Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si](C)(C)[N-][Si](C)(C)C.[K+].[CH:11]([C:13]12[CH2:20][CH2:19][C:16]([C:21]([O:23][CH3:24])=[O:22])([CH2:17][CH2:18]1)[CH2:15][CH2:14]2)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CCOC(C)=O>[CH:11]([C:13]12[CH2:20][CH2:19][C:16]([C:21]([O:23][CH3:24])=[O:22])([CH2:17][CH2:18]1)[CH2:15][CH2:14]2)=[CH2:1]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)C12CCC(C=O)(CC1)CC2
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC12CCC(C(=O)OC)(CC1)CC2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of methyltriphenylphosphonium bromide (9.1 g, 12.8 mmol) in THF (50 ml) at 0° C. was added potassium hexamethyldisilazide (0.5M in toluene, 48.6 ml), dropwise over 5 min. The resulting mixture was allowed to warm up to room temperature over 1 h, then cooled again to 0° C. and treated with methyl 4-formylbicyclo[2.2.2]octane-1-carboxylate (4-1) (Chapman, N. B. et al. J. Org. Chem., 1970, 35, 917) (2.5 g, 12.8 mmol). The reaction mixture was stirred at room temperature for 18 h then diluted with EtOAc (350 ml). The organic phase was washed with aqueous HCl (1 N), saturated aqueous sodium bicarbonate, and brine, then dried (Na2SO4) and concentrated in vacuo. The resulting solid was purified by flash silica gel chromatography, eluting with a gradient 0-4% EtOAc/hexanes. The resulting methyl 4-vinylbicyclo[2.2.2]octane-1-carboxylate (4-2) was isolated as a clear, colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[C:12]([NH2:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:14])[CH3:13].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:21][C:12]([CH3:14])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13])=[O:6]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(N)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(NC(=O)c1ccc(Cl)c(Cl)c1)c1ccccc1
Yield: 87.4 %

Procedure:
In a similar manner to Step 1 of Example 16, 3,4-dichlorobenzoyl chloride (3.00 g, 14.3 mmol) was dissolved in dichloromethane (60 mL), and the solution was treated with cumylamine (2.30 mL, 15.7 mmol), triethylamine (3.00 mL, 21.5 mmol) and DMAP (175 mg, 1.43 mmol), followed by purification by slurry using chloroform to obtain 3,4-dichloro-N-(1-methyl-1-phenylethyl)benzamide (3.85 g, yield 88%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]=[O:8].ClS([N:13]=[C:14]=O)(=O)=O.CN(C)C=O.[OH-].[Na+]>C(#N)C>[C:14]([C:5]1[CH:4]=[C:3]([CH:7]=[O:8])[N:2]([CH3:1])[CH:6]=1)#[N:13]
Reactant: Cn1cccc1C=O
Reactant: O=C=NS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cn1cc(C#N)cc1C=O
Temperature: -45 °C
Reaction time: 12 h
Yield: 35 %

Procedure:
1-Methylpyrrole-2-carbaldehyde (10 g, 91.6 mmol) was dissolved in acetonitrile (100 ml) and cooled to -45° C. Chlorosulfonyl isocyanate (38.9 g, 274.9 mmol) in acetonitrile (40 ml) was added dropwise over 40 min. The mixture was then stirred at room temperature for 12 h. After dropwise addition of dimethylformamide (35 ml), the mixture was heated at 50° C. for 1 h. After cooling to room temperature, the reaction mixture was added to ice (200 ml) and 2N sodium hydroxide solution (286 ml). The precipitate which formed was filtered off with suction. The filtrate were [sic] extracted with diethyl ether. The combined ether phases were washed with dilute sodium bicarbonate solution and water until neutral and dried over sodium sulfate. The solvent was distilled off under water pump vacuum, and the residue was combined with the previously obtained precipitate. Recrystallization from petroleum ether afforded 4-cyano-1-methylpyrrole-2-carbaldehyde (4.3 g) (see, for example, C. E. Loader et al. Can. J. Chem. 59 (1981) 2673-6).
