Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH3:5][C:6]1[CH2:11][CH2:10][CH2:9][C:8](=O)[CH:7]=1.[NH4+].[Cl-]>C1COCC1.CCOCC.[Cl-].[Cl-].C1([Zr+2]C2C=CC=C2)C=CC=C1.Cl[Ti](Cl)(Cl)Cl>[CH3:5][C:6]1[CH2:11][CH2:10][CH2:9][C:8]2([CH2:2][CH2:1]2)[CH:7]=1
Reactant: CC[Mg]Br
Reactant: CC1=CC(=O)CCC1
Agent: C1=CC([Zr+2]C2C=CC=C2)C=C1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1=CC2(CCC1)CC2
Temperature: -78 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
At −78° C., a of solution of bis(cyclopentadienyl)zirconium dichloride (18.68 g, 63.9 mmol) in THF (200 ml) was treated dropwise with a solution of 3M ethylmagnesium bromide in Et2O (42.5 ml). The resulting mixture was stirred for 1 h at −78° C., warmed to 0° C., stirred at 0° C. until the color of the solution turned red, and treated with a solution of 3-methylcyclohex-2-enone (7 g, 63.9 mmol) in THF (100 ml). After 3 h stirring at 20° C., the resulting mixture was concentrated. The residue was dissolved in dichloromethane (300 ml) and treated with TiCl4 (7.0 ml, 63.9 mmol). The resulting mixture was stirred for 20 min. and treated with a saturated aqueous solution of NH4Cl. The aqueous phase was extracted with dichloromethane. The combined organic phases were washed with a saturated aqueous solution of NaHCO3, with a saturated aqueous solution of NaCl, and concentrated. FC (SiO2, pentane) of the crude product (9.53 g) gave 5-methylspiro[2.5]oct-4-ene (3.42 g, 44%).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[CH2:17][CH2:16][C@H:15]([NH:18][C@@H:19]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[CH3:20])[CH2:14]2)=[CH:9][CH:8]=1)C.[OH-].[Na+].[ClH:34].C(OCC)(=O)C>C(O)C.C(Cl)Cl>[ClH:34].[C:21]1([C@H:19]([NH:18][C@H:15]2[CH2:16][CH2:17][C@@H:13]([C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]([OH:31])=[O:3])=[CH:12][CH:11]=3)[CH2:14]2)[CH3:20])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)COc1ccc([C@@H]2CC[C@H](N[C@H](C)c3cccc4ccccc34)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: ClCCl
Product: C[C@@H](N[C@H]1CC[C@@H](c2ccc(OCC(=O)O)cc2)C1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
{4-[(1R,3S)-3-{[(1R)-1-(Naphthalen-1-yl)ethyl]amino}cyclopentyl]phenoxy}acetic acid ethyl ester (720 mg, 1.7 mmol) was dissolved in ethanol (5 mL), followed by addition of 1N aqueous sodium hydroxide solution (5 mL), and the mixture was stirred for 1 hour at room temperature. 1N hydrochloric acid was added dropwise to the reaction mixture to make the reaction solution acidic, and then the solvent was distilled off under reduced pressure. The aqueous phase was extracted with methylene chloride, the extracted solution was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue obtained was dissolved in methylene chloride (6 mL), followed by addition of an ethyl acetate solution of 1N hydrochloric acid (2 mL), and then the solvent was distilled off under reduced pressure. Ethyl acetate and hexane were added to the residue, followed by treatment with ultrasonic waves, and then the solid matter generated was collected by filtration to give the title compound (237 mg, 87%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[O:11])OC(=O)[NH:7][C:6]=2[CH:13]=1.[CH:14]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)([CH2:16][CH3:17])[CH3:15]>CN(C=O)C>[NH2:7][C:6]1[CH:13]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[C:10]([NH:22][C:21]1[CH:23]=[CH:24][C:18]([CH:14]([CH2:16][CH3:17])[CH3:15])=[CH:19][CH:20]=1)=[O:11]
Reactant: O=c1[nH]c2cc(F)ccc2c(=O)o1
Reactant: CCC(C)c1ccc(N)cc1
Solvent: CN(C)C=O
Product: CCC(C)c1ccc(NC(=O)c2ccc(F)cc2N)cc1
Temperature: 116 °C

