Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[F:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.Br[CH2:18][CH2:19][CH2:20][OH:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:18][CH2:19][CH2:20][OH:21])[CH2:11][CH2:10]2)=[O:8])=[CH:15][CH:16]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: OCCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1)C1CCN(CCCO)CC1
Temperature: 110 °C
Yield: 47.1 %

Procedure:
To a solution of 4-(p-fluorobenzoyl)piperidine hydrobromide (0.3 g, 1.04 mmol) in DMF (10 mL) were added 3-bromo-1-propanol (0.11 mL, 1.25 mmol) and potassium carbonate (0.29 g, 2.08 mmol). This heterogeneous solution was heated at 110° C. for 3 h then cooled at 25° C., diluted with water (100 mL) and extracted with EtOAc (3×30 mL). The collected organic phase was washed with water (2×50 mL), dried and concentrated in vacuum. The crude compound was purified by filtration on silica gel using CH2Cl2/MeOH as eluant to afford the title compound as a pale yellow solid (0.13 g, 47%). m.p.=106-108° C. 1H NMR (CDCl3): 1.55-1.68 (m, 2H), 1.68-1.95 (m, SH), 2.05-2.2 (m, 2H), 2.642 (t, J=5.4Hz, 2H), 3.13 (bd, J=11.7Hz, 2H), 3.15-3.3 (m, 1H), 3.808 (t, J=4.8Hz, 2H), 7.137 (t, J=8.4Hz, 2H), 7.95 (dd, J=5.4 & 8.4, 2H). Anal. Calcd. for C15H20FNO2:C, 67.90; H, 7.60; N, 5.28; Found: C, 66.71; H, 7.38; N, 5.44.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:31]=[CH:30][C:19]([CH2:20][CH:21]([C:26]([O:28]C)=[O:27])[C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=1.[OH-].[Na+]>CO.O1CCCC1>[CH3:25][O:24][C:22]([CH:21]([CH2:20][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[CH:31][CH:30]=1)[C:26]([OH:28])=[O:27])=[O:23]
Reactant: COC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 6.6 %

Procedure:
Dimethyl 2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]malonate (8.46 g, 20 mmol) synthesized according to the method described in WO95/18125 was dissolved in a mixture of methanol (80 ml) and tetrahydrofuran (40 ml), and 2N aqueous sodium hydroxide solution (11 ml, 22 mmol) was added at 0° C. The mixture was stirred for 1.5 hr at room temperature and the solvent was evaporated. A saturated aqueous solution (5 ml) of sodium hydrogencarbonate was added and the aqueous layer was washed with ethyl acetate. To the obtained aqueous layer was added sodium chloride to saturate the solution, and the mixture was acidified with 1N hydrochloric acid and washed three times with ethyl acetate (50 ml). The extracted organic layers were combined, washed with brine, dried over sodium sulfate and dried to solidness to give a crude title compound (8.2 g, yield 100%). The obtained crude compound (750 mg) was recrystallized from a mixed solvent of ethyl acetate-hexane (1:2) to give the title compound (540 mg) as a white solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:7][CH:6]=1.FC(F)(F)C(O)=O.[N+:26]([O-])([OH:28])=[O:27]>>[F:1][C:2]([F:17])([F:18])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:9][C:10]=1[N+:26]([O-:28])=[O:27]
Reactant: FC(F)(F)COc1ccc(OCC(F)(F)F)cc1
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reaction time: 24 h

