Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][C:16]([F:19])([F:18])[F:17])[C:5]=2[CH2:20][O:21][CH:22]2[CH2:28][CH:27]3[N:29]([C:30]4[S:31][C:32]5[CH:38]=[C:37]([C:39]([O:41]C)=[O:40])[CH:36]=[C:35]([O:43][CH3:44])[C:33]=5[N:34]=4)[CH:24]([CH2:25][CH2:26]3)[CH2:23]2)[CH2:3][CH2:2]1.C(O)C.[OH-].[K+]>O1CCCC1>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][C:16]([F:18])([F:19])[F:17])[C:5]=2[CH2:20][O:21][CH:22]2[CH2:28][CH:27]3[N:29]([C:30]4[S:31][C:32]5[CH:38]=[C:37]([C:39]([OH:41])=[O:40])[CH:36]=[C:35]([O:43][CH3:44])[C:33]=5[N:34]=4)[CH:24]([CH2:25][CH2:26]3)[CH2:23]2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(OC)c2nc(N3C4CCC3CC(OCc3c(-c5ccccc5OC(F)(F)F)noc3C3CC3)C4)sc2c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(C(=O)O)cc2sc(N3C4CCC3CC(OCc3c(-c5ccccc5OC(F)(F)F)noc3C3CC3)C4)nc12
Temperature: 60 °C

Procedure:
The ester, methyl 2-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)-4-methoxybenzo[d]thiazole-6-carboxylate (161 mg, 0.26 mmol) was dissolved in tetrahydrofuran (1 mL) and ethanol (1 mL) and subjected to an aqueous solution of potassium hydroxide (100 mg, 2.5 mmol in 2 mL water). The mixture was heated to 60° C. for 2 hr and then the solvent was removed in vacuo. The mixture was diluted with 5% aqueous citric acid and extracted with ethyl acetate (2×100 mL). The organics were dried (MgSO4) then evaporated in vacuo. The product was purified by flash silica chromatography with a gradient of 0-100% ethyl acetate/hexanes to give 2-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)-4-methoxybenzo[d]thiazole-6-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[N:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](O)=[O:35])=[CH:29][CH:28]=1.CCN=C=NCCCN(C)C>>[N:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:35])=[CH:29][CH:28]=1
Reactant: O=C(O)Cc1ccncc1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)Cc4ccncc4)c3)c2c1
Yield: 4.4 %

