Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22]C)=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[NH:24][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.[OH-].[Na+]>O1CCCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[NH:24][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c(NC(=O)c3ccccn3)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(F)c(NC(=O)c2ccccn2)c1
Yield: 37.6 %

Procedure:
A mixture of methyl 2-(4-fluoro-3-(picolinamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (84 mg, 0.19 mmol) and sodium hydroxide (62 mg, 1.55 mmol) in tetrahydrofuran (10 mL), water (2 mL) was heated to reflux for 20 h. LC-MS showed the reaction was complete. The solvent was removed in vacuo and the residue was acidified by 1 M hydrochloric acid solution to pH=5-6. The precipitated white solid was collected by filtration and dissolved in acetone, dried over anhydrous magnesium sulfate. Removal of the solvent in vacuo gave crude product, which was purified by recrystallization from dichloromethane/Hexane/tetrahydrofuran to afford 30 mg of 2-(4-fluoro-3-(picolinamido)-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid. Yield: 42.1%. MS(ES+APCI) M+1=420.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[CH3:26][C:27]1([CH3:43])[O:32][CH:31]([C:33]([NH:35][CH2:36][CH2:37][C:38](O)=[O:39])=[O:34])[C:30]([CH3:42])([CH3:41])[CH2:29][O:28]1>>[C:7]([NH:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:38](=[O:39])[CH2:37][CH2:36][NH:35][C:33]([CH:31]1[C:30]([CH3:41])([CH3:42])[CH2:29][O:28][C:27]([CH3:43])([CH3:26])[O:32]1)=[O:34])(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)NCCCCN
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCCCCNC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Yield: 44.8 %

Procedure:
N-(4-Aminobutyl)oleamide (3.77 g) and 2.59 g of 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid were reacted in the same manner as in Example 1 to obtain 2.66 g of the title compound (yield: 45%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][CH3:16])[C:13]([CH2:17][CH2:18][CH2:19][OH:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClC(Cl)(Cl)[C:26]([N:28]=C=O)=[O:27].C(N(CC)CC)C>O1CCCC1.O>[C:26]([O:20][CH2:19][CH2:18][CH2:17][C:13]1[N:14]([CH2:15][CH3:16])[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:21]([CH3:22])[CH3:23])[N:12]=1)(=[O:27])[NH2:28]
Reactant: CCn1c(CCCO)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCn1c(CCCOC(N)=O)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
In 7 ml of dry tetrahydrofuran was dissolved 700 mg (1.9 mmol) of the alcohol (137b), and after the solution was cooled to -40° C., 530 mg (2.8 mmol) of trichloroacetyl isocyanate was added, the temperature was elevated to room temperature. After 30 minutes, 2 ml of water and 1 ml of triethylamine were added and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with water and extracted with ethyl acetate and the extract was washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3% methanol-ethyl acetate) and recrystallized from ethyl acetate-n-hexane to provide 705 mg (yield 90%) of Compound I-149 as crystals. mp 128-129° C.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:25])[C:7]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:8][C:9](=[N:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH3:20])[CH:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].O1CCCC1>[C:21]([C:7]1[CH:8]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH3:20])[CH:13]=2)[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:25])([CH3:23])([CH3:24])[CH3:22]
Reactant: CCOc1cccc(N=C2C=C(C(C)(C)C)C(=O)C(C(C)(C)C)=C2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOc1cccc(Nc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c1
Reaction time: 3 h