Procedure:
To 58.1 g. (0.212 mole) of 1,4-bis(2,2,2-trifluoroethoxy)benzene in 400 ml. of trifluoroacetic acid is added dropwise with stirring 13.7 ml. of concentrated nitric acid over 3.5 hours at 25 ± 2° C. Stirring is continued for 24 hours, then the mixture is concentrated to one-third the original volume. The concentrate is poured into 600 ml. of water, and the resulting solution is extracted twice with diethyl ether. The ether solution is washed thrice with saturated sodium chloride solution, then with dilute sodium hydroxide solution until the washings are basic. The solution is washed again with saturated sodium chloride solution, dried and evaporated. The liquid residue is distilled to provide 2,5-bis(2,2,2-trifluoroethoxy)nitrobenzene as a clear, pale yellow liquid, b.p. 116°-119° C/0.35 mm Hg.
Reaction SMILES: [Br:1][C:2]1[C:6]([CH:7]=[O:8])=[C:5]([Br:9])[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>CN(C)C=O>[Br:1][C:2]1[C:6]([CH:7]=[O:8])=[C:5]([Br:9])[N:4]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[N:3]=1
Reactant: COc1ccc(CBr)cc1
Reactant: O=Cc1c(Br)n[nH]c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(Br)c(C=O)c2Br)cc1
Reaction time: 0.17 h
Yield: 91.8 %

Procedure:
3,5-Dibromo-1H-pyrazole-4-carbaldehyde (987.9 mg, 3.89 mmol) and potassium carbonate (1.613 g, 11.67 mmol) were dissolved in N,N-dimethylformamide (39 mL) at 25° C. under Ar. 4-methoxybenzyl bromide (617 μl, 4.28 mmol) was added dropwise. The reaction mixture was allowed to stir for 2 h 10 min. The reaction was stopped, quenched by addition of saturated aqueous ammonium chloride (30 mL), and the mixture extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with saturated aqueous sodium chloride (1×20 mL), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography (RediSep SiO2, 120 g column) on a CombiFlash Rf purification system eluting with ethyl acetate-hexanes (0-55%). The title compound (L3342 g, 3.57 mmol, 92% yield) was recovered as a colorless, very viscous oil. LC-MS [M+1]=373.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][N:8]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH:18]([CH2:21][O:22][CH3:23])[O:17][C:16]=3[CH:24]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Cl:32][C:33]1[CH:34]=[CH:35][C:36](F)=[C:37]([CH:40]=1)[C:38]#[N:39].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([N:20]2[CH2:19][CH:18]([CH2:21][O:22][CH3:23])[O:17][C:16]3[CH:24]=[C:12]([S:9]([N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:31][CH:30]=4)[C:25]4[S:26][CH:27]=[CH:28][N:29]=4)(=[O:11])=[O:10])[CH:13]=[CH:14][C:15]2=3)=[C:37]([C:38]#[N:39])[CH:40]=1
Reactant: N#Cc1cc(Cl)ccc1F
Reactant: COCC1CNc2ccc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)cc2O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCC1CN(c2ccc(Cl)cc2C#N)c2ccc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)cc2O1
Temperature: 80 °C
Yield: 87.9 %

Procedure:
To a solution of N-(4-methoxybenzyl)-2-(methoxymethyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (150 mg, 0.324 mmol) and 5-chloro-2-fluorobenzonitrile (50.55 mg, 0.324 mmol, Aldrich) in DMF (5.0 mL) was added Cs2CO3 (210 mg, 7.95 mmol) and the reaction mixture was heated at 80° C. for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude material which was purified by column chromatography (silica gel 100-200 mesh and 0-30% ethyl acetate in hexane) to obtain 4-(4-chloro-2-cyanophenyl)-N-(4-methoxybenzyl)-2-(methoxymethyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (170 mg, 87.6%) as an off white solid. m/z (ESI) 596.8 (M+H)+.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1([CH2:10][CH2:11][N:12]2[C:16](=[O:17])[CH2:15][S:14][CH:13]2[CH2:18][CH2:19][CH2:20][C:21]2[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.CO.Cl>O>[OH:3][C:4]1([CH2:10][CH2:11][N:12]2[C:16](=[O:17])[CH2:15][S:14][CH:13]2[CH2:18][CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=2)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CCOC(=O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Temperature: 25 °C

