Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[C:15]3[CH:16]=[CH:17][CH2:18][O:19][C:14]=3[C:13]([O:20][CH3:21])=[C:12]([O:22][CH3:23])[CH:11]=2)=[CH:4][N:3]=1.CC(C)([O-:27])C.[K+]>CS(C)=O.O>[C:18]([OH:19])(=[O:27])[CH3:17].[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[C:15]3[CH2:16][CH:17]=[CH:18][O:19][C:14]=3[C:13]([O:20][CH3:21])=[C:12]([O:22][CH3:23])[CH:11]=2)=[CH:4][N:3]=1
Reactant: COc1cc(Cc2cnc(N)nc2N)c2c(c1OC)OCC=C2
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)O
Product: COc1cc(Cc2cnc(N)nc2N)c2c(c1OC)OC=CC2
Yield: 31.2 %

Procedure:
2,4-Diamino-5-(7,8-dimethoxy-2H-1-benzopyran-5-ylmethyl)pyrimidine (3.35 g, 10.6 mmol) and potassium t-butoxide (2.5 g) were warmed in dimethyl sulfoxide (25 mL) at 80° for 1.5 hr. The mixture was diluted with water and filtered. Two fractional crystallizations from 10% acetic acid gave 92% pure 2,4-diamino-5-(7,8-dimethoxy-4H-1-benzopyran-5-ylmethyl)pyrimidine acetate (0.62 g, 18%). The NMR was consistent with the structure with an 8% impurity of 2,4-diamino-5-(7,8-dimethoxy-2H-1-benzopyran-5-ylmethyl)pyrimdine acetate. Anal. calcd for C16H18N4O3.C2H4O2 : C, 57.75; H, 5.92; N, 14.96. Found: C, 57.68; H, 5.93; N, 14.96.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([CH:17]([CH2:26][C:27]([O-:29])=O)[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:6][O:7][C:8]=2[CH:9]2[CH2:12][CH:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10]2)[CH2:3][CH2:2]1.[Cl:30][C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=1[NH2:38].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O.CN(C=O)C>[Cl:30][C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=1[NH:38][C:27]([CH2:26][CH:17]([C:5]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[C:8]([CH:9]2[CH2:10][CH:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:12]2)[O:7][N:6]=1)[CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[O:29]
Reactant: CC(C)CC1CC(c2onc(C(CC(=O)[O-])CC(=O)OC(C)(C)C)c2C2CC2)C1
Reactant: Cc1ccc(N)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)CC(CC(=O)OC(C)(C)C)c2noc(C3CC(CC(C)C)C3)c2C2CC2)c(Cl)c1
Yield: 52.3 %

