Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=N[C:5]([N:8]2[CH2:12][CH:11]([C:13]([O:15]C(C)(C)C)=[O:14])[N:10]([CH3:20])[C:9]2=[O:21])=NC=1.[F:22][C:23](F)([F:27])C(O)=O.C1(C)C=CC=CC=1>ClCCl>[F:22][CH:23]([F:27])[CH2:20][N:10]1[CH:11]([C:13]([OH:15])=[O:14])[CH2:12][N:8]([CH3:5])[C:9]1=[O:21]
Reactant: CN1C(=O)N(c2ncc(F)cn2)CC1C(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CN1CC(C(=O)O)N(CC(F)F)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1,1-dimethylethyl 1-methyl-2-oxo-4-imidazolidinecarboxylate (200 mg, 0.999 mmol) (prepared as described in step (i) of Example 49 from 5-(1,1-dimethylethyl)1-(phenylmethyl)3-methyl-2-oxo-1,5-imidazolidinedicarboxylate, itself prepared as described in step (ii) of Example 13, starting originally from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) in N,N-dimethylformamide (10 ml) at −35° C. under argon was added sodium hydride (39.9 mg, 0.999 mmol). The mixture was stirred for 15 minutes, 2,2-difluoroethyl trifluoromethanesulfonate (428 mg, 1.998 mmol) was added and the reaction mixture was stirred at −35° C. for 30 minutes then slowly warmed to −15° C. After 1 hour the reaction mixture was quenched with water (10 ml), warmed to room temperature and extracted with ethyl acetate (20 ml×2). The combined organic layers were washed with sodium hydrogen carbonate saturated solution (15 ml), water (10 ml×2) and brine (15 ml). The organic layer was then dried (magnesium sulfate), filtered and evaporated. The crude residue was purified by silica gel chromatography eluting with 10-100% of ethyl acetate in isohexane to give 1,1-dimethylethyl 3-(2,2-difluoroethyl)-1-methyl-2-oxo-4-imidazolidinecarboxylate (178 mg). LC/MS [M+H]+=265. (ii) 1,1-Dimethylethyl 3-(2,2-difluoroethyl)-1-methyl-2-oxo-4-imidazolidinecarboxylate (178 mg, 0.674 mmol) was dissolved in dichloromethane (3.00 ml) and trifluoroacetic acid (1 ml) was added. The solution was stirred at room temperature for 2 hours. The solvent was evaporated and the residue co-evaporated with dichloromethane and toluene to give a crude 3-(2,2-difluoroethyl)-1-methyl-2-oxo-4-imidazolidinecarboxylic acid (assume 0.674 mmol) which was used for the next reaction. LC/MS [M+H]+=209.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Br:15])=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>>[Br:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:17][C:18]1[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=1)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]2
Reactant: BrCc1cccc2ccccc12
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Product: O=C(O)c1cc2cc(Br)ccc2n1Cc1cccc2ccccc12

Procedure:
Using general procedure B, 5-bromo-1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 380.1 ([M−H]−).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1[C:14]1[CH:15]=[C:16]([O:20][CH2:21][CH2:22][NH:23][S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])[CH:17]=[N:18][CH:19]=1.[H-].[Na+].[CH3:31]I>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1[C:14]1[CH:15]=[C:16]([O:20][CH2:21][CH2:22][N:23]([CH3:31])[S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])[CH:17]=[N:18][CH:19]=1
Reactant: CI
Reactant: CCS(=O)(=O)NCCOc1cncc(-c2cc3c(cc2F)N(C)C(=O)CC3)c1
Agent: [H-]
Agent: [Na+]
Product: CCS(=O)(=O)N(C)CCOc1cncc(-c2cc3c(cc2F)N(C)C(=O)CC3)c1

Procedure:
In analogy to the procedure described for the preparation of example 195, ethanesulfonic acid {2-[5-(7-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-pyridin-3-yloxy]-ethyl}-amide (example 243) has been reacted with sodium hydride and methyl iodide to give the title compound as orange amorphous solid. MS: 422.4 (M+H+).