Reaction SMILES: [NH2:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:32][CH3:33])[CH:3]=1.[CH:34](=O)[CH3:35].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:34][CH3:35])[CH2:22][C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:32][CH3:33])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2ccncc2)CC1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1ccncc1

Procedure:
4-Amino-5-chloro-2-methoxy-N-((1-(5-((4-pyridylmethyl)amino)-pentyl)piperidin-4-yl)methyl)benzamide (0.8 g) as starting compound, acetaldehyde (0.12 ml) and sodium cyanoborohydride (0.14 g) were reacted and treated in the same manner as in Example 136 to give 0.35 g of 4-amino-5-chloro-N-((1-(5-(N-ethyl-N-(4-pyridylmethyl)amino)pentyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [Li]CCCC.CN(CCN(C)C)C.[CH:14]([Si:17]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26])([CH3:16])[CH3:15].C1C[O:36][CH2:35]C1>CCOC(C)=O>[CH3:26][O:25][C:20]1[C:19]([O:18][Si:17]([CH:14]([CH3:16])[CH3:15])([CH:27]([CH3:29])[CH3:28])[CH:30]([CH3:32])[CH3:31])=[C:24]([CH:23]=[CH:22][CH:21]=1)[CH:35]=[O:36]
Reactant: C1CCOC1
Reactant: COc1ccccc1O[Si](C(C)C)(C(C)C)C(C)C
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Product: COc1cccc(C=O)c1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
nBuLi (2.5 M in hexanes) (36 mmol) is mixed with TMEDA (36 mmol) at 0° C. in a dry round bottom flask for 10 minutes. A solution of triisopropyl-(2-methoxy-phenoxy)-silane (24 mmol) in 25 mL of dry THF is added to the above mixture. The mixture is warmed up to room temperature in 2 hours by removal of the ice bath. The slightly yellow solution is then transferred to another dry flask containing dry 7.5 mL of DMF at room temperature. The mixture is stirred overnight. HCl (1 M) is added to the mixture to quench the reaction. The mixture is diluted with EtOAc (100 mL), washed with HCl (1 M) (2×100 mL) and brine (50 mL) and finally dried over anhydrous Na2 SO4. Purification is accomplished by silica flash chromatography (5% EtOAc/hexane) to yield 3-methoxy-2-triisopropylsilanyloxy-benzaldehyde as a colorless oil which needs to be stored at low temperatures: 1H NMR (400 MHz, CDCl3) δ 10.4 (s, 1H), 7.42 (dd, J1=7.7 Hz, J2=1.7 Hz, 1H), 7.67 (d, J1=8 Hz, J2=1.7 Hz, 1H), 7.04 (t, J=8.4 Hz, 1H), 3.96 (s, 3H), 1.26-1.35 (m, 3H), 1.13 (s, 9H), 1.12 (s, 9H). LC/MS (ES+): (M+1) 309.2. Rf=0.4 (5% EtOAc/hexane).
