Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:21][C:20]=1[O:29]CC1C=CC=CC=1)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:37])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:21][C:20]=1[OH:29])(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(C)=O)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(C)=O)cc1O
Yield: 87.3 %

Procedure:
3-(4-Acetylamino-2-benzyloxy-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester (0.99 g, 1.8 mmol) was dissolved in 50 mL methanol and 20% Pd/C (0.09 g) is added. The reaction was placed under 50 psi of hydrogen for approximately 1 hour. The reaction was filtered and concentrated in vacuo. The crude product was chromatographed with 2:1 ethyl acetate/hexane to yield 3-(4-acetylamino-2-hydroxy-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester 0.7 g (85%) of an brown solid. MS (APCI) m/z 444.2 (M−1).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[OH:11][C@@H:12]1[CH2:16][CH2:15][O:14][CH2:13]1>>[CH3:7][N:6]1[C:2]([O:11][C@@H:12]2[CH2:16][CH2:15][O:14][CH2:13]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: O[C@@H]1CCOC1
Product: Cn1ncc([N+](=O)[O-])c1O[C@@H]1CCOC1
Yield: 34 %

Procedure:
Following the procedure for Example 230 starting with 5-chloro-1-methyl-4-nitro-1H-pyrazole and (R)-(−)-3-hydroxy tetrahydrofuran gave (R)-1-methyl-4-nitro-5-(tetrahydrofuran-3-yloxy)-1H-pyrazole as a clear oil (90 mg, 34%). 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 5.65 (q, J=3.4 Hz, 1H), 4.10 (q, J=8.0 Hz, 1H), 4.02-3.87 (m, 2H), 3.81 (dd, J=11.3, 3.4 Hz, 1H), 3.71 (s, 3H), 2.26 (td, J=7.3, 3.4 Hz, 2H)
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:6][CH2:5][C@H:4]1[C:7]([O:9][CH3:10])=[O:8].[F:11][C:12]([F:20])(S(F)(=O)=O)C(O)=O.C([O-])(O)=O.[Na+]>C(#N)C>[F:11][CH:12]([F:20])[O:1][CH2:2][C@@H:3]1[CH2:6][CH2:5][C@H:4]1[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: COC(=O)[C@@H]1CC[C@H]1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)[C@@H]1CC[C@H]1COC(F)F
Temperature: 60 °C
Reaction time: 12 h
Yield: 74.2 %

Procedure:
To a solution of (1R,2R)-methyl 2-(hydroxymethyl)cyclobutanecarboxylate (100 mg, 0.694 mmol) in acetonitrile (5 mL) was added CuI(I) (66.1 mg, 0.347 mmol) and the reaction mixture was heated to 60° C. To the stirred solution was added 2,2-difluoro-2-(fluorosulphonyl)acetic acid (124 mg, 0.694 mmol) and the reaction mixture was stirred for an additional 12 h at 60° C. The reaction mixture was cooled to 0° C., a saturated aqueous solution of NaHCO3 was added and extracted with ethyl acetate (3×10 mL) The combined organic layer was dried over Na2SO4, filtered and the filtrate evaporated under reduced pressure to afford Intermediate 241A as a yellow oil (100 mg, 80%). The crude product was used in the next step without further purification. 1H NMR (300 MHz, chloroform-d) δ ppm 5.92-6.56 (m, 1H), 3.86 (d, J=5.29 Hz, 2H), 3.70 (s, 3H), 3.01 (d, J=8.88 Hz, 2H), 2.18 (d, J=10.15 Hz, 2H), 1.68-2.02 (m, 2H).
Reaction SMILES: C([O:3]P(OCC)OCC)C.[OH-].[K+].[CH3:13][N:14]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][N:16]=[C:15]1[CH:22]([CH3:24])[CH3:23].O=O>O=P(N(C)C)(N(C)C)N(C)C.O.C(O)(=O)C>[OH:3][C:22]([C:15]1[N:14]([CH3:13])[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][N:16]=1)([CH3:24])[CH3:23]
Reactant: CC(C)c1ncc([N+](=O)[O-])n1C
Reactant: CCOP(OCC)OCC
Agent: O=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(=O)O
Product: Cn1c([N+](=O)[O-])cnc1C(C)(C)O
Reaction time: 2.5 h
Yield: 21.6 %