Procedure:
Following Example 290, the reaction of 3-(3 aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (250 mg, 0.74 mmol) with 4-pyridylacetic acid hydrochloride (0.15 g, 0.89 mmol) and EDCI (0.21 g, 1.11 mmol) furnished 12 mg (4% yield) of the title compound. 1H NMR (DMSOd6) δ 13.2 (br s, 1H), 10.2 (s, 1H), 8.6 (s, 1H), 8.5 (dd, 1H), 8.2 (s, 1H), 8.1 (br s, 1H), 7.9 (d, 1H), 7.75 (m, 2H), 7.6 (d, 1H), 7.5 (t, 1H), 7.4-7.1 (m, 2H), 3.8 (s, 2H); ES-MS (m/z) 372 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][C:17]#[CH:18])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:38][O:39][CH:40]([O:43][CH3:44])[CH2:41][NH2:42].CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:38][O:39][CH:40]([O:43][CH3:44])[CH2:41][NH:42][C:13](=[O:15])[C@H:12]([NH:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])[CH2:16][C:17]#[CH:18]
Reactant: COC(CN)OC
Reactant: C#CC[C@@H](NS(=O)(=O)c1ccc(C)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#CC[C@@H](NS(=O)(=O)c1ccc(C)cc1)C(=O)NCC(OC)OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of (R)-2-(4-methylbenzenesulfonamido)pent-4-ynoic acid (11.0 g, 41.2 mmol), HOBt (6.67 g, 49.4 mmol), iPr2NEt (6.40 g, 49.4 mmol), (2,2-dimethoxyethyl)amine (8.70 g, 82.33 mmol), and EDCI (9.5 g, 49 mmol) in DMF (100 mL) was stirred for 24 h at RT. The reaction mixture was concentrated, taken up in H2O, and extracted with EtOAc (3×). The organic extracts were dried over MgSO4 and concentrated to give the title compound. 1H NMR (400 MHz, CDCl3): δ 2.15 (s, 1H), 2.43 (m, 1H), 2.51 (s, 3H), 2.88 (m, 1H), 2.94 (s, 3H), 2.96 (s, 3H), 3.37 (m, 3H), 3.85 (m, 1H), 4.33 (m, 1H), 6.78 (s, 1H), 7.33 (d, 8.0 Hz, 2H), 7.76 (d, 8.0 Hz, 2H), 8.01 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(O)C.[CH3:27][C:28]1[CH:29]=[C:30]([C:34]([N:36]=[C:37]=[S:38])=[O:35])[CH:31]=[CH:32][CH:33]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:37]([NH:36][C:34](=[O:35])[C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([CH3:27])[CH:29]=2)=[S:38])=[C:18]([F:23])[CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: Cc1cccc(C(=O)N=C=S)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(C)c4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 3-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (68 mg, yield 87%).
Reaction SMILES: [CH3:1][O-:2].[Na+].CO.CO.Cl[C:9]1[CH:14]=[C:13]([C:15]([O:17]C)=[O:16])[CH:12]=[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:10]=1.Cl>CC(N(C)C)=O>[CH3:1][O:2][C:9]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:10]=1
Reactant: COC(=O)c1cc(Cl)nc(-c2ccccc2)c1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CO
Product: COc1cc(C(=O)O)cc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
25% NaOMe/methanol solution (92 μL) was added to an MeOH (2 mL) solution of methyl 2-chloro-6-phenylpyridine-4-carboxylate (1100 mg), and stirred at room temperature for 2 hours. Further, 25% NaOMe/methanol solution (92 μL) was added to it, and stirred under heat with refluxing for 2 hours and 30 minutes. DMA (3 mL) was added to it, and stirred overnight at 130° C., then 25% NaOMe/methanol solution (92 μL) was added to it, and stirred at 130° C. for 7 hours. With cooling with ice, diluted hydrochloric acid was added to it, the formed precipitate was taken out through filtration, washed with water, dried, and purified through reversed-phase high-performance liquid chromatography [acetonitrile/water+0.11% trifluoroacetic acid] to obtain the title compound as a white powder.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[O:7][C:8]1[C:9]([CH2:18][CH3:19])=[N:10][N:11]([CH2:15][CH2:16][OH:17])[C:12]=1[CH2:13][CH3:14].Cl.Cl[CH2:26][CH2:27][NH2:28]>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[O:7][C:8]1[C:9]([CH2:18][CH3:19])=[N:10][N:11]([CH2:15][CH2:16][O:17][CH2:26][CH2:27][NH2:28])[C:12]=1[CH2:13][CH3:14]
Reactant: NCCCl
Reactant: CCc1nn(CCO)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nn(CCOCCN)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 18.6 %

Procedure:
Sodium hydride (60% dispersion in oil, 24 mg, 0.600 mmol) was added to a stirred solution of the pyrazole of Example 2 (100 mg, 0.303 mmol) in dry N,N-dimethylformamide (4 ml) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 30 minutes and 2-chloroethylamine hydrochloride (53 mg, 0.455 mmol) was added. The reaction mixture was stirred at 0° C. for 30 minutes and then stirred at room temperature for 30 minutes. The reaction was cooled to 0° C., further sodium hydride (60% dispersion in oil, 24 mg, 0.600 mmol) and 2-chloroethylamine hydrochloride (53 mg, 0.455 mmol) were added and the reaction was stirred for 1 hour. The reaction was quenched by the addition of water (5 ml) and extracted with ether (10 ml). The organic layer was washed with 2M aqueous hydrochloric acid (30 ml). The acid was neutralised with solid sodium carbonate and extracted with ether (3×20 ml). The combined ether layers were dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:4:1, by volume) to provide the title compound (21 mg) as a colourless oil.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:12])=[CH:5][C:6]=1[C:7]([O:9]CC)=[O:8].[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[O:3][C:4]([CH3:12])=[CH:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1cc(C)oc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(=O)O)c(C)o1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.1 %