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([NH2:9])[NH:6][N:5]=2)[CH2:3][CH2:2]1.Cl.Cl[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([C:4]2[CH:8]=[C:7]([NH2:9])[N:6]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: ClCCN1CCOCC1
Reactant: Nc1cc(C2CC2)n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1cc(C2CC2)nn1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-cyclopropyl-1H-pyrazole-5-amine (250 mg, 2.0 mmol), 4-(2-chloroethyl)morpholine HCl salt (372 mg, 2.0 mmol) and potassium carbonate (829 mg, 6.0 mmol) in dry DMF (10 mL) was stirred at room temperature overnight. After being diluted with ethyl acetate (50 mL), the reaction mixture was filtered through a pad of Celite and rinsed with ethyl acetate (2×15 mL). The combined filtrates were concentrated in vacuo and purified by ISCO (CH2Cl2-MeOH—NH4OH: 100:0:0 to 90:10:1) on silica gel to afford the desired amino-pyrazole.
Reaction SMILES: C([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH:10]=[N:9]1)C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[C:13](=[O:14])[NH:8][N:9]=[CH:10][C:11]=2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:20][CH:19]=1
Reactant: O=c1c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)cnn1Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=c1[nH]ncc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
The crude 2-benzyl-4,5-bis(4-chlorophenyl)pyridazin-3(2H)-one from the above reaction was dissolved in toluene (350 mL). Aluminum chloride (AlCl3, 46.3 g, 348.0 mmol) was then added to the toluene solution, producing an exotherm. The reaction was then placed in an oil bath preheated at 75° C. for 3 h. After this time, the reaction mixture was poured into ice-water (1000 mL), and the resulting mixture was extracted with EtOAc (3×500 mL). The combined organic layers were washed with water (500 mL), then filtered through a silica gel pad (˜50 g) to remove residual alumina salts. The organic solvents were evaporated under reduced pressure to nearly dryness. Diethyl ether (Et2O, 500 mL) was added with stirring. After stirring for 15 min at RT, hexane (1000 mL) was added subsequently. The resultant beige colored solid was collected by filtration and subsequently washed with a hexane-ether mixture (8:2). The title compound, 4,5-bis(4-chlorophenyl)pyridazin-3(2H)-one, (33.0 g, 92%) was obtained as a solid. MS: M+H=317. 1H NMR (CDCl3, 500 MHz): δ 11.94 (1H, br), 7.89 (1H, s), 7.23-7.32 (4H, m), 7.18 (2H, d, J=10.0 Hz), 7.07 (2H, d, J=10 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:29]1[CH2:30][CH2:31][N:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH2:28]1)=[O:19])=[N:5]2
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1nc2ccc(F)cc2nc1NC(=O)N1CCN(c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 7 h
Yield: 89.1 %

Procedure:
Ethyl N-(6-fluoro-2-methoxyquinoxalin-3-yl)carbamate (27 mg, 0.10 mmol) and 1-phenylpiperazine (24 mg, 0.15 mmol) were dissolved in tetrahydrofuran (2 ml) at room temperature and thereto DBU (23 mg, 0.15 mmol) was added. The resulting mixture was stirred at 70° C. for 7 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 34 mg of the titled compound (yield, 88%). 1H NMR (300 MHz, CDCl3): δ 3.29 (s, 4H), 3.77 (s, 3H), 4.14 (s, 4H), 6.89-6.97 (m, 4H), 7.24-7.56 (m, 5H), 7.62-7.71 (m, 1H)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)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>[C:5]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Brc1ccccc1