Procedure:
Sodium hydroxide solution (5 N, 2.5 ml., 12.5 mmol.) is added to a stirred mixture of ethyl 4-{3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoate (2.48 g., 5.91 mmol.), methanol (25 ml.) and water (5 ml.). The resulting mixture is stirred at ambient temperature for 16 l hours. Then, it is diluted with water, acidified with diluted hydrochloric acid, and extracted with ether. The ethereal extract is washed with water, dried over anhydrous magnesium sulfate, and filtered. Upon cooling the filtrate, the title compound precipitates out as a white solid, which is collected by filtration (7.06 g., 2.57 mmol., 42%). The product is recrystallized from chloroform-ether, m.p. 147°-148° C., ir (KBr) 3320, 1700, 1650 cm-1, pmr (CDCl3) δ3.54 (2H, s), 4.70 (1H, m), 7.22 (2H, d), 8.00 (2H, d).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([C:11]#[N:12])[CH:3]=1.[CH:13]1([C:16]2[CH:17]=[C:18]([CH3:28])[C:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:20][CH:21]=2)[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:25]2[CH2:26][CH2:27][N:22]([C:19]3[C:18]([CH3:28])=[CH:17][C:16]([CH:13]4[CH2:14][CH2:15]4)=[CH:21][N:20]=3)[CH2:23][CH2:24]2)=[O:8])=[C:4]([CH:3]=1)[C:11]#[N:12]
Reactant: N#Cc1cc(Br)ccc1C(=O)O
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2C#N)CC1
Yield: 82.2 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 90 and using 4-bromo-2-cyanobenzoic acid (2.14 g) described in Preparation Example 192 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (2.16 g) described in Preparation Example 96, the title compound (3.31 g) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[OH-].[Na+].Cl[CH:15]([F:17])[F:16]>O1CCOCC1.O>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH:15]([F:17])[F:16]
Reactant: O=[N+]([O-])c1ccc(O)c(Br)c1
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(OC(F)F)c(Br)c1
Temperature: 60 °C
Reaction time: 0.67 h

Procedure:
2-Bromo-4-nitrophenol (10.9 g) was dissolved in dioxane (60 ml), a solution of sodium hydroxide (18.4 g) in water (50 ml) was added thereto, and the resulting mixture was heated up to 60° C. while stirring vigorously. Chlorodifluoromethane gas was introduced therein, whereby the generation of heat was initiated. The reaction was continued for about 40 minutes. The reaction mixture was cooled to room temperature, poured onto ice-water and extracted with ether. The extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3-bromo-4-difluoromethoxynitrobenzene (8.7 g) as a pale yellow oil. nD20.5 1.5500.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[C:6]([CH3:12])=[N:7]2.[Cl:22][CH2:23][C:24](Cl)=[O:25].C(#N)C>CO>[Cl:22][CH2:23][C:24]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[C:6]([CH3:12])=[N:7]2)=[O:25]
Reactant: Cc1nc2cccc(N)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C(Cl)CCl
Solvent: CC#N
Solvent: CO
Product: Cc1nc2cccc(NC(=O)CCl)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 100 °C
Yield: 88.6 %