Procedure:
A solution containing 5.0 g (0.0147 mole) of 2,6-di-tertiary-butyl-4-(3-ethoxyphenylimino)-2,5-cyclohexadien-1-one and 0.1 g of 5% palladium on charcoal catalyst in 250 ml of tetrahydrofuran was hydrogenated at 50 psi. The hydrogenation was complete after three hours. The catalyst was removed by filtration and the filtrate was evaporated to give 2,6-di-tertiary-butyl-4-(3'-ethoxyanilino)phenol as an oil. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]3[CH2:14][CH2:13]3)[C:7](=[O:15])[C:6]3([CH3:20])[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1.O1CCOCC1.[CH3:27][NH:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=1)=[O:30].C([O-])(O)=O.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH:12]1([N:8]2[C:7](=[O:15])[C:6]3([CH3:20])[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]3[N:3]=[C:2]([C:35]4[CH:34]=[CH:33][C:32]([NH:31][C:29]([NH:28][CH3:27])=[O:30])=[CH:37][CH:36]=4)[N:11]=[CH:10][C:9]2=3)[CH2:14][CH2:13]1
Reactant: CC12COCCN1c1nc(Cl)ncc1N(C1CC1)C2=O
Reactant: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)Nc1ccc(-c2ncc3c(n2)N2CCOCC2(C)C(=O)N3C2CC2)cc1
Yield: 19.5 %

Procedure:
A microwave vial equipped with a magnetic stirrer was added 2-chloro-5-cyclopropyl-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (100 mg, 0.339 mmol), 1,4-dioxane (2 ml), 1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (141 mg, 0.509 mmol), NaHCO3 (585 μl), followed by PdCl2(dppf) (12.41 mg, 0.017 mmol). The reaction was irradiated in the microwave at 100° C. for 40 min. Upon completion the reaction solution was poured into water and the precipitate filtered. The collected solid was successively washed with water and small amount of ethanol and dried in-vacuo to obtain a solid. This solid was further purified by silica gel chromatography (2 to 5% gradient of MeOH in chloroform). The fractions were collected and concentrated in-vacuo to afford the title compound (27 mg, 0.066 mmol, 19.48% yield) as a white solid. 1H NMR (400 MHz, DMSO-d4, D2O) δ ppm 0.55 (m, 1H) 0.78-0.92 (m, 1H) 1.01-1.11 (m, 1H) 1.12-1.24 (m, 2H) 1.45 (s, 3H) 2.65 (s, 3H) 2.78 (s, 1H) 3.26-3.40 (m, 1H) 3.55 (m, 1H) 3.70 (d, J=11.6 Hz, 1H) 3.93 (d, J=11.4 Hz, 1 H) 4.02 (m, 1H) 4.30-4.39 (m, 1H) 7.54 (d, J=8.8 Hz, 2H) 8.08-8.16 (d, J=8.8 Hz, 2H) 8.20 (s, 1H). MS [M+H] found 409.
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[CH:34]([C:37]([C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=1)=[O:38])([CH3:36])[CH3:35]>O1CCCC1>[CH:40]1[C:41]2[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:47]=[CH:48][C:39]=1[C:37]([C:34]([Br:1])([CH3:36])[CH3:35])=[O:38]
Reactant: CC(C)C(=O)c1ccc2ccccc2c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(Br)C(=O)c1ccc2ccccc2c1
Yield: 172.2 %

Procedure:
2.16 g of phenyltrimethylammonium tribromide was added to a mixture comprising 1.14 g of 2-naphthyl isopropyl ketone and 25 ml of tetrahydrofuran, and the mixture was reacted at room temperature for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 1.59 g of oily α-bromoisopropyl 2-naphthyl ketone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH:15]2[CH2:20][CH2:19][C:18](O)([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][N:22]=3)[CH2:17][CH2:16]2)[CH2:11][CH2:10]1.N1C=CN=C1>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH:15]2[CH2:20][CH2:19][C:18]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][N:22]=3)=[CH:17][CH2:16]2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCN(C2CCC(O)(c3ncc(C)cc3C)CC2)CC1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: COc1ccccc1N1CCN(C2CC=C(c3ncc(C)cc3C)CC2)CC1
Reaction time: 8 h
Yield: 61.8 %

