Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[C@H:39]([CH3:40])[CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:41])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([CH2:42][CH2:43]OS(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[NH:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[C@H:35]([CH3:41])[CH2:36][CH2:37][CH2:38][C@@H:39]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([CH2:42][CH2:43][N:58]2[CH2:63][CH2:62][O:61][CH2:60][CH2:59]2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C1COCCN1
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCOS(C)(=O)=O)c4ccccc43)cn12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCN4CCOCC4)c4ccccc43)cn12
Temperature: 50 °C
Reaction time: 24 h
Yield: 40.5 %

Procedure:
To a solution of Intermediate 121a (0.07 mmol) in THF (2 mL) was added DIPEA (50 μL, 0.29 mmol) and morpholine (25 μL, 0.29 mmol) and the reaction stirred at 50° C. for 24 h. The crude reaction mixture was cooled and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% [2M NH3 in MeOH] in DCM followed by MDAP (Method 7) purification, to give the title compound (19 mg, 39%). LCMS (Method 5): Rt 3.65 min, m/z 670 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.56 (3H, d, J=6.2 Hz), 0.59 (3H, d, J=6.2 Hz), 1.16 (9H, s), 1.37-1.55 (3H, m), 1.63-1.69 (2H, m), 1.73-1.79 (1H, m), 1.85-2.00 (2H, m), 2.04-2.10 (2H, m), 2.34 (4H, t, J=4.5 Hz), 2.57 (2H, t, J=7.2 Hz), 3.09-3.19 (2H, m), 3.50 (4H, t, J=4.5 Hz), 3.95 (2H, t, J=7.2 Hz), 4.82 (1H, td, J=8.6, 5.7 Hz), 5.50 (1H, t, J=4.2 Hz), 5.99 (1H, s), 6.92 (1H, d, J=8.6 Hz), 7.18 (1H, dd, J=9.8, 2.3 Hz), 7.20-7.26 (1H, m), 7.30-7.36 (3H, m), 7.62 (1H, dd, J=9.7, 0.6 Hz), 7.86 (1H, d, J=2.1 Hz), 8.19 (1H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH2:18])=[CH:16][CH:15]=[C:14]([S:19]([CH3:22])(=[O:21])=[O:20])[N:13]=2)[CH2:8][CH2:7]1)[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](Cl)=[O:38]>C(#N)C>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH:18][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][CH:42]=[C:34]([Cl:33])[CH:35]=3)=[CH:16][CH:15]=[C:14]([S:19]([CH3:22])(=[O:21])=[O:20])[N:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CCOC(=O)CC1CCN(c2nc(S(C)(=O)=O)ccc2N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CC1CCN(c2nc(S(C)(=O)=O)ccc2NC(=O)c2cccc(Cl)c2)CC1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 49.8 %

Procedure:
To a mixture of 0.080 g (0.23 mmol) of (3′-amino-6′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid ethyl ester in acetonitrile (5 mL) is added 0.12 mL (0.70 mmol) of N,N-diisopropylethylamine followed by 0.032 mL (0.28 mmol) of 3-chlorobenzoyl chloride. The mixture is heated at 80° C. for 1 h then an additional 0.096 mL (0.84 mmol) of 3-chlorobenzoyl chloride is added. The mixture is stirred at 80° C. for an additional 10 minutes then cooled to room temperature and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography to provide 0.055 g (49%) of [3′-(3-chloro-benzoylamino)-6′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid ethyl ester as a colorless foam.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[N:6][N:7]([CH:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17]C(C)(C)C)=[O:16])[CH2:11][CH:10]2[C:22]#[N:23])[CH:8]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:4]1[C:5]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[N:6][N:7]([CH:9]2[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[CH2:11][CH:10]2[C:22]#[N:23])[CH:8]=1)(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)C1CCC(n2cc(C(N)=O)c(Nc3ccc(Cl)cc3)n2)C(C#N)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC1CC(C(=O)O)CCC1n1cc(C(N)=O)c(Nc2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (1S,3S,4S and 1R,3R,4R)-t-butyl 4-[4-carbamoyl-3-[(4-chlorophenyl)amino]-1H-pyrazol-1-yl]-3-cyanocyclohexane-1-carboxylate (500 mg, 1.1 mmol) in DCM (4 mL) was added TFA (2 mL) at 0° C. The resulting solution was stirred at ambient temperature for 16 hours and then concentrated in vacuo to afford the title compound as an off-white solid, which was used directly without further purification. 1H NMR (400 MHz, CD3OD) δ 8.14 (s, 1H), 7.58-7.53 (m, 2H), 7.26-7.21 (m, 2H), 4.32-4.30 (m, 1H), 3.50-3.46 (m, 1H), 2.58-2.48 (m, 2H), 2.33-2.15 (m, 3H), 1.98-1.88 (m, 1H), 1.77-1.64 (m, 1H). MS ESI: [M+H]+ m/z 388.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:13]N1C=CN=C1>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10](=[O:12])[CH3:13])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cn1ccnc1
Reactant: O=C(O)Cc1ccc(F)c(Cl)c1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Cc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a solution of 2-(3-chloro-4-fluorophenyl)acetic acid (18.46 g, 97.89 mmol) in acetic anhydride (463 mL) was added N-methylimidazole (3.9 mL) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution and organic layer was concentrated and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a colorless oil (14.5 g, 79%). 1H NMR (400 MHz, CDCl3) δ 7.23 (dd, J=6.9, 2.1 Hz, 1H), 7.14-7.00 (m, 2H), 3.66 (s, 2H), 2.19 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[C:12]([F:21])[CH:11]=2)=[CH:6][N:5]=[C:4]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[Cu]I>[CH:18]1([CH2:17][O:16][C:13]2[CH:14]=[CH:15][C:10]([C:9]3[O:22][C:2]4[CH:3]=[C:4]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26])[N:5]=[CH:6][C:7]=4[N:8]=3)=[CH:11][C:12]=2[F:21])[CH2:20][CH2:19]1
Reactant: C[C@@H](COc1cc(Cl)c(NC(=O)c2ccc(OCC3CC3)c(F)c2)cn1)NC(=O)OC(C)(C)C
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](COc1cc2oc(-c3ccc(OCC4CC4)c(F)c3)nc2cn1)NC(=O)OC(C)(C)C
Temperature: 160 °C
Reaction time: 5 h
Yield: 42.9 %

Procedure:
A suspension of tert-butyl ((2S)-1-((4-chloro-5-((4-(cyclopropylmethoxy)-3-fluorobenzoyl)amino)pyridin-2-yl)oxy)propan-2-yl)carbamate (990 mg), potassium carbonate (554 mg) and copper(I) iodide (38.2 mg) in DMF (10 mL) was stirred at 160° C. for 5 hr under microwave irradiation. To the reaction mixture was added water, and the obtained mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and subjected to silica gel column chromatography (NH, ethyl acetate). The solvent was evaporated, and the obtained solid was washed with ethyl acetate/hexane to give the title compound (393 mg).
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:12][C:13]1[CH:14]=[N:15][C:16]([N:19]2[CH2:26][CH:25]3[C:21]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)([NH:22][O:23][CH2:24]3)[CH2:20]2)=[N:17][CH:18]=1>O1CCCC1>[F:12][C:13]1[CH:18]=[N:17][C:16]([N:19]2[CH2:26][CH:25]3[C:21]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)([N:22]([C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[S:11])[O:23][CH2:24]3)[CH2:20]2)=[N:15][CH:14]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Fc1cnc(N2CC3CONC3(c3cccnc3)C2)nc1
Solvent: C1CCOC1
Product: O=C(NC(=S)N1OCC2CN(c3ncc(F)cn3)CC21c1cccnc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 109.5 %

Procedure:
Benzoyl isothiocyanate (511 μL 3.79 mmol) is added drop wise to a stirred solution of 5-(5-fluoropyrimidin-2-yl)-6a-(3-pyridyl)-3,3a,4,6-tetrahydro-1H-pyrrolo[3,4-c]isoxazole (640 mg, 2.23 mmol) in tetrahydrofuran (20 mL) at 0° C. The resulting mixture is stirred at 0° C. for 1 hour and is warmed to room temperature over 1 hour. The solvent is evaporated under vacuum and the resulting residue is purified by silica gel chromatography using a 0-5% gradient of 0.14 M ammonia/methanol solution in dichloromethane to give the title compound (1.1 g, quantitative). ES/MS (m/e): 451 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2]1.CCN(C(C)C)C(C)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>ClCCl>[C:26]([N:1]1[CH2:6][CH2:5][O:4][CH:3]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2]1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(OCc1ccccc1)C1CNCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCOC(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.5 %

