mixture was poured into saturated ammonium chloride (20 ml) and extracted with ethyl acetate (3×20 ml). The combined organics were washed with saturated aqueous sodium hydrogen carbonate (15 ml), then evaporated in vacuo. The resultant residue was chromatographed on silica gel eluting with 10% ethyl acetate in hexane to give the title compound (0.32 g, 26%) as a yellow solid.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[C:15]([F:16])=[CH:14][C:13]([O:17][CH2:18][CH3:19])=[CH:12][C:11]=3[F:20])[N:7]=[C:6]([C:21]3[N:26]=[C:25]([NH:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][C:29]=4[C:34]([O:36]CC)=[O:35])[C:24]([O:39][CH3:40])=[CH:23][N:22]=3)[C:5]=2[CH3:41])[CH2:3][CH2:2]1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO>[CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[C:11]([F:20])=[CH:12][C:13]([O:17][CH2:18][CH3:19])=[CH:14][C:15]=3[F:16])[N:7]=[C:6]([C:21]3[N:26]=[C:25]([NH:27][C:28]4[C:29]([C:34]([OH:36])=[O:35])=[CH:30][N:31]=[CH:32][CH:33]=4)[C:24]([O:39][CH3:40])=[CH:23][N:22]=3)[C:5]=2[CH3:41])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cnccc1Nc1nc(-c2nn(Cc3c(F)cc(OCC)cc3F)c(C3CC3)c2C)ncc1OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1cc(F)c(Cn2nc(-c3ncc(OC)c(Nc4ccncc4C(=O)O)n3)c(C)c2C2CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 86.7 %

Procedure:
To a solution of 722 mg of ethyl 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino)-pyridine-3-carboxylate 2-6-5 (1.28 mmol, 1.0 eq) in 13 mL THF and 1.6 mL methanol were added 256 mg sodium hydroxide (6.39 mmol, 5.0 eq). The mixture was stirred for 45 minutes at rt. Using 10% aqueous citric acid the pH of the mixture was adjusted to 3.5. The resulting suspension was filtered. The precipitate was washed with water and ethanol and subsequently dried to provide 660 mg of the desired product (1.11 mmol, 87%) as 90% pure target compound.
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].C(N(CC)CC)C.[F:14][C:15]1[CH:16]=[C:17]([N:22]2[CH2:26][C@H:25]([CH2:27][N:28]3[CH:32]=[C:31]([CH3:33])[N:30]=[N:29]3)[O:24][C:23]2=[O:34])[CH:18]=[CH:19][C:20]=1I>[Cu](I)I>[F:14][C:15]1[CH:16]=[C:17]([N:22]2[CH2:26][C@H:25]([CH2:27][N:28]3[CH:32]=[C:31]([CH3:33])[N:30]=[N:29]3)[O:24][C:23]2=[O:34])[CH:18]=[CH:19][C:20]=1[C:2]#[C:1][Si:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1cn(C[C@H]2CN(c3ccc(I)c(F)c3)C(=O)O2)nn1
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: Cc1cn(C[C@H]2CN(c3ccc(C#C[Si](C)(C)C)c(F)c3)C(=O)O2)nn1
Temperature: 60 °C
Yield: 94 %

Procedure:
Ethynyl(trimethyl)silane (432 mg, 4.4 mmol), copper iodide(76 mg, 0.4 mmol), triethylamine (2.02 g, 20 mmol) and palladium tetrakis triphenylphosphine (231 mg, 0.2 mmol) were added to a solution of (5R)-3-(3-fluoro-4-iodophenyl)-5-[(4-methyl-1H-1,2,3-triazol-1-yl)methyl]-1,3-oxazolidin-2-one (WO2003072575) (Intermediate 2,1.61 g, 4.0 mmol) in a sealed reaction vessel. The reaction mixture was stirred at 60° C. over night, then cooled down to room temperature and filtered through celite. The filtrate was concentrated and purified by flash chromatography on silica gel with 30% hexanes in ethyl acetate. The product was obtained as a yellowish solid (1.4 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[N:13][C:12](O)=[C:11]1[C:6]=2[CH:7]=[CH:8][CH:9]=[CH:10]1.P(Cl)(Cl)([Cl:19])=O.CN(C)C=O>>[Cl:19][C:12]1[N:13]=[C:14]2[C:5](=[C:6]3[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]3)[CH:4]=[CH:3][C:2]([F:1])=[CH:15]2