Procedure:
A total of 11.2 ml of triethylphosphite and 6 g of powdered potassium hydroxide were added to a solution of 8.5 g of 1-methyl-2-isopropyl-5-nitroimidazole in 40 ml of hexametapol while cooling in an ice-bath. While the solution was further cooled with ice, oxygen was conducted through the solution with vigorous stirring. After 2.5 hours, 6.1 ml of glacial acetic acid were added and the mixture was then poured into 600 ml of water and extracted four times with 150 ml portions of ether. The ether extracts were washed with a small amount of water, evaporated on a rotary evaporator and finally dried at 85°/0.5 Torr. The residue was crystallized from 15 ml of isopropyl ether. There were obtained 2.0 g of 2-(2-hydroxy-2-propyl)-1-methyl-5-nitroimidazole, melting point 102°-107°. The yield was 21.6%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[CH3:24][N:25]1[CH:29]=[C:28](B(O)O)[CH:27]=[N:26]1.C(N(CC)C(C)C)(C)C>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:8][C:6]1[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=[C:2]([C:28]2[CH:27]=[N:26][N:25]([CH3:24])[CH:29]=2)[N:7]=1
Reactant: Cn1cc(B(O)O)cn1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C(=O)OC)c1c(C)nc(-c2cnn(C)c2)nc1-c1ccc(C)cc1
Yield: 63 %

Procedure:
Methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (100 mg; 0.300 mmol), 1-Methyl-1H-pyrazole-4-boronic acid, pinacol ester (188 mg; 0.901 mmol), tetrakis(triphenylphosphine) palladium(0) (34.7 mg; 0.030 mmol) were placed in a 5 mL reaction tube and dissolved in a mixture of degassed DME (1.50 mL) and water (0.5 mL). N,N-Diisopropylethylamine (0.185 mL; 1.202 mmol) was added, the tube was sealed and irradiated in a microwave oven at 130° C. for 1 h. The reaction mixture was partitioned between brine and dichloromethane, filtered over a phase separator filter (1PS) and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (10-80%) in heptane to give 114 mg (63%) of the title compound as a colorless oil.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:15]=[CH:14][C:7]2[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[CH:21]=[C:20]([Cl:30])[C:19]=1[F:31]>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([C:24]2([C:26]([F:29])([F:28])[F:27])[O:1][N:2]=[C:3]([C:4]3[CH:15]=[CH:14][C:7]4[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=4[CH:5]=3)[CH2:25]2)[CH:21]=[C:20]([Cl:30])[C:19]=1[F:31]
Reactant: CC1(C)OB(O)c2ccc(C(Cl)=NO)cc21
Reactant: C=C(c1cc(Cl)c(F)c(Cl)c1)C(F)(F)F
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)C3)cc21
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a solution of the crude compound N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (383 mg, 1.60 mmol) and 1,3-dichloro-2-fluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (455 mg, 1.76 mmol) in DMF (12 mL) at rt was added TEA (445 μL, 3.20 mmol). The reaction mixture was stirred for 12 h, poured into ice-water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC eluted with PE-EA (3:2) and then purified by combiflash to give the title compound 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (180 mg; yield 24% over the 3 steps from the aldehyde) as a white solid. 1H NMR (500 MHz, DMSO-d6): δ 9.236 (s, 1 H), 7.803 (d, J=6.5 Hz, 2 H), 7.757-7.770 (m, 2H), 7.693-7.710 (m, 1H), 4.414 (d, J=18.0 Hz, 1 H), 4.316 (d, J=18.0 Hz, 1 H), 1.481 (s,6 H) ppm; HPLC purity: 99.13% at 220 nm and 99.15% at 254 nm; MS: m/z=461.9 (M+1, ESI+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[N:19]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][CH2:14][NH:15][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCCc1coc(-c2ccc(Cl)cc2)n1
Product: O=C(NCCc1coc(-c2ccc(Cl)cc2)n1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 2 %

