Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9]C(=O)C(F)(F)F)#[N:2].Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>>[NH2:2][C:1]1[C:3]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:9][C:17]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#Cc1ccccc1NC(=O)C(F)(F)F
Product: CC(C)(C)OC(=O)c1[nH]c2ccccc2c1N

Procedure:
Follow the procedure of Example 3 (Steps B3–B5) but start with N-(2-cyano-phenyl)-2,2,2-trifluoroacetamide (synthesis described in J. Fluorine Chem. 1981, 18, (2), 185–95) and tert-butyl bromoacetate to obtain the title compound: MS 310(M+H), TLC (silica gel, dichloromethane/methanol, 7:1) Rf=0.38.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:32]([F:35])([F:34])[F:33])[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][C:28](=[O:30])[NH:27][CH2:26]4)=[O:24])=[C:19]([CH3:31])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[H-].[Na+].[F:38][C:39]([F:44])([F:43])[CH2:40][CH2:41]I>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:32]([F:33])([F:34])[F:35])[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][C:28](=[O:30])[N:27]([CH2:41][CH2:40][C:39]([F:44])([F:43])[F:38])[CH2:26]4)=[O:24])=[C:19]([CH3:31])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: FC(F)(F)CCI
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C(=O)N1CNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C(=O)N1CC(=O)N(CCC(F)(F)F)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylphenyl)carbonyl]imidazolidin-4-one (200 mg, 0.38 mmol, 1.00 equiv), N,N-dimethylformamide (5 mL). This was followed by the addition of sodium hydride (46 mg, 1.15 mmol, 3.00 equiv, 60%), in portions at 0° C. The resulting solution was stirred for 30 min at 0° C. To this was added 1,1,1-trifluoro-3-iodopropane (863 mg, 3.85 mmol, 10.00 equiv). The resulting solution was allowed to react, with stirring, for an additional 4 days at 30° C. The reaction was then quenched by the addition of 10 ml of water. The resulting solution was extracted with 3×10 ml of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×20 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a TLC plate with EA/PE (5:1). This resulted in 10.9 mg (4%) of 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylphenyl)carbonyl]-3-(3,3,3-trifluoropropyl)imidazolidin-4-one as a light yellow semi solid. (ES, m/z): [M+H]+ 616; 1H NMR (300 MHz, CDCl3) δ: 7.97 (s, 1H), 7.88 (d, J=6.0 Hz, 2H), 7.69-7.71 (m, 2H), 7.43 (d, J=7.8 Hz, 1H), 5.12 (s, 1H), 4.69 (s, 1H), 4.05-4.39 (m, 3H), 3.87 (s, 1H), 3.70 (t, J=7.2 Hz, 1H), 3.56 (t, J=7.2 Hz, 1H), 2.46-2.65 (m, 3H), 2.39 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15].[OH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[I:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([CH3:13])[C:3]([S:14]([CH3:17])(=[O:16])=[O:15])=[C:2]2[N:22]1[CH2:23][CH2:24][CH:19]([OH:18])[CH2:20][CH2:21]1
Reactant: OC1CCNCC1
Reactant: Cc1nc2ccc(I)cc2c(Cl)c1S(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc2ccc(I)cc2c(N2CCC(O)CC2)c1S(C)(=O)=O
Yield: 62.1 %

Procedure:
4-Chloro-6-iodo-3-methanesulfonyl-2-methyl-quinoline (compound of example D.2) (300 mg, 0.786 mmol), 4-hydroxypiperidine (87 mg, 0.865 mmol) and N,N-diisopropyl ethyl amine (0.148 mL, 0.865 mmol) were heated in dry N,N-dimethylformamide (3 mL) for 0.5 h at 100° C. N,N-Dimethylformamide was evaporated at 40° C./0.1 mbar, and the residue directly purified by chromatography on silica gel in dichloromethane/methanol 20:1. One obtained a yellow oil which was triturated with ethyl acetate and the resulting white crystals were filtered off. One obtained 218 mg (62%) of white crystals. MS: m/z=447 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[S:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>CCOCCO>[O:24]=[C:23]1[C:22]2[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=2[S:20][N:1]1[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: O=C(Cl)c1ccccc1SCl
Solvent: CCOCCO
Solvent: CCN(CC)CC
Product: O=C(O)Cc1ccc(-n2sc3ccccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.4 %