Reactant: Oc1nc2cc(F)ccc2c2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Fc1ccc2c(c1)nc(Cl)c1ccccc12
Temperature: 65 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To a mixture of 3-fluorophenanthridin-6-ol (Example 1a, 1.58 g, 7.41 mmol) in phosphorus oxychloride (11.7 g, 7.1 mL, 76 mmol) was added dimethylformamide (0.34 g, 0.46 mmol), and the reaction mixture was warmed to 65° C. and stirred under nitrogen for 1 h. The reaction mixture was cooled to room temperature, followed by the careful addition of ice to the reaction mixture. The mixture was stirred for 20 min, and the extracted with ethyl acetate. The resulting organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and evaporated to provide the title compound (1.2 g, 70% yield), which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:26](=[O:28])[CH3:27])[CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:27][C:26]([C:18]2[CH:19]=[C:20]([O:24][CH3:25])[C:21]([O:22][CH3:23])=[C:16]([O:15][CH3:14])[CH:17]=2)=[O:28])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10]
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Product: COc1cc(C(=O)C=Cc2cc(O)c(O)c([N+](=O)[O-])c2)cc(OC)c1OC

Procedure:
The procedure described in Example 8 was repeated using 0.55 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.63 g of 3',4',5'-trimethoxyacetophenone. Yield 0.50 g (44%), m.p.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[OH-].[K+].[OH:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]>O>[CH3:5][O:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]
Reactant: O=C(CO)c1ccccc1
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
250 g (1.98 mol) of dimethyl sulfate is added dropwise to a mixture of 130 g of potassium hydroxide in 1.1 of water and 260 g (1.90 mol) of 2-hydroxyacetophenone with cooling and vigorous stirring in such a way that the reaction solution is not heated above 40° C. After the reaction temperature has then been kept at 80° C. for 30 minutes, the mixture is allowed to cool to room temperature and extracted by shaking with a total of 250 ml of chloroform. The organic phase is shaken three times with 100 ml of 2N sodium hydroxide solution each time and dried over sodium sulfate. After filtration and removal of the solvent on a rotary evaporator, the oil obtained is distilled in vacuo.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:15]([CH3:24])[CH:16]([OH:23])[CH2:17][C:18]([O:20]CC)=[O:19])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C>O>[C:1]([C:9]1[CH:10]=[C:11]([CH:15]([CH3:24])[CH:16]([OH:23])[CH2:17][C:18]([OH:20])=[O:19])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(O)C(C)c1cccc(C(=O)c2ccccc2)c1
Solvent: O
Solvent: CCO
Product: CC(c1cccc(C(=O)c2ccccc2)c1)C(O)CC(=O)O

Procedure:
A mixture of 818 mg of ethyl 4-(m-benzoyl-phenyl)-3-hydroxy-4-methyl-butyrate, 8 ml of ethanol, 0.8 ml of water and 0.2 ml of 14N potassium hydroxide was refluxed for 11/2 hours and then was evaporated to dryness under reduced pressure. The residue was taken up in 20 ml of water and the solution was acidified to a pH of 1 by progressive addition of a 1N hydrochloric acid solution and was then extracted with methylene chloride. The organic phase was washed with water and evaporated to dryness under reduced pressure to obtain 4-(m-benzoyl-phenyl)-3-hydroxy-4-methyl-butyric acid in the form of a product soluble in alcohols, methylene chloride and chloroform.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.Cl[S:12]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=[O:19])(=[O:14])=[O:13]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]([CH3:10])[S:12]([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([OH:20])=[O:19])(=[O:14])=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: CNCc1cccc(Br)c1
Solvent: ClCCl
Product: CN(Cc1cccc(Br)c1)S(=O)(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
1-(3-Bromophenyl)-N-methylmethanamine (0.100 g, 0.5 mmol) in DCM (5 mL) was added TEA (0.139 mL, 1.000 mmol) and 3-(chlorosulfonyl)benzoic acid (0.110 g, 0.500 mmol). The resulting mixture was stirred at room temperature for 0.5 h. The reaction was quenched with HCl (1 N), concentrated and redissolved in EtOAc (10 mL) which was washed with H2O (2×3 mL), brine (3 mL), then dried with Na2SO4. It was then filtered and concentrated to afford the title compound (0.1505 g, 78%). LC-MS m/z 384 (M+H)+.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([CH2:30][OH:31])[C:25]=1[CH2:32][O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1>C1COCC1>[Cl:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([CH:30]=[O:31])[C:25]=1[CH2:32][O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1
Reactant: OCc1nccc(Cl)c1COC1CCCCO1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Product: O=Cc1nccc(Cl)c1COC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dess-Martin periodinane (370 mg. 0.873 mmol) was added to a stirred solution of [4-chloro-3-(tetrahydro-pyran-2-yloxymethyl)-pyridin-2-yl]-methanol (150 mg. 0.582 mmol) in THF (5 mL). After stirring for 2 h at room temperature the reaction was concentrated. Sat. NaHCO3 solution (20 mL) was added and extracted three times with DCM (50 mL). The combined organic layers were dried over Na2SO4 filtered and concentrated in vacuo. The resulting title compound was used for the next reaction without purification. MS (m/z): 255.7 [M+H+].
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)=[N:5][CH:4]=[C:3]1[C:19]([NH2:21])=O.N1C=CC=CC=1>P(Cl)(Cl)(Cl)=O>[O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)=[N:5][CH:4]=[C:3]1[C:19]#[N:21]
Reactant: NC(=O)c1cnc(-c2ccccc2OCC2CC2)[nH]c1=O
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cnc(-c2ccccc2OCC2CC2)[nH]c1=O
Reaction time: 18 h
Yield: 59.7 %

Procedure:
1,6-Dihydro-6-oxo-2-(2-cyclopropylmethoxyphenyl)pyrimidine-5-carboxamide (13.6 g., 0.0476 mole) was added to a stirred, cold solution of pyridine (18.9 g., 0.24 mole) in phosphorus oxychloride (136 ml.), and the mixture heated under reflux for 15 minutes. The mixture was evaporated to dryness and the residue added to a mixture of ice and mthylene chloride. The mixture was neutralized with sodium bicarbonate. The methylene chloride layer was dried (sodium sulfate) and concentrated. To the residual oil was added 1N sodium hydroxide (15 ml.) and tetrahydrofuran (10 ml.). The mixture was allowed to stand at 25° for 18 hours. The mixture was washed with diethyl ether, filtered, and the filtrate acidified with acetic acid. The precipitate was recrystallized from toluene to give the title compound (7.6 g., 59.6%), m.p. 188°-190°. Two recrystallizations from ethyl acetate gave analytical material, m.p. 187°-189°.