Procedure:
This compound was synthesized from 2-(2-(4-chlorophenyl)oxazol-4-yl)ethanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (4 mgs, 2% yield). 1H NMR (CDCl3) δ 8.55 (s, 1H), 8.25 (d, J=7.8 Hz, 1H), 8.12 (d, J=7.8 Hz, 1H), 7.98 (d, J=7.8 Hz, 2H), 7.68-7.54 (m, 2H), 7.41 (d, J=8.4 Hz, 2H), 3.86 (m, 2H), 3.94 (m, 2H). MS (ESI) m/z: Calculated for C21H14ClF3N4O3: 462.07. found: 463.1 (M+H)+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1.[OH-].[K+].CN(C)[CH:20]=[O:21]>O>[CH3:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH:20]=[O:21])=[CH:12][NH:13]2)=[CH:9][CH:8]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc2cc[nH]c2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc2c(C=O)c[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A 12-l. three-necked flask, equipped with a mechanical stirrer, a thermometer and a dropping funnel provided with a Drierite drying tube was charged with 610 ml (7.9 moles) of N,N-dimethylformamide. The flask was immersed in an ice bath and 217 g (1.42 moles) of phosphorus oxychloride was added at 5°-10° with stirring over 1 hour. The dropping funnel was rinsed with 20 ml of dimethylformamide and the light pink orange oil was stirred for further 10 minutes in the ice bath. Then a solution of 156 g (1.19 moles) of 6-methylindole in 156 ml of dimethylformamide was added at 5°-10° C over a period of 1 hour. The ice bath was removed and the red orange solution was stirred for an additional hour, while the flask content warmed up to room temperature. At the end of the reaction period, 1.17 kg of crushed ice was added. The temperature fell to -10° and after a short time a light yellow slurry was formed. The reaction mixture was stirred for 1 hour, as the temperature came to 15°. Then a solution of 840 g (13.0 moles) of potassium hydroxide pellets (87% assay) in 2 l of water was added over 30 minutes, during which time the pot temperature rose to 50°. After the additiom was complete, the dropping funnel was replaced by a reflux condenser and the orange solution was heated rapidly with stirring on a steam bath to 93° and kept at this temperature for 30 minutes. The mixture was allowed to stand at room temperature overnight. The precipitate was collected by suction filtration, washed with water and dried at 60° (constant weight) to give 186.5 g (98%) of product as orange crystals, m.p. 183°-186°.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1COCC1>[Br:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][O:11]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C1=COCCC1
Reactant: Brc1cccc2[nH]cnc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: Brc1cccc2c1ncn2C1CCCCO1
Temperature: 80 °C
Reaction time: 14 h
Yield: 70.1 %

Procedure:
To a mixture of 52 (1.30 g, 6.6 mmol) and 3,4-dihydro-2H-pyran (2.78 g, 33.0 mmol) in THF (15 mL) was added p-TsOH.H2O (0.11 g, 0.66 mmol). The mixture was stirred at 80° C. for 14 h, then the solvent was removed in vacuo. The residue was purified by SiO2 chromatography eluting with 10% petroleum ether/EtOAc to afford 1.3 g (70%) 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole (54) as brown oil: MS (ESI) m/z=281.0 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[CH2:10]([O:14][CH2:15][CH2:16][CH:17]([CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[CH3:18])[CH2:11][CH2:12][CH3:13].Cl(O)(=O)(=O)=O.C(Cl)Cl>O>[CH2:10]([O:14][CH2:15][CH2:16][CH:17]([CH3:18])[CH2:19][CH2:20][CH2:21][C:22]([C:6]1[CH:5]=[C:4]([CH3:8])[C:3]([OH:9])=[C:2]([CH3:1])[CH:7]=1)([CH3:24])[CH3:23])[CH2:11][CH2:12][CH3:13]
Reactant: Cc1cccc(C)c1O
Reactant: CCCCOCCC(C)CCC=C(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: ClCCl
Product: CCCCOCCC(C)CCCC(C)(C)c1cc(C)c(O)c(C)c1

Procedure:
12.2 Parts of 2,6-dimethylphenol, 5.3 parts of citronellyl n-butyl ether, and 1.0 parts of 70% perchloric acid in 30 parts of methylene chloride were stored at room temperature for 3 days. The reaction mixture after pouring into water was extracted with ether, and the ether solution washed with sodium bicarbonate solution, then water and evaporated. Distillation of the residual oil gave 1-n-butyloxy-7-(4-hydroxy-3,5-dimethyl-phenyl)-3,7-dimethyl-octane as a fraction with b0.8, 168°-76° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[O:6][C:7]=1[CH3:8].[O:17]=[CH:18][C:19]1[CH:27]=[CH:26][C:24]([OH:25])=[C:21]([O:22][CH3:23])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:18]([C:19]1[CH:27]=[CH:26][C:24]([O:25][CH2:2][C:3]2[N:4]=[C:5]([C:9]3[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=3)[C:12]#[N:13])[O:6][C:7]=2[CH3:8])=[C:21]([O:22][CH3:23])[CH:20]=1)=[O:17]
Reactant: COc1cc(C=O)ccc1O
Reactant: Cc1oc(-c2cccc(C#N)c2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)ccc1OCc1nc(-c2cccc(C#N)c2)oc1C
Temperature: 90 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
A mixture of 3-(4-chloromethyl-5-methyl-1,3-oxazol-2-yl)benzonitrile (26.3 g), vanillin (17.19 g), anhydrous potassium carbonate (15.62 g) and N,N-dimethylformamide (300 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give 3-{4-[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzonitrile as colorless crystals (33.9 g, yield 86%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 166-167° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].N1C=CC=CC=1.Cl.Cl.[F:16][C:17]1[CH:18]=[C:19]([NH:28][C:29]([C:31]2[CH:36]=[N:35][CH:34]=[CH:33][N:32]=2)=[O:30])[CH:20]=[CH:21][C:22]=1[CH:23]1[CH2:27][CH2:26][CH2:25][NH:24]1>C(Cl)(Cl)Cl>[C:1]([N:24]1[CH2:25][CH2:26][CH2:27][CH:23]1[C:22]1[CH:21]=[CH:20][C:19]([NH:28][C:29]([C:31]2[CH:36]=[N:35][CH:34]=[CH:33][N:32]=2)=[O:30])=[CH:18][C:17]=1[F:16])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Nc1ccc(C2CCCN2)c(F)c1)c1cnccn1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCCC1c1ccc(NC(=O)c2cnccn2)cc1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1.5 ml of acetic anhydride was added to a pyridine (50 ml) solution of 4.3 g of N-(3-fluoro-4-pyrrolidin-2-ylphenyl)pyrazine-2-carboxamide dihydrochloride, and the reaction liquid was stirred at room temperature for 20 minutes. The reaction liquid was diluted with chloroform, washed with water and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: chloroform/methanol=50/1) to obtain the entitled compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:22].[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[O:33].CO>C(Cl)(Cl)Cl.CN(C)C=O>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[NH:31][C:32]([NH:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:22])=[O:33]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: COc1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1O
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(F)c3)ccnc2cc1O
Reaction time: 3 h