Procedure:
To a mixture of 7.55 g (0.05 mol) of 4-aminophenylacetic acid and 15.15 g (0.15 mol) of triethylamine in 25 mL of ethyl cellosolve was added 10.3 g (0.05 mol) of 2-chlorosulfenylbenzoyl chloride (Arzneimittel. Forsch., 1964;14:1301). The mixture was stirred at room temperature for 3 hours, concentrated in vacuo, and water was added to the residue. The mixture was acidified with HCl and filtered to give 9.9 g of the title compound, mp 173-175° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[C:24](Cl)(=[O:26])[CH3:25].C(N(CC)CC)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][N:15]([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:24](=[O:26])[CH3:25])=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CNCCc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)N(CCc1ccccc1)Cc1c(C)noc1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl]-phenethyl-amine (0.055 g, 0.15 mmol), acetyl chloride (0.05 mL, 0.75 mmol), and triethylamine (0.13 mL, 0.95 mmol) were combined and stirred at room temperature for 30 minutes. The mixture was loaded directly onto silica gel and purified by silica gel chromatography (30-50% EtOAc in hexanes) to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH2:28])=[O:27])=[CH:21][CH:20]=1>CN1C(=O)CCC1.O>[CH:13]1([O:12][C:4]2[N:3]=[C:2]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][C:26]([NH2:28])=[O:27])=[CH:23][CH:24]=3)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NC(=O)Cc1ccc(N)cc1
Reactant: FC(F)(F)c1cc(Cl)nc(OC2CCCC2)n1
Solvent: O
Solvent: CN1CCCC1=O
Product: NC(=O)Cc1ccc(Nc2cc(C(F)(F)F)nc(OC3CCCC3)n2)cc1
Temperature: 120 °C
Yield: 51.8 %

Procedure:
A 10-mL microwave vial was charged with 4-chloro-2-(cyclopentyloxy)-6-(trifluoromethyl)pyrimidine (0.090 g, 0.34 mmol) and (4-aminophenyl)acetamide (0.076 g, 0.51 mmol) in NMP (3 mL). The resulting mixture was heated at 120° C. under microwave irradiation for 1 h. The reaction mixture was cooled, diluted with water (50 mL) affording a solid. The solid was isolated by filtration and chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as eluent to afford the title compound (0.067 g, 52%) as a white solid. MW=380.36. M.p. 208-210° C. 1H NMR (DMSO-d6, 500 MHz) δ 10.05 (s, 1H), 7.58 (br d, J=7.5 Hz, 2H), 7.42 (s, 1H), 7.25 (d, J=7.5 Hz, 2H), 6.85 (s, 1H), 6.74 (s, 1H), 5.31 (septet, J=3.0 Hz, 1H), 2.01-1.90 (m, 2H), 1.80-1.66 (m, 4H), 1.65-1.55 (m, 2H); APCI MS m/z 381 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2S([O-])(=O)=O)[CH:4]=[CH:3][CH:2]=1.[Na+].[OH-:16].[Na+]>O>[OH:16][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[CH:2][CH:3]=[CH:4]2
Reactant: [OH-]
Reactant: O=S(=O)([O-])c1cccc2cccnc12
Agent: [Na+]
Solvent: O
Product: Oc1cccc2cccnc12
Yield: 97.2 %

Procedure:
Sodium quinoline-8-sulfonate (231 g) was added to 170 g of a 50% aqueous solution of sodium hydroxide, and the mixture was stirred. Then, 900 g of a hydrogenated triphenyl mixture was mixed, and the mixture was dehydrated. The dehydrated mixture was reacted at 260° C. for 15 minutes in a nitrogen stream. After cooling, 600 ml of water was added to the reaction mixture to separate the reaction medium layer. The aqueous layer was decolorized with activated carbon, acidified and then extracted with 200 ml of chloroform. The chloroform was recovered to give 140.9 g (yield 97.2%) of 8-hydroxyquinoline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:16])[CH:11]=[CH:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[ClH:17]>C(C(C)=O)C(C)C.O>[Cl:17][CH:12]([CH2:11][C:10]([C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=1)=[O:16])[C:13]([OH:15])=[O:14]
Reactant: Cc1c(Cl)cc(C(=O)C=CC(=O)O)cc1Cl
Reactant: Cl
Solvent: CC(=O)CC(C)C
Solvent: O
Product: Cc1c(Cl)cc(C(=O)CC(Cl)C(=O)O)cc1Cl
Yield: 100 %