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: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cccc(-c2ccccc2)c1
Reaction time: 4 h
Yield: 67.3 %

Procedure:
To a solution of 3-cyanophenylboronic acid (1.0 g, 6.81 mmol) and bromobenzene (1.07 g, 6.81 mmol) in N,N-dimethylformamide (100 mL) were added tetrakis(triphenylphosphine)palladium(0) (0.393 g, 0.341 mmol) and cesium carbonate (2.77 g, 8.51 mmol) under nitrogen atmosphere, and the mixture was stirred for 4 hours under reflux. The reaction mixture was allowed to room temperature, ethyl acetate and water were added for partitioning, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), and biphenyl-3-carbonitrile (821 mg, 67%) was obtained as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.O>CN1CCCC1=O>[ClH:1].[ClH:1].[Cl:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH:11]=[CH:10]2
Reactant: C1CNCCN1
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cl
Product: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CCNCC3)ccc12
Temperature: 120 °C
Yield: 69 %

Procedure:
To a stirred solution of N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1 (a)) (170 mg) and potassium carbonate (350 mg) in N-methylpyrrolidinone (4 mL) was added piperazine (600 mg). The mixture was heated at 120° C. for 3 hours after which it was cooled and poured into water. The mixture was extracted with dichloromethane and the combined extracts evaporated to give a residue which was then partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer further extracted with ethyl acetate. The combined organic extracts were concentrated to give a residue which was purified by chromatography (SiO2, methanol:dichloromethane:ammonium hydroxide solution 19:80:1 as eluant) and the resultant product was converted to its hydrochloride salt by treatment with hydrochloric acid (4M in 1,4-dioxane). Recrystallisation (methanol/ethyl acetate) afforded the title compound as a solid (80 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:18]=[CH:17][C:11]3[NH:12][C:13](=O)[N:14]([CH3:15])[C:10]=3[C:9]=2CC(C)(C)C)[CH:5]=[CH:4][CH:3]=1.[C:24](=[O:27])([O-])[O-].[K+].[K+].[C:30]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)#[N:31]>CS(C)=O>[CH3:6][C:8]([CH3:18])([CH3:9])[CH2:13][N:12]1[C:11]2[CH:17]=[CH:18][C:8]([C:6]3[N:7]=[C:2]([O:38][C:35]4[CH:36]=[CH:37][C:32]([C:30]#[N:31])=[CH:33][CH:34]=4)[CH:3]=[CH:4][CH:5]=3)=[CH:9][C:10]=2[N:14]([CH3:15])[C:24]1=[O:27]
Reactant: N#Cc1ccc(O)cc1
Reactant: Cn1c(=O)[nH]c2ccc(-c3cccc(Cl)n3)c(CC(C)(C)C)c21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cccc(Oc4ccc(C#N)cc4)n3)cc21
Reaction time: 0.33 h

Procedure:
A solution of 5-(6-chloropyridin-2-yl)-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-benzimidazol-2-one (5-2, 55 mg, 0.17 mmol) in DMSO (1 ml), was charged with Potassium carbonate (34.6 mg, 0.25 mmol, 1.5 eq) and 4-Cyanophenol (39.7 mg, 0.33 nmol, 2.0 eq), then irradiated in a microwave at 160 deg C. for 20 min. A second addition of Potassium carbonate (34.6 mg, 0.25 mmol, 1.5 eq) and 4-Cyanophenol (39.7 mg, 0.33 mmol, 2.0 eq) was necessary, then the reaction was irradiated again at 160 deg C. for 20 min. The crude, dark mixture was filtered through a fritted