Procedure:
4-(4-Amino-3-fluorophenoxy)-6-methoxy-7-quinolinol (70 mg) was dissolved in chloroform (1.5 ml) and N,N-dimethylformamide (1 ml). 2,4-Difluorophenyl isocyanate (43 mg) was then added to the solution, and a reaction was allowed to proceed at room temperature for 3 hr. Methanol was added to the reaction solution. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography on silica gel by development with chloroform/methanol (20/1) to quantitatively give the title compound.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[N:6]=[C:5]([CH3:16])[CH:4]=1)=[O:2].[Cl-].[CH2:18]([O:22][NH3+:23])[CH2:19][CH2:20][CH3:21]>>[CH:1]([C:3]1[C:4](=[N:23][O:22][CH2:18][CH2:19][CH2:20][CH3:21])[CH:5]([CH3:16])[N:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[N:8]=1)=[O:2]
Reactant: Cc1cccc(-c2nc(C)cc(C=O)n2)n1
Reactant: CCCCO[NH3+]
Agent: [Cl-]
Product: CCCCON=C1C(C=O)=NC(c2cccc(C)n2)=NC1C

Procedure:
If 6-formyl-4-methyl-2-(6-methyl-2-pyridyl)pyrimidine is used instead of 4-formyl-2-(2-pyridyl)pyrimidine and O-n-butylhydroxylammonium chloride instead of hydroxylammonium chloride, 6-formyl-O-n-butyloximino-4-methyl-2-(6-methyl-2-pyridyl)-pyrimidine (compound 133c) is obtained in a corresponding manner.
Reaction SMILES: [CH:1]1([N:4]2[C:13]([CH3:15])([CH3:14])[CH:12](C(O)=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]2=[O:19])[CH2:3][CH2:2]1.C([O-])(=[O:22])C.[K+].C([O-])(=O)C.[Pb+4].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.O[Li].O>C(O)(=O)C.O.C1C=CC=CC=1>[CH:1]1([N:4]2[C:13]([CH3:15])([CH3:14])[CH:12]([OH:22])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]2=[O:19])[CH2:3][CH2:2]1
Reactant: CC1(C)C(C(=O)O)c2ccccc2C(=O)N1C1CC1
Reactant: CC(=O)[O-]
Agent: [K+]
Agent: [Li]O
Agent: [Pb+4]
Solvent: O
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CC1(C)C(O)c2ccccc2C(=O)N1C1CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-cyclopropyl-3,3-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline-4-carboxylic acid (4.1 g, 15.8 mmol) in acetic acid (300 mL) is added benzene (150 mL), potassium acetate (10.9 g, 111 mmol), cupric acetate (0.145 g, 0.8 mmol) and lead (IV) acetate (12.7 g, 28.6 mmol). The green reaction mixture is heated to reflux for 2.5 h. The reaction mixture is then cooled to room temperature and quenched by the addition of ethylene glycol (ca. 6 mL). The resulting solution is the concentrated in vacuo to near dryness. The resulting dark green oil is dissolved in ethyl acetate (ca. 500 mL) and stirred vigorously while cautiously treating with saturated aqueous sodium bicarbonate (ca. 200 mL), followed by solid NaHCO3 until the aqueous layer reached a pH greater than 8. The layers are separated and the aqueous layer is extracted three times with ethyl acetate. The organic layer is dried with Na2SO4 filtered and concentrated. The resulting brown oil is then dissolved in THF (150 mL). Water (30 ml) and LiOH H2O (3.5 g, 83.4 mmol) are added. The reaction mixture is placed at 45° C. for 18 h, whereupon it is cooled to room temperature. The reaction is concentrated in vacuo to ca. ¾ of its original volume, diluted with methylene chloride and saturated aqueous NaHCO3. The layers are separated and the aqueous layer is extracted three times with ethyl acetate. The organic layers are combined, dried with Na2SO4, filtered and concentrated in vacuo to afford a brown oil. Purification by silica gel flash chromatography (ethyl acetate-dichloromethane, 1:19 to 1:4) gave 2-cyclopropyl-4-hydroxy-3,3-dimethyl-3,4-dihydro-2H-isoquinolin-1-one as an off-white solid; MS (ESI) m/z 232.1 (M+H).