Procedure:
A suspension of 5.18 g (0.02 mole) of 4-(3,5-dichloro-4-methylphenyl)-4-oxo-2-butenoic acid, prepared as described in Example 1(b), in 50 ml of methyl isobutyl ketone was saturated with dry hydrogen chloride gas, by blowing the gas through the suspension whilst ice-cooling and stirring it. The mixture was then stirred at room temperature for a further 1 hour, after which it was diluted with 30 ml of cold water and extracted with ethyl acetate. The extract was washed with water and then dried over anhydrous sodium sulphate, after which the solvent was distilled off and the residue was washed with a small amount of hexane and then dried, giving 5.91 g (yield 100%) of the desired 2-chloro-4-(3,5-dichloro-4-methylphenyl)-4-oxobutyric acid, melting at 129°-132° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:12])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[CH2:13]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](Cl)=[CH:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[O:32][CH3:33])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH2:13]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([O:1][C:2]3[C:3]([CH3:12])=[N:4][C:5]4[C:10]([CH:11]=3)=[CH:9][CH:8]=[CH:7][N:6]=4)=[CH:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[O:32][CH3:33])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: Cc1nc2ncccc2cc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1OCc1ccccc1
Temperature: 140 °C
Reaction time: 4 h
Yield: 69.6 %

Procedure:
3-Hydroxy-2-methyl-[1,8]naphthyridine (400 mg), 7-benzyloxy-4-chloro-6-methoxyquinoline (2.25 g), and 4-dimethylaminopyridine (915 mg) were suspended in o-dichlorobenzene (8 ml), and the mixture was stirred at 140° C. for 4 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (736 mg, yield 70%).
Reaction SMILES: CC(C)([O-])C.[K+].[NH:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1F.O1CCOCC1>O>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][C:18]=1[N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: c1c[nH]cn1
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(Br)c(-n2ccnc2)c1
Temperature: 180 °C
Yield: 53.3 %

Procedure:
A microwave vial charged with potassium tert-butoxide (1.108 g, 9.88 mmol), 1H-imidazole (0.672 g, 9.88 mmol), 1-bromo-2-fluoro-4-(trifluoromethyl)benzene (1.180 ml, 8.23 mmol), and 10 mL dioxane was heated to 180° C. in the microwave for 2 hours. LC/MS showed mostly product, so the reaction mixture was poured into water and was extracted with DCM. The organics were dried over MgSO4 and concentrated. The crude residue was purified by silica gel column chromatography (0 to 100% EtOAc/heptane) yielding 1-(2-bromo-5-(trifluoromethyl)phenyl)-1H-imidazole (1.277 g, 4.39 mmol, 53.3% yield). m/z (ESI) 291.9 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C@@:3]([C:9]1[CH:14]=[C:13](Br)[CH:12]=[CH:11][C:10]=1[F:16])([CH:6]([F:8])[F:7])[CH2:4][OH:5].C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25](Cl)=[O:26]>O>[F:7][CH:6]([F:8])[C@:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])[NH:2][C:25](=[O:26])[CH2:24][O:5][CH2:4]1
Reactant: N[C@@](CO)(c1cc(Br)ccc1F)C(F)F
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C1COC[C@](c2ccccc2F)(C(F)F)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of (R)-2-amino-2-(5-bromo-2-fluoro-phenyl)-3,3-difluoro-propan-1-ol HCl salt (0.5 g, 1.56 mmol) in IPAc (5 ml) was added under argon a solution of K2CO3 (0.862 g, 6.24 mmol) in 5 ml water below 25° C. After stirring for 30 min at 25° C. to provide a diphase clear solution, cooled down to −5° C., a solution of 2-chloroacetyl chloride (0.41 g, 3.59 mmol) in IPAc (2 mL) was added slowly with the temperature below 10° C. After stirring for 30 min at 20° C., the organic phase was collected and used for next step directly. THF (3 ml) was added to the above solution, the mixture was cooled to 0° C. The solution was added under argon KOtBu (0.35 g, 3.12 mmol) below 10° C. After stirring at 20° C. for 3 h, water was added to quench the reaction. The organic phase was washed by 1N HCl water solution (5 ml). The organic phase was collected and used for next step directly. The above solution was added water (5 ml) and Pd/C (10%, 50 mg), the mixture was stirred under H2 (1.5 bar) at 25° C. for 3 h. The catalyst was filtered out. The filtration was washed by 15% NaCl water solution. The solvent was removed under vacuum to provide the title compound as yellowish solid. ESIMS: 246 [(M+H)+]. 1H NMR (400 MHz, DMSO-d6): δ 9.08 (s, 1H), 7.57 (m, 1H), 7.48 (m, 1H), 7.30 (m, 1H), 7.81 (m, 1H), 7.30 (m, 2H), 6.55 (t, 1H), 4.1 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][C:7](=[O:13])[N:6]([CH:14]([CH3:16])[CH3:15])[C:5]2=[O:17].[H-].[Na+].[Br:20][C:21]1[CH:25]=[C:24]([C:26](O)=[O:27])[N:23]([C:29]2[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][N:30]=2)[N:22]=1.C(Cl)(=O)C(Cl)=O>CN(C)C=O.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([C:26]([C:24]1[N:23]([C:29]3[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][N:30]=3)[N:22]=[C:21]([Br:20])[CH:25]=1)=[O:27])[C:7](=[O:13])[N:6]([CH:14]([CH3:15])[CH3:16])[C:5]2=[O:17]
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Reactant: Cc1cc(Br)cc2c(=O)n(C(C)C)c(=O)[nH]c12
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc2c(=O)n(C(C)C)c(=O)n(C(=O)c3cc(Br)nn3-c3ncccc3Cl)c12
Temperature: 25 °C

Procedure:
To a solution of the quinazolinedione of Step G (245 mg, 0.825 mmol) in dimethylformamide (5 mL) was added sodium hydride (60% oil dispersion, 36 mg, 0.90 mmol) and the reaction was allowed to stir at room temperature. In a separate reaction flask containing a solution of the pyrazole acid of Step D (500 mg, 1.65 mmol) in dichloromethane (10 mL) was added oxalyl chloride (0.17 mL, 1.95 mmol) and one drop of DMF. This mixture was stirred for 2 hours, then concentrated and placed under vacuum. The acid chloride was divided into two equal portions. One of these portions was taken up in 5 mL of DMF and added to the quinazolinedione/NaH reaction mixture and the resulting mixture was stirred at room temperature for 3 hours. The reaction was partitioned between ethyl acetate and water, washed twice with water, then with brine and dried over sodium sulfate. The crude product was purified by chromatography on silica gel with 99:1 chloroform/acetone as eluent to afford the title compound, a compound of the present invention.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][C:5]1[N:13]=[CH:12][C:11]([F:14])=[CH:10][C:6]=1[C:7](O)=[O:8].S(Cl)([Cl:22])=O>ClCCl>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][C:5]1[N:13]=[CH:12][C:11]([F:14])=[CH:10][C:6]=1[C:7]([Cl:22])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(F)cnc1Oc1cc(Cl)ccc1Cl
Solvent: ClCCl
Product: O=C(Cl)c1cc(F)cnc1Oc1cc(Cl)ccc1Cl

Procedure:
To a solution of 2-(2,5-dichloro-phenoxy)-5-fluoro-nicotinic acid (2.14 g, 7.08 mmol, 1.0 equiv; Example 80, Step 1) in dichloromethane (15 mL) was added thionyl chloride (16.4 g, 10 mL, 138 mmol, 19.5 equiv; [CAS RN 7719-09-7]) and the reaction mixture heated to reflux for 2 h. The reaction mixture was concentrated under reduced pressure and remaining thionyl chloride removed by azotropic distillation with toluene. The crude material was used in the consecutive reaction step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]23[CH2:14][C:13](=[CH:15][C:16]([O:18]C)=[O:17])[CH2:12][N:11]2[C:10](=[O:20])[N:9]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)[C:8]3=[O:29])=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]23[CH:14]=[C:13]([CH2:15][C:16]([OH:18])=[O:17])[CH2:12][N:11]2[C:10](=[O:20])[N:9]([C:21]2[CH:22]=[C:23]([Cl:28])[CH:24]=[C:25]([Cl:27])[CH:26]=2)[C:8]3=[O:29])=[CH:30][CH:31]=1
Reactant: COC(=O)C=C1CN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)C2(Cc2ccc(Br)cc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CC1=CC2(Cc3ccc(Br)cc3)C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)N2C1
Reaction time: 2 h
Yield: 11.5 %