Procedure:
Methyloxalyl chloride (0.35 ml) was added to a mixture of 1-(2-methoxyphenyl)-4-[1-hydroxy-1(3,5-dimethylpyridin-2-yl)-cyclohex-4-yl]piperazine (0.7 g, 1.8 mmol) and imidazole (0.25 g) in THF (15 ml) at reflux. Heating was continued overnight when the solvent was evaporated in vacuo and replaced with toluene (15 ml). The mixture was heated under reflux overnight, then, when cool, added to dilute NaOH (aq) and extracted by ether (3×50 ml). The combined organic extracts were washed with brine (50 ml) and water (50 ml), dried over magnesium sulphate and evaporated to dryness. The crude product was chromatographed (SiO2, 2% methanol in dichloromethane) giving the title compound (0.42 g) which was recrystallised from hexane then treated with ethanolic HCl to give the title compound as the trihydrochloride 2.25 hydrate, m.p. 235°-236° C.
Reaction SMILES: [C:1]([C:9]1[CH:19]=[CH:18][C:12]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:26][CH2:27][N:28]([CH2:31][CH2:32]Cl)[CH2:29][CH3:30]>C(#N)C>[C:1]([C:9]1[CH:19]=[CH:18][C:12]([N:13]([CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: CCN(CC)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(CC)CCN(c1ccc(C(=O)c2ccccc2)cc1)S(C)(=O)=O
Reaction time: 16 h
Yield: 95 %

Procedure:
4'-Benzoylmethanesulfonanilide (69.5 g., 0.252 mole) is dissolved in 1.4 1. of acetonitrile and heated to reflux. Potassium carbonate (35.0 g., 0.253 mole) is added followed by dropwise addition of 2-chlorotriethylamine (34.2 g., 0.252 mole) during 15 min. The reaction mixture is refluxed for 2 hrs. and then kept at room temperature for about 16 hrs. The mixture is filtered and the filtrate concentrated under vacuum. The resulting oil is dissolved in 3N HCl, the acidic solution washed with ethyl ether, and then basified with 50% aqueous NaOH to pH 11.0. The amine which separates is extracted into ethyl ether, and the ether solution is washed first with water, then with saturated sodium chloride, and dried (MgSO4). The ether is removed under reduced pressure to give 89.2 g. (95% yield) of oil which solidifies, m.p. 74°-76°C.
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10]([OH:12])=O)=[C:8]([CH3:13])[CH:7]=[C:6]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.[NH2:28][CH2:29][CH2:30][CH:31]([OH:36])[C:32]([F:35])([F:34])[F:33]>O1CCCC1.C(OCC)(=O)C.[Cl-].[NH4+]>[CH:1]([C:4]1[C:9]([C:10]([NH:28][CH2:29][CH2:30][CH:31]([OH:36])[C:32]([F:35])([F:34])[F:33])=[O:12])=[C:8]([CH3:13])[CH:7]=[C:6]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:5]=1)([CH3:2])[CH3:3]
Reactant: NCCC(O)C(F)(F)F
Reactant: Cc1cc(N2CCOCC2)nc(C(C)C)c1C(=O)O
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(N2CCOCC2)nc(C(C)C)c1C(=O)NCCC(O)C(F)(F)F
Reaction time: 18 h
Yield: 60 %

Procedure:
To a solution of 2-isopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid (synthesized similar to the methods described in sections a) to d) of example X1) (1.40 g, 5.30 mmol) in tetrahydrofuran (40 ml) are added triethylamine (2.9 ml, 21.2 mol) and 0-(7-azabenzotriazol-1-yl)N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.9 g, 5.3 mmol). The mixture is stirred for 15 min at RT, before 4-amino-1,1,1-trifluorobutan-2-ol hydrochloride (1.05 g, 5.8 mmol) is added and stirring is continued for 18 h. After completion of the reaction, the mixture is diluted with ethyl acetate and 10% aqueous ammonium chloride. The organic layer is separated and washed with saturated sodium hydrogencarbonate solution and brine, dried over magnesium sulphate and evaporated to dryness. The crude product is purified by flash chromatography (silica gel, 50% ethyl acetate/cyclohexane) to yield 2-Isopropyl-4-methyl-6-morpholin-4-yl-N-(4,4,4-trifluoro-3-hydroxy-butyl)-pyridine-3-carboxylic acid amide (example X6) (1.24 g, 3.18 mmol, 60%). [M+H]+390.2.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:26]=[CH:25][C:9]2[N:10]=[C:11]([NH:14][C@H:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[N:27]1([CH2:2][C:3]([NH:5][C:6]2[CH:26]=[CH:25][C:9]3[N:10]=[C:11]([NH:14][C@H:15]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH2:18][CH2:17][CH2:16]4)[O:12][CH2:13][C:8]=3[CH:7]=2)=[O:4])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: C1COCCN1
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(N[C@@H]1CCCc3ccccc31)=N2
Product: O=C(CN1CCOCC1)Nc1ccc2c(c1)COC(N[C@@H]1CCCc3ccccc31)=N2
Yield: 92 %

