Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(Cl)Cl>O>[CH3:16][S:17]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:19])=[O:18]
Reactant: OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccccc1
Temperature: -5 °C
Yield: 85 %

Procedure:
Under nitrogen methylene chloride (1.4 liter), benzyl alcohol (129.6 g., 1.2 moles) and triethylamine (182 g., 1.8 moles) were combined, stirred and cooled to -5° C. in an ice-water-acetone bath. A solution of methanesulfonyl chloride (150 g., 1.31 moles) in 100 ml. of methylene chloride was added over 49 minutes, maintaining the temperature between -5° and 2° C. After stirring for 10 minutes at 0°-2° C., the reaction was diluted with 500 ml. of water, precooled to 5° C. The organic layer was separated, washed 2×500 ml. of cold water, dried over MgSO4, filtered and evaporated in vacuo to yield title product as a light yellow oil [190 g.; 85%, 1H-NMR (CDCl3) delta (ppm): 2.9 (s, 3H), 5.2 (s, 2H), 7.4 (m, 5H); Rf 0.75 (CH2Cl2 )]. This product was refrigerated until used in the next step.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[CH:15]N(C)C)[C:10](OCC)=[O:11])=[C:5]([O:19][CH3:20])[CH:4]=1)#[N:2].[NH:21]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][N:24]=1)[NH2:22].Cl.CCN(C(C)C)C(C)C>CC(O)C.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:15]=[N:22][N:21]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][N:24]=3)[C:10]=2[OH:11])=[C:5]([O:19][CH3:20])[CH:4]=1)#[N:2]
Reactant: CCOC(=O)C(=CN(C)C)c1ccc(C#N)cc1OC
Reactant: NNc1ccc(C(=O)O)cn1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Temperature: 50 °C
Reaction time: 32 h
Yield: 48.5 %

Procedure:
Combined ethyl 2-(4-cyano-2-methoxyphenyl)-3-(dimethylamino)acrylate (1.427 g, 5.20 mmol), 6-hydrazinylnicotinic acid (0.664 g, 4.34 mmol), and HCl (4.34 mL, 4.34 mmol) in 2-propanol (21.7 mL) and stirred at room temperature for 8 hours to give a solid. The solid was collected by filtration and combined with Hunig's base (1.50 mL, 8.61 mmol) in 2-propanol (10 mL) and water (1 mL) and stirred for 32 hours at 50° C., then 10 mL of 1 N HCl was added and the reaction was filtered to give a solid. The solid was washed with 30 mL MeOH and 30 mL of ether and dried in vacuo to give the title compound (708 mg, 73.3%) as a beige solid. MS m/z [M+H]+ 337.3.
Reaction SMILES: F[C:2]1[C:3]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[C:22]1([SH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH3:15][S:12]([C:3]1[C:2]([S:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])(=[O:14])=[O:13]
Reactant: COC(=O)c1cccc(F)c1S(C)(=O)=O
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cccc(Sc2ccccc2)c1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 46.3 %

Procedure:
A mixture of methyl 3-fluoro-2-methylsulphonylbenzoate (10.9 g), potassium carbonate (7.8 g) and thiophenol (5.4 g) in N,N-dimethylformamide was stirred at 25° C. for six hours. Water and ethyl acetate were added and the resulting solid collected by filtration and combined with the solid obtained from washing the organic phase of the flitrate with brine, drying over magnesium sulphate, filtering and evaporating. This product was recrystallised from ethyl acetate to give 7.0 g of methyl 2-methylsulphonyl-3-phenylsulphenylbenzoate as white crystals, mp 151.1° C.
Reaction SMILES: CNN(NC)[C:4]([S:6][C:7]1[C:8]([C:13]([O:15][CH3:16])=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=1)=O.CO.C[O-].[Na+].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29](CS)=[CH:28][CH:27]=1>CO>[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:4][S:6][C:7]2[C:8]([C:13]([O:15][CH3:16])=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:28][CH:27]=1
Reactant: CNN(NC)C(=O)Sc1cccnc1C(=O)OC
Reactant: COc1ccc(CS)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ncccc1SCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.2 %