Procedure:
A mixture of 3.2 g of ethyl 2,5-dimethylfuran-3-carboxylate, 35 ml of ethanol and 20 ml of 2 N sodium hydroxide was stirred at room temperature for 1.5 hours followed by heating under reflux for an hour. After the reaction mixture was allowed to cool to room temperature, it was concentrated under reduced pressure. The residue was dissolved in water and acidified with diluted sulfuric acid. Precipitated crystals were collected by filtration, washed with water and dried to give 2.27 g of 2,5-dimethylfuran-3-carboxylic acid in a 85% yield.
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C@@H:14]([OH:20])[CH:15]=[CH:16][C@@H:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.[C:23](OC(=O)C)(=[O:25])[CH3:24].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:24][C:23]([O:20][C@@H:14]1[C@@H:13]2[O:12][C:11]3=[C:10]([O:21][CH3:22])[CH:9]=[CH:8][C:7]4=[C:6]3[C@:5]32[CH2:4][CH2:3][N:2]([CH3:1])[C@H:18]([CH2:19]4)[C@@H:17]3[CH:16]=[CH:15]1)=[O:25]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc2c3c1O[C@H]1[C@@H](OC(C)=O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Reaction time: 12 h
Yield: 99.4 %

Procedure:
A solution of codeine (30 g, 100.2 mmol), acetic anhydride (18.4 g, 180.2 mmol), triethylamine (18.25 g, 180.2 mmol) and 4-dimethylaminopyridine (0.5 g) in dry ethyl acetate (620 ml) was stirred at rt. under nitrogen for 12 hr, added saturated aqueous sodium bicarbonate solution until no acetic anhydride detected. The organic portion was separated, in washed with water (3×120 ml), dried over anhydrous sodium sulfate, and evaporated in vacuo to dryness to give 6-acetylcodeine as white solids (34.0 g, 99% yield). IR (KBr)(v, cm-1): 1725 (st, sharp, 3-AcO); NMR (δH)(CDCl3): 6.66 (1, d, J, 8.2, 2-H), 6.53 (1, d, J, 8.2, 1-H), 5.63 (1, ddd, J, 10.0, 2.4 & 1.0, 7-H), 5.42 (1, dt, J, 9.9 & 2.3, 8-H), 5.22-5.51 (1, m, 6-H), 5.06 (dd, J, 6.7 & 1.0, 5-H), 3.85 (3, s, 3-OCH3), 3.39 (1, dd, J, 6.0 & 3.3, 9-H), 3.03 (1, d, Jjem, 18.6, 10-Hβ), 2.78 (1, dd, J, 5.2 & 2.6, 14-H), 2.63 (1, dd, J, 11.9 & 4.6, 16-Ha), 2.45 (3, s, N--CH3), 2.40 (1, td, J, 12.0 & 3.8, 16-He), 2.33 (1, dd, J, 18.5 & 6.0, 10-Hα), 2.15 (3, s, 6-OAc), 2.06 (1, td, J, 12.0 & 5.0, 15-Ha) and 1.85 (1, dm, J, 12.0, 15-He).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: ClCc1ccccc1
Reactant: Oc1ccc(Br)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(Br)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 80.6 %

Procedure:
Then, 8.47 g of 4-bromo-2-trifluoromethylphenol, 5.34 g of potassium carbonate, 4.49 g of benzyl chloride and 100 ml of N,N-dimethylformamide were charged into a reaction vessel, and stirred under ice cooling. After 24 hours, the reaction solution was poured into ice-water and extracted three times with 50 ml of diethyl ether. The ether layers were combined, washed with an aqueous 10 % sodium hydroxide solution, dried over anhydrous magnesium sulfate and then concentrated to give a crude product. This crude product was subjected to silica gel chromatography to give 9.38 g of 4-bromo-2-trifluoromethyl-1-benzyloxybenzene (yield, 81%).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:14]([CH2:15][CH2:16][CH3:17])[N:13]=[CH:12][N:11]=1)(C(C)(C)C)(C)C.CO.[OH-].[Na+]>C(O)C>[CH2:15]([N:14]1[C:10]([CH2:9][OH:8])=[N:11][CH:12]=[N:13]1)[CH2:16][CH3:17]
Reactant: CCCn1ncnc1CO[Si](C)(C)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CCCn1ncnc1CO
Temperature: 25 °C
Reaction time: 19 h
Yield: 87 %