Procedure:
Prepared from 2-chloro-N-{2-[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)amino]-4H-benzo[d][1,3]oxazin-6-yl}-acetamide (Example 38 step A) (150 mg, 0.406 mmol, HPLC 1.185 min) and morpholine (707 ul, 8.1 mmol) according to the procedure described for Example 3 step B. Obtained the title compound as a white foam (157 mg, 92%, HPLC 0.586 min), MS (ISP) m/e=421.2 [(M+H)+].
Reaction SMILES: [CH3:1][NH2:2].Cl[CH2:4][C:5]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[O:7][N:6]=1>CCO>[Cl:16][C:12]1[CH:11]=[C:10]([C:8]2[O:7][N:6]=[C:5]([CH2:4][NH:2][CH3:1])[N:9]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1noc(-c2cccc(Cl)c2)n1
Reactant: CN
Solvent: CCO
Product: CNCc1noc(-c2cccc(Cl)c2)n1
Yield: 100 %

Procedure:
MeNH2 in EtOH (6 mL, 8 M, 48 mmol) was added to 3-(chloromethyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole (1.5 g, 6.5 mmol) in EtOH (20 mL). After 20 h the solvent was evaporated and the residue was dried in vacuum to give 1.47 g (100%) of the title compound. LC-MS (M++1): 224
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[NH:18]2)=[C:9]1[CH3:28])(C)(C)C.I[CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34]>>[CH3:28][C:9]1[N:8]([CH2:7][C:6]([OH:5])=[O:29])[C:16]2[C:11]([C:10]=1[CH:17]1[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:26])(=[O:27])[N:18]1[CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: CC(C)CCI
Reactant: Cc1c(C2NS(=O)(=O)c3ccccc32)c2ccccc2n1CC(=O)OC(C)(C)C
Product: Cc1c(C2c3ccccc3S(=O)(=O)N2CCC(C)C)c2ccccc2n1CC(=O)O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 3, step c) and 1-iodo-3-methyl-butane. MS: ESI (negative): 425 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]2[C:14](=O)[CH:13]=[CH:12][NH:11][C:10]=2[CH3:16])[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:14]1[CH:13]=[CH:12][N:11]=[C:10]([CH3:16])[C:9]=1[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1[nH]ccc(=O)c1Cc1cccc(F)c1
Product: Cc1nccc(Cl)c1Cc1cccc(F)c1
Temperature: 25 °C

Procedure:
A solution of 3-[(3-fluorophenyl)methyl)-2-methylpyridin-4(1H)-one (0.07 g, 0.32 mmol) in phosphorous oxychloride (3 mL) was heated to 55° C. for 16 h. Then the solution was cooled to room temperature and concentrated. The remaining residue was dissolved in ethyl acetate (10 mL), washed with 5% sodium bicarbonate (2×5 mL), and saturated sodium chloride (5 mL), dried over sodium sulfate, filtered and concentrated to afford 4-chloro-3-[(3-fluorophenyl)methyl]-2-methylpyridine. 1H NMR (400 MHz, CDCl3): 8.33 (d. 1H), 7.30-7.23 (m, 2H), 6.92-6.85 (m, 2H), 6.76 (d, 1H), 4.22 (s, 2H), 2.54 (s, 3H). MS (EI) for C13H11ClF: 236.0 (MH+).
Reaction SMILES: [O:1]=[C:2]([N:23]1[CH2:28][CH2:27][N:26]2[C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][CH:31]=[C:25]2[CH2:24]1)[CH2:3][C@H:4]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[F:14].[Br:36]N1C(=O)CCC1=O.C(=O)([O-])[O-].[K+].[K+].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(O)C>[O:1]=[C:2]([N:23]1[CH2:28][CH2:27][N:26]2[C:29]([C:32]([F:33])([F:34])[F:35])=[N:30][C:31]([Br:36])=[C:25]2[CH2:24]1)[CH2:3][C@H:4]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[F:14]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(cnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(Br)c2C1)Cc1cc(F)c(F)cc1F
Yield: 86.3 %

