Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([CH3:15])[CH2:3][CH:4]([C:10](OCC)=[O:11])[C:5](OCC)=[O:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[OH:6][CH2:5][CH:4]([CH2:3][CH:2]([OH:1])[CH3:15])[CH2:10][OH:11]
Reactant: CCOC(=O)C(CC(C)=O)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)CC(CO)CO
Temperature: 25 °C
Yield: 100.1 %

Procedure:
A solution of 11.4 g of diethyl 2-oxopropylmalonate in 30 ml of tetrahydrofuran was added dropwise under ice-cooling over 20 minutes to a suspension of 5.00 g of lithium aluminum hydride in 100 ml of tetrahydrofuran. The reaction fluid was stirred for an hour under ice-cooling and for 4.5 hours at room temperature, and 10 ml of water was added thereto dropwise under ice-cooling over 20 minutes. The reaction fluid was refluxed for an hour and filtrated. The unfiltered solid was suspended in 200 ml of ethanol and the suspension was refluxed. The suspension was filtrated, and the filtrate combined with the foregoing filtrate was concentrated under a reduced pressure to obtain 7.08 g of 2-hydroxymethyl-1,4-pentanediol as a colorless oily matter.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]([N:23]([CH3:25])[CH3:24])[CH:5]=2.N1C=CC=CC=1.[C:32](Cl)(=[O:35])[CH2:33][CH3:34]>ClCCl.CCCCCC.CCOC(C)=O>[C:12]([C:11]1[CH:10]([C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:9]2[C:4](=[CH:5][C:6]([N:23]([CH3:25])[CH3:24])=[CH:7][CH:8]=2)[O:3][C:2]=1[NH:1][C:32](=[O:35])[CH2:33][CH3:34])#[N:13]
Reactant: CCC(=O)Cl
Reactant: CN(C)c1ccc2c(c1)OC(N)=C(C#N)C2c1ccc2c(c1)OCO2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCC(=O)NC1=C(C#N)C(c2ccc3c(c2)OCO3)c2ccc(N(C)C)cc2O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 14 %

Procedure:
To a solution of 2-amino-3-cyano-7-dimethylamino-4-(3,4-methylenedioxyphenyl)-4H-chromene (102 mg, 0.30 mmol) in dichloromethane (5 ml) was added pyridine (0.7 ml) at 0° C., followed by propionyl chloride (0.3 ml). The mixture was then stirred at room temperature for 4 h, diluted with 1:1 hexane/EtOAc (80 ml), washed with water, 2N HCl, water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (4:1 hexane/EtOAc) to yield the title compound as a yellow solid (16 mg, 14%). 1H NMR (CDCl3): 6.85-6.76 (m, 4H), 6.51-6.48 (m, 1H), 6.31 (m, 1H), 6.00-5.95 (m, 2H), 4.80 (s, 1H), 2.95 (s, 6H), 2.31 (q, J=7.5, 2H), 1.14 (t, J=7.5, 3H).
Reaction SMILES: [N:1]([C:4]1[N:9]=[C:8]([C:10]([C:12]2[C:17]([N:18]([CH2:32][O:33][CH3:34])[S:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)(=[O:21])=[O:20])=[CH:16][C:15]([Cl:35])=[CH:14][N:13]=2)=[O:11])[CH:7]=[CH:6][CH:5]=1)=[N+]=[N-].C(CCP(CCC(O)=O)CCC(O)=O)(O)=O>C1COCC1>[NH2:1][C:4]1[N:9]=[C:8]([C:10]([C:12]2[C:17]([N:18]([CH2:32][O:33][CH3:34])[S:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:30])([CH3:31])[CH3:29])=[CH:24][CH:23]=3)(=[O:20])=[O:21])=[CH:16][C:15]([Cl:35])=[CH:14][N:13]=2)=[O:11])[CH:7]=[CH:6][CH:5]=1
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1cccc(N=[N+]=[N-])n1)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: O=C(O)CCP(CCC(=O)O)CCC(=O)O
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)c1cccc(N)n1)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a mixture of N-[2-(6-azido-pyridine-2-carbonyl)-5-chloro-pyridin-3-yl]-4-tert-butyl-N-methoxymethyl-benzenesulfonamide (0.3 mmol, 155 mg) in THF (3 mL) was added 3-[bis-(2-carboxy-ethyl)-phosphanyl]-propionic acid (1 mmol, 250 mg). The mixture was stirred at 50° C. for 3 h. Upon completion of the reduction, the THF was removed under reduced pressure. The residue was diluted with EtOAc and the organics were washed with saturated sodium bicarbonate, dried with sodium sulfate, concentrated in vacuo, and purified via automated silica gel chromatography to generate the desired product. MS m/z: 489.1 (M+H)+.