Procedure:
To a solution of 5-(tert-butyldimethylsilanyloxymethyl)-1-propyl-1H-1,2,4-triazole (from Step a) (4.10 g, 16.1 mmol) in ethanol (18 ml) and methanol (36 ml) was added 4 M aqueous NaOH (6 ml, 24 mmol) and the mixture was stirred at room temperature for 19 h, then at 45° C. for another 5 h. The solvents were removed in vacuo and the residue was purified by flash chromatography (silica gel, EtOAc, then 10% MeOH/CH2Cl2) to leave 1.976 g (87%) of the title compound as a pale yellow oil: 1H NMR (250 MHz, CDCl3) δ 0.95 (3H, t, J=7.4 Hz), 1.91 (2H, sextet, J=7.4 Hz), 4.16 (2H, t, J=7.3 Hz), 4.76 (2H, s), 7.81 (1H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH:4]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:5]1([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[C:20]([O:26][CH2:27]Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:20]([O:26][CH2:27][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH:4]([C:5]2([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:3][N:2]([CH3:1])[CH3:19])=[CH:17][CH:16]=1)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: CN(C)CC(c1ccc(O)cc1)C1(O)CCCCC1
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(C)CC(c1ccc(OCOC(=O)C(C)(C)C)cc1)C1(O)CCCCC1

Procedure:
4-[2-(Dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenol (1 g, 3.79 mmol), chloromethyl pivalate (0.75 g, 5 mmol), anhydrous K2CO3 (0.7 g, 5 mmol) and KI (75 mg, 0.5 mmol) were stirred in acetonitrile (50 mL) and refluxed overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The ethyl acetate was dried (MgSO4) and evaporated to give the title compound as a minor component.
Reaction SMILES: Br[C:2]1[C:3]([CH3:10])=[C:4]([CH3:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:11]([Cu])#[N:12].C(N)CN>CC(N(C)C)=O>[NH2:8][C:5]1[C:4]([CH3:9])=[C:3]([CH3:10])[C:2]([C:11]#[N:12])=[CH:7][N:6]=1
Reactant: Cc1c(Br)cnc(N)c1C
Reactant: N#C[Cu]
Solvent: CC(=O)N(C)C
Solvent: NCCN
Product: Cc1c(C#N)cnc(N)c1C
Temperature: 170 °C
Reaction time: 20 h
Yield: 98.8 %

Procedure:
A mixture of 5-bromo-3,4-dimethyl-pyridin-2-ylamine (500 mg, 2.49 mmol), CuCN (445 mg, 4.97 mmol) and DMA (3.5 mL) was stirred under nitrogen for 20 h at 170° C. The reaction mixture was cooled and added to 50 mL of a 20% aqueous solution of ethane-1,2-diamine. The layers were separated and the aqueous layer was extracted 3× with EtOAc. The combined organics were washed with water, followed by brine and dried over MgSO4. Concentration in vacuo afforded compound 850A (362 mg, 99%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:14])[CH:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:17]=1[C:18]([N:20]=[C:21]=[O:22])=[O:19]>C(#N)C>[Cl:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:17]=1[C:18]([NH:20][C:21]([NH:14][C:4]1[CH:5]=[N:6][C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:2]([CH3:1])[CH:3]=1)=[O:22])=[O:19]
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Reactant: Cc1cc(N)cnc1-c1ccccc1
Solvent: CC#N
Product: Cc1cc(NC(=O)NC(=O)c2c(Cl)cccc2Cl)cnc1-c1ccccc1
Reaction time: 4.5 h

