Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[C:9]([O-:17])(=[S:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cs+]>CN(C=O)C.CCOCC>[C:9]([S:16][C@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])(=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)[C@H](Br)C(=O)O
Reactant: [O-]C(=S)c1ccccc1
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)[C@@H](SC(=O)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.5 %

Procedure:
To a solution of (S)-(−)-2-bromo-3-methylbutyric acid (4.20 g, 23.2 mmol) in DMF (41 mL) was added cesium thiobenzoate (6.08 g, 22.5 mmol). The mixture was stirred at rt for 20 h. The resulting solution was diluted with ether (200 mL) and washed with H2O (4×40 mL). The ethereal layer was dried (Na2SO4), and concentrated. The crude residue was recrystallized from hexanes to afford (R)-2-benzoylthio-3-methylbutanoic acid as a pale yellow solid (4.05 g, 75%); 1H NMR (300 MHz, CDCl3) δ 1.09 (d, J=7.4 Hz, 3H), 1.11 (d, J=7.4 Hz, 3H), 2.40 (m, 1H), 4.37 (d, J=5.9 Hz, 1H), 7.45 (t, J=7.4 Hz, 2H), 7.57 (t, J=7.4 Hz, 1H), 7.97 (d, J=7.4 Hz, 2H), 11.9 (br s, 1H); 13C NMR (75 MHz, CDCl3) δ 19.8, 20.6, 30.5, 53.1, 127.6, 128.8, 133.9, 136.3, 177.9, 190.3; IR (neat) 3100, 2967, 1709, 1669 cm−1; [α]D22=+95.6 (c 1, CH2Cl2). All spectral data was identical to that previously published (Strijtveen, B.; Kellogg, R. M. J. Org. Chem. 1986, 51, 3664).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.C([Mg]Br)(C)C.[CH2:31]([Sn:35](Cl)([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH3:34]>ClCCl>[CH2:40]([Sn:35]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:36][CH2:37][CH2:38][CH3:39])[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC(C)[Mg]Br
Solvent: ClCCl
Product: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
Under an argon atmosphere, a solution of 4-iodo-1-trityl-1 H-imidazole (1.00 g, 2.29 mmol) in dichloromethane (10 mL) was treated with isopropylmagnesium bromide (2.75 mL of 1M, 2.75 mmol, in tetrahydrofuran) and stirred at ambient temperature for 1 hour. After this time, the reaction was treated with tributyltin chloride (0.81 mL, 2.98 mmol) and the resulting mixture stirred overnight at ambient temperature. The reaction mixture was then diluted with dichloromethane (50 mL) and successively washed with saturated ammonium chloride (50 mL), water (50 mL) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 1.37 g of crude 4-tributylstannyl-1-trityl-1H-imidazole.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]1.[OH-].[Na+].Cl[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:12]([Cl:19])[N:11]=1>C1COCC1>[Cl:19][C:12]1[N:11]=[C:10]([O:6][C@H:3]2[CH2:4][CH2:5][O:1][CH2:2]2)[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: O[C@H]1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Cl)nc1O[C@H]1CCOC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
A mixture of THF and 320 mg (3.6 mmol) (3S)-tetrahydrofuran-3-ol is cooled to 0° C. and 145 mg (3.6 mmol) NaOH are added and the mixture stirred for 1 h. 700 mg (3.6 mmol) 2,6-dichloro-3-nitro-pyridine are slowly added and the mixture is stirred at RT for 3 days. The reaction mixture is filtered and evaporated The residual is purified by FC, giving rise to 600 mg (68%) 6-chloro-3-nitro-2-[(3S)-tetrahydrofuran-3-yl]oxy-pyridine.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:11][CH2:12][NH:13][C:14](=O)[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1.C(=O)(O)[O-].[Na+].O>C(#N)C>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[C:14]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)=[N:13][CH2:12][CH2:11]2
Reactant: COc1ccc(CCNC(=O)CCc2ccc(C(F)(F)F)cc2)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CC#N
Product: COc1cc2c(cc1OC)C(CCc1ccc(C(F)(F)F)cc1)=NCC2
Temperature: 25 °C
Yield: 99.9 %

Procedure:
Phosphorous oxychloride (4.77 g, 2.9 mL, 31.0 mmol, 2.2 eq) was added to a suspension of 44a (5.37 g, 14.1 mmol, 1.0 eq) in acetonitrile (100 mL) resulting in the formation of a clear solution. The mixture was heated at reflux for 3.5 h. The resulting yellow solution was cooled to rt and concentrated under reduced pressure to a thick yellow oil. The oil was dissolved in methanol (10 mL) and water (100 mL) was added slowly with stirring. After several minutes, a thick suspension formed. The mixture was made alkaline by the slow addition of saturated sodium bicarbonate solution, adding water (˜100 mL) to facilitate stirring. The thick white suspension was extracted with ethyl acetate (1×200 mL, 1×100 mL). The combined organic solution was washed with brine (100 mL), dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure to give 5.12 g (100%) of 45a as an off-white solid.
Reaction SMILES: [Sb:1].[C:2]([OH:11])(=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].CCCCCCC.[N+]([O-])(O)=O>O>[C:2]([O-:11])(=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Sb+3:1].[C:2]([O-:11])(=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:2]([O-:11])(=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: [Sb]
Reactant: CCCCCCCC(=O)O
Solvent: CCCCCCC
Solvent: O=[N+]([O-])O
Solvent: O
Product: CCCCCCCC(=O)[O-]
Product: [Sb+3]

Procedure:
The procedure of Example 5 was followed using a reaction mixture composed of 1 g. of antimony metal, 50 g. of octanoic acid, 20 ml. of n-heptane and 0.45 g. of 70% aqueous HNO3. The reaction temperature was about 120° C. and the HNO3 was added dropwise as in Example 5. The water of reaction was removed azeotropically with n-heptane and was collected in the Dean-Stark tube as in Example 6. The clear solution which resulted was concentrated and dried to produce a quantitative solid residue of Antimony(III) octanoate which had an UV-visible spectrum band at about 297 nm.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH:16](OC)(OC)[O:17]C.F[C:24](F)(F)S(O)(=O)=O.C(=O)(O)[O-].[Na+]>[N+](C)([O-])=O.CO>[CH3:24][O:13][C:3]([O:17][CH3:16])([C:2]([F:14])([F:15])[F:1])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[F:1][C:2]([F:14])([F:15])[C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1
Reactant: COC(OC)OC
Reactant: O=S(=O)(O)C(F)(F)F
Agent: O=C(CCc1ccc(O)cc1)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C[N+](=O)[O-]
Product: COC(CCc1ccc(O)cc1)(OC)C(F)(F)F
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 44 %

Procedure:
To a solution of 1,1,1-trifluoro-4-[4-hydroxyphenyl]-2-butanone (40.4 g, 0.185 mol) in nitromethane (300 ml) were added methanol (40 ml), trimethyl orthoformate (100 ml) and trifluoromethanesulfonic acid (1 ml). The resulting mixture was heated to 75° C. for 20 h, then cooled to r.t. and poured into sat. sodium bicarbonate (700 ml). After stirring for 10 min., the mixture was extracted with ethyl acetate (2×2 L). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (dichloromethane/methanol 98:2 to 97:3) to afford the title compound (21.5 g, 44%) as a yellow oil and 1,1,1-trifluoro-4[4-hydroxyphenyl]-2-butanone (23 g, 57%). Analytically pure sample (20.2 g, 41%) of 4-(4,4,4-trifluoro-3,3-dimethoxybut-1-yl)phenol was obtained by bulb-to-bulb distilation (98-102° C., 0.02mmHg).
Reaction SMILES: [NH2:1][C:2]([C:4]1([C:7]([OH:9])=O)[CH2:6][CH2:5]1)=[O:3].[F:10][C:11]1[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=1)[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.Cl.CN(C)CCCN=C=NCC>ClCCl>[F:10][C:11]1[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=1)[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:7]([C:4]2([C:2]([NH2:1])=[O:3])[CH2:5][CH2:6]2)=[O:9])=[CH:18][CH:17]=1
Reactant: NC(=O)C1(C(=O)O)CC1
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: NC(=O)C1(C(=O)Nc2ccc(OCc3cccc(F)c3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.2 %

Procedure:
A solution of 126 mg (1 mmol) of 1-(aminocarbonyl)-1-cyclopropan-carboxylic acid and of 212 mg (1 mmol) 4-(3-fluoro-benzyloxy)-phenylamine (prepared as in example 1b) in 10 ml dichloromethane is cooled to 0° C. and treated with 206 mg (1.1 mmol) N-(-3-dimethylaminopropyl)-N′-ethyl-carbodiimide-hydrochloride (EDCI). The mixture is stirred for additional 2 h at room temperature, evaporated and acidified with dil. citric acid. Extraction with ethyl acetate and recrystallisation from methanol yields 178 mg (56%) of the title compound. Yellowish solid; MS: m/e=329.3 (M++H).
Reaction SMILES: N1C=CC=CC=1.C([O:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)C(C)=C.O>C1COCC1>[C:14]1([C:13]([OH:12])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=C(C)C(=O)OC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
The procedure of Example 2 was repeated except that 3.96 g (0.05 mol) of dry pyridine was used in place of triethylamine and the reaction was carried out in THF. It was confirmed when the reaction solution was examined by means of thin-layer chromatography that triphenylmethyl methacrylate was quantitatively formed. After the amine salt was removed by filtration, the solvent and excess pyridine were evaporated. The intended product was obtained as a syrup. An attempt to recrystallize it from ether and n-hexane failed, since hydrolysis took place due to water contained in the solvents for recrystallization and triphenylmethyl alcohol was formed.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][S:24][CH3:25])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:34])C=1.ClC1C=C(C=CC=1)C(O)=O>C(Cl)(Cl)Cl>[CH2:1]([C:5]1[N:6]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][S:24]([CH3:25])=[O:34])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCCSC
Agent: O=C(O)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCCS(C)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A round bottom flask was charged with a magnetic stir bar, 2-butyl-1-[5-(methylthio)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 2.80 mmol) and chloroform (14 mL). Solid 3-chloroperbenzoic acid (0.69 g, 3.09 mmol) was added portion wise over 5 minutes and the reaction was stirred at ambient temperature for 20 minutes at which time the starting material was completely consumed. The solution was partitioned between chloroform and saturated aqueous sodium bicarbonate. The layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford an off-white solid which was shown by 1H-NMR to be the 3-chlorobenzoic acid salt of the desired product. The solid was stirred in water and then made basic (pH 10) by addition of solid sodium carbonate. The resulting free base was collected by filtration to provide a white solid which was recrystallized from acetonitrile to give 2-butyl-1-[5-(methylsulfinyl)pentyl]-1H-imidazo[4,5-c]quinolin-4-amine (0.40 g, 1.07 mmol) as a white powder, m.p. 119-121° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6](=[S:12])[NH:5][C:4](=[O:13])[CH:3]=1.[N:14]([O-])=[O:15].[Na+].O>C(O)(=O)C>[NH2:1][C:2]1[N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6](=[S:12])[NH:5][C:4](=[O:13])[C:3]=1[N:14]=[O:15]
Reactant: O=N[O-]
Reactant: CC(C)Cn1c(N)cc(=O)[nH]c1=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)Cn1c(N)c(N=O)c(=O)[nH]c1=S
Temperature: 75 °C
Yield: 96.4 %

Procedure:
6-Amino-1-isobutyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (1.0 g, 5.0 mmol) was suspended in 10% acetic acid (20 mL). Sodium nitrite (0.38 g, 5.5 mmol) was added and the resulting mixture was heated at 75° C. for 1 h. The reaction mixture became first pink and then purple. The purple mixture was cooled to room temperature. Then water (20 mL) was added and the purple solid was collected by filtration and washed with water to give the title compound (1.1 g, 92% yield). This solid was used in the following step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[O:21][N:20]=[C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)[CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[O:21][N:20]=[C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)[CH:18]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2cc(OCc3ccc4ccccc4n3)no2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(Cc2cc(OCc3ccc4ccccc4n3)no2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
After a mixture of ethyl 3-[3-ethoxy-1-[3-(2-quinolylmethoxy)-5-isoxazolylmethyl]-1H-pyrazol-4-yl]propionate (721 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, 1 N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[3-(2-quinolylmethoxy)-5-isoxazolylmethyl]-1H-pyrazol-4-yl]propionic acid (608 mg, yield: 90%). This was recrystallized from ethanol-hexane. Melting point: 123–124° C.
Reaction SMILES: [NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[NH:4][C:2]1=[O:3].[CH2:12](OC(=O)C)C>>[CH3:12][N:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[NH:4][C:2]1=[O:3]
Reactant: O=c1[nH]c(=O)c2[nH]cnc2[nH]1
Reactant: CCOC(C)=O
Product: Cn1c(=O)[nH]c2nc[nH]c2c1=O

Procedure:
The first step in the synthesis involves blocking the 7 position in 1-methyl xanthine. The procedure of Hu, Singh and Ullman, J. Am. Chem. Soc., 45: 1711-1713 (1980) was followed. To 700 ml of dry DMF in a 1-liter conical flask was added 3.2 g (18.9 mmoles) of 98% 1-methylxanthine (Aldrich Chemical Co., cat. #28,098-4), the mixture was stirred magnetically and warmed until dissolution occurred and then cooled to room temperature. To the stirred solution was added 2.0 g (18.9 mmoles) of anhydrous sodium carbonate followed by the dropwise addition, over a period of 1 hour, of 3.0 g (19.3 mmoles) of 97% chloromethyl pivalate (Aldrich Chemical Co., cat. #14,118-6) dissolved in 50 ml of DMF. The reaction mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness and the residue treated with 50 ml of methylene chloride. The insoluble material was collected by filtration and washed with 1N HCl to give 1.24 g of 1-methylxanthine. The methylene chloride solution was evaporated to dryness to yield a mixture of mono- and bis- protected xanthine. The mono-protected 1-methyl-7-}pivaloyloxy)methyl1 xanthine was separated from the bis protected xanthine by crystallization from ethyl acetate. By this method there was obtained 1.5 g of the monoprotected xanthine (m.p. 204°-206°). The ethylacetate filtrate from the isolation of the monoprotected xanthine, containing the bis-protected xanthine, was evaporated to dryness and refluxed with 20 ml of 2N sodium hydroxide for 18 hours. The reaction mixture was cooled and acidified with concentrated HCl and extracted with chloroform. Evaporation of the aqueous layer yielded 0.5 g of 1-methylxanthine.
Reaction SMILES: [CH3:1][CH:2](O)[CH:3]=[CH2:4].[H-].[K+].[Cl:8][C:9]([Cl:13])([Cl:12])[C:10]#[N:11].C1C[O:17]CC1>CCOCC>[CH2:1]([NH:11][C:10](=[O:17])[C:9]([Cl:13])([Cl:12])[Cl:8])[CH:2]=[CH:3][CH3:4]
Reactant: C=CC(C)O
Reactant: C1CCOC1
Reactant: N#CC(Cl)(Cl)Cl
Agent: [H-]
Agent: [K+]
Solvent: CCOCC
Product: CC=CCNC(=O)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 3-butene-2-ol (8.7 mL, 100 mmol) in THF (50 mL) was added to potassium hydride (KH, 600 mg, 15 mmol) over 15 min. The resulting alkoxide solution was added to a stirred solution of trichloroacetonitrile (10.03 mL, 100 mmol) in ether (100 mL) at -10° C. The solution was stirred at 0° C. for 3 h, followed by removal of solvent under reduced pressure (temperature <25 ° C.); pentane (400 mL) and methanol (1 mL) were added, and the mixture filtered. Concentration afforded a yellow oil (17.4 g). The oil was dissolved in xylene (450 mL) and refluxed for 2.5 h. The solvent was removed to yield 16.8 g of the title compound as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:31]([CH3:33])[CH3:32])[C:6]2[O:10][C:9]([C:11]3[CH:29]=[CH:28][C:14]([C:15]([NH:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([CH2:25][CH:26]=O)[CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:30]=1)#[N:2].[F:34][C:35]([F:49])([F:48])[C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:39][NH2:40].C([BH3-])#N.[Na+]>CO.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[F:34][C:35]([F:48])([F:49])[C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([C:44]([F:47])([F:45])[F:46])[CH:43]=1)[CH2:39][NH:40][CH2:26][CH2:25][C@H:22]1[CH2:23][CH2:24][C@H:19]([CH2:18][NH:17][C:15](=[O:16])[C:14]2[CH:28]=[CH:29][C:11]([C:9]3[O:10][C:6]4[C:5]([CH:31]([CH3:32])[CH3:33])=[CH:4][C:3]([C:1]#[N:2])=[CH:30][C:7]=4[N:8]=3)=[CH:12][CH:13]=2)[CH2:20][CH2:21]1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CC[C@H](CC=O)CC4)cc3)oc12
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CC[C@H](CCNCc5cc(C(F)(F)F)cc(C(F)(F)F)c5)CC4)cc3)oc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-{[trans-4-(2-oxoethyl)cyclohexyl]methyl}benzamide (25 mg, 0.056 mmol) in methanol (2 ml) were added 3,5-bis(trifluoromethyl)benzylamine (20 mg, 0.082 mmol) and sodium cyanoborohydride (10 mg, 0.159 mmol). The mixture was stirred overnight at room temperature, at which point LC/MS analysis showed a new peak at the desired molecular weight. The reaction mixture was then diluted with 10 ml of saturated sodium bicarbonate solution and 10 ml of ethyl acetate. The phases were separated and the aqueous phase was extracted with 2×10 ml of ethyl acetate. The combined organics were washed with 10 ml of brine, dried (sodium sulfate), and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 100% ethyl acetate in dichloromethane over 10 column volumes to provide the title compound (11.9 mg, 0.018 mmol, 31.5% yield). Mass spectrum (ESI) 671.5 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.33 (d, J=8.5 Hz, 2H); 7.96 (d, J=8.5 Hz, 2H), 7.93 (d, J=1.5 Hz, 1H); 7.83 (s, 2H), 7.75 (s, 1H), 7.51 (s, 1H), 6.35 (br t, J=5.5 Hz, 1H), 5.30 (s, 2H), 3.85 (s, 2H), 3.48 (septet, J=6.5 Hz, 1H), 3.35 (t, J=6.5 Hz, 2H), 2.65 (t, J=6.5 Hz, 2H), 1.80 (m, 4H), 1.60 (m, 1H), 1.46 (d, J=7.0 Hz, 6H), 1.40-1.52 (m, 1H), 0.90-1.15 (m, 4H).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1.[H-].[Na+].Br[CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1>CN(C)C=O.C(OCC)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([I:9])[C:5]([O:8][CH2:13][CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[CH:6][N:7]=1
Reactant: Oc1cnc(F)cc1I
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1cc(I)c(OCCOC2CCCCO2)cn1
Reaction time: 1 h
Yield: 75.6 %

Procedure:
Add 6-fluoro-4-iodo-pyridin-3-ol (0.5 g, 2.09 mmol) to a suspension of sodium hydride (60% dispersion in mineral oil, 0.1 g, 2.51 mmol) in dimethylformamide (6 mL). Stir the mixture for 1 hour. Add 2-(2-bromo-ethoxy)-tetrahydro-pyran (0.51 g, 2.34 mmol). Stir the solution at room temperature overnight. Dilute the mixture with ethyl acetate and water. Wash the organic layer with saturated aqueous sodium chloride and water. Dry the mixture over sodium sulfate. Concentrate the solution in vacuo to give yellow oil. Purify the oil by column chromatography (10% ethyl acetate in hexane) to afford the title compound (0.58 g, 75.5%) as a light yellow oil. MS (EI) m/z 368 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2.[CH3:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[C:18]2Cl>CN1CCCC1=O.C(OCC)C>[CH3:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[C:20]([C:10]1[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:11])[CH:8]=3)[NH:3][C:2]=1[CH3:1])[CH:19]=[CH:18]2
Reactant: Cc1cccc2c(Cl)ccnc12
Reactant: Cc1ccc2[nH]c(C)cc2c1
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: Cc1ccc2[nH]c(C)c(-c3ccc4cccc(C)c4n3)c2c1
Temperature: 140 °C
Reaction time: 0.75 h
Yield: 99.7 %

Procedure:
2,5-Dimethylindole (290 mg) and 8-methyl-4-chloroquinoline (360 mg) were suspended in N-methylpyrolidinone (0.5 ml), and maintained under a nitrogen atmosphere. The reaction was heated to 140° C. with stirring for 45 minutes. On cooling a deep red precipitate formed, the mixture was diluted with diethylether and the solid collected by filtration, and dried to give the sub-title compound (570 mg).
Reaction SMILES: C(S([C:6]1[N:15]=[C:14]2[C:9]([C:10](=[O:24])[C:11]([C:19]([O:21]CC)=[O:20])=[CH:12][N:13]2[CH2:16][CH2:17][F:18])=[CH:8][C:7]=1[F:25])(=O)=O)C.[CH3:26][N:27]([CH3:33])[CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1>>[CH3:26][N:27]([CH3:33])[CH:28]1[CH2:32][CH2:31][N:30]([C:6]2[N:15]=[C:14]3[C:9]([C:10](=[O:24])[C:11]([C:19]([OH:21])=[O:20])=[CH:12][N:13]3[CH2:16][CH2:17][F:18])=[CH:8][C:7]=2[F:25])[CH2:29]1
Reactant: CN(C)C1CCNC1
Reactant: CCOC(=O)c1cn(CCF)c2nc(S(=O)(=O)CC)c(F)cc2c1=O
Product: CN(C)C1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3CCF)C1

Procedure:
The same reaction as in Example 4 was carried out using ethyl 7-ethylsulfonyl-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate and 3-dimethylaminopyrrolidine as starting materials. There was obtained the compound 5, m.p. 247°-249° C.