Procedure:
To a solution of 7-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (1.00 g, 5.52 mmol) in anhydrous DMF (15 mL), 4-(sec-butyl)-aniline (B) (0.824 g, 5.52 mmol) was added and the reaction mixture was heated at 116° C. for 16 hours. The product was extracted with ethyl acetate and washed with brine. The solvent was evaporated in vacuo to leave a crude material which was purified by column chromatography (silica gel; 230-400 mesh; ethyl acetate/hexane=1:9) to give 2-amino-N-(4-sec-butyl-phenyl)-4-fluoro-benzamide (N) as white solid. Yield: 0.92 g (58%).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].O[N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19]>C1COCC1>[C:13]1(=[O:14])[N:9]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][C:5]#[CH:6])[C:10](=[O:19])[C:11]2=[CH:18][CH:17]=[CH:16][CH:15]=[C:12]12
Reactant: C#CCCCCO
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: C1CCOC1
Product: C#CCCCCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 5-Hexyn-1-ol is added N-hydroxyphthalimide (1.1 equivalent) in dry THF. To this mixture is added diethylazo-dicarboxylate (DEAD) dropwise with stirring at ambient temperature for 18 hours. Evaporation of the reaction mixture followed by silica column purification yielded the 1-phthalimidooxy-hex-5-yne.
Reaction SMILES: [CH2:1]([O:5][C:6]1[NH:7][C:8]([NH2:17])=[C:9]2[C:13]([N:14]=1)=[N:12][C:11]([O:15][CH3:16])=[N:10]2)[CH2:2][CH2:3][CH3:4].[CH2:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26]O)[CH2:22][CH2:21]1)[CH3:19].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:15][CH3:16])[N:12]2[CH2:26][CH:23]2[CH2:24][CH2:25][N:20]([CH2:18][CH3:19])[CH2:21][CH2:22]2)=[C:8]([NH2:17])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: CCN1CCC(CO)CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCCOc1nc(N)c2nc(OC)n(CC3CCN(CC)CC3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.1 %

Procedure:
2-(Butyloxy)-8-(methyloxy)-1H-purin-6-amine (300 mg, 1.264 mmol), (1-ethyl-4-piperidinyl)methanol (362 mg, 2.53 mmol) and tributylphosphine (0.624 ml, 2.53 mmol) were dissolved in THF (12 ml). 1,1′-(Azodicarbonyl)dipiperidine (638 mg, 2.53 mmol) was added and the reaction mixture stirred at rt overnight. The solvent was removed in vacuo and the residue purified by column chromatography, loading in dichloromethane and purified on Flashmaster II silica (Si) 20 g using a 0-100% ethyl acetate in cyclohexane+0-20% methanol (+1% Et3N) gradient over 30 mins. The appropriate fractions were combined and evaporated in vacuo. The material (300 mg) was dissolved in 1:1 MeOH:DMSO 3 ml and re-purified by Mass Directed AutoPrep (Method A). The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus to give the title compound as a clear gum (60 mg). LCMS (System A): tRET=0.57 min; MH+ 363
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]([OH:22])=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:25])=O>C(Cl)Cl>[Si:1]([O:18][CH2:19][C:20]([Cl:25])=[O:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)[Si](OCC(=O)O)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCC(=O)Cl)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
In a 500ml round-bottom flask was mixed {[tert-butyl(diphenyl)silyl]oxy}acetic acid (17g, 54.0mmoles, 1eq), thionyl chloride (11.7g, 0.162moles, 3eq) and dry CH2Cl2(120ml, 0.45M). This mixture was refluxed for 5hours. After cooling to room temperature the volatiles were removed in vacuo. The resulting residue washed twice with toluene and the toluene was subsequently removed in vacuo to remove excess thionyl chloride. This resulted in 18g (100%) of titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[C:5]([F:11])=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH:19]([CH:22]2[CH2:24][CH2:23]2)[CH2:20][CH3:21])[C:13]=1[N+:25]([O-])=O.Cl[Sn]Cl.O>>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH3:9])[CH3:10])[C:5]([F:11])=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH:19]([CH:22]2[CH2:23][CH2:24]2)[CH2:20][CH3:21])[C:13]=1[NH2:25]
Reactant: CCC(Nc1nccc(-c2cc(F)c(N(C)C)cc2Cl)c1[N+](=O)[O-])C1CC1
Agent: Cl[Sn]Cl
Solvent: O
Product: CCC(Nc1nccc(-c2cc(F)c(N(C)C)cc2Cl)c1N)C1CC1
Yield: 100.1 %