Procedure:
A solution of 1.20 g (5 mmol) of methyl 3-(N,N-dimethylaminocarbamoylthio)pyridine-2-carboxylate in 5 mL of methanol and 1.5 mL (6 mmol) of 4.lM sodium methoxide methanol was stirred at room temperature for 10 minutes. Then the solvent was concentrated and the residue was dissolved in 5 mL of N,N-dimethylformamide and 5 mL of tetrahydrofuran. 0.936 g (6 mmol) of p-methoxybenzylmercaptan was added and the solution was stirred at room temperature for 18 hours. The solution was partitioned between ether and water and the aqueous layer was extracted with two portions of ether. The combined extracts were washed with brine, dried and concentrated. Recrystallization from methanol afforded 0.90 g (62%) of pale tan needles, m.p. 99°-100° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[C:4]=1[CH2:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[NH:9][C:8](=[O:18])[CH2:7]1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:33][C:34]([F:38])([F:37])[CH2:35]I>CN(C=O)C.C(OCC)(=O)C.O>[F:33][C:34]([F:38])([F:37])[CH2:35][N:9]1[C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12](=[O:13])[N:6]([CH2:5][C:4]2[C:19]([O:25][CH3:26])=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:3]=2[O:2][CH3:1])[CH2:7][C:8]1=[O:18]
Reactant: COc1cc(OC)c(CN2CC(=O)Nc3ccccc3C2=O)c(OC)c1
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)c(CN2CC(=O)N(CC(F)(F)F)c3ccccc3C2=O)c(OC)c1
Temperature: 55 °C
Reaction time: 16 h
Yield: 34.9 %

Procedure:
The product from Step 4B (6 g, 0.017 mol) was dissolved in DMF (40 ml) at room temperature under nitrogen. Caesium carbonate (8.2 g, 0.025 mol) was added followed by trifluoroethyl iodide (8.8 g, 0.025 mol) and the mixture stirred at 55° C. for 16 hr. The reaction mixture was taken up in ethyl acetate/water, the organic layer washed (water, brine), dried (MgSO4) and evaporated in vacuo. Purification by chromatography (SiO2, ethyl acetate/dichloromethane) afforded the product as a white solid (2.6 g, 35%). (1H NMR, CDCl3) δ 3.68–3.83 (11H, m), 4.13–4.17 (1H, m), 4.72 (1H, S d, J=13.6 Hz), 4.84–4.88 (1H, m) 5.04 (1H, d, J=13.6Hz), 6.13 (2H, s), 7.18 (1H, d, J=8.3 Hz), 7.32–7.50 (2H, m), 7.96 (1H, m).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19](=[O:24])[CH2:20][C:21](=[O:23])[CH3:22].S(Cl)(Cl)=O>CC(O)C>[C:1]1([S:7]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[C:20]([C:19](=[O:24])[CH3:18])[C:21](=[O:23])[CH3:22])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)CC(C)=O
Reactant: O=Cc1ccc(S(=O)(=O)c2ccccc2)cc1
Solvent: O=S(Cl)Cl
Solvent: CC(C)O
Product: CC(=O)C(=Cc1ccc(S(=O)(=O)c2ccccc2)cc1)C(C)=O
Temperature: 20 °C

Procedure:
To a solution containing 2.1 g of 4-phenylsulfonylbenzaldehyde and 1.5 g of 2,4-pentanedione in 10 ml of 2-propanol was added 1 ml of thionyl chloride with stirring at 20° C. The solution was stirred for 1 h at 20° C. and evaporated to dryness in vacuo. The residue was crystallized from toluene, mp 102°-105° C.
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]1([CH:22]=[CH2:23])[CH2:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24](Br)[CH:25]=[CH2:26].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6]([C@@:8]1([CH:22]=[CH2:23])[C@H:12]([CH2:26][CH:25]=[CH2:24])[C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCBr
Reactant: C=C[C@]1(C(=O)OC(C)(C)C)CC(=O)N([C@H](C)c2ccccc2)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@@H]1C(=O)N([C@H](C)c2ccccc2)C[C@@]1(C=C)C(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 50.6 %