Procedure:
The stirred mixture of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (4.0 g, 14 mmol) and chloroacetyl chloride (7.7 mL, 98 mmol) was heated in a 100° C. oil bath for 15 minutes. The mixture was allowed to cool to room temperature. Acetonitrile (5 mL) was added to the mixture. The suspension was filtered and washed with ethyl acetate (2×10 mL) to give a white solid. The solid was stirred in methanol (50 mL) overnight. The suspension was filtered and washed with methanol (20 mL) to give 2-chloro-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-yl]-acetamide as a white solid (4.5 g, 90% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 20/80 CH3CN/0.1% H3PO4, 12.79 min (97.6%); mp: 275-277° C.; 1H NMR (DMSO-d6) δ 2.18-2.25 (m, 1H, CH2), 2.61-2.80 (m, 5H, CH3, 2CHH), 2.86-2.91 (m, 1H, CHH), 4.48-4.53 (m, 2H, CH2), 5.36 (dd, J=6, 11 Hz, 1H, NCH), 7.39 (dd, J=1, 8 Hz, 1H, Ar), 7.83 (t, J=8 Hz, 1H, Ar), 8.57 (dd, J=1, 8 Hz, 1H, Ar), 10.7 (brs, 1H, HCl), 11.11 (s, 1H, NH), 12.26 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.66, 23.10, 30.60, 43.56, 56.84, 107.89, 115.65, 120.87, 135.77, 138.87, 147.17, 155.49, 162.67, 165.55, 169.14. 172.60; LCMS: MH=363, 365; Anal Calcd for C16H15N4O4Cl+1.05HCl: C, 47.92; H, 4.03; N, 13.97; Cl, 18.12. Found: C, 48.24; H, 3.79; N, 13.84; Cl, 18.27.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:12]([OH:18])=[N:13][CH:14]=[CH:15][C:16]=2[Cl:17])[CH:9]=1)[C:5]#[N:6].[Cl:19]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:12](=[O:18])[NH:13][CH:14]=[C:15]([Cl:19])[C:16]=2[Cl:17])[CH:9]=1)[C:5]#[N:6]
Reactant: O=C1CCC(=O)N1Cl
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccnc2O)c1
Solvent: CC(=O)O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)c(Cl)c[nH]c2=O)c1
Temperature: 70 °C

Procedure:
To a suspension of 3-chloro-5-[(4-chloro-2-hydroxypyridin-3-yl)oxy]benzonitrile (50 mg, 0.178 mmol) in acetic acid (1 mL) was added N-chlorosuccinimide (35.6 mg, 0.267 mmol) and the resulting mixture heated to 70° C. for 2 hours. This mixture was allowed to cool to room temperature and the resulting white solid was filtered and washed with methanol (1 mL) to provide the title compound. LRMS (M+1): 314.6.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([O:11][CH2:12][S:13][CH3:14])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.CO>[Fe].C(O)(=O)C>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([O:11][CH2:12][S:13][CH3:14])=[CH:10][C:4]=1[NH2:1]
Reactant: CSCOc1ccc(N)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: CSCOc1ccc(N)c(N)c1

Procedure:
4.5 G. of 2-nitro-4-methylthiomethoxyaniline in 95 ml. of methanol and 5 ml. of acetic acid is treated with 8 g. of iron powder and the mixture is refluxed for 4 hours. The hot solution is filtered and the solvent evaporated. The residue is treated with hot tetrahydrofuran. The mixture is filtered and the solvent evaporated to give 1,2-diamino-4-methylthiomethoxybenzene.
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[CH3:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Br>CC#N>[CH3:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1
Reactant: O=C1CCNCC1
Reactant: Cc1ccccc1CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1ccccc1CN1CCC(=O)CC1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
To a suspension of 2.00 g of 4-piperidone monohydrate hydrochloride and 5.40 g of potassium carbonate in 30 ml of CH3CN was added dropwise 1.57 ml of 2-methyl benzyl bromide at 0° C. After stirred at 0° C. or 3.5 h, the mixture was stirred at room temperature for an hour. At 0° C., the mixture was quenched with water and extracted with CHCl3. The organic layer was washed with water, aqueous NaOH, and brine, and dried over anhydrous Na2SO4. The organic solvent was evaporated to give the crude product of 2.52 g of N-(2-methylbenzyl)-4-piperidone as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21]CC2C=CC=CC=2)[CH2:12][CH2:11]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:29])[N:7]([CH2:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:14][CH2:15]1)[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C[C@H]1CC[C@H](OCCCCOCc2ccccc2)CC1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CN(C[C@H]1CC[C@H](OCCCCO)CC1)C(=O)OC(C)(C)C