Reaction SMILES: O1CCC[CH2:2]1.[O:6]=[C:7]1[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][CH2:8]1.C[Li]>O>[OH:6][C:7]1([CH3:2])[CH2:8][CH2:9][CH:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Reactant: C1CCOC1
Agent: [Li]C
Solvent: O
Product: CC1(O)CCC(NC(=O)OC(C)(C)C)CC1
Reaction time: 1.5 h

Procedure:
To a 6 ml anhydrous tetrahydrofuran solution of 303 mg (1.42 mmol) of tert-butyl N-(4-oxocyclohexyl)carbamate, 2.7 ml of methyl lithium (1.1M in hexane, 2.98 mmol) was dropwise added at −78° C. under an argon atmosphere and stirred for 1.5 hours, after adding 20 ml of water thereto to return room temperature, followed by extracting with 30 ml of methylene chloride after drying over anhydrous sodium sulfate, the solvent was distilled off and the residue was purified by a silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain 150 mg (46%) of non-polar side diastereomer as a colorless crystal and 54 mg (17%) of polar side diastereomer as a colorless crystal.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][F:17])[C:11](=[O:18])[CH2:10]2)=[C:6]([F:8])[CH:7]=1.N1C=CC=CC=1.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>ClCCl>[CH2:29]([O:28][C:26]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][F:17])[C:11](=[O:18])[CH2:10]2)=[C:6]([F:8])[CH:7]=1)=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Nc1ccc(N2CCN(CCF)C(=O)C2)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(N2CCN(CCF)C(=O)C2)c(F)c1)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
5-Amino-2-(4-[2-fluoroethyl]-3-oxopiperazin-1-yl)fluorobenzene (2.6 g) is dissolved in dry dichloromethane (50 ml) under argon. Pyridine (1.03 ml) is added, and the mixture cooled to −20°. Benzyl chloroformate (1.6 ml) is added and the mixture stirred for 10 minutes at −20°, before allowing the temperature to rise to 20-25° over 1.5 hours. The solvents are removed and the residue is dissolved in dichloromethane and washed with sodium bicarbonate solution. After drying over magnesium sulfate and removal of the solvent, the residue is chromatographed (silica, eluting with a gradient increasing in polarity from 0 to 5% methanol in dichloromethane) to give 5-benzyloxycarbonylamino-2-(4-[2 fluoroethyl]-3-oxopiperazin-1-yl)fluorobenzene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([O-])(=[O:11])=[O:10])=[CH:4][C:3]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na+].P(Cl)(Cl)(Cl)(Cl)[Cl:22]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([Cl:22])(=[O:11])=[O:10])=[CH:4][C:3]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)([O-])Cc1ccc(F)c(Oc2ccccc2)c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Product: O=S(=O)(Cl)Cc1ccc(F)c(Oc2ccccc2)c1
Temperature: 0 °C

Procedure:
The sodium sulfonate obtained in step 1 is mixed with phosphorous pentachloride at room temperature for two days. An ice-water mixture is added and the aqueous solution is extracted with methylene chloride. The organic extract is washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain (4-fluoro-3-phenoxyphenyl)methanesulfonyl chloride as a syrup (2.05 g).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=2)[N:9]=[C:8]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:7]=1)=[O:4].[N-:30]=[N+:31]=[N-:32].[Na+]>C(#N)C.C(OCC)(=O)C>[N:30]([CH2:2][C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=2)[N:9]=[C:8]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:7]=1)=[O:4])=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)CCl)c2c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)CN=[N+]=[N-])c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
To a solution of 2-chloro-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]acetamide (120 mg, 0.28 mmol) in acetonitrile (3 mL) was added sodium azide (72 mg, 1.1 mmol). The resulting mixture was stirred at room temperature for 6 hours. The reaction was diluted with ethyl acetate (20 mL), washed with water (10 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (20% ethyl acetate in petroleum ether) to give 110 mg of the product as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C@H:10]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[F:19])[C@H:9]([NH:20][C:21](=[O:36])[C@H:22]([CH3:35])[NH:23][C:24](=[O:34])[CH2:25][C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=3)[C:8](=[O:37])[NH:7][C:6]=2[CH:38]=1.[H-].[Na+].I[CH3:42]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C@H:10]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[F:19])[C@H:9]([NH:20][C:21](=[O:36])[C@H:22]([CH3:35])[NH:23][C:24](=[O:34])[CH2:25][C:26]3[CH:27]=[C:28]([F:33])[CH:29]=[C:30]([F:32])[CH:31]=3)[C:8](=[O:37])[N:7]([CH3:42])[C:6]=2[CH:38]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H]1C(=O)Nc2cc(Cl)ccc2S[C@@H]1c1cc(F)ccc1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H]1C(=O)N(C)c2cc(Cl)ccc2S[C@@H]1c1cc(F)ccc1F