Procedure:
Mono-tert-butyl 3-[4-cyclopropyl-5-(3-isobutylcyclobutyl)isoxazol-3-yl]glutarate (245 mg) and DMF (2 mL) were mixed. After an addition of 2-chloro-4-methylphenylamine (67 mg), HOBt.H2O (87 mg) and WSC.HCl (108 mg) to the mixture, the reaction mixture was stirred at RT. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water and brine, then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo. The resultant residue was purified by preparative chromatography (Eluent: ethyl acetate/hexane=1/4) to give the title compound (131 mg).
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:28]([CH:29]([O:31][Si](C(C)(C)C)(C)C)[CH3:30])=[CH:27][C:16]([C:17]([NH:19][S:20]([N:23]4[CH2:26][CH2:25][CH2:24]4)(=[O:22])=[O:21])=[O:18])=[C:15]([F:39])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl>O1CCCC1.ClCCl>[C:1]12([CH2:11][O:12][C:13]3[C:28]([CH:29]([OH:31])[CH3:30])=[CH:27][C:16]([C:17]([NH:19][S:20]([N:23]4[CH2:26][CH2:25][CH2:24]4)(=[O:22])=[O:21])=[O:18])=[C:15]([F:39])[CH:14]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1cc(C(=O)NS(=O)(=O)N2CCC2)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(O)c1cc(C(=O)NS(=O)(=O)N2CCC2)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
To a mixture of 4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-5-(1-((tert-butyldimethylsilyl)oxy)ethyl)-2-fluorobenzamide in tetrahydrofuran (5 mL) was added 1 N hydrochloric acid (10 mL) and the reaction mixture was stirred for 16 hours at ambient temperature. After diluting the mixture with dichloromethane (50 mL), the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by reverse-phase preparative HPLC to afford the title compound as a colorless solid (0.073 g, 22%): 1H NMR (300 MHz, DMSO-d6) δ 11.66 (br s, 1H), 7.80-7.70 (m, 1H), 6.97-6.85 (m, 1H), 5.29-5.16 (m, 1H), 5.01-4.90 (m, 1H), 4.15-3.90 (m, 4H), 3.71-3.51 (m, 2H), 3.38-3.29 (m, 2H), 2.23-1.90 (m, 3H), 1.80-1.53 (m, 12H), 1.35-1.23 (m, 3H); MS (ES−) m/z 465.2 (M−1).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:8][C:7]2[C:9]3[C:14]([C:15](=[O:18])[C:16](=[O:17])[C:6]=2[S:5][CH2:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:28])[O:1][CH2:2][CH:3]2[O:8][C:7]3[C:9]4[C:14]([C:15](=[O:18])[C:16](=[O:17])[C:6]=3[S:5][CH2:4]2)=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:22][CH:21]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC(CO)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)cc1)OCC1CSC2=C(O1)c1ccccc1C(=O)C2=O
Temperature: 40 °C
Reaction time: 3 h
Yield: 25.5 %

Procedure:
To a solution of 2-(hydroxymethyl)-2,3-dihydronaphtho[1,2-b][1,4]oxathiine-5,6-dione (0.13 g, 0.50 mmol) in N,N-dimethylformamide (1.5 mL) was added 1-fluoro-4-isocyanatobenzene (0.024 mL, 0.55 mmol) and potassium carbonate (0.026 g, 0.50 mmol). The mixture was stirred at 40° C. for 3 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The crude mixture was purified by flash column chromatography (SiO2, 10% methanol in EtOAc) to give the product as a purple solid (0.051 g, 26%). M.p.=235-237° C.; 300 MHz 1H NMR (DMSO-d6) δ: 9.89 (s, 1H), 7.89 (d, J=7.5, 1H), 7.71 (br. s, 2H), 7.50 (m, 3H), 7.12 (m, 2H), 4.78 (m, 1H), 4.53 (m, 2H), 3.18 (m, 2H); LCMS: 400 [M+H].
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:7]=[N:8][C:9]=1[NH:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.CCN(CC)CC.[CH3:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[Cl:3][C:4]1[CH:5]=[C:6](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:7]=[N:8][C:9]=1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:31][C:32]2[CH:39]=[CH:38][C:35]([CH3:36])=[CH:34][CH:33]=2)[CH2:13][CH2:12]1
Reactant: CCOC(=O)/C=C/c1cnc(NC2CCNCC2)c(Cl)c1
Reactant: Cc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1cnc(NC2CCN(Cc3ccc(C)cc3)CC2)c(Cl)c1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl (2E)-3-[5-chloro-6-(4-piperidylamino)-3-pyridyl]acrylate dihydrochloride (710 mg) in CH2Cl2 (14 ml) was added Et3N (0.517 ml), the mixture was stirred at 23° C. for 30 minutes. To the mixture was added 4-Methyl-benzaldehyde (0.241 ml) and SODIUM triacetoxyborohydride (590 mg), the mixture was stirred at 23° C. for 24 hours. The reaction mixture was poured into sat.NaHCO3aq. (20 ml)-AcOEt (20 ml). The organic layer was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography eluted with 5% MeOH in dichloromethane to give ethyl (2E)-3-(5-chloro-6-{[1-(4-methylbenzyl)-4-piperidyl]amino}-3-pyridyl)acrylate (671 mg).
Reaction SMILES: CN(C)[CH:3]=[O:4].[Na].[C:7]([O:10][CH2:11][C:12]1[CH2:19][S:18][CH:17]2[N:14]([C:15](=[O:41])[CH:16]2[NH:20][C:21](=[O:40])[C:22]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([NH2:32])[C:23]2[CH:24]=[CH:25][C:26]3[O:30][CH2:29][CH2:28][C:27]=3[CH:31]=2)[C:13]=1[C:42]([OH:44])=[O:43])(=[O:9])[CH3:8].ClC[CH2:47][C:48]([CH3:53])([CH3:52])[C:49]([O-])=[O:50]>C(OCC)(=O)C>[C:49]([O:4][CH2:3][O:43][C:42]([C:13]1[N:14]2[CH:17]([S:18][CH2:19][C:12]=1[CH2:11][O:10][C:7](=[O:9])[CH3:8])[CH:16]([NH:20][C:21](=[O:40])[C:22]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])([NH2:32])[C:23]1[CH:24]=[CH:25][C:26]3[O:30][CH2:29][CH2:28][C:27]=3[CH:31]=1)[C:15]2=[O:41])=[O:44])(=[O:50])[C:48]([CH3:53])([CH3:52])[CH3:47]
Reactant: CC(C)(CCCl)C(=O)[O-]
Reactant: CN(C)C=O
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(N)(C(=O)OC(C)(C)C)c3ccc4c(c3)CCO4)C2SC1
Agent: [Na]
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)C(N)(C(=O)OC(C)(C)C)c3ccc4c(c3)CCO4)C2SC1
Reaction time: 3 h

Procedure:
To dimethylformamide is added the sodium salt of 3-[(acetyloxy)methyl]-7-[[(tert-butoxycarbonyl)amino(2,3-dihydro-5-benzofuranyl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid one equivalent, and the solution is stirred at room temperature for about 30 minutes after which an equivalent of chloromethylpivalate is added. Stirring is continued for about 3 hours. The solution is diluted with ethyl acetate and washed with water. The organic layer is separated and evaporated to dryness. The residue is recrystallized from ethyl acetate to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](C(OC)=O)=[N:6][CH:7]=1.[CH3:12][Mg]Br.CC[O:17][CH2:18][CH3:19]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:18]([OH:17])([CH3:19])[CH3:12])=[N:6][CH:7]=1
Reactant: COC(=O)c1ncc(Br)cn1
Reactant: CCOCC
Reactant: C[Mg]Br
Product: CC(C)(O)c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cold solution of methyl 5-bromopyrimidine-2-carboxylate (10 g, 46.1 mmol) in Et2O (200 mL) was added drop wise methyl magnesium bromide (3.0 M in Et2O, 61.4 mL, 184 mmol) over 30 min. The reaction mixture was slowly warmed up to RT and continued to stir for 2 h. The mixture was quenched with saturated NH4Cl solution at 0° C. and the organic layer separated from the biphasic solution. The aqueous layer was re-extracted with EtOAc (2×250 mL). The combined organic layers were washed with brine solution, dried over Na2SO4, filtered and evaporated in vacuo. The crude residue was purified over silica eluting with 20% EtOAc:hexane to obtain i (6.0 g, 62%). 1HNMR (DMSO-d6, 400 MHz): δ 8.97 (s, 2H), 5.15 (s, 1H) and 1.47 (s, 6H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([N+]([O-])=O)=[C:6](Cl)[C:7](Cl)=[C:8]([CH:17]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])([O-])=O.[H][H].O.[NH3:26]>[Pd].COCCO>[NH2:1][C:4]1[CH:17]=[C:8]([CH:7]=[CH:6][CH:5]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH2:26])[CH:12]=1)=[O:10]
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])c([N+](=O)[O-])c(Cl)c1Cl
Reactant: [H][H]
Reactant: N
Agent: [Pd]
Solvent: COCCO
Solvent: O
Product: Nc1cccc(C(=O)c2cccc(N)c2)c1
Temperature: 30 °C

Procedure:
Then, in a closed glass vessel with a thermometer and a stirrer, there are charged 34 g (0.1 moles) of said crude dinitro-dichloro benzophenone, 1 g of 5% Pd/C and 100 ml of methyl cellosolve. While stirring the mixture, at 40°-50° C., there is introduced hydrogen so that 13.9 l (0.62 moles) of hydrogen is absorbed in the mixture during twelve hours. Then, the mixture is cooled down to 30° C. and added with 18.2 g (0.3 moles) of 28% ammonia water. There is introduced hydrogen, with the mixture being stirred at 30°-35° C., so that 4.3 l (0.19 moles) of hydrogen is absorbed during five hours. After completion of reaction, the mixture is heated up to 70° C. for hot filtering to remove the catalyst. After being added with 100 ml of hot water, the filtrate is allowed to cool to give yellow crystals of 3,3'-diamino benzophenone. The crystals are filtered, washed with 10 ml of ethanol and dried. Yield 16.8 g (79.2%). M.P. 148°-150° C. Recrystallization from ethanol yields slightly yellow needle-like crystals of the diamino benzophenone. M.P. 150° to 151° C.
Reaction SMILES: CS[C:3]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([Cl:16])[CH:10]=1)([CH3:8])[C:4]([O:6][CH3:7])=[O:5].O.C(OCC)C>C(O)(=O)C.[Zn].S([O-])([O-])(=O)=O.[Cu+2]>[Cl:16][C:11]1[CH:10]=[C:9]([CH:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5])[CH:14]=[CH:13][C:12]=1[NH2:15]
Reactant: COC(=O)C(C)(SC)c1ccc(N)c(Cl)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)C(C)c1ccc(N)c(Cl)c1
Yield: 95.7 %

Procedure:
Methyl α-methylthio-α-(3-chloro-4-aminophenyl)propionate (380 mg) was dissolved in 4 ml of acetic acid, and an intimate mixture of 406 mg of zinc powder and 1.5 mg of anhydrous copper sulfate was added. The entire mixture was heated under reflux for 1 hour. Water (40 ml) and 15 ml of diethyl ether were added to the reaction mixture. The insoluble matter was separated by filtration, and then the organic layer was separated. Furthermore, the aqueous layer was extracted with 5 ml of diethyl ether. The organic layer and the extract were combined, washed with 15 ml of a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to afford 299 mg of methyl α-(3-chloro-4-aminophenyl)propionate in a yield of 95.6% as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=1.[Cl:15][C:16]1[N:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[N:21]=[CH:20][C:19]([S:22]([N:12]2[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[CH:9][C:10]([CH:13]=[O:14])=[CH:11]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: O=Cc1c[nH]c(-c2ccccc2F)c1
Product: O=Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2ccc(Cl)nc2)c1

Procedure:
By a similar reaction as in Reference Example 65 and using 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (893 mg) and 6-chloropyridine-3-sulfonyl chloride (1.30 g), the title compound was obtained as a pale-red solid (yield 1.14 g, 66%). More specifically, 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (893 mg) was dissolved in tetrahydrofuran (10 mL), sodium hydride (60% in oil, 226 mg) was added and the mixture was stirred at room temperature for 15 min. 15-Crown-5 (1.1 mL) was added and the mixture was further stirred at the same temperature for 15 min. 6-Chloropyridine-3-sulfonyl chloride (1.30 g) was added. The reaction mixture was stirred at room temperature for 15 min. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→3:2) to give the title compound as a pale-red solid (yield 1.14 g, 66%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[S:8][C:9]([C:11]([O:13]C)=[O:12])=[CH:10][C:5]2=[N:4][CH:3]=1.[OH-].[Na+].O.C1C[O:21][CH2:20][CH2:19]1>CO>[CH2:20]([O:21][C:2]1[N:7]=[C:6]2[S:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]2=[N:4][CH:3]=1)[CH3:19]
Reactant: COC(=O)c1cc2ncc(Cl)nc2s1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOc1cnc2cc(C(=O)O)sc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of methyl 3-chlorothieno[2,3-b]pyrazine-6-carboxylate 92 (0.044 mmol, 10 mg) in methanol 250 uL and THF 250 uL was added sodium hydroxide 2N in water (0.219 mmol, 109 μA) and stirred overnight at rt. The reaction mixture was quenched in 2N HCl and extracted with CH2Cl2/methanol (9/1). The organic layer was dried and concentrated under reduced pressure to give 3-ethoxythieno[2,3-b]pyrazine-6-carboxylic acid 97 (9.3 mg, 100%).
Reaction SMILES: [C:1](=O)(OC(Cl)(Cl)Cl)[O:2]C(Cl)(Cl)Cl.[CH3:13][O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1.[CH3:24][O:25][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:35]=1[CH:34]([NH:36][C:37]1[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[C:42]([NH2:47])[CH:43]=3)[N:38]=1)[CH2:33][CH2:32][CH2:31]2>>[CH3:13][O:14][CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][CH:20]([NH:23][C:1]([NH:47][C:42]2[CH:43]=[C:44]3[C:39](=[CH:40][CH:41]=2)[N:38]=[C:37]([NH:36][CH:34]2[C:35]4[C:30](=[CH:29][CH:28]=[CH:27][C:26]=4[O:25][CH3:24])[CH2:31][CH2:32][CH2:33]2)[CH:46]=[CH:45]3)=[O:2])[CH2:21][CH2:22]1
Reactant: COCCN1CCC(N)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CCC2
Product: COCCN1CCC(NC(=O)Nc2ccc3nc(NC4CCCc5cccc(OC)c54)ccc3c2)CC1

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 1-(2-methoxy-ethyl)-piperidin-4-ylamine and rac-N2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinoline-2,6-diamine; MS: m/e=504.5 (M+H+).
Reaction SMILES: [Na].[C:2]([O:10]CC)(=[O:9])[CH2:3][C:4]([O:6]CC)=[O:5].[CH2:13]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26](OS(C2C=CC=CC=2)(=O)=O)[CH2:25][CH2:24]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.[OH-].[Li+]>C(O)C.CO.O>[CH2:13]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH:3]([C:4]([OH:6])=[O:5])[C:2]([OH:10])=[O:9])[CH2:25][CH2:24]1)=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(OCc1ccccc1)N1CCC(OS(=O)(=O)c2ccccc2)CC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Li+]
Agent: [Na]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCO
Product: O=C(O)C(C(=O)O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56 %

Procedure:
Sodium metal (3.2 g) was dissolved in ethanol (50 ml) under a nitrogen atmosphere at room temperature. A solution of diethyl malonate (56.4 ml) in ethanol (50 ml) was added dropwise, followed by a solution of 4-benzenesulfonyloxy-piperidine-1-carboxylic acid benzyl ester (31.88 g) in ethanol (50 ml), also added dropwise. The mixture was heated to reflux for 16 h then the solvent was removed under reduced pressure. The residue was partitioned between water (100 ml) and diethyl ether (100 ml) and the aqueous washed with further diethyl ether (60 ml). The combined organics were washed with 10% citric acid solution (50 ml), water (50 ml) and brine (50 ml). After drying (Na2SO4) and filtering the solvent was removed under reduced pressure to leave a yellow liquid. Half of this crude diester was taken and dissolved in methanol (150 ml) and water (50 ml). Lithium hydroxide monohydrate (18.14 g) was added slowly and the reaction left to stir at room temperature for 16 h then the methanol was removed under reduced pressure. The aqueous was washed with diethyl ether (3×40 ml), acidified to pH=3 with citric acid and extracted with ethyl acetate (2×40 ml). The combined organics were washed with water (2×40 ml) and brine (40 ml), dried (Na2SO4), filtered and evaporated under reduced pressure to give the title compound (8.29 g, 56%) as a white crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].FC(F)(F)C(O)=O.[N:17]([O-:19])=[O:18].[Na+]>O>[CH3:8][C:7]1[C:2]([CH3:1])=[CH:3][C:4]([OH:9])=[C:5]([N+:17]([O-:19])=[O:18])[CH:6]=1
Reactant: Cc1ccc(O)cc1C
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(O)c([N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 14 h
Yield: 80 %

Procedure:
To 3,4-dimethylphenol(12.1 g, 0.1 mol), trifluoroacetic acid(250 ml) was added, and in water bath sodium nitrite(12.4 g, 0.18 mol) was added slowly. The resulting mixture was stirred at room temperature for 14 hours and concentrated under the reduced pressure to remove trifluoroacetic acid, followed by addition of water(150 ml), extracted with ether and purified by column chromatography to obtain the titled compound.
Reaction SMILES: [CH:1]([C:3]1[CH:26]=[CH:25][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[S:19][C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:27][CH3:28])[CH:4]=1)=[O:2].C(O)C.[BH4-].[Na+].O>O1CCCC1>[OH:2][CH2:1][C:3]1[CH:26]=[CH:25][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[S:19][C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:27][CH3:28])[CH:4]=1
Reactant: CCOC(=O)c1ccc(-c2nc(COc3ccc(C=O)cc3OC)c(C)o2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2nc(COc3ccc(CO)cc3OC)c(C)o2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a solution of ethyl 5-{4-[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}thiophene-2-carboxylate (5.60 g) in tetrahydrofuran (100 mL)-ethanol (10 mL) was gradually added sodium borohydride (0.26 g) at 0° C. After stirring at room temperature for 1 hr, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl 5-{4-[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}thiophene-2-carboxylate as colorless crystals (5.22 g, yield 92%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 108-109° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:15][CH3:16])[CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[C:17]([CH2:19][N:20]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=1)[CH2:21][C:22]([OH:24])=O)#[N:18].[C:33]([NH:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)(=[O:35])[CH3:34]>>[C:33]([NH:36][C:37]1[CH:42]=[CH:41][C:40]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([N:15]([CH3:16])[C:22](=[O:24])[CH2:21][N:20]([CH2:19][C:17]#[N:18])[C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=3)[CH2:9][N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:4][CH:3]=2)=[CH:39][CH:38]=1)(=[O:35])[CH3:34]
Reactant: N#CCN(CC(=O)O)c1ccc(Cl)c(Cl)c1
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Reactant: CN[C@@H](CN1CCCC1)c1ccc(Br)cc1
Product: CC(=O)Nc1ccc(-c2ccc([C@H](CN3CCCC3)N(C)C(=O)CN(CC#N)c3ccc(Cl)c(Cl)c3)cc2)cc1

Procedure:
Proceeding in a similar manner as in example 85, but replacing 1-(4-bromophenyl)-N-methyl-2-(1-pyrrolidinyl)ethanamine with (1R)-1-(4-bromophenyl)-N-methyl-2-(1-pyrrolidinyl)ethanamine and replacing (6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetic acid with N-(cyanomethyl)-N-(3,4-dichlorophenyl)glycine in step a) and replacing 3,4-dimethoxyphenylboronic acid with [4-(acetylamino) phenyl]boronic acid in step b), the title compound was prepared. MS (ES) m/e 578 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[CH2:10]([C:12](=O)[C:13]([O-:15])=[O:14])[CH3:11].[Br:17][C:18]1[CH:25]=[CH:24][C:21](C=C)=[CH:20][CH:19]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>C(#N)C.C(O)C>[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH:11]2[C:3]3[C:4](=[CH:6][C:7]([Cl:9])=[CH:8][C:2]=3[Cl:1])[NH:5][CH:12]([C:13]([OH:15])=[O:14])[CH2:10]2)=[CH:20][CH:19]=1
Reactant: CCC(=O)C(=O)[O-]
Reactant: C=Cc1ccc(Br)cc1
Reactant: Nc1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCO
Product: O=C(O)C1CC(c2ccc(Br)cc2)c2c(Cl)cc(Cl)cc2N1

Procedure:
Compound 40 was prepared by the basic process from 5.0 mmol 3,5-dichloroaniline, 5.5 mmol ethylglyoxalate solution (50% toluene), 15.0 mmol 4-bromostyrene and 5.0 mmol trifluoroacetic acid in 30.0 ml acetonitrile. Subsequent saponification was carried out using 1.0 ml of sodium hydroxide solution (6N water) in 20.0 ml of ethanol.