Reaction SMILES: [CH2:1]([S:5][C:6]1[N:11]=[C:10](Cl)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[N+:13]([C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][NH:20]2)([O-:15])=[O:14].[H-].[Na+].CN1C(=O)CCC1>O>[CH2:1]([S:5][C:6]1[N:11]=[C:10]([N:20]2[C:21]3[C:17](=[C:16]([N+:13]([O-:15])=[O:14])[CH:24]=[CH:23][CH:22]=3)[CH:18]=[N:19]2)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Reactant: CCCCSc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCCSc1nccc(-n2ncc3c([N+](=O)[O-])cccc32)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
To a flask loaded with 2-butylsulfanyl-4-chloro-pyrimidine (202 mg) was added 4-nitro-1H-indazole (228 mg), followed by NaH (60% dispersion in mineral oil, 84 mg) and NMP (4 mL). The resulting mixture was stirred at RT overnight, water added, and the mixture extracted with EtOAc. The combined organic extracts were washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (hexane/EtOAc, 80:20) to give 1-(2-butylsulfanyl-pyrimidin-4-yl)-4-nitro-1H-indazole (156 mg).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]3[CH:13]=[N+:14]([O-])[CH:15]=[CH:16][CH:17]=3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(=O)C)(=[O:21])C>>[O:21]=[C:13]1[C:12]([C:9]2[S:10][CH:11]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)=[CH:17][CH:16]=[CH:15][NH:14]1
Reactant: [O-][n+]1cccc(-c2nc(-c3ccccc3)cs2)c1
Reactant: CC(=O)OC(C)=O
Product: O=c1[nH]cccc1-c1nc(-c2ccccc2)cs1

Procedure:
In 25 ml of acetic anhydride was dissolved 2.8 g of 3-(4-phenylthiazol-2-yl)pyridine-N-oxide. The solution was refluxed for 6 hours with heating. The solvent was removed by distillation. The residue was treated with ammonia water and extracted with dichloromethane. The extract was water-washed, dried and subjected to solvent removal by distillation. The residue was mixed with a small amount of dichloromethane. The resulting crystals were collected by filtration and recrystallized from methanol to obtain 60 mg of 2-(2-oxopyridin-3-yl)4-phenylthiazole as light brown plate crystals.
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[NH+:8]([O-:13])[C:7]([CH3:15])([CH3:14])[CH2:6]1)[CH2:2][CH3:3].[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>C1(C)C=CC=CC=1.O.[Pt]>[CH3:18][C:17]([CH3:20])([CH3:19])[C:16]([O:13][N:8]1[C:7]([CH3:14])([CH3:15])[CH2:6][CH:5]([O:4][CH2:1][CH2:2][CH3:3])[CH2:10][C:9]1([CH3:12])[CH3:11])=[O:21]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCCOC1CC(C)(C)[NH+]([O-])C(C)(C)C1
Agent: [Pt]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCOC1CC(C)(C)N(OC(=O)C(C)(C)C)C(C)(C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
21.4 g (0.1 mol) of 4-propoxy-2,2,6,6-tetramethylpiperidine N-oxide (for preparation, see DE-A-4 219 459) are hydrogenated to saturation at 4 bar in 20 ml of toluene using 0.05 g of platinum (10% on carbon). The catalyst is filtered off and 13 g (0.108 mol) of pivaloyl chloride are slowly added dropwise to the colourless filtrate under nitrogen. After the slightly exothermic reaction has abated, the mixture is stirred for another 1 hour at room temperature and diluted with 20 ml of water. The organic phase is washed with 4% NaOH solution, dried over MgSO4 and freed of the toluene on a rotary evaporator. This gives 13.5 g (45%) of the compound 110 which is in the form of a colourless oil.