Procedure:
2.15 g (5.3 mmol) of trans-[4-(4-benzyloxy-butoxy)-cyclohexylmethyl]-methyl-carbamic acid tert-butyl ester were dissolved in 20.0 ml of methanol, 0.3 g palladium on charcoal (10%) were added and the reaction mixture hydrogenated at normal pressure until the consumption of hydrogen came to an end. Then, it was filtered over celite and evaporated giving 1.60 g (95.6%) of trans-[4-(4-hydroxy-butoxy)-cyclohexylmethyl]-methyl-carbamic acid tert-butyl ester as colorless viscous oil, MS: 315 (M+).
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[N:7][C:8](SC)=[N:9][CH:10]=2)[N:5]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C@H:22]([OH:24])[CH3:23])[N:17]=1)[CH:2]=[CH2:3].[CH3:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:32]=1[N:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1)[NH2:29]>>[CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[N:7][C:8]([NH:29][C:28]3[CH:30]=[CH:31][C:32]([N:33]4[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]4)=[C:26]([CH3:25])[CH:27]=3)=[N:9][CH:10]=2)[N:5]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([OH:24])[CH3:23])[N:17]=1)[CH:2]=[CH2:3]
Reactant: C=CCn1c(=O)c2cnc(SC)nc2n1-c1cccc([C@@H](C)O)n1
Reactant: Cc1cc(N)ccc1N1CCN(C)CC1
Product: C=CCn1c(=O)c2cnc(Nc3ccc(N4CCN(C)CC4)c(C)c3)nc2n1-c1cccc(C(C)O)n1

Procedure:
83.2 mg of the entitled compound was obtained as a white solid in the same manner as in Example 86-1 to 86-3, for which, however, a racemic starting material thereof was used in place of the chiral starting material of 2-allyl-1-{6-[(1R*)-1-hydroxyethyl]pyridin-2-yl}-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one used in Example 86-2, and 3-methyl-4-(4-methylpiperazin-1-yl)aniline was used in place of 4-(4-methylpiperazin-1-yl)aniline used in Example 86-3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:2].[C:18]([CH2:21][N:22]1[CH:30]=[C:28]([CH3:29])[C:26](=[O:27])[NH:25][C:23]1=[O:24])(O)=[O:19].C(Cl)Cl.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:18](=[O:19])[CH2:21][N:22]1[CH:30]=[C:28]([CH3:29])[C:26](=[O:27])[NH:25][C:23]1=[O:24])[CH3:2]
Reactant: CCOC(=O)CNCCNC(=O)OC(C)(C)C
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)CN(CCNC(=O)OC(C)(C)C)C(=O)Cn1cc(C)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N-(N-Boc-2-aminoethyl)glycine ethyl ester (8, 13.5 g; 54.8 mmol), DhbtOH (9.84 g; 30 60.3 mmol) and N-1-carboxymethyl thymine (4, 11.1 g; 60.3 mmol) were dissolved in DMF (210 ml). Methylene chloride (210 ml) then was added. The solution was cooled to 0° C. in an ethanol/ice bath and DCC (13.6 g; 65.8 mmol) was added. The ice bath was removed after 1 hour and stirring was continued for another 2 hours at ambient temperature. The precipitated DCU was removed by filtration and washed twice with methylene chloride 5 (2×75 ml). To the combined filtrate was added more methylene chloride (650 ml). The solution was washed successively with diluted sodium hydrogen carbonate (3×500 ml), diluted potassium hydrogen sulfate (2×500 ml), and saturated sodium chloride (1×500 ml). Some precipitate was removed from the organic phase by filtration, The organic phase was dried over magnesium sulfate and evaporated to dryness, in vacuo. The oily residue was dissolved in methylene chloride (150 ml), filtered and the title compound was precipitated by the addition of petroleum ether (350 ml) at 0° C. The methylene chloride/petroleum ether procedure was repeated once. This afforded 16.0 g (71%) of the title compound which was more than 99% pure by HPLC.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[O:27]1[CH:31]=[CH:30][CH:29]=[CH:28]1>>[F:23][C:21]1[CH:20]=[CH:19][C:18]([O:24][CH3:25])=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[O:27][CH:31]=[CH:30][CH:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)[CH:22]=1
Reactant: c1ccoc1
Reactant: COc1ccc(F)cc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: COc1ccc(F)cc1-c1cccc(-n2cnc(C(=O)c3ccco3)c2)c1