Procedure:
[4-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-propyl)-amine (300 mg, 0.76 mmol) and SnCl2.H2O (1.2 g, 6.1 mmol) were treated substantially as described in Part D of Example 74a to yield 276 mg of crude 4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-N2-(1-cyclopropyl-propyl)-pyridine-2,3-diamine: MS (EI) m/z 363.24 [(M+H)+, 100].
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH3:4].[CH:6]1[C:11](=[O:12])[C:10]([OH:13])=[CH:9][O:8][C:7]=1[CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[CH2:1]([O:13][C:10]1[C:11](=[O:12])[CH:6]=[C:7]([CH2:14][OH:15])[O:8][CH:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCBr
Reactant: O=c1cc(CO)occ1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1coc(CO)cc1=O
Temperature: 90 °C
Reaction time: 3 h

Procedure:
48.3 g (0.352 mole) 1-butyl bromide are added at ambient temperature, with vigorous stirring, to a mixture of 50 g (0.352 mole) kojic acid, 48.7 g (0.352 mole) potassium carbonate, 1 g potassium iodide and 420 mL anhydrous dimethylformamide. Thereafter, the reaction mixture is stirred for 3 hours at 90° C. After cooling, the solvent is removed under vacuum and the residue is mixed with water and extracted with dichloromethane. The organic phase is separated off and dried, the solvent is evaporated and the residue is recrystallized from ethyl acetate. There is obtained a solid, colorless product; m.p. 68°-73° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[S:14][C:13]([NH2:15])=[N:12][C:11]=2[C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)=[O:9])=[CH:4][N:3]=1.[C:21](O)(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:11]1[N:12]=[C:13]([NH:15][C:21]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[O:28])[S:14][C:10]=1[C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[N:3][CH:4]=1)=[O:9]
Reactant: O=C(O)c1ccncc1
Reactant: Cc1ccc(C(=O)c2sc(N)nc2-c2ccco2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=O)c2sc(NC(=O)c3ccncc3)nc2-c2ccco2)cn1
Temperature: 60 °C
Reaction time: 3 h
Yield: 62.1 %

Procedure:
Compound 312 (200 mg, 0.701 mmol) was dissolved in DMF (3.5 mL), and isonicotinic acid (259 mg, 2.10 mmol), EDC hydrochloride (403 mg, 2.10 mmol) and 1-hydroxybenzotriazole monohydrate (322 mg, 2.10 mmol) were added thereto, followed by stirring at 60° C. for 3 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was recrystallized from 2-propanol to afford the entitled Compound 313 (170 mg, 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([CH2:12][C:13](=[O:27])[C:14]([NH:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[C:22](=[O:23])[O:21][CH2:20]3)=[O:15])[CH2:11][CH2:10]1.[F:28][C:29]([Si](C)(C)C)([F:31])[F:30].C(=O)([O-])[O-].[Cs+].[Cs+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C)C=O.O1CCCC1.O>[OH:27][C:13]([C:29]([F:31])([F:30])[F:28])([CH2:12][C:9]1([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1)[C:14]([NH:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:22](=[O:23])[O:21][CH2:20]2)=[O:15]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1ccccc1C1(CC(=O)C(=O)Nc2ccc3c(c2)COC3=O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccccc1C1(CC(O)(C(=O)Nc2ccc3c(c2)COC3=O)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
500 mg of 5-{3-[1-(2-methoxyphenyl)-cyclopropyl]-2-oxo-propionylamino}-phthalide is dissolved under argon in 15 ml of dimethylformamide and mixed with 0.77 ml of trifluoromethyl-trimethylsilane and 500 mg of cesium carbonate while being cooled with ice. After 18 hours of stirring at room temperature, 5 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran and a few drops of water are added and stirred for one hour at room temperature. After 100 ml of water is added, it is extracted with ethyl acetate, the organic phase is dried (Na2SO4) and concentrated by evaporation. The crude product is chromatographed on silica gel. With hexane/ethyl acetate (80:20), the title compound is obtained in a pure state.
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][O:9][C:10](=[O:32])[C@H:11]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]2[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:24]=2[Cl:31])=[O:22])=[CH:16][CH:15]=1)[NH2:12].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:57][O:58][CH2:59][CH2:60][C:61]1([C:66](O)=[O:67])[CH2:65][CH2:64][CH2:63][CH2:62]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:8][O:9][C:10](=[O:32])[C@H:11]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]2[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:24]=2[Cl:31])=[O:22])=[CH:18][CH:19]=1)[NH:12][C:66]([C:61]1([CH2:60][CH2:59][O:58][CH3:57])[CH2:65][CH2:64][CH2:63][CH2:62]1)=[O:67]
Reactant: COCCC1(C(=O)O)CCCC1
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2cc(C#N)ccc2Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COCCC1(C(=O)N[C@@H](Cc2ccc(NC(=O)c3cc(C#N)ccc3Cl)cc2)C(=O)OC)CCCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.8 %