Reaction SMILES: COP([CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[O:8]1)(=O)OC.[F:17][C:18]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22][C:19]=1[C:20]#[N:21].C(N(CC)CC)C>O1CCCC1>[F:17][C:18]1[CH:25]=[CH:24][C:23]([CH:26]=[C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[O:8]2)=[CH:22][C:19]=1[C:20]#[N:21]
Reactant: COP(=O)(OC)C1OC(=O)c2ccccc21
Reactant: N#Cc1cc(C=O)ccc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1cc(C=C2OC(=O)c3ccccc32)ccc1F
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a mixture of (3-oxo-1,3-dihydro-isobenzofuran-1-yl)phosphonic acid dimethyl ester (35.0 g, 0.14 mol) in tetrahydrofuran (200 ml) and 2-fluoro-5-formylbenzonitrile (20.9 g, 0.14 mol) in tetrahydrofuran (130 ml) was added triethylamine (14 ml, 0.14 mol) drop-wise over 25 min, with the temperature kept below 15° C. The reaction mixture was warmed slowly to 20° C. over 1 hour and concentrated in vacuo. The white residue was slurried in water (250 ml) for 30 minutes, filtered, washed with water, hexane and ether, and dried to yield 2-fluoro-5-(3-oxo-3H-isobenzofuran-1-ylidenemethyl)benzonitrile as a 50:50 mixture of E and Z isomers (37.2 g, 96%); m/z [M+1]+ 266 (98% purity)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](=O)[O:9][CH:10]([CH2:11][CH3:12])[C:4]=2[C:3]=1[Cl:14].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][C:16]1=[O:24]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](=[C:17]3[C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[NH:15][C:16]3=[O:24])[O:9][CH:10]([CH2:11][CH3:12])[C:4]=2[C:3]=1[Cl:14]
Reactant: O=C1Cc2ccccc2N1
Reactant: CCC1OC(=O)c2cnc(Cl)c(Cl)c21
Product: CCC1OC(=C2C(=O)Nc3ccccc32)c2cnc(Cl)c(Cl)c21

Procedure:
In a manner similar to Example 46, 6,7-dichloro-1-ethyl-1H-furo[3,4-c]pyridine-3-one and 1,3-dihydroindol-2-one are converted to the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:10]2[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:35]([S:37](Cl)(=[O:39])=[O:38])[CH3:36]>ClCCl>[CH2:13]([CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([CH2:2][NH:1][S:37]([CH2:35][CH3:36])(=[O:39])=[O:38])[CH:12]=2)[CH2:7][CH2:8][CH:9]1[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(CN)cc2C1Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)NCc1ccc2c(c1)C(Cc1ccccc1)C(NC(=O)OC(C)(C)C)CC2
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
tert-Butyl 7-(aminomethyl)-1-benzyl-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (0.600 g, 1.637 mmol) was suspended in dichloromethane (5 mL) and triethylamine (0.228 mL, 1.637 mmol) and cooled to 0° C. Ethanesulfonyl chloride (0.155 mL, 1.64 mmol) was added and the solid gradually dissolved. After 30 minutes the reaction was stopped by washing it with brine (1×50 mL). The organic phase was collected and dried on MgSO4, evaporated. The residue was purified by flash-chromatography on silica gel (100% DCM). Product was obtained as yellow solid (0.653 g, 1.42 mmol, 87%).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH2:3][CH2:2]1.FC(F)(F)S(O[C:22]1[CH:35]=[C:34]2[C:25]([O:26][C:27]3[CH:28]=[CH:29][C:30]([C:41]4[CH:42]=[N:43][CH:44]=[N:45][CH:46]=4)=[CH:31][C:32]=3[C@:33]32[CH2:39][O:38][C:37]([NH2:40])=[N:36]3)=[CH:24][C:23]=1[F:47])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.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>[O:1]1[CH2:2][CH:3]=[C:4]([C:22]2[C:23]([F:47])=[CH:24][C:25]3[O:26][C:27]4[C:32](=[CH:31][C:30]([C:41]5[CH:46]=[N:45][CH:44]=[N:43][CH:42]=5)=[CH:29][CH:28]=4)[C@@:33]4([CH2:39][O:38][C:37]([NH2:40])=[N:36]4)[C:34]=3[CH:35]=2)[CH2:5][CH2:6]1
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cncnc3)ccc1Oc1cc(F)c(OS(=O)(=O)C(F)(F)F)cc12
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
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: CN(C)C=O
Solvent: O
Product: NC1=N[C@@]2(CO1)c1cc(-c3cncnc3)ccc1Oc1cc(F)c(C3=CCOCC3)cc12
Temperature: 85 °C

Procedure:
A 0.5-2 ml microwave vial was charged with tetrakis(triphenylphosphine)palladium(0) (27.9 mg, 0.024 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (86 mg, 0.411 mmol). A solution of (S)-2-amino-6′-fluoro-2′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl trifluoromethanesulfonate (120 mg, 0.242 mmol) in DMF (1612 μL) was added followed by sodium carbonate (2M solution) (363 μL, 0.725 mmol). The vial was sealed and heated in microwave reactor at 85° C. for 1 hr. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, filtered through celite and concentrated to leve brown oil. The crude material was purified by silica gel chromatography on 12 g RediSep column using (15-60% DCM/MeOH/NH4OH 90:10:1 in DCM) to afford (S)-2′-(3,6-dihydro-2H-pyran-4-yl)-3′-fluoro-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine. Found MS: MH+=431.