Reaction SMILES: [C:1]([NH:8][C@H:9]([CH2:13][OH:14])[CH2:10][CH2:11][CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1(C)C=CC=CC=1.C(Cl)CCl.ClC(Cl)C(O)=O>CS(C)=O>[C:1]([NH:8][C@H:9]([CH:13]=[O:14])[CH2:10][CH2:11][CH3:12])([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: CCC[C@@H](CO)NC(=O)OC(C)(C)C
Agent: O=C(O)C(Cl)Cl
Solvent: ClCCCl
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CCC[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To Boc-norvalinol (7.77 g, 38 mmol), in anhydrous dimethylsulfoxide (153 mL) and toluene (153 mL) was added EDC (73.32 g, 382 mmol). After the solution was cooled to 0° C., dichloroacetic acid (15.8 mL, 191 mmol) was added dropwise. After addition was complete, the reaction was stirred for 15 min. The solution was allowed to warm to room temperature over a period of 2 h. The reaction mixture was concentrated to remove the toluene, then dissolved in ethyl acetate. The solution washed successively with 1 N sodium bisulfate, saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated to afford crude Boc-norvalinal which was used directly in the next step. TLC Rf=0.84 (40% ethyl acetate/hexanes).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:8][O:9][C:5]=2[CH:4]=1.B(Br)(Br)Br.Cl[CH2:21]Cl>>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[C:7]([CH2:10][C:11]([O:13][CH3:21])=[O:12])=[CH:8][O:9][C:5]=2[CH:4]=1
Reactant: ClCCl
Reactant: COc1ccc2c(CC(=O)O)coc2c1
Agent: BrB(Br)Br
Product: COC(=O)Cc1coc2cc(OC)ccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of 2-(6-methoxybenzofuran-3-yl)acetic acid (0.6 g, 2.9 mmol) in anhydrous dichloromethane (20 mL) at −78° C. was added boron tribromide (1.5 eq.) The reaction was stirred at −78° C. for 30 minutes, 0° C. for 2 hours, and at room temperature overnight. The reaction mixture was cooled to 0° C. and quenched slowly with methanol. After stirring for 15 minutes a saturated sodium bicarbonate solution was added slowly to the mixture and allowed to stir at 0° C. for 30 minutes. Ethyl acetate was added and the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give methyl 2-(6-methoxybenzofuran-3-yl)acetate (745) (67%).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:10]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)=[N:9]1)(=O)=O.[F-:33].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([C:10]2[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:12][N:8]([CH2:7][CH2:6][F:33])[N:9]=2)=[CH:20][CH:21]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: [F-]
Reactant: CS(=O)(=O)OCCn1cc(-c2ccncc2)c(-c2ccc(OCc3ccccc3)cc2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: FCCn1cc(-c2ccncc2)c(-c2ccc(OCc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
Intermediate 3A, 2-(3-(4-(benzyloxy)phenyl)-4-(pyridin-4-yl)-1H-pyrazol-1-yl)ethyl methanesulfonate (11 g) was added to a 1M solution of tetrabutylammonium fluoride in THF (150 mL) and the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography to obtain the desired Intermediate 3B, 4-(3-(4-(benzyloxy)phenyl)-1-(2-fluoroethyl)-1H-pyrazol-4-yl)pyridine (2.1 g, 23%) and the side product 4-(3-(4-(benzyloxy)phenyl)-1-vinyl-1H-pyrazol-4-yl)pyridine (2.0 g, 30%).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[CH2:11]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23](Cl)=[N:24][CH:25]=[N:26]2)=[CH:21][C:20]=1[O:30][CH3:31])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CN1CCCC1=O>[CH2:11]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([O:9][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[N:24][CH:25]=[N:26]2)=[CH:21][C:20]=1[O:30][CH3:31])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1ccccc1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc2c(Oc3ccccc3)ncnc2cc1OCc1ccccc1