Procedure:
To a solution of 4-[(2-chloro-5-cyanophenylcarbonyl)amino]-L-phenylalanine methyl ester TFA salt (0.55 mmol, 0.35 g), HBTU (0.65 mmol, 0.24 g) and 1-(2-methoxyethyl)cyclopentane carboxylic acid (0.65 mmol, 0.11 g) in DMF (3 mL) was added diisopropylethylamine (1.65 mmol, 0.29 mL) at room temperature. The clear solution was stirred for 15 h at room temperature and diluted with 50 mL of ethyl acetate. Then, the ethyl acetate layer was washed successively with 0.5N hydrochloric acid (2×20 mL), saturated sodium bicarbonate solution (2×20 mL) and brine solution and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent gave a crude product which was purified by silica gel column chromatography to afford 0.25 g (87%) of a white solid: mp 172-175° C. HR MS (C27H30ClN3O5): Obs mass, 512.1949. Calcd mass, 512.1953 (M+H).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1([C:7]([O:9]CC)=[O:8])[CH2:6][CH2:5]1>C(O)C.[OH-].[Na+]>[CH3:1][S:2][CH2:3][C:4]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5]1
Reactant: CCOC(=O)C1(CSC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSCC1(C(=O)O)CC1
Temperature: 23 °C
Reaction time: 20 h
Yield: 46 %

Procedure:
A 50% solution of sodium hydroxide (12.63 mL, 243 mmol) was added to a stirred solution of ethyl 1-(methylthiomethyl)cyclopropanecarboxylate (5.43 g, 31.20 mmol) in absolute ethanol (62.30 mL) at 23° C. The resulting solution was stirred at 23° C. for 20 h. The reaction mixture was diluted with a 0.5 M solution of sodium hydroxide and washed with dichloromethane. The aqueous layer was acidified to pH≈1 with concentrated hydrochloric acid and extracted with dichloromethane. The combined organic layers were dried (Na2SO4), filtered, and concentrated and concentrated to dryness to give the desired product as a light brown oil (2.10 g, 46%): 1H NMR (300 MHz, CDCl3) δ 2.82 (s, 2H), 2.17 (s, 3H), 1.41 (dd, J=7, 4 Hz, 2H), 0.99 (dd, J=7, 4 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[O:16][CH3:17].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[N:26]=[C:27]=[O:28].CCN(CC)CC>C1COCC1>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[NH:26][C:27](=[O:28])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1c(Cl)cccc1Cl
Reaction time: 18 h
Yield: 59 %

Procedure:
To a mixture of tert-butyl 4-amino-3-methoxyphenylacetate (2.15 g, 9.04 mmol), 2,6-dichlorophenyl isocyanate (1.70 g, 9.04 mmol) in THF (40 ml) was added Et3N (0.25 ml, 9.04 mmol) at room temperature. After 18 h stirring, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane, to give tert-butyl 4-[N′-(2,6-dichlorophenyl)ureido]-3-methoxyphenylacetate (2.27 g, 59%) as a colorless powder. mp 177-181° C. (dec.); 1H-NMR (CDCl3) δ1.43 (s, 9H), 3.74 (s, 2H), 3.83 (s, 3H), 6.34 (s, 1H), 6.81 (s, 1H), 6.84 (d, J=8.3 Hz, 1H), 7.06 (br, 1H, 7.27 (t, J=8.1 Hz, 1H), 7.39 (d, J=8.1 Hz, 2H), 8.04 (d, J=8.3 Hz, 1H).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].C(=O)([O-])[O-].[K+].[K+].[CH:14](=O)[CH2:15][CH3:16]>ClCCl>[CH2:15]([CH:16]1[N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][O:4]1)[CH3:14]
Reactant: CCC=O
Reactant: OCCNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCC1OCCN1CCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.8 %