disk, then purified via reverse-phase HPLC (Acetonitrile/Water gradient with 0.1% TFA present) to afford the title compound, 4-({6-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]pyridin-2-yl}oxy)benzonitrile (5-3), as an orange oil. 1H NMR (500 MHz, CDCl3) δ 7.80 (t, 1H, J=Hz), 7.71 (d, 2H, J=9.0 Hz), 7.62 (d, 1H, J=7.1 Hz), 7.55 (d, 1H, J=7.3 Hz), 7.51 (s, 1H), 7.34-7.31 (m, 2H), 7.06-7.04 (d, 2H, 8.3 Hz), 6.87 (d, 1H, J=8.1 Hz), 3.68 (s, 2H), 3.44 (s, 3H), 1.04 (s, 9H). LRMS m/z: Calcd for C25H25N4O2 (M+H) 414.2, found 414.3.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:12]=[C:6]2[C:5]=1Cl)(=[O:3])[NH2:2].[NH2:19][C@H:20]1[C@@H:24]([CH3:25])[CH2:23][N:22]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:21]1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[CH2:29]([O:28][C:26]([N:22]1[CH2:23][C@H:24]([CH3:25])[C@H:20]([NH:19][C:5]2[C:6]3[N:7]([CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:12]=3)[N:8]=[CH:9][C:4]=2[C:1](=[O:3])[NH2:2])[CH2:21]1)=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)c1cc2c(Cl)c(C(N)=O)cnn2c1
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cc2c(N[C@@H]3CN(C(=O)OCc4ccccc4)C[C@@H]3C)c(C(N)=O)cnn2c1
Temperature: 100 °C
Yield: 99.6 %

Procedure:
A mixture of ethyl 3-carbamoyl-4-chloropyrrolo[1,2-b]pyridazine-6-carboxylate (Intermediate 1, 375 mg, 1.401 mmol), (3S,4S)-benzyl 3-amino-4-methylpyrrolidine-1-carboxylate (Intermediate 5, 361 mg, 1.541 mmol) and diisopropylethylamine (0.734 mL, 4.20 mmol) in DMA (5 mL) was heated to 100° C. for 3 hr. After cooling, the volatiles were removed in vacuo and the residue was triturated with water. Filtration and drying afforded a tan solid that was rinsed with hexane and redried to afford ethyl 4-(((3S,4S)-1-((benzyloxy)carbonyl)-4-methylpyrrolidin-3-yl)amino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylate (650 mg, 1.396 mmol, 100% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 11.29 (d, J=7.3 Hz, 1H), 8.34 (s, 1H), 8.13 (d, J=2.4 Hz, 1H), 7.50-7.06 (m, 7H), 5.15-4.96 (m, 2H), 4.81 (d, J=4.8 Hz, 1H), 4.35-4.20 (m, 2H), 3.85-3.63 (m, 2H), 3.45 (dd, J=10.9, 3.4 Hz, 1H), 3.09 (dt, J=16.1, 10.2 Hz, 1H), 2.72-2.58 (m, 1H), 1.34-1.27 (m, 3H), 1.07 (d, J=6.8 Hz, 3H). MS (ES+) m/z: 466.3 (M+H); LC retention time: 3.095 min (analytical HPLC Method O).
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10](Cl)(=O)[C:11](Cl)=O.CN(C)[CH:18]=[O:19]>ClCCl>[CH:1]1([C:7]([O:19][CH2:18][C:11]2[CH:10]=[CH:3][CH:2]=[CH:1][CH:6]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1CCCCC1
Reactant: CN(C)C=O
Solvent: ClCCl
Product: O=C(OCc1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of cyclohexanecarboxylic acid (2.56 g) in dichloromethane (50 ml) and N,N-dimethylformamide (0.5 mL) was added oxalyl chloride (1.92 mL) under ice cooling. The solution was stirred at room temperature for 1 hour and then concentrated under reduced pressure. A solution of the resulting residue in dichloromethane (30 mL) was added to a solution of benzyl alcohol (2.4 g) and triethylamine (8.4 mL) in dichloromethane (30 mL) under ice cooling. The solution was stirred under ice cooling for 1 hour, and then it was washed in turn with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The solution was dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane:ethyl acetate=9:1) to give the title compound (3.44 g).
Reaction SMILES: [C:1]([C@H:9]([CH:32]([CH3:34])[CH3:33])[CH2:10][C@@H:11]1[O:15]C(C)(C)[N:13](C(OC(C)(C)C)=O)[C@H:12]1[CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)(=[O:8])C1C=CC=CC=1.Cl.C(OC)(OC)OC.[C:43]1(C)[CH:48]=[CH:47][C:46](S(O)(=O)=O)=[CH:45][CH:44]=1.[C:54](=O)(O)[O-].[Na+]>CO>[CH:26]1([CH2:25][C@@H:12]([C@@H:11]2[CH2:10][C@@H:9]([CH:32]([CH3:33])[CH3:34])[C:1]([O:8][CH3:54])([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[O:15]2)[NH2:13])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)[C@H](C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1CCCCC1)C(=O)c1ccccc1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: COC1(c2ccccc2)O[C@H]([C@@H](N)CC2CCCCC2)C[C@H]1C(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
400 mg (0.85 mmol) of t-butyl (4S,5S)-5-[(S)-2-benzoyl-3-methylbutyl]-4-(cyclohexylmethyl)-2,2-dimethyl-3-oxazolidinecarboxylate are dissolved in 15 ml of methanol and treated with 4.7 ml (18 mmol) of 3.9M hydrochloric acid in methanol. The reaction mixture is thereafter stirred at room temperature for 20 hours and subsequently evaporated under reduced pressure. The residue is dissolved in 5 ml of methanol and the solution is treated with 0.2 ml (1.8 mmol) of trimethyl orthoformate and a few crystals of p-toluenesulphonic acid and stirred at room temperature for 2 hours and at 50° for 2 hours. Thereafter, the reaction mixture is poured into 2N sodium bicarbonate solution and extracted with methylene chloride. The methylene chloride extracts are dried over magnesium sulphate and evaporated under reduced pressure, whereby there is obtained 0.27 g of (αS,2S,4S)-α-(cyclohexylmethyl)tetrahydro-4-isopropyl-5-methoxy-5-phenyl-2-furanmethanamine as an oil, MS: 313 (M-CH3OH)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:35]=[N:34][N:33]([CH:36]([CH3:38])[CH3:37])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([C:26]([CH:28]3[CH2:31][N:30]([CH3:32])[CH2:29]3)=[O:27])[CH2:24][CH:25]=2)[CH:19]=1)=[O:13]>CCO.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:35]=[N:34][N:33]([CH:36]([CH3:38])[CH3:37])[C:16]=2[N:17]=[C:18]([CH:20]2[CH2:21][CH2:22][N:23]([C:26]([CH:28]3[CH2:29][N:30]([CH3:32])[CH2:31]3)=[O:27])[CH2:24][CH2:25]2)[CH:19]=1)=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C(=O)C4CN(C)C4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CCN(C(=O)C4CN(C)C4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 9.5 h
Yield: 62 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1-(1-methylazetidine-3-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) in EtOH, 10% Pd/C in catalytic amount was added and stirred it at room temperature under hydrogen pressure (bladder pressure) for 3-16 h hr. On completion of reaction, reaction mass was filtered through celite bed, then filtrate was concentrated under reduced pressure to give the desired product 62% yield). LCMS: 520.35 (M+1)+; HPLC: 93.45% (@ 254 nm) (Rt;6.931); 1H NMR (DMSO-d6, 400 MHz) δ 11.54 (s, 1H), 8.75 (t, 1H, J=4.8 Hz), 8.27 (s, 1H), 7.51 (s, 1H), 5.88 (s, 1H), 5.20-5.17 (m, 1H), 4.50 (d, 1H, J=12.4 Hz), 4.36 (d, 2H, J=4.8 Hz), 3.69 (d, 1H, J=13.2 Hz), 3.43 (s, 3H), 3.13-3.06 (m, 4H), 2.69 (t, 1H, J=12 & 11.6 Hz), 2.20 (s, 3H), 2.17 (s, 3H), 2.12 (s, 3H), 1.93 (d, 2H, J=12 Hz), 1.65 (m, 2H), 1.48 (d, 6H, J=7.2 Hz).