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
Sodium hydride (400 mg of an 80% suspension in paraffin oil, 13.3 mmol) was added to a solution of phenol (1.26 g, 13.3 mmol) in dry N-methylpyrrolidone (20 ml) and the mixture stirred for 10 minutes. 7-Benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (1.6 g, 4.7 mmol), (prepared as described for the starting material in Example 1), was then added and the reaction mixture heated at 110° C. for 2 hours. The mixture was allowed to cool, water was added and the mixture extracted with ethyl acetate (3×100 ml). The combined extracts were then washed with 2M sodium hydroxide solution, water and brine. Removal of the solvent under reduced pressure gave 7-benzyloxy-6-methoxy-4-phenoxyquinazoline (1.6 g, 95%) as a yellowish solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:28])[N:11]([CH:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].[O:37]1[CH2:41][CH:40](O)[CH:39]([OH:43])[CH2:38]1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:28])[N:11]([CH:21]2[CH2:22][CH2:23][C:24]3([O:43][C@H:39]4[CH2:38][O:37][CH2:41][C@H:40]4[O:27]3)[CH2:25][CH2:26]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17]
Reactant: OC1COCC1O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC3(CC2)O[C@H]2COC[C@H]2O3)c2ncnn12
Temperature: 110 °C
Reaction time: 3 h
Yield: 110.4 %

Procedure:
A mixture of 3′-fluoro-4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1 g), tetrahydrofuran-3,4-diol (0.26 g), p-toluenesulfonic acid monohydrate (0.005 g) and toluene (50 mL) was subjected to an azeotropic dehydration reaction by stirring at 110° C. for 3 hr in a reaction vessel equipped with a Dean-stark trap. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.3 g, 100%).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:15]=[C:16]([F:35])[C:17]([O:27][C:28]2[CH:29]=[N:30][C:31]([Cl:34])=[CH:32][CH:33]=2)=[C:18]([CH:26]=1)[C:19](N(CC)CC)=[O:20]>C1COCC1>[Br:13][C:14]1[CH:26]=[C:18]2[C:17](=[C:16]([F:35])[CH:15]=1)[O:27][C:28]1[CH:29]=[N:30][C:31]([Cl:34])=[CH:32][C:33]=1[C:19]2=[O:20]
Reactant: CCN(CC)C(=O)c1cc(Br)cc(F)c1Oc1ccc(Cl)nc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=c1c2cc(Cl)ncc2oc2c(F)cc(Br)cc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium, 2.5 M (44.8 mL, 112 mmol) was added slowly to a solution of diisopropylamine (19.16 mL, 134 mmol) in THF (400 mL) at −78° C. The resulting solution was stirred at 0° C. for 15 minutes before cooling to −78° C. A solution of 5-bromo-2-(6-chloropyridin-3-yloxy)-N,N-diethyl-3-fluorobenzamide (30 g, 74.7 mmol) in THF (400 mL), cooled to −78° C., was added dropwise via cannula under positive pressure. The resulting solution was stirred 3 hours at −78° C. before being quenched with saturated ammonium chloride (200 mL). The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×250 mL). The combined organic extracts were washed with saturated aqueous ammonium chloride, water, saturated aqueous sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to provide an off white solid that was triturated with methanol. The derived solid was dried under a stream of nitrogen to provide 7-bromo-3-chloro-9-fluoro-5H-chromeno[2,3-c]pyridin-5-one. MS m/z=330.1 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=[O:5].