Procedure:
tert-Butyl(R)-[3-oxo-1-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-propyl]-carbamate 1m (20.0 g, 39.6 mmol) was dissolved in 300 mL of anhydrous ethanol, and N-bromosuccinimide (14.1 g, 79.2 mmol) was then added to the solution. After stirring for an hour, potassium carbonate (10.9 g, 79.2 mmol) and di-tert-butyl dicarbonate (8.6 g, 39.6 mmol) were added to the mixture, and the mixture was stirred for another one hour. The reaction mixture was filtered through a pad of coarse silica gel, and then the filtrate was concentrated under reduced pressure. The resulting residues were purified by silica gel column chromatography with system B as eluant to obtain the title compound tert-butyl (R)-[3-oxo-1-(2,4,5-trifluoro-benzyl)-3-(1-bromo-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-propyl]-carbamate 1n (20.0 g, yield 86%) as a white solid. 1HNMR (400 MHz, CDCl3, ppm): δ 7.063 (m, 1H), 6.88 (m, 1H), 4.72 (s, 1H), 4.56 (s, 1H), 4.13 (m, 3H), 3.88 (m, 2H), 2.94 (m, 2H), 2.62 (m, 2H), 1.36 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([F:16])([CH3:15])[CH3:14])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN.[CH:20]([N:23](CC)C(C)C)(C)C.O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>ClCCl>[F:16][C:13]([CH3:15])([CH3:14])[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]([NH:23][CH3:20])=[O:11]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)C(C)(C)F
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CNC(=O)C(NC(=O)OC(C)(C)C)C(C)(C)F
Reaction time: 18 h

Procedure:
Intermediate 66A (290 mg, 1.23 mmol) and methylamine hydrochloride (100 mg, 1.48 mmol) were dissolved in dichloromethane (5 mL) and N,N-diisopropylethylamine (0.65 mL, 3.70 mmol). 1-Hydroxybenzotriazole hydrate (283 mg, 1.85 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (354 mg, 1.85 mmol) were added, and the solution was stirred for 18 hours. The mixture was diluted additional dichloromethane and washed with saturated aqueous ammonium chloride solution and brine. The organic layer was separated, dried (Na2SO4), and concentrated under reduced pressure to provide intermediate 66B as an off-white solid in quantitative yield. 1H-NMR (400 MHz, (CD3)2SO) δ: 1.27 (d, 3H), 1.32 (d, 3H), 1.37 (s, 9H), 2.59 (d, 3H), 4.14 (dd, 1H), 6.72 (d, 1H), 7.93 (q, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][N:5]([CH2:20][CH:21]=[CH2:22])[C:6](=[O:19])[CH:7]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]C=C.CS(C)=O>Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:23])[CH2:4][N:5]1[CH2:20][CH:21]=[CH:22][CH2:8][CH:7]([NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[C:6]1=[O:19]
Reactant: C=CCC(NC(=O)OC(C)(C)C)C(=O)N(CC=C)CC(=O)OC
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)CN1CC=CCC(NC(=O)OC(C)(C)C)C1=O
Reaction time: 12 h