Procedure:
(3R)-5-oxo-1-[(1R)-1-phenylethyl]-3-vinylpyrrolidine-3-carboxylic acid tert-butyl ester (236.0 mg, 0.75 mmol) and allyl bromide (271.6 mg, 2.24 mmol) were dissolved in tetrahydrofuran. A 1 M solution of lithium hexamethyldisilazide in tetrahydrofuran (1.12 mL, 1.12 mmol) was added dropwise in a nitrogen atmosphere at 0° C. After stirring for 1.5 hours, a saturated ammonium chloride solution was added, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (10% ethyl acetate/hexane) to give 135 mg of the title compound as a colorless oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C@H:8]1[NH:13][C@@H:12]([CH3:14])[CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9]1.Br[CH2:23][CH2:24][N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35].[I-].[Na+]>>[O:35]=[C:26]1[C:27]2[C:28](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](=[O:30])[N:25]1[CH2:24][CH2:23][N:13]1[C@@H:8]([CH3:7])[CH2:9][N:10]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:11][C@H:12]1[CH3:14]
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 20.2 %

Procedure:
Potassium carbonate (1.79 g) was added to a solution of tert-butyl (cis)-3,5-dimethyl-1-piperazinecarboxylate (2.57 g) [see Preparation 5] in acetronitrile (10 ml). The reaction mixture was stirred at room temperature for 5 minutes, after which time N(2-bromoethyl) phthalimide (3.36 g) was added and the mixture was stirred for a further 4 hours. Sodium iodide (0.1 g) was added and the reaction mixture was heated to reflux for 18 hours. The mixture was then cooled and the solvent removed under reduced pressure. The residue was partitioned between ethyl acetate and water, the organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 4:1:0, changing to 0:95:5, by volume, hexane:ethyl acetate:0.88 aqueous ammonia solution. to afford tert-butyl (cis)-4-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3,5-dimethyl-1-piperazinecarboxylate (0.94 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[CH:3]=1.FC(F)(F)C(O)=O.S(=O)(=O)(O)O.C1C(=O)N([Br:29])C(=O)C1.[OH-].[Na+]>>[Br:29][C:3]1[C:4]([CH3:9])=[N:5][C:6]([CH3:8])=[CH:7][C:2]=1[Cl:1]
Reactant: Cc1cc(Cl)cc(C)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Cl)c(Br)c(C)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 21.4 %

Procedure:
4-chloro-2,6-dimethylpyridine (1.5 g) was added to a mixed solvent of trifluoroacetic acid (3 mL) and concentrated sulfuric acid (6 mL). NBS (22 g) was added to the solution, and the mixture was stirred at room temperature for 12 hours. A 5 N aqueous sodium hydroxide solution was added to the reaction mixture, followed by separation with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 5% to 30%) to give the title compound (500 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][CH:10]2[CH2:15][CH2:14][CH:13]([NH:16]C(=O)OC(C)(C)C)[CH2:12][CH2:11]2)=[CH:4][C:3]=1[C:24]([NH:26][CH2:27][C:28]12[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2)=[O:25].CO.[ClH:40]>O1CCOCC1>[ClH:1].[ClH:40].[NH2:16][CH:13]1[CH2:12][CH2:11][CH:10]([NH:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:4]=2)[C:24]([NH:26][CH2:27][C:28]23[CH2:29][CH:30]4[CH2:36][CH:34]([CH2:33][CH:32]([CH2:31]4)[CH2:37]2)[CH2:35]3)=[O:25])[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1CCC(NCc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC1CCC(NCc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1

Procedure:
Prepared from [4-[[[4-chloro-3-[[(tricyclo[3.3.1.1 3,7]dec-1-ylmethyl)amino]carbonyl]phenyl]methyl]amino]cyclohexyl]-carbamic acid, 1,1-dimethylethyl ester (0.26 g, Example 33a), methanol (5 ml) and 4N hydrochloric acid solution in dioxane (1 ml). Solvents were removed under reduced pressure and the residue was triturated with diethyl ether to give the title compound as a white powder (0.190 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=2)[NH2:31])[CH2:24][CH2:23]1.Cl>C(O)C>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:7][C:2]([NH:31][C:30]2[CH:32]=[CH:33][CH:34]=[C:28]([N:25]3[CH2:24][CH2:23][N:22]([CH3:21])[CH2:27][CH2:26]3)[CH:29]=2)=[N:3][CH:4]=1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: CCOC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccccc1Nc1nc(Nc2cccc(N3CCN(C)CC3)c2)ncc1Cl
Temperature: 95 °C
Reaction time: 24 h
Yield: 97.9 %

Procedure:
Ethyl 2-[(2,5-dichloro-4-pyrimidinyl)amino]benzoate (10.2 g, 32.8 mmol) and 3-(4-methyl-1-piperazinyl)aniline (6.6 g, 34.4 mmol) were combined in a vessel with ethanol (200 mL) and concentrated HCl (3.2 mL, 38.4 mmol, 12N). The vessel was sealed and heated with stirring at 95° C. for 24 h. The reaction was cooled to room temperature and poured onto water (1.3 L). The aqueous layer was extracted with ethyl acetate (2×250 mL) and neutralized to pH 7 by the slow addition of 6N NaOH. The precipitated solid was filtered off and washed with water and ethyl ether to afford the product (15.0 g, 98% yield) as a tan solid. MS: M(C24H27ClN6O2)=466.97, (M+H)+=467.2 and 469.2.
Reaction SMILES: C([O:7][C:8](=[O:24])[CH2:9][C:10]1[S:11][C:12]([CH:15]=[CH:16][C:17](=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:13][CH:14]=1)CCCCC.[OH-].[K+]>C(O)C.O>[O:23]=[C:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:16]=[CH:15][C:12]1[S:11][C:10]([CH2:9][C:8]([OH:24])=[O:7])=[CH:14][CH:13]=1
Reactant: CCCCCCOC(=O)Cc1ccc(C=CC(=O)CCCCC)s1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCC(=O)C=Cc1ccc(CC(=O)O)s1
Yield: 45 %

Procedure:
3.5 G of 2-[5-(3-oxooct-1-enyl)thien-2-yl]acetic acid hexyl ester was dissolved in 20 ml of ethanol; then, a solution of 0.6 g of potassium hydroxide in 10 ml ethanol was added portionwise over aperiod of 4 hours. The resultant solution was stirred for an additional 4 hours, then was diluted with water. The water solution was extracted several times with ether, and the ether phases were discarded. The water solution was adjusted to pH 5.5 to 6 with dilute hydrochloric acid and extracted with ether, and the ether phase was washed with water, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, using benzene and ethyl acetate as eluants). There were thus obtained 1.2 g (45% yield) of the desired product, melting at 51° C.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][O:7][C:8]2[N:9]=[N:10][CH:11]=[C:12]3[C:16]([CH3:17])=[C:15]([CH3:18])[N:14]([CH2:19][C@H:20]4[CH2:22][C@@H:21]4[CH3:23])[C:13]=23)=[CH:4][CH:3]=1.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.O.[C:49]([OH:52])(=[O:51])[CH3:50]>>[C:49]([O:52][CH2:17][C:16]1[C:12]2[C:13](=[C:8]([O:7][CH2:6][C:5]3[CH:24]=[CH:25][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]=[N:10][CH:11]=2)[N:14]([CH2:19][C@H:20]2[CH2:22][C@@H:21]2[CH3:23])[C:15]=1[CH3:18])(=[O:51])[CH3:50]
Reactant: CC(=O)O
Reactant: Cc1c(C)n(C[C@H]2C[C@@H]2C)c2c(OCc3ccc(F)cc3)nncc12
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Product: CC(=O)OCc1c(C)n(C[C@H]2C[C@@H]2C)c2c(OCc3ccc(F)cc3)nncc12
Temperature: 60 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
To a solution of 7-(4-fluorobenzyloxy)-2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]pyridazine (0.679 g, 2.00 mmol) in acetic acid (40 ml) was added ammonium cerium (IV) nitrate (6.58 g, 12.0 mmol) at room temperature. The mixture was stirred at 60° C. for 3 hours, poured into water and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel column using hexane/ethyl acetate=1/1 as the eluant to afford an oil which was crystallized in hexane to give the title compound (0.255 g, 28%) as pale yellow crystals.
Reaction SMILES: [P:1]([F:5])([F:4])(=[O:3])[OH:2].F[P-](F)(F)(F)(F)F.[Li+:13].[Cl-].[Na+:15]>>[P:1]([F:5])([F:4])([O-:3])=[O:2].[Na+:15].[P:1]([F:5])([F:4])([O-:3])=[O:2].[Li+:13]
Reactant: O=P(O)(F)F
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [Li+]
Product: O=P([O-])(F)F
Temperature: 130 °C
Reaction time: 1 h

Procedure:
Difluorophosphoric acid (reagent, produced by Fluorochem Ltd.) (18.3 g) was weighed into a 250 ml-volume PFA vessel, and 4.0 g of lithium hexafluorophosphate (reagent, produced by Stella Chemifa Corporation) was added. Furthermore, 10.4 g of sodium chloride (reagent, produced by Wako Pure Chemical Industries, Ltd.) was added, and the mixture was stirred for 1 hour under nitrogen flow and after heating at 130° C. for 17 hours, cooled to room temperature to obtain a mixed crystal of sodium difluorophosphate and lithium difluorophosphate. Anion analysis was performed in the same manner as in Example 2-6, as a result, the obtained difluorophosphate ion was 93% in terms of the relative area.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[N:9]=[C:10]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[CH:11]=[C:12]([C:13]([OH:15])=O)[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2].[NH2:23][CH2:24][C:25]1[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=1[CH3:31].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C([O-])(O)=O.[Na+]>CS(C)=O.C(Cl)Cl>[CH3:31][C:30]1[CH:29]=[C:28]([CH3:32])[NH:27][C:26](=[O:33])[C:25]=1[CH2:24][NH:23][C:13]([C:12]1[C:7]2[CH:6]=[N:5][N:4]([CH:1]([CH3:2])[CH3:3])[C:8]=2[N:9]=[C:10]([N:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)[CH:11]=1)=[O:15]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(N3CCN(C)CC3)nc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(N3CCN(C)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 12 h
Yield: 53 %

Procedure:
A solution of 1-isopropyl-6-(4-methylpiperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (0.2 g, 0.600 mmol) and 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (0.182 g, 1.197 mmol) in DMSO (2 mL) and was stirred at room temperature for 15 min. Then PyBOP (0.468 g, 0.900 mmol) was added to it and stirring was continued for 12 hr. After completion of the reaction, saturated NaHCO3 solution was added to it and extraction was carried out using DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by prep. HPLC to give the desired compound (53% yield). LCMS: 438.15 (M+1)+; HPLC: 96.67% (@ 254 nm), (Rt; 4.516); 1H NMR (DMSO-d6, 400 MHz) δ 11.54 (s, 1H), 9.75 (s, 1H), 8.62 (s, 1H), 8.06 (s, 1H), 7.20 (s, 1H), 5.89 (s, 1H), 5.04-4.99 (m, 1H), 4.58 (d, 2H, J=14 Hz), 4.36 (d, 2H, J=4.4 Hz), 3.55 (d, 2H, J=11.20 Hz), 3.24 (t, 2H, J=12.40 Hz), 3.12 (m, 2H), 2.84 (s, 3H), 2.20 (s, 3H), 2.12 (s, 3H), 1.45 (d, 6H, J=6.8 Hz).
Reaction SMILES: [F:1][C:2]1[CH2:11][CH2:10][C:9]2[CH2:8][CH2:7][N:6]3[C:12]([C@@H:15]([NH2:17])[CH3:16])=[N:13][CH:14]=[C:4]([C:5]=23)[CH:3]=1.Cl[C:19]1[N:27]=[CH:26][N:25]=[C:24]2[C:20]=1[N:21]=[CH:22][N:23]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH2:11][CH2:10][C:9]2[CH2:8][CH2:7][N:6]3[C:12]([C@@H:15]([NH:17][C:19]4[N:27]=[CH:26][N:25]=[C:24]5[C:20]=4[N:21]=[CH:22][NH:23]5)[CH3:16])=[N:13][CH:14]=[C:4]([C:5]=23)[CH:3]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)C1=NC=C2C=C(F)CCC3=C2N1CC3
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)C1=NC=C2C=C(F)CCC3=C2N1CC3
Temperature: 90 °C
Reaction time: 16 h
Yield: 69.1 %

Procedure:
A mixture of (S)-1-(5-fluoro-6,7,8,9-tetrahydro-2,9a-diazabenzo[cd]azulen-1-yl)ethylamine (70 mg, 0.30 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (71.8 mg, 0.30 mmol), and DIPEA (0.153 mL, 0.90 mmol) in n-butanol (1.5 mL) was stirred in a sealed vial at 90° C. for 16 h. After cooling to RT, volatiles were removed under reduced pressure. The residue was dissolved in MeOH (5 mL) and cooled in an ice bath. HCl in isopropanol (1.25 M, 3 mL) was added and the mixture stirred at 0° C. for 1.5 h and then concentrated under reduced pressure. The residue was dissolved in MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5 M NH3 in MeOH, further purification by column chromatography (Si—PCC, gradient 2-12% 2M NH3/MeOH in DCM) afforded 405 as a white solid (72.8 mg, 69%). LCMS (Method K): RT 2.68 min [M+H]+ 352.0. 1H NMR ((CD3)2SO, 400 MHz): 12.93 (1H, bs), 8.24 (1H, s), 8.15 (1H, s), 7.89 (1H, d, J=7.9 Hz), 7.43 (1H, dd, J=8.7, 4.8 Hz), 6.99 (1H, dd, J=10.8, 8.8 Hz), 5.83 (1H, bs), 4.31-4.29 (2H, m), 3.04-3.01 (2H, m), 2.08-1.94 (4H, m), 1.66 (3H, d, J=6.7 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:13]2[N:21](S(C3C=CC=CC=3)(=O)=O)[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH:14]=2)=[CH:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:13]2[NH:21][C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH:14]=2)=[CH:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C=C(c1cccc(Cl)c1)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)C=C(c1cccc(Cl)c1)c1cc2cccnc2[nH]1
Temperature: 70 °C
Reaction time: 16 h
Yield: 76.8 %

Procedure:
A solution of 2-(1-(3-chloro-phenyl)-3-methyl-but-1-enyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (2.5 g, 5.7 mmol) in ethanol (45 mL) and tetrahydrofuran (90 mL) was treated with a 10% aqueous sodium hydroxide solution (15 mL). The reaction was stirred at 70° C. for 16 h. The solvent was removed in vacuo and the obtained precipitate was filtered and washed with water (3×50 mL) and ethyl acetate (20 mL) to afford 2-(1-(3-chloro-phenyl)-3-methyl-but-1-enyl)-1H-pyrrolo[2,3-b]pyridine (1.3 g, 77%) as a white solid: 1H NMR (300 MHz, d6-DMSO) δ ppm 11.57 (s, 1H), 8.17 (dd, 1H, J1=4.5 Hz, J2=1.5 Hz), 7.93 (dd, 1H, J1=8.4 Hz, J2=1.8 Hz), 7.31 (m, 2H), 7.21 (m, 1H), 7.15 (m, 1H), 7.05 (m, 1H), 6.40 (s, 1H), 6.21 (d, 1H, J=9.9 Hz), 2.57 (m, 1H), 1.03-1.01 (m, 6H).