Procedure:
5-Methyl-6-phenyl-3-pyridylamine (0.4 gram) in 20 ml of acetonitrile was added to 2,6-dichlorobenzoyl isocyanate (0.5 gram) under nitrogen and at room temperature. After about 10-20 minutes a precipitate formed. The reaction mixture was then stirred for about 4-5 hours and the product was filtered and washed with acetonitrile, yield, 580 mg, m.p. 202°-205° C. A small portion of the product was recrystallized from ethanol, m.p. 204°-209° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][CH:12]3[CH2:21][CH2:20][C:15]4(OCC[O:16]4)[CH2:14][CH2:13]3)[C:4]=2[O:3]1.O>C(O)(=O)C>[CH3:1][C:2]1([CH3:22])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][CH:12]3[CH2:21][CH2:20][C:15](=[O:16])[CH2:14][CH2:13]3)[C:4]=2[O:3]1
Reactant: CC1(C)Cc2cccc(CC3CCC4(CC3)OCCO4)c2O1
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)Cc2cccc(CC3CCC(=O)CC3)c2O1

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 2, using 5.4 grams (0.01 8 mole) of 8-(2,3-dihydro-2,2-dimethylbenzofuran-7-ylmethyl)-1,4-dioxaspiro[4.5]decane and 25 mL of water in 100 mL of acetic acid, yielding 4-(2,3-dihydro-2,2-dimethylbenzofuran-7-ylmethyl)cyclohexanone.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:15][CH2:14]2)=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CN(C=O)C>[CH3:24][C:22]([O:21][C:20]([NH:19][CH:16]1[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][NH:10][C:3]2[C:2]([NH:1][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:7][CH:6]=[C:5]([O:8][CH3:9])[N:4]=2)[CH2:18][CH2:17]1)=[O:26])([CH3:23])[CH3:25]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(N)c(NCCN2CCC(NC(=O)OC(C)(C)C)CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1ccc(OC)nc1NCCN1CCC(NC(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
A mixture of 1,1-dimethylethyl [1-(2-{[3-amino-6-(methyloxy)-2-pyridinyl]amino}ethyl)-4-piperidinyl]carbamate (2.8 g, 7.6 mmol), ethyl bromoacetate (0.85 ml, 1.3 g, 7.6 mmol) and potassium carbonate (2 g, 15.2 mmol) in acetonitrile (40 ml) and DMF (20 ml) was stirred under argon overnight. The mixture was filtered, washing with acetonitrile, and evaporated. The residue was dissolved in the minimum volume of DCM (20 ml) and washed with water (20 ml). The organic extract was added to a silica column which was then eluted with 0-100% ethyl acetate in hexane affording a brown oil (1.3 g, 38%).
Reaction SMILES: [CH2:1]([N:3]1[C@H:8]([CH3:9])[CH2:7][N:6]([C:10]([N:12]2[CH2:19][C:18]3[C:17]([NH2:20])=[N:16][NH:15][C:14]=3[C:13]2([CH3:22])[CH3:21])=[O:11])[C@@H:5]([CH3:23])[CH2:4]1)[CH3:2].Cl[C:25]1[C:30]([F:31])=[CH:29][N:28]=[C:27]([O:32][CH3:33])[N:26]=1>C(O)(=O)C.O>[CH2:1]([N:3]1[C@H:8]([CH3:9])[CH2:7][N:6]([C:10]([N:12]2[CH2:19][C:18]3[C:17]([NH:20][C:25]4[C:30]([F:31])=[CH:29][N:28]=[C:27]([O:32][CH3:33])[N:26]=4)=[N:16][NH:15][C:14]=3[C:13]2([CH3:22])[CH3:21])=[O:11])[C@@H:5]([CH3:23])[CH2:4]1)[CH3:2]
Reactant: COc1ncc(F)c(Cl)n1
Reactant: CCN1C[C@H](C)N(C(=O)N2Cc3c(N)n[nH]c3C2(C)C)C[C@H]1C
Solvent: O
Solvent: CC(=O)O
Product: CCN1C[C@H](C)N(C(=O)N2Cc3c(Nc4nc(OC)ncc4F)n[nH]c3C2(C)C)C[C@H]1C