Reaction SMILES: O[C:2]1([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH3:10])[CH2:4][CH2:3]1.O>C1(C)C=CC=CC=1>[CH2:8]([C@H:5]1[CH2:4][CH2:3][C@H:2]([C:11]2[CH:12]=[C:13]([F:18])[CH:14]=[C:15]([F:17])[CH:16]=2)[CH2:7][CH2:6]1)[CH2:9][CH3:10]
Reactant: CCCC1CCC(O)(c2cc(F)cc(F)c2)CC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC[C@H]1CC[C@H](c2cc(F)cc(F)c2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In a nitrogen atmosphere, 132 g of crude 1-(1-hydroxy-4-propylcyclohexyl)-3,5-difluorobenzene and 2.99 g of p-toluenesulfonic monohydrate were dissolved in 250 mL of toluene, and the resultant solution was stirred for 2 hours under reflux while the produced water was removed. After the solution was allowed to cool to room temperature, an organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated brine, and dried by adding sodium sulfate, and then the solvent was distilled off under reduced pressure. Then, the whole amount of the resultant residue was dissolved in 280 mL of ethyl acetate, and 7.1 g of palladium 5%/carbon was added to the solution, followed by stirring in a hydrogen atmosphere at 5 Mpa for 6 hours. After the palladium catalyst was filtered off, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. Then, the whole amount of the resultant product and 3.39 g of tertiary butoxypotassium were dissolved in 350 mL of DMF, followed by stirring at room temperature for 4 hours. Then, water and hexane were added to separate an organic layer. Further, an aqueous layer was subjected to extraction with hexane, and the hexane extract was combined with the organic layer and washed with saturated brine. The resultant mixture was dried by adding sodium sulfate, the solvent was distilled off, and distillation under reduced pressure (206 Pa, b. p.=110° C. to 112° C.) yielded 58.05 g of 1-(trans-4-propylcyclohexyl)-3,5-difluorobenzene.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])C=CC=CC=1.[CH2:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][N:12]1[C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=O)=[O:21].C1C2C(=CC=CC=2)CN1[C:41](NC1C=CC(C(O)=O)=CC=1)=[O:42]>>[O:31]=[C:29]([NH:10][CH2:9][C@H:8]1[CH2:7][CH2:1][O:42][CH2:41]1)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][NH:22][C:20]([N:12]1[CH2:11][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)=[O:21]
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Reactant: O=C(O)CCCCCCNC(=O)N1Cc2ccccc2C1
Reactant: NCCCc1ccccc1
Product: O=C(CCCCCCNC(=O)N1Cc2ccccc2C1)NC[C@H]1CCOC1

Procedure:
The title compound was prepared as described in Example 1C, substituting (R)-(tetrahydrofuran-3-yl)methanamine for 3-phenylpropan-1-amine and 7-(isoindoline-2-carboxamido)heptanoic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.85 (t, J=5.76 Hz, 1H) 7.20-7.37 (m, 4H) 6.26 (t, J=5.59 Hz, 1H) 4.57 (s, 4H) 3.49-3.79 (m, 3H) 3.35 (dd, J=8.48, 5.43 Hz, 1H) 2.94-3.15 (m, 4H) 2.18-2.38 (m, 1H) 2.05 (t, J=7.29 Hz, 2H) 1.79-1.98 (m, 1H) 1.35-1.60 (m, 7H) 1.17-1.35 (m, 2H); MS (ESI(+)) m/e 374 (M+H)+.