Reaction time: 0.08 h
Yield: 83.3 %

Procedure:
To a stirred solution of N1-[(2R,3R)-7-chloro-2-(2,5-difluorophenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl]-N2-[(3,5-difluorophenyl)acetyl]-L-alaninamide (92) (100 mg, 0.177 mmol) in DMF (800 uL) under nitrogen at ambient temperature was added sodium hydride powder (60% in mineral oil) (7 mg, 0.182 mmol). After 5 minutes, iodomethane (25 mg, 0.176 mmol) was added via micro-syringe. After stirring for 3½ hours, the reaction was carefully quenched with 1N aqueous HCl then diluted with water and extracted with ethyl acetate. The organic extracts were combined and evaporated. The residue was purified by flash chromatography on silica gel eluting first with 1:1 (v/v) hexanes:ethyl acetate and finally with ethyl acetate to afford the title compound (85 mg, 82%) as a white solid. 1H NMR (300 MHz, Acetone-d6) δ1.07 (d, 1.5H, J=7.0 Hz), 1.13 (d, 1.5H, J=7.0 Hz), 3.46-3.58 (m, 5H), 4.28 (m, 0.5H), 4.40 (m, 0.5H), 4.87 (m, 1H), 5.52 (m, 1H), 6.80-6.98 (m, 3H), 7.11-7.26 (m, 3H), 7.33 (m, 0.5H), 7.40-7.51 (m, 2.5H), 7.70 (d, 1H, J=2.2 Hz), 7.81 (d, 1H, J=8.3 Hz). MS APCI, m/z=580 (M+1). LC/MS: 2.89 min.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([F:23])([F:22])[F:21])[C:9]([CH2:24]Cl)=[CH:8]2.CN(C=O)C.[N-:31]=[N+:32]=[N-:33].[Na+]>>[N:31]([CH2:24][C:9]1[C:10]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])=[N:11][C:12]2[C:7]([CH:8]=1)=[CH:6][CH:5]=[CH:4][C:3]=2[Cl:2])=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: Fc1ccc(C(F)(F)F)c(-c2nc3c(Cl)cccc3cc2CCl)c1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cc2cccc(Cl)c2nc1-c1cc(F)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirring solution of 8-chloro-3-(chloromethyl)-2-(5-fluoro-2-(trifluoro-methyl)phenyl)quinoline hydrochloride (0.3482 g, 0.8480 mmol) in DMF (4.240 mL, 0.8480 mmol) was added sodium azide (0.1103 g, 1.696 mmol) at room temperature and the mixture was stirred at room temperature. After 1.5 h, the mixture was partitioned between EtOAc (100 mL) and H2O (100 mL). The organic layer was washed with brine (50 mL×1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 14 min, then 50% isocratic of EtOAc for 5 min as eluent to give 3-(azidomethyl)-8-chloro-2-(5-fluoro-2-(trifluoromethyl)phenyl)quinoline as a colorless syrup: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.65 (1H, s), 8.12 (1H; dd, J=8.3, 1.3 Hz), 7.99-8.06 (2H, m), 7.69 (1H, dd, J=8.1, 7.5 Hz), 7.58-7.66 (2H, m), 4.44-4.59 (2H, m); LC-MS (ESI) m/z 381.1 [M+H]+. To a solution of 3-(azidomethyl)-8-chloro-2-(5-fluoro-2-(trifluoromethyl)phenyl)-quinoline (0.2573 g, 0.676 mmol) in methanol (6.76 mL, 0.676 mmol) was added palladium, 10 wt. % on activated carbon (0.0360 g, 0.0338 mmol). After repeating three times of evacuation of air in the flask by house vacuum and filling the flask with H2, the mixture was stirred under H2. After 30 min, the mixture was filtered through a pad of Celite™ and rinsed the pad with MeOH. The filtrate was concentrated under reduced pressure to give green syrup. The green syrup was purified by column chromatography on a 40 g of Redi-Sep™ column using 0% to 20% gradient of CH2Cl2:MeOH:NH4OH (89:9:1) in CH2Cl2 over 14 min, and then 20% isocratic of CH2Cl2:MeOH:NH4OH (89:9:1) for 20 min as eluent to give (8-chloro-2-(5-fluoro-2-(trifluoromethyl)phenyl)quinolin-3-yl)methanamine as a yellow syrup: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.62 (1H, s), 8.04 (1H, dd, J=8.4, 1.2 Hz), 8.01 (1H, dd, J=8.5, 5.4 Hz), 7.93 (1H, dd, J=7.4, 1.4 Hz), 7.54-7.67 (3H, m), 3.48-3.74 (2H, m), 1.96 (2H, br. s.); LC-MS (ESI) m/z 355.1 [M+H]+.