Procedure:
Grubbs catalyst (0.3 g) is added to a solution of [allyl-(2-tert-butoxycarbonylamino-pent-4-enoyl)amino]acetic acid methyl ester, 1, (0.815 g, 2.5 mmol) in 50 mL of CH2Cl2. The solution is refluxed for 12 hours after which additional catalyst (0.29 g) is added and the solution is refluxed for another 3 hours. The solution is then cooled, 1 mL of DMSO is added, and stirring continued at room temperature for an additional 12 hours. The solvent is removed in vacuo and the residue purified over silica gel to afford the desired product.
Reaction SMILES: C1C=CC=CC=1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[NH:18][CH2:17][CH2:16][O:15]2)=[CH:10][CH:9]=1.[Cl:19][CH:20]([Cl:24])[C:21](Cl)=[O:22]>C(N(CC)CC)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[N:18]([C:21](=[O:22])[CH:20]([Cl:24])[Cl:19])[CH2:17][CH2:16][O:15]2)=[CH:12][CH:13]=1
Reactant: O=C(Cl)C(Cl)Cl
Reactant: Clc1ccc(C2NCCO2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(C(Cl)Cl)N1CCOC1c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
Twenty-two (22) ml. of a benzene solution containing 5.5 g. of 2-p-chlorophenyl oxazolidine was mixed with 25 ml. of benzene and 3.1 g. of triethylamine and stirred at room temperature, while 4.4 g. of dichloroacetyl chloride was added dropwise. The mixture was allowed to stand for about 30 minutes, washed with water, separated, dried over magnesium sulfate and then stripped. There was obtained a yield of 3.4 g. of an oil, the title compound, ND30 =1.5668.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:27])[C:8]2[CH:9]=[C:10]3[CH:23]=[C:22]([F:24])[C:21](F)=[C:20]([F:26])[C:11]3=[N:12][C:13]=2[N:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:15]=1)=[O:5])[CH3:2].[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:27])[C:8]2[CH:9]=[C:10]3[CH:23]=[C:22]([F:24])[C:21]([N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[C:20]([F:26])[C:11]3=[N:12][C:13]=2[N:14]([C:16]([CH3:18])([CH3:17])[CH3:19])[CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Reactant: C1CNCCN1
Product: CCOC(=O)c1cn(C(C)(C)C)c2nc3c(F)c(N4CCNCC4)c(F)cc3cc2c1=O

Procedure:
The 3-ethoxycarbonyl-7,9-difluoro-4-oxo-8-(1-piperazinyl)-1-tert.-butyl-1,4-dihydro-benzo[b][1,8]naphthyridine was prepared under the conditions of Example 35, but starting from 1.9 g of 3-ethoxycarbonyl-7,8,9-trifluoro-4-oxo-1-tert.-butyl-1,4-dihydro-benzo[b][1,8]naphthyridine and 4.3 g of piperazine. After recrystallizing once from 50 cm3 of diisopropyl ether and 10 cm3 of propan-2-ol, 2 g of 3-ethoxycarbonyl-7,9-difluoro-4-oxo-8-(1-piperazinyl)-1-tert.-butyl-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a yellow solid melting at 186° C.
Reaction SMILES: C([NH:8][C@H:9]([C:14]([NH:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[C:22]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:23](=[O:27])[O:24]2)=[CH:19][CH:18]=1)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])(OC(C)(C)C)=O.[BrH:34]>C(O)(=O)C.C(O)C>[NH2:8][C@H:9]([C:14]([NH:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[C:22]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:23](=[O:27])[O:24]2)=[CH:19][CH:18]=1)=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13].[BrH:34]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc2cc(-c3ccccc3)c(=O)oc2c1
Agent: Br
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)C[C@H](N)C(=O)Nc1ccc2cc(-c3ccccc3)c(=O)oc2c1
Reaction time: 0.17 h

Procedure:
The product of Example I, above, (175.1 mg, 0.39 mmol) was dissolved at room temperature in 2 mL of 32% hydrobromic acid in acetic acid. After 10 min., 40 mL of 2/1 ether/petroleum ether was added. The precipitated solid was separated and dried overnight at room temperature and 5 Pa to yield a glassy, orange foam which was twice dissolved in 1 mL of absolute ethanol and reprecipitated by addition of 30 mL of ether. After drying overnight at room temperature and 5 Pa, there remained 73 mg (44.5%) of white solid; TLC (SiO2 : 10% methanol in methylene chloride) Rf =0.63; mp=190.1°; NMR (CD3OD) δ(LeuCH3)=1.08 D (6), J=5 Hz, δ(LeuCH2) 1.86 D (2), δ(LeuCH)=4.0 M (1), δ(ArH)=7.7 M (9); IR (KBr) C=O=1700 cm-1.