Procedure:
To a solution of 5-(4-Bromobenzyl)-3-(3,5-dichlorophenyl)-7-methoxycarbonylmethylene-1,3-diazabicyclo[3.3.0]octane-2,4-dione (0.564 g) in THF (4 mL) and methanol (1 mL) at 0° C. was added 2N LiOH (1.20 mL). After 2 hours, the reaction mixture was concentrated and the residue was suspended in 1 N HCl and filtered. A solution of the filtrate (0.10 g) in thionyl chloride (5 mL) was refluxed for 30 minutes. The reaction mixture was concentrated and the residue was diluted with EtOAc and water. The organic solution was collected and dried (Na2SO4), filtered, and concentrated. Purification by chromatography (Silica gel: 4% MeOH/CH2Cl2, Chromatotron) afforded 0.063 g of the titled compound. MS (m/z) 509 (MH+), mp 101.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:20]1.O.O.O.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([N:19]1[CH2:24][CH2:23][CH2:22][CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:20]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: c1ccc(C2CCCNC2)nc1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: C[C@@H](N1CCCC(c2ccccn2)C1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 35.7 %

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (0.87 g, 3.5 mmol) and 2-piperidin-3-ylpyridine (2.80 g, 17.26 mmol) were dissolved in acetonitrile (50 ml), and lithium perchlorate trihydrate (1.50 g, 9.3 mmol) was added thereto and refluxed for 40 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was dissolved in ethyl acetate and washed with water. The solvent was again evaporated under a reduced pressure, and the residue was purified using a silica gel column to obtain 0.35 g of the intended substance (yield 35.7%).
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[N:33][CH:34]=[C:35]([F:38])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:39])[CH2:21]3)C(=O)C(F)(F)F)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.CO.C(=O)([O-])[O-].[K+].[K+]>O>[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][NH:12][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[N:33][CH:34]=[C:35]([F:38])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:39])[CH2:21]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C(N(Cc1cc2c(cn1)OCCO2)CC1CCCN(CCn2c(=O)ccc3ncc(F)cc32)C1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=c1ccc2ncc(F)cc2n1CCN1CCCC(CNCc2cc3c(cn2)OCCO3)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 103.9 %

Procedure:
To a solution of 0.15 g of N-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)-2,2,2-trifluoro-N-(piperidin-3-ylmethyl)acetamide in 2 mL of dichloromethane, 85 mg of (7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde and 24 μL of acetic acid were added, subsequently, 0.13 g of sodium triacetoxyborohydride was added, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture, chloroform was added, and a saturated aqueous sodium hydrogen carbonate solution was added thereto under cooling with ice and adjusted to pH 8.0. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.21 g of N-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)-2,2,2-trifluoro-N-(1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-3-ylmethyl)acetamide as a yellow solid. To 0.21 g of N-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)-2,2,2-trifluoro-N-(1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-3-ylmethyl)acetamide, 3 mL of methanol and 0.7 mL of water were added, and thereto was added 62 mg of potassium carbonate. The mixture was stirred at room temperature for 1 hour 15 minutes, then stirred at 40 to 50° C. for 1 hour, and stirred at 50 to 60° C. for 1 hour 30 minutes. The solvent was distilled off under reduced pressure, chloroform and water were added to the resultant residue, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by basic silica gel column chromatography using gradient elution with hexane:ethyl acetate=92:8 to 88:12 to obtain 0.18 g of 1-(2-(3-(((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)methyl)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one as a light yellow oily substance.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[C:15]([C:22]([F:25])([F:24])[F:23])[CH:14]=1>>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:11][C@@H:7]2[CH2:8][CH2:9][CH2:10][C@@H:6]2[N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:18])=[C:15]([C:22]([F:23])([F:24])[F:25])[CH:14]=1
Reactant: O=C(O)c1ccc(Cl)cc1C(F)(F)F
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Product: O=C(N[C@@H]1CCC[C@@H]1N1CCCC1)c1ccc(Cl)cc1C(F)(F)F

Procedure:
The title compound, yellow oil, MS: m/e=361.3 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 4-chloro-2-(trifluoromethyl)benzoic acid.