Reaction SMILES: P([N:17]=[N+:18]=[N-:19])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.N12CCCN=C1CCCCC2.[Br:31][C:32]1[C:33]([O:40][CH3:41])=[C:34]([CH2:38]O)[CH:35]=[CH:36][CH:37]=1>C1(C)C=CC=CC=1>[N:17]([CH2:38][C:34]1[CH:35]=[CH:36][CH:37]=[C:32]([Br:31])[C:33]=1[O:40][CH3:41])=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: COc1c(Br)cccc1CO
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: COc1c(Br)cccc1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.00 g of diphenyl phosphorazidate and 4.1 g of 1,8-diazabicyclo[5.4.0]undec-7-ene were added to 4.0 g of 3-bromo-2-methoxy-phenyl-methanol 6 in 100 mL of toluene at 0° C. The mixture was stirred at room temperature overnight. The reaction mixture was quenched with aqueous ammonium chloride. The aqueous layer was extracted with ethyl acetate/THF. The pooled organic extracts were washed with brine and dried over magnesium sulfate. The mixture was filtered. The solvents were removed under vacuum. The residue was purified by chromatography on silica gel to give 1-azidomethyl-3-bromo-2-methoxy-benzene 7.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][CH:39]=[C:40]([CH:43]=2)[C:41]#[N:42])O1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:6]2[CH:21]=[C:2]([C:36]3[CH:37]=[N:38][CH:39]=[C:40]([C:41]#[N:42])[CH:43]=3)[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[O:8])=[CH:11][CH:12]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Product: N#Cc1cncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cnc2N2CC[C@@H](O)C2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 171.1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afford a white solid. UPLC-MS (Condition 3) tR=1.02 min, m/z=486.2 [M+H]+, m/z=530.0 [M+ formic acid-H]; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.69-1.80 (m, 1H) 1.80-1.91 (m, 1H) 2.85 (d, J=11.42 Hz, 1H) 3.16-3.26 (m, 2H) 3.35-3.43 (m, 1H) 4.20 (br. s, 1H) 4.90 (d, J=3.64 Hz, 1H) 7.35 (d, J=9.16 Hz, 2H) 7.82-7.89 (m, 2H) 8.10 (d, J=2.38 Hz, 1H) 8.41 (t, J=2.07 Hz, 1H) 8.79 (d, J=2.38 Hz, 1H) 8.90 (d, J=2.26 Hz, 1H) 9.03 (d, J=1.88 Hz, 1H) 10.20 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[N:12]=[C:13]([C:15](OC)=[O:16])[CH:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[CH:25]=1.[CH3:26][NH:27][CH3:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[N:12]=[C:13]([C:15]([N:27]([CH3:28])[CH3:26])=[O:16])[CH:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[CH:25]=1
Reactant: COC(=O)c1cc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reactant: CNC
Product: CN(C)C(=O)c1cc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
This compound was prepared from 700 mg. (1.99 mmol) of the end product of Example 9 and dimethylamine according to a procedure similar to that described above in Example 11. The reaction mixture was heated to 60°-65° in a sealed glass bomb for 16 hours. Recrystallization from acetone/ether/hexane yielded the desired end product: mp 176°-178°.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8](F)=[CH:9][CH:10]=2)[C:5]([O:13][CH3:14])=[CH:4][N:3]=1.[CH3:15][CH2:16][O-:17].[Na+]>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH2:16][CH3:15])=[CH:9][CH:10]=2)[C:5]([O:13][CH3:14])=[CH:4][N:3]=1
Reactant: CC[O-]
Reactant: COc1cnc(Cl)c2ccc(F)cc12
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOc1ccc2c(Cl)ncc(OC)c2c1
Reaction time: 16 h
Yield: 53.4 %

Procedure:
1-chloro-6-fluoro-4-methoxyisoquinoline (533 mg, 2.52 mmol) was dissolved in DMSO (5 mL) then NaOEt (171 mg, 2.52 mmol) was added to the solution. The reaction was stirred for 16 h. The reaction was diluted with EtOAc and washed with 1N HCl, then brine. The organic layer was collected, dried over sodium sulfate and concentrated under vacuum. The crude material was purified by silica gel chromatography using DCM as eluent. The product fractions were collected and solvent was removed under vacuum to give 1-chloro-6-ethoxy-4-methoxyisoquinoline (320 mg, 54% yield). MS m/z 238.0 (M++1).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][C:14]=1[NH2:19]>N1C=CC=CC=1>[C:1]1([N:7]2[C:12](=[O:11])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][C:14]=3[NH:19][C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: COC(=O)c1cccnc1N
Solvent: c1ccncc1
Product: O=c1[nH]c2ncccc2c(=O)n1-c1ccccc1
Yield: 61.2 %

Procedure:
17.22 g (144.6 mmol, 15.7 ml) phenylisocyanate was added to a suspenssion of 7.00 g (46.0 mmol) 2-aminonicotinic acid methyl ester in dry pyridine. The mixture was refluxed for 16 hours. The pyridine is was removed under reduced pressure and the residue was treated with 280 ml ethanol. The mixture is refluxed for 10 minutes. Upon cooling down 3-phenyl-1H-pyrido[2,3-d]pyrimidine-2,4-dione crystallized from the medium and was recrystallized from methoxypropanol. 6.73 g (61%) 3-phenyl-1H-pyrido[2,3-d]pyrimidine-2,4-dione was isolated (m.p. 304° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([O:21]C4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=O)=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:33])=[C:4]([O:34][CH3:35])[CH:3]=1.[N:36]1[CH:41]=[CH:40][CH:39]=[C:38]([NH2:42])[N:37]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:42][C:38]4[N:37]=[N:36][CH:41]=[CH:40][CH:39]=4)(=[O:20])=[O:21])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:33])=[C:4]([O:34][CH3:35])[CH:3]=1
Reactant: Nc1cccnn1
Reactant: COc1cc(Br)ccc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(Br)ccc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3cccnn3)ccc21
Temperature: 0 °C
Yield: 120.4 %

Procedure:
A flask was charged with perfluorophenyl 1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (3.33 g, 5.78 mmol) and pyridazin-3-amine (0.659 g, 6.93 mmol). A septum was attached and THF (28.9 ml) was added. The mixture was cooled to 0° C. and a THF solution of lithium bis(trimethylsilyl)amide (12.13 ml, 12.13 mmol, 1 M) was added dropwise to give a brown solution. The solution was maintained at 0° C. for 20 min. The reaction mixture was partitioned between 1 N HCl (200 mL) and EtOAc (200 mL), the layers were separated and the aqueous layer was extracted with DCM (100 mL) and EtOAc (200 mL). The combined organic layers were dried (Na2SO4) and concentrated to provide 1-(4-bromo-2-methoxyphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (3.39 g, 6.96 mmol, 120% yield) as a light yellow foam. Although contaminated with solvent, the product was of sufficient purity for use in the next step. m/z (ESI) 485.1 (M−H)−.