Reaction SMILES: O[Li].O.[OH:4][C:5]1[C:10]([C:11]([O:13]C)=[O:12])=[CH:9][N:8]=[CH:7][N:6]=1>O.O1CCCC1>[OH:4][C:5]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=[CH:7][N:6]=1
Reactant: COC(=O)c1cncnc1O
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cncnc1O
Reaction time: 0.75 h

Procedure:
The moist sodium salt of methyl 4-hydroxypyrimidine-5-carboxylate obtained as in Example 2a) was taken up in water/tetrahydrofuran=1:1, and 1.0 eq of LiOH.H2O was added. Following hydrolysis of the ester over 3.5 hours at 0° C. and 2 hours at room temperature, most of the tetrahydrofuran was evaporated and, at 0° C., a pH of 3 was adjusted using eq. HCl solution. After about 45 minutes at 0° C., the title product was filtered off. Drying gave the acid in a yield of 3.55 g (78%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=2[N:7]=1.[CH3:28][N:29]([CH3:48])[S:30]([C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)(=[O:32])=[O:31].C(=O)(O)[O-].[Na+].O>COCCOC.O>[CH3:28][N:29]([CH3:48])[S:30]([C:33]1[CH:34]=[CH:35][C:36]([C:2]2[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]3[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=3[CH3:25])=[O:16])[C:5]3[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=3[N:7]=2)=[CH:37][CH:38]=1)(=[O:31])=[O:32]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2c(C)nn3C(C)C)c(=O)[nH]1
Reactant: CN(C)S(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(S(=O)(=O)N(C)C)cc3)nc3c2c(C)nn3C(C)C)c(=O)[nH]1
Yield: 81.4 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (75 mg, 0.19 mmol) and N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (90 mg, 0.29 mmol) in DME/water (3 ml:1 ml). PdCl2 (dppf)-CH2Cl2 adduct (7.9 mg, 0.009 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (48.7 mg, 0.58 mmol) was added, the vessel was sealed, and the reaction mixture was irradiated (microwave) at 150° C. for 30 min. After cooling, 2 mL of water was added and solids that precipitated were filtered. DCM/MeOH (1:1) was added, the mixture was pre-absorbed on silica gel and purified by silica gel chromatography (eluent: gradient 0 to 90:10:1 DCM/MeOH/NH4OH). The isolated product was treated with EtOH/EtOAc (1:1), the solids filtered and washed with EtOAc and DCM, and then dried to afford the title compound (83 mg, 78%) as a white solid. LCMS E-S (M+H)=537.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1H) 8.79 (t, J=4.93 Hz, 1H) 8.47 (m, J=8.59 Hz, 2H) 7.90 (m, J=8.59 Hz, 2H) 7.80 (s, 1H) 5.89 (s, 1H) 5.28 (quin, J=6.69 Hz, 1H) 4.40 (d, J=5.05 Hz, 2H) 2.66 (s, 6H) 2.47 (s, 3H) 2.25 (s, 3H) 2.12 (s, 3H) 1.53 (s, 3H) 1.51 (s, 3H).