Procedure:
To a 250 mL flask containing diethanolamine (2,9 mL, 30 mmol d=1,0955) in dichloromethane (60 mL) under nitrogen atmosphere, was added potassium carbonate (8,3 g, 60 mmol, 2 eq.) before adding at 0° C. dropwise propionaldehyde (2,73 mL, 37,5 mmol, 1,25 eq.). The reaction was warmed to room temperature and stirred for 3 h. The potassium carbonate was filtered with a sinter funnel and washed several times with dichloromethane. After evaporation of the combined organic phases, 4,994 g of crude product was obtained. The product was purified by distillation under vacuum to give the title compound (3,87 g, 87% yield). 1H NMR (CDCl3, 400 MHz) d?(ppm): 3,93 (dd, J=4,3 Hz, J=6,4 Hz, H); 3,92-3,82 (m, 2H); 3,71-3,58 (m, 2H); 3,26 (ddd, J=5,5 Hz, J=6,5 Hz, J=12,2 Hz, H); 2,83 (ddd, J=4,9 Hz, J=8,2 Hz, J=12,7 Hz, H); 2,66 (dt, J=7,0 Hz, J=10,0 Hz, H); 2,55 (dt, J=3,9 Hz, J=12,2 Hz, H); 1,60 (ddq, J=4,3 Hz, J=7,4 Hz, J=14,1 Hz); 1,51 (ddq, J=6,4 Hz, J=7,4 Hz, J=14,1 Hz); 0,95 (t, J=7,4 Hz, 3H). 13C NMR (CDCl3, 129,9 MHz) d?(ppm): 97,5; 64,1; 60,0; 55,1; 51,7; 26,8; 8,9.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH:11]1[CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[CH:6][N:7]=1
Reactant: Oc1ccc(Br)nc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(OCC2CC2)cn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
A mixture of 6-bromopyridin-3-ol (10.0 g), (bromomethyl)cyclopropane (7.76 g), potassium carbonate (11.9 g), and DMF (100 mL) was stirred at 60° C. overnight. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (12.0 g) as a colorless oil.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[CH:8](Br)[C:9]([C:11]([F:14])([F:13])[F:12])=O.[NH2:16][CH:17]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:18]([NH2:20])=[O:19].Cl>O>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:17]2[C:18](=[O:19])[NH:20][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:8][N:16]=2)=[CH:26][CH:25]=1
Reactant: O=C(C(Br)Br)C(F)(F)F
Reactant: NC(=O)C(N)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=c1[nH]c(C(F)(F)F)cnc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixed solution of 28 g of sodium carbonate and 100 ml of water was added dropwise 18.0 g of 1,1-dibromo-3,3,3-trifluoroacetone at such a rate that the temperature of the reaction mixture became not higher than 55° C. After completion of the dropwise addition, the mixture was stirred at room temperature for 30 minutes, followed by adding 125 ml of water and then 8.4 g of 2-amino-2-(4-fluorophenyl)acetamide, and the reaction was allowed to proceed at 60° C. for 2 hours. After completion of the reaction, the reaction mixture was cooled to 10° C. or lower, made acidic by adding 20 ml of concentrated hydrochloric acid at the same temperature, and extracted with ethyl acetate. The organic layer was washed with water and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent, hexane/ethyl acetate=5:1), which afforded 2.45 g (yield, 19%) of the desired compound, 3-(4-fluorophenyl)-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (compound 1-1001).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]([NH:7][C:8]2[S:9][C:10]3[N:18]=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[N:13]=2)=[CH:5][CH:4]=1.[H-].[Li+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([N:13]1[C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[N:18][C:10]=2[S:9][C:8]1=[N:7][C:6]1[CH:19]=[CH:20][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:4][CH:5]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=c1nc(Nc2ccc(C(F)(F)F)cc2)sc2ncccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Li+]
Product: O=c1c2cccnc2sc(=Nc2ccc(C(F)(F)F)cc2)n1Cc1ccccc1

Procedure:
The reaction procedure of Example 11 was followed except that 646 mg of 2-(4-trifluoromethylanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 18 mg of lithium hydride and 0.24 ml of benzyl bromide were used. As a result, 630 mg of 3-benzyl-2-[(4-trifluoromethylphenyl)imino]-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained.