Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:7]=1[NH2:21])=O)C.[NH4+:22].[OH-]>CO.C1COCC1>[NH2:21][C:7]1[C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[N:9][O:10][C:6]=1[C:4]([NH2:22])=[O:3]
Reactant: [NH4+]
Reactant: CCOC(=O)c1onc(-c2ccc(S(C)(=O)=O)cc2)c1N
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)c1ccc(-c2noc(C(N)=O)c2N)cc1
Reaction time: 24 h

Procedure:
To a solution of 4-amino-3-(4-methanesulfonyl-phenyl)-isoxazole-5-carboxylic acid ethyl ester (4.0 g, 12.9 mmol) in methanol (50 mL) and THF (50 mL), was added a NH4OH solution (100 mL) at room temperature. The reaction was stirred for 24 h. The precipitates were filtered and washed with H2O (100 mL). The compound was dried in vacuo to afford the crude product which was used for the next step without further purification. LCMS 282.1 [M+H].
Reaction SMILES: [OH-].[Na+].[CH:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[CH:5]=1.[N+:13]([CH3:16])([O-:15])=[O:14].C(O)(=O)C>CO>[CH3:11][O:10][C:6]1[CH:5]=[C:4]([CH:3]([OH:12])[CH2:16][N+:13]([O-:15])=[O:14])[CH:9]=[CH:8][CH:7]=1
Reactant: COc1cccc(C=O)c1
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cccc(C(O)C[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.5 %

Procedure:
An aqueous sodium hydroxide solution (1.5 g of sodium hydroxide (37 mmol) was dissolved in 15 ml of water) was added dropwise to a solution of m-anisaldehyde (5.0 g, 37 mmol) and nitromethane (4.0 ml, 73 mmol) in methanol (50 ml) keeping the temperature of the solution at not higher than 30° C. The reaction mixture was then stirred at room temperature for 4 hours. Upon cooling on ice, an aqueous acetic acid solution (glacial acetic acid (37 mmol) was dissolved in 250 ml of water) was added, the resulting reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and a 5% aqueous sodium hydrogencarbonate solution, dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (6.09 g).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[CH2:13][CH:12]([CH2:16][N:17]3[CH:21]=[C:20]([C:22]4[NH:30][C:29]5[C:28](=[O:31])[N:27]([CH2:32][CH2:33][CH3:34])[C:26](=[O:35])[N:25]([CH2:36][CH2:37][CH3:38])[C:24]=5[N:23]=4)[CH:19]=[N:18]3)[CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:39](=O)([O-])[O-].[K+].[K+].CI.CN(C=O)C>O>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[CH2:13][CH:12]([CH2:16][N:17]3[CH:21]=[C:20]([C:22]4[N:30]([CH3:39])[C:29]5[C:28](=[O:31])[N:27]([CH2:32][CH2:33][CH3:34])[C:26](=[O:35])[N:25]([CH2:36][CH2:37][CH3:38])[C:24]=5[N:23]=4)[CH:19]=[N:18]3)[CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCCn1c(=O)c2[nH]c(-c3cnn(CC4CC(=O)N(c5ccc(C(C)C)cc5)C4)c3)nc2n(CCC)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CCCn1c(=O)c2c(nc(-c3cnn(CC4CC(=O)N(c5ccc(C(C)C)cc5)C4)c3)n2C)n(CCC)c1=O
Temperature: 50 °C
Yield: 85.8 %

Procedure:
A mixture of 8-{1-[1-(4-Isopropyl-phenyl)-5-oxo-pyrrolidin-3-ylmethyl]-1H-pyrazol-4-yl}-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (0.030 g, 0.057 mmol), potassium carbonate (0.016 g, 0.115 mmol), methyl iodide (0.0039 ml, 0.0639 mmol) and DMF (1 ml) was heated at 50° C. for 20 hour. The mixture was cooled to room temperature and diluted with water (10 ml). The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine solution, and dried over Na2SO4. The solvent was evaporated and the residue obtained was triturated with hexane to obtain the title compound (0.026 g, 84%).
Reaction SMILES: CC(OC[C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10](N)[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O>CN(C)C=O>[O:12]=[C:11]1[N:8]2[CH:9]([S:14][CH2:15][CH:6]=[C:7]2[C:16]([OH:18])=[O:17])[CH2:10]1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Solvent: CN(C)C=O
Product: O=C(O)C1=CCSC2CC(=O)N12
Temperature: 20 °C
Reaction time: 2 h