Procedure:
Phenylmethyl 2-morpholinecarboxylate (450 mg, 2.034 mmol) was dissolved in dichloromethane (30 ml). DIPEA (0.71 ml, 4.07 mmol) and acetic anhydride (0.23 ml, 2.441 mmol) were added and the mixture was stirred under nitrogen at room temperature for 18 hr. The solvent was removed in vacuo, the residue was portioned between dichloromethane (20 ml) and water (20 ml) and separated by hydrophobic frit. The aqueous layer was washed with dichloromethane (2×10 ml) and to the combined organic phases was added saturated sodium bicarbonate solution (20 ml). The phases were separated by hydrophobic frit and the aqueous layer was washed with dichloromethane (2×10 ml). The solvent was removed in vacuo, the residue was dissolved in dichloromethane (˜5 ml) and the residue was purified by flash chromatography (20 g silica, gradient elution, 0-100% EtOAc-Cyclohexane then 0-20% MeOH). The solvent was removed in vacuo to give the title compound (313 mg, 1.19 mmol) as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:11][C@@H:10]2[CH2:12][O:13][C:14]2[C:23]([CH:24]3[CH2:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]3)=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][N:20]=3)[N:15]=2)=[N:7][CH:8]=1.C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:11][C@@H:10]2[CH2:12][O:13][C:14]2[C:23]([CH:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][N:20]=3)[N:15]=2)=[N:7][CH:8]=1
Reactant: COc1ccc([C@H]2C[C@@H]2COc2nc3cccnc3cc2C2CCCN(C(=O)OC(C)(C)C)C2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc([C@H]2C[C@@H]2COc2nc3cccnc3cc2C2CCCNC2)nc1
Reaction time: 0.08 h

Procedure:
To a solution of tert-butyl 3-(2-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]methoxy}-1,5-naphthyridin-3-yl)piperidine-1-carboxylate (RR2) (38 mg, 0.08 mmol) in DCM (3 mL) was added concentrated TFA (0.5 mL, 6.5 mmol). After five minutes, saturated sodium bicarbonate (3 mL) was added and the mixture was extracted with EtOAc (3×15 mL). The combined organics were dried over MgSO4, filtered and concentrated in vacuo to afford the title compound, which was sufficiently pure to use in the subsequent step without further purification. HRMS m/z (M+H) 391.2133 found, 391.2129 required.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]([C@H:12]1[C:20]2[C:15](=[C:16]([C:21]3[N:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[C:28]([C:36]#[N:37])[CH:27]=4)[O:23][N:22]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)[S:8]([CH3:11])(=[O:10])=[O:9])(=O)C.C([O-])([O-])=O.[K+].[K+]>CO.O>[C:36]([C:28]1[CH:27]=[C:26]([C:24]2[O:23][N:22]=[C:21]([C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:15]=3[CH2:14][CH2:13][C@H:12]4[N:7]([CH2:6][CH2:5][OH:4])[S:8]([CH3:11])(=[O:9])=[O:10])[N:25]=2)[CH:31]=[CH:30][C:29]=1[O:32][CH:33]([CH3:35])[CH3:34])#[N:37]
Reactant: CC(=O)OCCN([C@@H]1CCc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4N(CCO)S(C)(=O)=O)no2)cc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)methylsulfonamido)ethyl acetate (12 mg, 0.22 mmol) in a 1:1 mixture of MeOH/H2O was added K2CO3 (9.48 mg, 0.06 mmol). The reaction mixture was stirred at room temperature for 2 h and concentrated to dryness. The crude reaction mixture purified by preparative HPLC to afford (R)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-N-(2-hydroxyethyl)methanesulfonamide 112. LCMS-ESI (m/z) calculated for C24H26N4O5S: 482.2. found 505.1 [M+Na]+, tR=3.55 min.
Reaction SMILES: C([N:8](C(OC(C)(C)C)=O)[C@H:9]1[CH2:13][C@@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:24])=[N:18][C:19]=3[Cl:23])[C@H:11]([OH:25])[C@@H:10]1[OH:26])(OC(C)(C)C)=O.ClC1N=C2C(N=CN2[C@@H]2C[C@H](N3[N:53]=[C:52]([CH2:54][CH3:55])[CH:51]=[N:50]3)C=C2)=C(Cl)N=1>>[Cl:24][C:17]1[N:16]=[C:15]2[C:20]([N:21]=[CH:22][N:14]2[C@@H:12]2[CH2:13][C@H:9]([N:8]3[N:53]=[C:52]([CH2:54][CH3:55])[CH:51]=[N:50]3)[C@@H:10]([OH:26])[C@H:11]2[OH:25])=[C:19]([Cl:23])[N:18]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: CCc1cnn([C@@H]2C=C[C@H](n3cnc4c(Cl)nc(Cl)nc43)C2)n1
Product: CCc1cnn([C@H]2C[C@@H](n3cnc4c(Cl)nc(Cl)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
The titled compound is prepared analogously to (1S,2R,3S,5R)-3-(di-Boc-amino)-5-(2,6-dichloro-purin-9-yl)-cyclopentane-1,2-diol (AA4) by replacing di-Boc-[(1S,4R)-4-(2,6-dichloro-purin-9-yl)-cyclopent-2-enyl]-amine with 2,6-dichloro-9-[(1R,4S)-4-(4-ethyl-[1,2,3]triazol-2-yl)-cyclopent-2-enyl]-9H-purine (Step 1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([C:10]2[NH:14][CH:13]=[C:12]([S:15](Cl)(=[O:17])=[O:16])[CH:11]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:19]([NH:26][S:15]([C:12]1[CH:11]=[C:10]([C:8]([C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:9])[NH:14][CH:13]=1)(=[O:17])=[O:16])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(c1cc(S(=O)(=O)Cl)c[nH]1)c1cccnc1Cl
Reactant: NCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cc(S(=O)(=O)NCc2ccccc2)c[nH]1)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-3-sulfonyl chloride (500 mg, 1.64 mmol) (from Example 17), benzylamine (351.5 mg, 3.28 mmol) and triethylamine (1 mL) in DCM (5 mL) was stirred at room temperature for 4 hours. The reaction was diluted with DCM, washed with water, dried and concentrated. The residue was purified on a silica gel column to give 5-(2-chloro-pyridine-3-carbonyl)1H-pyrrole-3-sulfonic acid benzylamide.
Reaction SMILES: [NH2:1][CH:2]([CH3:34])[CH2:3][CH2:4][N:5](CC1C=CC=CC=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:22][CH2:23][CH:24]([NH2:26])[CH3:25])CC1C=CC=CC=1>[OH-].[OH-].[Pd+2].C(O)C>[NH2:26][CH:24]([CH3:25])[CH2:23][CH2:22][NH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3][CH:2]([NH2:1])[CH3:34]
Reactant: CC(N)CCN(CCCCCCCCN(CCC(C)N)Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(N)CCNCCCCCCCCNCCC(C)N
Yield: 55.5 %

Procedure:
Combine 5.0 g (0.01 mol) of the product of Step D, 0.5 g of 20% Pd(OH)2 on carbon (Pearlman's Catalyst), and 50 ml of ethanol and treat the mixture with H2 at 45 lb/in2 in a shaker flask until no more gas is taken up. Remove the catalyst by filtration and remove the solvent at reduced pressure. Subject the residue to short path distillation to yield 1.59 g of the title compound (bp 145°-148° C. at 0.012
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=1)(=O)=O.[CH3:19][N:20](C=O)C>CCOCC.[C-]#N.[Zn+2].[C-]#N>[C:13]([C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[C:19]#[N:20])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cccc(OS(=O)(=O)C(F)(F)F)c1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOCC
Product: CC(C)(C)c1cccc(C#N)c1
Temperature: 120 °C
Yield: 75 %

Procedure:
To a solution of 3-tert-butylphenyl trifluoromethanesulfonate (1.5 g, 6.70 mmol) in DMF (10 mL), zinc cyanide (1.57 g, 13.40 mmol) was added. The reaction mixture was heated to 120° C. for 4 h. Then reaction mixture was cooled, diluted with ether (2500 mL) and washed twice with 2N ammonium hydroxide (50 mL). The ether solution was washed with brine (20 mL) and concentrated in vacuo to provide the crude mixture. The crude was then purified by column chromatography (5% EtOAc in hexanes) to afford 3-tert-butylbenzonitrile in 75% yield.