Procedure:
This compound was prepared by method C using compound 12b and furan.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH2:12][CH3:13])[CH:5]([CH3:11])[CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9].[OH:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][CH2:21][O:22]2)=[CH:17][CH:16]=1>>[CH2:12]([C:4]([CH:5]([CH3:11])[CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])=[CH:3][CH2:2][O:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][CH2:21][O:22]2)=[CH:17][CH:16]=1)[CH3:13]
Reactant: Oc1ccc2c(c1)OCCC2
Reactant: CCC(=CCBr)C(C)CC=C(C)C
Product: CCC(=CCOc1ccc2c(c1)OCCC2)C(C)CC=C(C)C

Procedure:
Following the procedure of Example 1, 1-bromo-3-ethyl-4,7-dimethyl-2,6-octadiene and 7-hydroxy-chromane are reacted to form 7-(3-ethyl-4,7-dimethyl-2,6-octadienyloxy)-chromane, nD20 = 1.5286.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([CH:23]2[O:27][C:26](=O)[CH:25]([CH2:29][CH2:30][C:31]([O:34]C(=O)C(F)(F)F)([CH3:33])[CH3:32])[CH2:24]2)[NH:10][C:11]([C:13]2[CH:22]=[N:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][CH:9]([NH:10][C:11]([C:13]1[CH:22]=[N:21][C:20]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:14]=1)=[O:12])[CH:23]([OH:27])[CH2:24][CH:25]([C:26]1[NH:10][CH:11]=[CH:13][N:14]=1)[CH2:29][CH2:30][C:31]([OH:34])([CH3:33])[CH3:32]
Reactant: CC(C)(CCC1CC(C(Cc2cccc(F)c2)NC(=O)c2cnc3ccccc3n2)OC1=O)OC(=O)C(F)(F)F
Solvent: CO
Product: CC(C)(O)CCC(CC(O)C(Cc1cccc(F)c1)NC(=O)c1cnc2ccccc2n1)c1ncc[nH]1
Reaction time: 336 h
Yield: 206.2 %

Procedure:
To a solution of trifluoro-acetic acid 3-(5-{2-(3-fluoro-phenyl)-1-[(quinoxaline-2-carbonyl)-amino]-ethyl}-2-oxo-tetrahydro-furan-3-yl)-1,1-dimethyl-propyl ester (212 mg, 0.378 mmol) in methanol (4 mL) was added aminoacetalaldehyde dimethyl acetal (0.375 mL, 3.44 mM) and stirred for 14 days. The reaction was concentrated to provide the crude product which was purified by silica get chromatography to yield the title compound (197 mg, 91%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[CH3:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:27]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:22])[CH:28]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: Cc1cccc(B(O)O)c1
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Product: COc1ccc(-c2nc3cc(-c4cccc(C)c4)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 3-methylphenylboronic acid (117 mg, 0.86 mmol) the subtitle compound was obtained, (69 mg, 33%). 1H NMR (DMSO) δ 8.64(d, 1H), 847(dd, 1H), 8.14(d, 1H), 7.86(d, 1H), 7.72(dd, 1H), 7.64(d, 1H), 7.55(m, 2H), 7.39(t, 1H), 7.22(d, 1H), 4.07(s, 1H), 2.40(s, 3H).