Reaction SMILES: [C:1]([Li])([CH3:4])(C)[CH3:2].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:14][C:15]([CH:26]([CH3:28])[CH3:27])(C=O)[S:16][C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:9][CH:8]=1.C1(C)C=CC(S(O)(=O)=[O:36])=CC=1.C(=O)(O)[O-].[Na+]>C1COCC1.C1COCC1.O>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14]([CH:2]=[CH:1][CH:4]=[O:36])=[C:15]([CH:26]([CH3:27])[CH3:28])[S:16][C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:9][CH:8]=1
Reactant: CC(C)C1(C=O)CC(c2ccc(F)cc2)=C(c2ccccc2)S1
Reactant: [Li]C(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1sc(-c2ccccc2)c(-c2ccc(F)cc2)c1C=CC=O
Reaction time: 2 h
Yield: 259.7 %

Procedure:
To a solution of 2.4 g of cis-2-bromo-ethoxyethylene in 75 ml of THF at -78°, was added dropwise 2.0 g of t-butyllithium (2.2 m in pentane). After stirring at -78° for 2 hours, a solution of 3.5 g of the aldehyde product of Step 2, above, in 30 ml of THF was added dropwise. The reaction was stirred at -78° for 10 minutes, then was quenched by the addition of saturated aq. ammonium chloride solution. The mixture was extracted once with MTBE and then once with methylene chloride. The organic solutions were combined, dried over anhyd. magnesium sulfate and concentrated under reduced pressure to obtain a residue. The residue was dissolved in 100 ml of THF/water (90:10). p-toluenesulfonic acid (0.7 g) was added and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 10% aq. sodium bicarbonate solution and the organic material was extracted with MTBE. The solution was dried and the solvent removed under reduced pressure to give 3.7 g (98% yield) of the title product of this step for use in the next step (4). An analytical sample was crystallized from hexane; m.p. 138°-140°;
Reaction SMILES: C(O[C:6]1[O:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:8][CH:7]=1)CCC.[F:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]=[CH:24][C:23]2=[O:28])=[CH:19][CH:18]=1.FC(F)(F)C(O)=O>CCOCC>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][N:22]2[CH2:27][CH2:26][C:25]3[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:8][CH:7]=[C:6]([OH:10])[C:24]=3[C:23]2=[O:28])=[CH:29][CH:30]=1
Reactant: CCCCOc1cnc(C(=O)OCC)o1
Reactant: O=C1C=CCCN1Cc1ccc(F)cc1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ncc(O)c2c1CCN(Cc1ccc(F)cc1)C2=O
Temperature: 130 °C
Reaction time: 72 h

Procedure:
In a heavy walled round bottom flask with screw top were combined ethyl 5-butoxy-1,3-oxazole-2-carboxylate (2.53 g, 11.88 mmol) and 1-(4-fluorobenzyl)-5,6-dihydropyridin-2-(1H)-one (1.22 g, 5.94 mmol; see Example 1, Step 3) and trifluoroacetic acid (0.46 mL, 5.94 mmol). The vessel was sealed and placed in an oil bath heated to 130° C. The reaction mixture was stirred for 3 days. The dark brown reaction mixture was cooled and a crystalline precipitate formed. The mixture was diluted with ether and the solids collected by filtration and washed with ether to give the product as tan shiny plates. Further product can be obtained by evaporating the mother liquor, adding more trifluoroacetic acid and re-heating the mixture.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:12])[N:3]=1.Cl.[CH2:14]([O:16][C:17](=[O:20])[CH2:18][NH2:19])[CH3:15].C(N(CC)CC)C>C(O)C>[CH3:12][C:4]1[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[N:7]=[C:2]([NH:19][CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:20])[N:3]=1
Reactant: Cc1nc(Cl)nc(C)c1[N+](=O)[O-]
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CNc1nc(C)c([N+](=O)[O-])c(C)n1
Yield: 87.7 %

Procedure:
A solution of Compound 2 (69 mg), glycine ethyl ester hydrochloride (102 mg) and triethylamine (103 μL) in ethanol was stirred for 3 hours under reflux. After the reaction was completed, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3) to give 82 mg (86% yield) of the desired product as a pale yellow amorphous.