Reaction SMILES: [CH2:1]([C:3]1([CH2:19][CH3:20])[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[O:4]1)[CH3:2].C(O)(=O)C.[Br:25]Br>C(Cl)(Cl)Cl>[Br:25][C:6]1[C:7](=[O:8])[C:3]([CH2:1][CH3:2])([CH2:19][CH3:20])[O:4][C:5]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: CCC1(CC)OC(c2ccc(S(C)(=O)=O)cc2)=CC1=O
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCC1(CC)OC(c2ccc(S(C)(=O)=O)cc2)=C(Br)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2,2-diethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone (4.5 g) in 200 ml chloroform with 3 ml acetic acid, was added dropwise 1.5 ml bromine at 0° C. The solution was then allowed to warm to room temperature and was stirred for another 4 hours. The reaction was quenched by adding saturated aqueous sodium thiosulfate until the characteristic color of bromine disappeared. The reaction mixture was then extracted with dichloromethane (100 ml×2) and the organic layer was dried over anhydrous magnesium sulfate. After the magnesium sulfate was removed by filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by recrystallization from hexane and ethylacetate to afford 4.5 g of 4-bromo-2,2-diethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone. mp: 130-131° C. NMR: δ0.88 (t, J=7.5 Hz, 6H), 1.95 (q, J=7.5 Hz, 4H), 3.11 (s, 3H), 8.12 (d, J=8.7 Hz, 2H), 8.42 (d, J=8.7 Hz, 2H). IR (cm−1): 2973, 1705, 1583, 1558, 1315, 1160, 1084.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[O:33]1[CH:37]=[C:36]([C:38](O)=[O:39])[N:35]=[CH:34]1>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([C:38]([C:36]3[N:35]=[CH:34][O:33][CH:37]=3)=[O:39])[CH2:17][CH2:18]1)=[N:7]2
Reactant: O=C(O)c1cocn1
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Product: Cc1c(N2CCN(C(=O)c3cocn3)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure Q using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (40.0 mg, 0.09 mmol) and oxazole-4-carboxylic acid to give (4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)piperazin-1-yl)(oxazol-4-yl)methanone. 1H NMR (DMSO-d6) δ ppm 2.11 (br s, 3H), 3.05 (t, J=4.4 Hz, 4H), 3.32-3.37 (m, 4H), 3.69 (t, J=4.4 Hz, 4H), 3.80 (br s, 2H), 4.00-4.07 (m, 2H), 6.51 (s, 1H), 7.11-7.16 (m, 1H), 7.27-7.32 (m, 1H), 7.53 (s, 1H), 7.78 (s, 1H), 8.36 (s, 1H), 8.54 (s, 1H), 8.62 (s, 1H). Mass Spectrum (ESI) m/e=536.0 (M+1).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:6])#[N:2].[Cl:14][C:15]([Cl:19])([Cl:18])[S:16]Cl.C(N(CC)CC)C>C(Cl)Cl>[C:1]([CH2:3][N:4]([S:16][C:15]([Cl:19])([Cl:18])[Cl:14])[C:5]([C:7]1[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:6])#[N:2]
Reactant: Cc1ccccc1C(=O)NCC#N
Reactant: ClSC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)N(CC#N)SC(Cl)(Cl)Cl
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
To a stirred mixture of 5.0 g (0.029 mole) N-cyanomethyl-o-toluamide (the product of Example 10) and 5.8 g (0.031 mole) trichloromethylsulfenyl chloride in 125 ml methylene chloride, 3.6 g (0.036 mole) triethylamine in 25 ml methylene chloride were added dropwise over 40 minutes. The reaction mixture was stirred 30 minutes. The reaction mixture was washed three times with 75 ml water, dried over magnesium sulfate and stripped to give a brown oil. The oil did not crystallize when rubbed with hexane. The oil was column chromatographed through 125 g of silica gel, eluting with chloroform to give 5.6 g of a glass-like product which crystallized partly upon cooling to room temperature.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[C:23]3[C:18](=[N:19][C:20]([CH3:24])=[CH:21][CH:22]=3)[N:17]([CH2:25][CH3:26])[C:16](=[O:27])[C:15]=2[CH2:28][CH2:29][C:30]([OH:32])=O)[CH:11]=[CH:12][CH:13]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.Cl>CN(C=O)C.C1COCC1>[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[C:23]3[C:18](=[N:19][C:20]([CH3:24])=[CH:21][CH:22]=3)[N:17]([CH2:25][CH3:26])[C:16](=[O:27])[C:15]=2[CH2:28][CH2:29][C:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])[CH:11]=[CH:12][CH:13]=1
Reactant: C1COCCN1
Reactant: CCn1c(=O)c(CCC(=O)O)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCn1c(=O)c(CCC(=O)N2CCOCC2)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 0.3 ml portion of oxalyl chloride and one drop of DMF were added to a 20 ml THF solution containing 1.00 g of 3-[4-(3-chlorophenyl)-l-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]propanoic acid, followed by stirring at room temperature for further 30 minutes. The reaction mixture was added dropwise to an ice-cooled 10 ml THF solution containing 1.0 ml of morpholine, followed by stirring for 30 minutes. To the reaction mixture was added 1M hydrochloric acid and the whole was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then the solvent was evaporated. The resulting residue was purified by a silica gel column chromatography (chloroform-methanol) and then recrystallized from diisopropyl ether-ethyl acetate to obtain 780 mg of 4-(3-chlorophenyl)-1-ethyl-7-methyl-3-[3-(morpholin-4-yl)-3-oxopropyl]-1,8-naphthyridin-2(1H)-one as colorless crystals.