[S:20](Cl)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>N1C=CC=CC=1>[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4](=[O:5])[C:3]1[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:2]=1[NH:1][S:20]([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc([N+](=O)[O-])cc2C(=O)c2ccccc2F)cc1

Procedure:
A mixture containing 10 g of 2-amino-5-nitro-2'-fluorobenzophenone and 7.5 g of tosyl chloride is refluxed in 50 ml of pyridine for 24 hours. The solvent is evaporated off to dryness, water and ethyl acetate are added, an insoluble material is filtered off and the organic phase is washed with a dilute solution of hydrochloric acid, water and an aqueous solution of sodium chloride and then dried over magnesium sulfate and evaporated. The residue is chromatographed on silica and the expected product is eluted with DCM.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[CH2:9])[CH:5]=[C:4]([CH2:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[C:29]1[CH:34]=[C:33]([CH3:35])[N:32]=[N:31][CH:30]=1)[NH2:25].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:11]([O:10][C:8]([C:6]1[CH:5]=[C:4]([CH2:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:3]=[C:2]([NH:25][C:24]2[CH:26]=[CH:27][C:28]([C:29]3[CH:34]=[C:33]([CH3:35])[N:32]=[N:31][CH:30]=3)=[C:22]([O:21][CH3:20])[CH:23]=2)[N:7]=1)=[CH2:9])[CH3:12]
Reactant: C=C(OCC)c1cc(COCC(F)(F)F)nc(Cl)n1
Reactant: COc1cc(N)ccc1-c1cnnc(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C=C(OCC)c1cc(COCC(F)(F)F)nc(Nc2ccc(-c3cnnc(C)c3)c(OC)c2)n1
Temperature: 120 °C
Yield: 62.6 %

Procedure:
2-Chloro-4-(1-ethoxyvinyl)-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (0.70 g, 2.36 mmol), 3-methoxy-4-(6-methylpyridazin-4-yl)aniline (0.508 g, 2.36 mmol), cesium carbonate (1.538 g, 4.72 mmol), palladium(II) acetate (0.079 g, 0.35 mmol) and 2-(dicyclohexylphosphino)biphenyl (0.124 g, 0.35 mmol) were mixed in dioxane (16 mL). The vial was capped, evacuated and flushed with nitrogen. The reaction mixture was heated at 120° C. for 1.5 h. The mixture was filtered and the filter was washed with mixtures of methanol and DCM. The filtrate was concentrated. The residue was purified by column chromatography on silica column eluting with a gradient of methanol and DCM to give the title compound as a solid 702 mg (63%).
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=O.[N+:14]1([O-:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([OH:25])=[O:24]>>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:2]([CH2:3][CH2:4][C:5]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([OH:25])=[O:24])=[O:7])=[O:1].[N+:14]1([O-:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)CCC(=O)c1ccccn1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [O-][n+]1ccccc1
Product: O=C(CCC(=O)N1CCC[C@H]1C(=O)O)c1ccccn1

Procedure:
As for Example 11, γ-oxo-2-pyridinebutyric acid, pyridine-1-oxide is coupled to L-proline to give 1-[3-(2-pyridylcarbonyl)propionyl]-L-proline, pyridine-1-oxide. Reaction of the preceding compound with bromine in acetic acid and reaction of the brominated compound with sodium thioacetate in acetonitrile gives the product of the Example as a glass.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11])[CH:5]=O.N1CCCCC1.C(O)=O.[CH3:23][C:24](=[O:29])[CH2:25][C:26](=[O:28])[CH3:27]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:25]([C:24](=[O:29])[CH3:23])[C:26](=[O:28])[CH3:27])[CH:7]=[CH:8][C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: CC(=O)CC(C)=O
Reactant: CS(=O)(=O)c1ccc(C=O)cc1Br
Solvent: C1CCNCC1
Solvent: O=CO
Solvent: O
Product: CC(=O)C(=Cc1ccc(S(C)(=O)=O)c(Br)c1)C(C)=O
Temperature: 20 °C

Procedure:
To a solution containing 0.68 g 3-bromo-4-methylsulfonylbenzaldehyde, 0.03 ml piperidine and 0.02 ml formic acid in 20 ml DMF was added 0.59 ml 2,4-pentanedione with stirring at 20° C. The solution was stirred overnight at 20° C. and poured into water. The product was extracted with ethyl acetate, washed with water and evaporated to dryness in vacuo. The residue was crystallized from methanol, yield 0.18 g (20%), mp 135-139° C. 1H-NMR (DMSO-d6, 400 MHz): 2.28 (s, 3 H, CH3), 2.50 (s, 3 H, CH3), 3.36 (s, 3 H, CH3), 7.60 (d, 1 H, Ar), 7.99 (d, 1 H, Ar), 8.12 (d, 1 H, Ar), 7.71 (s, 1 H, CH).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[N+:12]([O-])([OH:14])=[O:13].[N+]([O-])([O-])=O.[K+]>OS(O)(=O)=O.O>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc2ccccc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1cccc2c(Cl)nccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-chloroisoquinoline (3.6 g, 22.09 mmol) in conc. H2SO4 (24 mL) was added conc. HNO3 (8 mL) drop wise at 0-5° C. Then KNO3 (2.90 g, 28.71 mmol) was added to the reaction mixture portion wise at 0-5° C. The reaction mass was stirred at rt for 2 h and diluted with water then the reaction mixture was filtered. The filter cake was dissolved in 5% methanol in chloroform and was dried over Na2SO4. The organic layer was filtered and concentrated to afford 4.0 g of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.74 (t, J=6.9 Hz, 2H), 8.55 (d, J=6.3 Hz, 1H), 8.32 (d, J=6.0 Hz, 1H), 8.02 (t, J=8.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Br:8].[CH:10]1([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])[C:14]=2[CH2:26]O)[CH2:12][CH2:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1.C(Cl)Cl>[Br:8][C:7]1[CH:6]=[CH:5][C:4]([O:9][CH2:26][C:14]2[C:15]([C:18]3[C:19]([Cl:25])=[CH:20][CH:21]=[CH:22][C:23]=3[Cl:24])=[N:16][O:17][C:13]=2[CH:10]2[CH2:12][CH2:11]2)=[CH:3][C:2]=1[Cl:1]
Reactant: Oc1ccc(Br)c(Cl)c1
Reactant: OCc1c(-c2c(Cl)cccc2Cl)noc1C1CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Clc1cc(OCc2c(-c3c(Cl)cccc3Cl)noc2C2CC2)ccc1Br
Temperature: 25 °C
Reaction time: 21 h

Procedure:
3-Chloro-4-bromophenol (3.8 g, 18.3 mmol) was mixed with (5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methanol (3.47 g, 12.2 mmol) and triphenylphosphine (6.41 g, 24.4 mmol) in toluene (150 mL). The mixture was cooled in an ice-bath and DIAD (4.8 mL, 24.4 mmol) as a solution in toluene (10 mL) was added drop-wise. The reaction was stirred at rt for 21 h and the solvents were removed on a rotavap leaving a yellow oily residue. This was dissolved in DCM (200 mL), silica (˜20 g) was added and the mixture was evaporated to dryness. This material was loaded on the top of a silica column and purified eluting with hexanes/MTBE 9:1. The product containing fractions were pooled and the solvent removed under reduced pressure, leaving pure product 8e as a colourless oil that crystallized upon drying under vacuum overnight. Yield: 5.07 g (88%). 1H-NMR (CDCl3), δ (ppm): 7.45-7.30 (m, 4H), 6.90 (s, 1H), 6.60-6.55 (m, 1H), 2.15-2.07 (m, 1H), 1.32-1.25 (m, 2H), 1.20-1.11 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]2([F:25])[CH2:7][N:6]([C:8]3[N:13]=[C:12]([S:14]([CH3:17])(=O)=O)[N:11]=[C:10]([NH:18][C:19]4[NH:23][N:22]=[C:21]([CH3:24])[CH:20]=4)[CH:9]=3)[CH2:5]2)[CH2:3][CH2:2]1.[NH2:26][C:27]1[N:32]=[CH:31]C(S)=[CH:29][CH:28]=1>CN(C=O)C.C(OC(=O)C)C.C([O-])(O)=O.[Na+]>[NH2:26][C:27]1[N:32]=[CH:31][C:17]([S:14][C:12]2[N:11]=[C:10]([NH:18][C:19]3[NH:23][N:22]=[C:21]([CH3:24])[CH:20]=3)[CH:9]=[C:8]([N:6]3[CH2:7][C:4]([CH:1]4[CH2:3][CH2:2]4)([F:25])[CH2:5]3)[N:13]=2)=[CH:29][CH:28]=1
Reactant: Nc1ccc(S)cn1
Reactant: Cc1cc(Nc2cc(N3CC(F)(C4CC4)C3)nc(S(C)(=O)=O)n2)[nH]n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2cc(N3CC(F)(C4CC4)C3)nc(Sc3ccc(N)nc3)n2)[nH]n1
Reaction time: 2 h
Yield: 30 %

Procedure:
A solution of 6-(3-cyclopropyl-3-fluoroazetidin-1-yl)-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylsulfonyl)pyrimidin-4-amine (880 mg, 2.4 mmol) and 6-aminopyridine-3-thiol) (300 mg, 2.4 mmol) in DMF (10 ml) was heated to 80° C. and stirred for 2 hrs. The reaction was diluted with ethylacetate (150 ml) and Sat. NaHCO3 (50 ml) and the organic layer washed with brine (50 ml), dried (MgSO4) and concentrated to give an oil. The residue was purified by flash column chromatography eluting with Pentane/EtOAc (5% MeOH) 0 to 100%. The resulting compound was triturated in 10:1 DCM:MeOH and filtered to give the title compound as a white solid (300 mg, 30%). 1H NMR (DMSO, 400 MHz) 0.42-0.44 (2H, m), 0.55-0.60 (2H, m), 1.35-1.45 (1H, m), 2.11 (3H, s), 3.81-3.90 (4H, m), 5.55-5.80 (2H, m), 6.35 (2H, s), 6.49-6.52 (1H, d), 7.46-7.49 (1H, d), 7.97 (1H, s), 9.30-9.35 (1H, s). ES+413
Reaction SMILES: C(O[C:4](=[O:14])[CH:5]([CH3:13])[C:6]([C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)=O)C.[NH:15]([C:17]1[CH:36]=[CH:35][C:20]([C:21]([NH:23][CH:24]2[CH2:29][C:28]([CH3:31])([CH3:30])[N:27]([CH3:32])[C:26]([CH3:34])([CH3:33])[CH2:25]2)=[O:22])=[CH:19][CH:18]=1)[NH2:16]>C(O)(=O)C>[O:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[C:6]1[NH:16][N:15]([C:17]2[CH:36]=[CH:35][C:20]([C:21]([NH:23][CH:24]3[CH2:25][C:26]([CH3:33])([CH3:34])[N:27]([CH3:32])[C:28]([CH3:31])([CH3:30])[CH2:29]3)=[O:22])=[CH:19][CH:18]=2)[C:4](=[O:14])[C:5]=1[CH3:13]
Reactant: CN1C(C)(C)CC(NC(=O)c2ccc(NN)cc2)CC1(C)C
Reactant: CCOC(=O)C(C)C(=O)c1ccco1
Solvent: CC(=O)O
Product: Cc1c(-c2ccco2)[nH]n(-c2ccc(C(=O)NC3CC(C)(C)N(C)C(C)(C)C3)cc2)c1=O

Procedure:
3-furan-2-yl-2-methyl-3-oxo-propionic acid ethyl ester (49 mg) and 4-Hydrazino-N-(1,2,2,6,6-pentamethyl-piperidin-4-yl)-benzamide (85 mg) in 0.5 ml of acetic acid were heated up at 65° C. for 2 h. Concentration in vacuo and purification by HPLC gave the expected product. MH+=437.3