Procedure:
A solution of 5-{[(2S,5R)-4-ethyl-2,5-dimethylpiperazin-1-yl]carbonyl}-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine (289 mg, 0.9 mmol) and 4-chloro-5-fluoro-2-methoxypyrimidine (257 mg, 2 eq) in 5 mL of 50% acetic acid in water was heated in a microwave for 30 min at 80° C. Purification as described in Example A1 afforded the title compound AA1 as a white powder (13.1 mg, 3%). See Table 1 below for NMR data.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[CH:5][C:3]=1[NH2:4].[Cu][C:11]#[N:12].C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([C:11]#[N:12])=[CH:8][C:2]=1[F:1]
Reactant: Nc1ccc(I)cc1F
Reactant: N#C[Cu]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(N)c(F)c1
Reaction time: 0.08 h
Yield: 67 %

Procedure:
A 50 ml of two-neck round bottom flask was filled with argon gas, and the solution of 2-fluoro-4-iodoaniline (1 g, 5.219 mmol, 1 equiv.) in DMF was put into the flask. To the solution was added Copper (I) cyanide (453.4 mg, 5.063 mmol, 1.2 equiv.) and heated to reflux for 5 hours. After confirming the completion of the reaction with TLC, saturated sodium bicarbonate solution was added to the solution and stirred for 5 minutes. The resulting solution was extracted with methylenechloride, washed with water and brine, dried over Na2SO4, filtered and evaporated. The obtained liquid was column-chromatographed (n-hexane/ethyl acetate=2/1) to yield a pale yellow solid (461.6 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH2:7])[CH:4]=[N:3]1.[Si]([O:15][CH2:16][C@@H:17]([N:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][N:35]=[C:34](S(C)(=O)=O)[N:33]=2)=[CH:28][C:27]1=[O:42])[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([F:25])[CH:19]=1)(C(C)(C)C)(C)C>C(O)(CC)C>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C@H:17]([N:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([NH:7][C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[N:33]=3)=[CH:28][C:27]2=[O:42])[CH2:16][OH:15])=[CH:19][C:20]=1[F:25]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(F)c1)n1ccc(-c2ccnc(S(C)(=O)=O)n2)cc1=O
Reactant: Cn1cc(N)cn1
Solvent: CCC(C)O
Product: Cn1cc(Nc2nccc(-c3ccn([C@H](CO)c4ccc(Cl)c(F)c4)c(=O)c3)n2)cn1
Temperature: 25 °C
Yield: 26.8 %

Procedure:
A solution of 1-methyl-1H-pyrazol-4-amine (0.054 g, 0.56 mmol) and (S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (0.060 g, 0.11 mmol) in sec-BuOH (1 mL) was heated to 120° C. in a microwave reactor for 2 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was diluted with ethyl acetate and washed with H2O (2×). The organic layer was dried, filtered and concentrated. The crude product was purified by column chromatography, eluting with DCM/MeOH (25:1) to give (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.013 g, 26%). 1H NMR (400 MHz, CD3OD) δ 8.50 (d, J=5.0 Hz, 1H), 7.96 (s, 1H), 7.85 (d, J=7.0 Hz, 1H), 7.58 (s, 1H), 7.48 (m, 1H), 7.34-7.28 (m, 2H), 7.20-7.17 (m, 2H), 7.06 (m, 1H), 6.12 (m, 1H), 4.28 (m, 1H), 4.19 (m, 1H), 3.88 (s, 3H); m/z (APCI-pos) M+1=441.1, 443.1.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH:12]=[O:13])=[C:9]([CH3:11])[CH:10]=1)=[O:5])C.[OH-].[K+]>O.C(O)C>[CH:12]([C:8]1[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:10][C:9]=1[CH3:11])=[O:13]
Reactant: CCOC(=O)c1cc(C)c(C=O)[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(C(=O)O)[nH]c1C=O
Temperature: 100 °C
Yield: 99.4 %

Procedure:
To a solution of 0.8 g (4.4 mmol) of 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester in 35 mL of water and 15 mL of ethanol was added 0.5 gram (8.9 mmol) of potassium hydroxide. The reaction mixture was heated to 100° C. for 1 h, cooled to room temperature, and evaporated ethanol. The water layer was acidified to pH=3 using 2N hydrogen chloride solution. The precipitate was filtered and washed with water to afford 0.67 g (68%) of 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid as a tan solid.