Procedure:
In a second flask, 64 mg of (7R)-7-aminocephalosporanic acid and 124 mg of N,O-bis-(trimethylsilyl)acetamide in 1 ml of N,N-dimethylformamide were stirred at 20° C. for 20 minutes. A clear solution was obtained which was added at 0° C. to the solution in the first flask. The reaction mixture was stirred at 0° C. for 1 hour and at 20° C. for 2 hours. The precipitate was filtered off under suction and the filtrate was partitioned between 2% aqueous sodium hydrogen carbon solution and ethyl acetate. The aqueous phase was adjusted to pH 7 with 3N hydrochloric acid, concentrated in a vacuum to a volume of about 5 ml and the concentrated solution was chromatographed on MCI gel CHP2OP (Mitsubishi Chemical Industries Ltd.). Elution was carried out first with 1% aqueous acetic acid and then with mixtures of 1% aqueous acetic acid/methanol, using increasing amounts of methanol. By lyophilization of the product fractions, which were concentrated in a vacuum, there was obtained (6R,7R)-3-(acetoxymethyl)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl)]methoxy]imino]acetamido]-8-oxo-5-thia-1azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[CH2:14][CH:13]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:14][CH:13]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(C2=CCC(N3CCN(C(=O)OC(C)(C)C)CC3)CC2)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C2=CCC(N3CCNCC3)CC2)ccc1[N+](=O)[O-]
Yield: 77.8 %

Procedure:
A solution of 1,1-dimethylethyl 4-{4-[3-(methyloxy)-4-nitrophenyl]-3-cyclohexen-1-yl}-1-piperazinecarboxylate (0.75 g, 1.80 mmol, combined batches) was stirred at rt under N2 in 20% TFA in DCM (40 mL) for approximately 2 h. The solution was then concentrated under vacuum. The residue was dissolved in DCM and aqueous (saturated) NaHCO3. The aqueous layer was separated and extracted with DCM (3×). The combined organic layers were dried over MgSO4, filtered, then concentrated and purified by silica gel chromatography to give the title compound of step F (446 mg, 1.40 mmol, 78%) as a light tan solid. MS (ESI): 318 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].[CH:15]1[C:27]2[CH:26]([CH2:28][O:29][C:30](ON3C(=O)CCC3=O)=[O:31])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1.Cl>O.O1CCCC1>[CH:15]1[C:27]2[CH:26]([CH2:28][O:29][C:30]([N:1]3[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]3)=[O:31])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)C1CCNCC1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Reaction time: 0.17 h
Yield: 84.7 %

Procedure:
Piperidine-4-carboxylic acid (15.00 g, 116 mmol) was added to a solution of sodium hydrogen carbonate (12.7 g, 151 mmol) in water (200 mL) and the mixture was stirred for 10 min. A solution of 1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy-2,5-pyrrolidinedione (Fmoc-Osu; 46.9 g, 139 mmol) in tetrahydrofuran (400 mL) was added. The solution was stirred at room temperature for 20 h and then acidified to pH 1 with 3 M HCl (500 mL). The mixture was extracted with ethyl acetate (200 mL then 100 mL) and the combined organic layers were washed with saturated brine (3×100 mL), dried (Na2SO4), filtered and concentrated to approximately 100 mL. Crystallization occurred on concentration. The mixture was allowed to stand for 2 h, then the solid was filtered off, washed with ethyl acetate and dried in a vacuum oven at 60° C. to give N-[(9H-fluoren-9-ylmethoxy)carbonyl]piperidine-4-carboxylic acid (34.51 g, 85%) as a white solid, mp 187-189° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][NH2:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:14])[CH:8]=2)[N:3]=1.[C:15](OCC)(OCC)(OCC)[CH2:16][CH3:17]>>[Cl:1][C:2]1[C:11]2[N:10]([C:15]([CH2:16][CH3:17])=[N:13][N:12]=2)[C:9]2[C:4]([N:3]=1)=[CH:5][CH:6]=[C:7]([Cl:14])[CH:8]=2
Reactant: NNc1nc2cc(Cl)ccc2nc1Cl
Reactant: CCOC(CC)(OCC)OCC
Product: CCc1nnc2c(Cl)nc3ccc(Cl)cc3n12
Temperature: 25 °C
Yield: 62 %

Procedure:
2,6-Dichloro-3-hydrazinoquinoxaline (1.0 g., 0.0044 mole), the product of Preparation L(a), was refluxed with 15 ml. of triethyl orthopropionate for 4 hours and cooled to room temperature. The precipitate was recovered by filtration, washed with cyclohexane and air dried to afford 730 mg. (62% yield) of 4,8-dichloro-1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. >250° C. Mass spectrum: m/e, 266 (P); m/e, 268 (P.+2).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH:16]([CH3:19])[NH:15][C:14]3=[O:20])[CH:10]=[N:9]2)=[C:5]([CH3:21])[O:4][N:3]=1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:15]1[CH:16]([CH3:19])[C:17](=[O:18])[N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:21])[CH:12]=2)[C:14]1=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)C2=O)cn1
Reactant: BrCc1ccccc1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)C(C)N(Cc3ccccc3)C2=O)cn1
Yield: 50 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5-methylimidazolidine-2,4-dione (example 10-41) and benzyl bromide. Yield: 50%. 1H NMR (CDCl3, 400 MHz): δ 1.44 (s, 3H), 2.19 (s, 3H), 3.88 (s, 3H), 4.18 (d, J=8 Hz, 2H), 4.22 (t, 1H, J=4 Hz)), 5.06 (s, 2H), 7.39-7.29 (m, 5H), 7.94 (s, 1H), 8.10 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.02 μM.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][C:2]=1[CH2:15][OH:16].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][C:2]=1[CH:15]=[O:16]
Reactant: OCc1ccc2cc3ccccc3cc2c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1ccc2cc3ccccc3cc2c1
Yield: 50.5 %

Procedure:
2-Antracenylmethanol (46A, 1.0 g, 0.0048 mol) in CH2Cl2 (700 mL) was treated with pyridinium chlorochromate (PCC) (Aldrich, 21.56 g, 0.1 mol) and heated for 4 h. The reaction was cooled and filtered through a plug of SiO2 (500 g) using CH2Cl2 as the eluting solvent. After removal of the solvent the crude material was chromatographed on SiO2 with PhCH3 as the eluting solvent to afford 0.5 g (51%) of 2-anthracenecarbaldehyde mp 201°-202.5° (lit mp 202°-203°, P. H. Gore, J. Chem. Soc. 1616 (1959)), (C, H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]3[CH2:17][CH:16]([C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=4[CH:20]=[O:21])[O:15][N:14]=3)[N:12]=2)[CH2:4][CH2:3]1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([N:34]=[C:35]=[O:36])[CH:28]=1.O>ClCCl.C(N(C(C)C)CC)(C)C.N12CCCN=C1CCCCC2>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([NH:34][C:35]([N:2]2[CH2:3][CH2:4][CH:5]([C:8]3[S:9][CH:10]=[C:11]([C:13]4[CH2:17][CH:16]([C:18]5[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=5[CH:20]=[O:21])[O:15][N:14]=4)[N:12]=3)[CH2:6][CH2:7]2)=[O:36])[CH:28]=1
Reactant: O=Cc1ccccc1C1CC(c2csc(C3CCNCC3)n2)=NO1
Reactant: Cc1ccc(Cl)cc1N=C=O
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(Cl)cc1NC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4C=O)C3)cs2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-{3-[2-(piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzaldehyde hydrochloride (1.43 g) in dichloromethane (30 ml) and diisopropylethylamine (0.73 ml) were added, at room temperature, 4-chloro-2-isocyanato-1-methylbenzene (700 mg) and one drop of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The mixture was stirred at room temperature overnight, and water was then added. The aqueous phase was removed and extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography. This gave N-(5-chloro-2-methylphenyl)-4-{4-[5-(2-formylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxamide (1.23 g).
Reaction SMILES: [F:1][C:2]([F:19])([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([F:18])=[CH:10][CH:9]=1)[C:3]([O:5]CC)=[O:4].C1COCC1.[OH-].[Na+]>CO.O>[F:19][C:2]([F:1])([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([F:18])=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(F)(F)c1ccc(F)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(F)(F)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To a solution of ethyl 2,2-difluoro-2-(4-fluoronaphthyl)acetate (9.6 g, 35.8 mmol), as prepared in the preceding step, in methanol (20 mL) and THF (20 mL) was added a solution of NaOH (2.0 g, 50 mmol) in water (40 mL). The reaction mixture was stirred at room temperature for 2 hours. After evaporating the methanol and THF in vacuo, the aqueous phase was acidified to pH 2 using 10% HCl, and extracted with DCM (3×50 mL). The extracts were combined, washed with brine, dried over Na2SO4, and concentrated to give the title compound (8.1 g, 94% yield) as an off white solid. 1H-NMR (400 MHz, CDCl3) δ 9.68 (br s, 1H), 8.18 (m, 2H), 7.83 (dd, J=8.1, 5.3 Hz, 1H), 7.62 (m, 2H), 7.19 (t, J=8.3 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]2[C:11](=O)[N:10]([C:14]3[C:19]([F:20])=[CH:18][C:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][C:15]=3[F:27])[CH:9]([OH:28])[C:8]=2[C:7]([O:29][CH2:30][CH3:31])=[C:6]2[CH:32]=[CH:33][CH:34]=[CH:35][C:5]=12)[CH3:2].C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]1[C:12]2[CH2:11][N:10]([C:14]3[C:19]([F:20])=[CH:18][C:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][C:15]=3[F:27])[C:9](=[O:28])[C:8]=2[C:7]([O:29][CH2:30][CH3:31])=[C:6]2[CH:32]=[CH:33][CH:34]=[CH:35][C:5]=12)[CH3:2]
Reactant: CCOC(=O)Cc1cc(F)c(N2C(=O)c3c(c(OCC)c4ccccc4c3OCC)C2O)c(F)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cc1cc(F)c(N2Cc3c(c(OCC)c4ccccc4c3OCC)C2=O)c(F)c1
Yield: 20.2 %

Procedure:
To a stirred solution of ethyl {4-[4,9-bis(ethyloxy)-1-hydroxy-3-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]-3,5-difluorophenyl}acetate (0.240 g, 0.495 mmol) in TFA (3 ml) at 0° C. was added triethylsilane (0.118 ml, 0.742 mmol) drop wise. The bright red solution turned light yellow on addition. The mixture was evaporated then purified by MDAP. The fractions were evaporated to give a yellow solid (0.049 g, 0.10 mmol) LC/MS: Rt=3.62, [MH]+ 470.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[CH2:9][NH:10][CH3:11])=[CH:4][CH:3]=1.[O:13]=[C:14]1[C:19]2[S:20][CH:21]=[C:22]([S:23](Cl)(=[O:25])=[O:24])[C:18]=2[CH2:17][CH2:16][CH2:15]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:12])[CH2:9][N:10]([CH3:11])[S:23]([C:22]2[C:18]3[CH2:17][CH2:16][CH2:15][C:14](=[O:13])[C:19]=3[S:20][CH:21]=2)(=[O:24])=[O:25])=[CH:6][CH:7]=1
Reactant: CNCC(O)c1ccc(F)cc1
Reactant: O=C1CCCc2c(S(=O)(=O)Cl)csc21
Product: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1csc2c1CCCC2=O

Procedure:
From 1-(4-fluorophenyl)-2-methylamino-ethanol (the compound of Preparation Example 17) (433 mg) and 7-oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-3-sulfonyl chloride (the compound of Preparation Example 7), the title compound (769 mg) was obtained as a colorless amorphous substance, in the same way as Preparation Example 41.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])=[O:5].[Cl-].[Al+3].[Cl-].[Cl-]>>[OH:13][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[NH:6][C:4](=[O:5])[CH2:3][CH2:2]2
Reactant: O=C(CCCl)Nc1ccccc1O
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1CCc2cccc(O)c2N1
Temperature: 25 °C
Reaction time: 5 h
Yield: 46.6 %

Procedure:
A mixture of 3-chloro-N-(2-hydroxyphenyl)propanamide (0.25 g, 1.25 mmol) and aluminium chloride (AlCl3) (0.5 g) was heated with stirring at 130–135° C. for 5 h. After cooling to room temperature, the reaction mixture was quenched with water (3 ml), and extracted with ethyl acetate (3×5 ml). Evaporation of the solvent and flash chromatography of the residue on silica gel with ethyl acetate/heptane (1:1) afforded colourless crystals of the subtitled compound (95 mg, 46.5%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[NH:11][C:10](=[O:12])[O:9][C:8](=O)[C:7]=2[CH:14]=1)[CH3:2].[NH2:15]C(N)=O.O>CN(C)C=O>[CH2:1]([C:3]1[CH:14]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:11][C:10](=[O:12])[NH:15][C:8]2=[O:9])[CH3:2]
Reactant: CCc1ccc2[nH]c(=O)oc(=O)c2c1
Reactant: NC(N)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc2[nH]c(=O)[nH]c(=O)c2c1
Temperature: 25 °C
Yield: 60.4 %

Procedure:
A mixture of 6-ethyl-2H-3,1-benzoxazine-2,4(1H)-dione (19.55 g) and urea (6.18 g) in dry N,N-dimethylformamide (98 ml) was heated under reflux for 3 hours and 40 minutes. After the reaction mixture was cooled to ambient temperature, to the mixture was added water with stirring to give crystals, which were separated by filtration, washed with water and dried under reduced pressure to give crystalline 6-ethyl-1H,3H-quinazoline-2,4-dione (11.74 g).
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=[C:2]1[C:9]1[S:10][CH:11]=[CH:12][CH:13]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:36][N:37]1[C:41]([C:42]2[CH:43]=[C:44]([CH:46]=[CH:47][CH:48]=2)[NH2:45])=[CH:40][N:39]=[C:38]1[CH3:49]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:49][C:38]1[N:37]([CH3:36])[C:41]([C:42]2[CH:43]=[C:44]([NH:45][C:6]([C:5]3[S:1][C:2]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[CH:3][CH:4]=3)=[O:8])[CH:46]=[CH:47][CH:48]=2)=[CH:40][N:39]=1
Reactant: Cc1ncc(-c2cccc(N)c2)n1C
Reactant: O=C(O)c1ccc(-c2cccs2)s1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ncc(-c2cccc(NC(=O)c3ccc(-c4cccs4)s3)c2)n1C
Reaction time: 0.25 h
Yield: 61.7 %

Procedure:
To a suspension of [2,2′]bithiophenyl-5-carboxylic acid (105 mg) and 1-hydroxybenzotriazole (81 mg) in dichloromethane (2 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (144 mg) and the mixture was stirred for 15 minutes. After adding 3-(1,2-dimethylimidazol-5-yl)aniline (94 mg) and 4-dimethylaminopyridine (92 mg), the mixture was stirred for 24 hours. The mixture was diluted with dichloromethane and washed with water and brine. The mixture was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by a silica gel column chromatography eluting with 3% methanol in dichloromethane to give N-[3-(2,3-dimethyl-3H-imidazol-4-yl)-phenyl]-[2,2′]bithiophenyl-5-carboxamide (117 mg, 61.6%).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:26]=[CH:27][C:28]=3[O:29][CH3:30])[C:14]([S:16][C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=3)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C1(NC2CCCCC2)CCCCC1.S(Cl)([Cl:46])=O>ClCCl>[C:1]12([C:11]3[CH:12]=[C:13]([CH:26]=[CH:27][C:28]=3[O:29][CH3:30])[C:14]([S:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([Cl:46])=[O:22])=[CH:19][CH:18]=3)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COc1ccc(C(=O)Sc2ccc(C(=O)O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Reactant: O=S(Cl)Cl
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: ClCCl
Product: COc1ccc(C(=O)Sc2ccc(C(=O)Cl)cc2)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 1 h
Yield: 100 %

Procedure:
Into a round bottom flask there are introduced 3.80 g (9 mmoles) of 4-[3-(1-adamantyl)-4-methoxybenzoylthio]benzoic acid, 40 ml of dichloromethane and 1.8 ml (9 mmoles) of dicyclohexylamine. The reaction mixture is stirred for one hour. To the resulting solution 720 μl (9.9 mmoles) of thionylchloride are added and the mixture is stirred at ambient temperature for 2 hours. It is then evaporated to dryness, and taken up in 500 ml of ethyl ether. The dicyclohexylammonium chloride is filtered and the solvent is evaporated. 3.97 g (100% yield) of crude 4-[3-(1-adamantyl)-4-methoxybenzoylthio]benzoic acid chloride which is used as such for the following synthesis are obtained.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][N:4]=[N:3]1.[F:11][C:12]1[CH:40]=[CH:39][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@@H:26]3[CH2:30][C@@H:29]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=4)[CH2:28][NH:27]3)=[O:25])=[CH:19][CH:18]=2)=[CH:14][CH:13]=1>>[N:2]1([CH2:7][C:8]([CH:28]2[NH:27][C@H:26]([C:24]([NH:23][C:20]3[CH:19]=[CH:18][C:17]([O:16][C:15]4[CH:39]=[CH:40][C:12]([F:11])=[CH:13][CH:14]=4)=[CH:22][CH:21]=3)=[O:25])[CH2:30][C@H:29]2[CH2:31][C:32]2[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=2)=[O:10])[CH:6]=[CH:5][N:4]=[N:3]1
Reactant: Cc1ccc(C[C@H]2CN[C@H](C(=O)Nc3ccc(Oc4ccc(F)cc4)cc3)C2)cc1
Reactant: O=C(O)Cn1ccnn1
Agent: Cl
Product: Cc1ccc(C[C@@H]2C[C@@H](C(=O)Nc3ccc(Oc4ccc(F)cc4)cc3)NC2C(=O)Cn2ccnn2)cc1

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,3-triazol-1-yl)acetic acid hydrochloride and (2S,4R)—N-(4-(4-fluorophenoxy)phenyl)-4-(4-methylbenzyl)pyrrolidine-2-carboxamide, gave Compound 3, (2S,4R)-5-(2-(1H-1,2,3-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(4-methylbenzyl)pyrrolidine-2-carboxamide. 1H-NMR (400 MHz, CDCl3): σ 8.96 (br s, 1H), 7.77 (s, 1H), 7.74 (s, 1H), 7.42 (m, 2H), 7.13 (d, 2H), 7.08 (d, 2H), 7.03-6.98 (m, 2H), 6.94-6.87 (m, 4H), 5.27 (d, 1H), 5.13 (d, 1H), 4.76 (d, 1H), 3.66 (m, 1H), 3.26 (t, 1H), 3.02-2.85 (m, 2H), 2.66-2.57 (m, 2H), 2.33 (s, 3H), 1.76-1.68 (m, 1H); MS (EI) for C29H28FN5O3. found 514.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)[N:5]=[C:4](S(C)(=O)=O)[N:3]=1.[CH3:22][O-:23].[Na+].CO>COCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)[N:5]=[C:4]([O:23][CH3:22])[N:3]=1
Reactant: C[O-]
Reactant: COc1ccc(-c2cc(Cl)nc(S(C)(=O)=O)n2)cc1OC
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Product: COc1nc(Cl)cc(-c2ccc(OC)c(OC)c2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
A mixture of 4-chloro-6-(3,4-dimethoxy-phenyl)-2-methanesulfonyl-pyrimidine [5.05 g, 0.0154 mol, Intermediate (49)] in ethylene glycol dimethyl ether (100 mL) is chilled to 0° C. and added 25 wt % sodium methoxide in MeOH (1.32 mL, 0.0231 mol). After 15 minutes the reaction is allowed to warm to ambient temperature and stirred overnight. The mixture is concentrated to afford 4-chloro-6-(3,4-dimethoxy-phenyl)-2-methoxy-pyrimidine [4.3 g, 100%, Intermediate (50)]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5](Cl)=[O:6].[NH2:14]C1SC(C(COC(=O)COC(=O)C)(C)C)=NN=1>C1(C)C=CC=CC=1.CCCCC>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5]([NH2:14])=[O:6]
Reactant: CC(=O)OCC(=O)OCC(C)(C)c1nnc(N)s1
Reactant: COc1cccc(OC)c1C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCCCC
Product: COc1cccc(OC)c1C(N)=O
Temperature: 25 °C
Yield: 3 %

Procedure:
A solution of 300 mg of 2,6-dimethoxybenzoyl chloride in 20 ml of toluene containing 300 mg of 2-amino-5-[(2-acetoxy-1-acetoxymethyl)-1-methylethyl]-1,3,4-thiadiazole was heated at reflux for eighteen hours. The reaction mixture was cooled to room temperature and diluted with pentane. A solid precipitate which formed was collected by filtration and air dried to give N-[5-(2-acetoxy-1-acetoxymethyl)-1-methylethyl)-1,3,4-thiadiazol-2-yl]-2,6-dimethoxybenzamide in 3% yield.