Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH2:9])(=O)C1C=CC=CC=1.[Cl:10][C:11]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12]>>[Cl:10][C:11]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12].[NH2:9][C:11]([O:13][CH2:14][CH3:19])=[O:12]
Reactant: NC(=O)c1ccccc1
Agent: O=C(Cl)Oc1ccccc1
Product: CCOC(N)=O

Procedure:
We have now discovered a method for the preparation of benzoylureas such as those disclosed in U.S. Pat. No. 3,748,356 and Belgian Pat. No. 833,288, which comprises the reaction of a benzamide, a C1 -C7 alkyllithium, a phenyl chloroformate and an amine. In one embodiment of the reaction, the benzamide is treated with the alkyllithium and a phenyl chloroformate in an inert solvent at a temperature of from about -80° to about -40° C. to form an intermediate urethane, the intermediate urethane is treated with an amine in an inert solvent at about -80° to about -40° C., and the temperature is slowly raised to from about 50° to about 100° C. to obtain the desired benzoylurea. In a second embodiment of the reaction, the benzamide is treated with the alkyllithium in an inert solvent at a temperature from about -80° to about -40° C. and the lithium salt so obtained is then treated with a carbamate at a temperature of about -80° to about -40° C., and the mixture is allowed to warm to from about 20° to about 40° C. to obtain the desired benzoylurea. The carbamate is obtained by the reaction of an amine with a phenyl chloroformate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([C:10](=[O:13])[CH2:11][Br:12])[CH:7]=[CH:6][C:5]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.O1CCCC1>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([C@@H:10]([OH:13])[CH2:11][Br:12])[CH:7]=[CH:6][C:5]=1[O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1cc(C(=O)CBr)ccc1OCc1ccccc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Reaction time: 0.25 h
Yield: 96.4 %

Procedure:
(R)-2-Methyl-CBS-oxazoborolidine (1.38 mL of a 1.0 M solution in toluene) was added to a solution of α-bromoketone 45 (5.00 g, 13.80 mmol) in tetrahydrofuran (80 mL). After stirring for 15 min, borane tetrahydrofuran complex (8.5 mL of a 1 M solution in tetrahydrofuran) was added dropwise over a 15 min period. After stirring at ambient temperature for 1.5 h, the reaction was quenched by the slow addition of methanol (8.5 mL). The solvent was removed under vacuum. The residue was taken up in a mixed solvent of hexanes and ethyl acetate (2:1). The solid was vacuum filtered through a pad of silica gel. Concentration of the filtrate and drying under vacuum gave 46 (4.86 g, 97%) as a white solid: 1H NMR (500 MHz, DMSO-d6) δ 3.32-3.58 (m, 1H), 3.64-3.68 (m, 1H), 3.81 (s, 3H), 4.78-4.80 (m, 1H), 5.21 (s, 2H), 5.83 (d, 1H), 7.22 (d, 1H), 7.31-7.33 (m, 1H), 7.38-7.49 (m, 5H), 7.61 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([C:12](=O)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[NH2:21][NH2:22].[OH:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>C(O)C>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:28]([C:27]3[CH:30]=[CH:31][C:24]([OH:23])=[CH:25][CH:26]=3)=[N:11][C:10]3[NH:21][N:22]=[C:12]([CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:9]=3[C:5]=2[CH:4]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COc1cccc(C(C#N)C(=O)Cc2ccccc2)c1
Reactant: NN
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: COc1ccc2c(-c3ccc(O)cc3)nc3[nH]nc(Cc4ccccc4)c3c2c1
Temperature: 70 °C
Yield: 34 %

Procedure:
2-[3-(methyloxy)phenyl]-3-oxo-4-phenylbutanenitrile (100 mg, 0.38 mmol) was dissolved in ethanol (1 mL), and anhydrous hydrazine (98%, 14 μL, 0.45 mmol) was added. The resulting mixture was heated at reflux for 1 hour. It was cooled, concentrated, and the residue was dried under vacuum for one hour. To this residue was added of 4-hydroxybenzaldehyde (69 mg, 0.57 mmol) and trifluoroacetic acid (1 mL), and the mixture was heated at 70° C. for 18 hours. Then the reaction mixture was concentrated, dissolved in 10 mL of N,N-dimethylformamide and purified by preparatory reverse phase HPLC (Shimadzu LC-8A HPLC, Waters Xterra C18 30 mm×100 mm column, acetonitrile-water-trifluoroacetic eluent). After concentration then lyophillization of the pure fractions 4-[8-(methyloxy)-1-(phenylmethyl)-3H-pyrazolo[3,4-c]isoquinolin-5-yl]phenol trifluoroacetic acid salt (63 mg, 0.13 mmol, 34% yield) was obtained. 1H NMR (400 MHz, d6-DMSO): 7.97-7.94 (d, 1H), 7.50-7.48 (d, 2H), 7.30-7.25 (m, 6H), 7.06-7.02 (m, 1H), 6.95-6.93 (d, 2H), 4.60 (s, 2H), 3.76 (s, 3H); MS (EI) for C24H19N3O2: 382 (MH+).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:24]2[CH:29]=[CH:28][C:27]([O:30]C)=[CH:26][CH:25]=2)=[C:10]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.B(Br)(Br)[Br:33]>>[BrH:33].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:24]2[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=2)=[C:10]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[C:11]2[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=C(c2ccc(C#N)cc2)n2ccnc2)c2ccc(OC)cc2)cc1
Reactant: BrB(Br)Br
Product: Br
Product: N#Cc1ccc(C(=C(c2ccc(O)cc2)c2ccc(O)cc2)n2ccnc2)cc1

Procedure:
Treatment of 2,2-bis-(4-methoxyphenyl)-1-(1-imidazolyl)-1-(4-cyanophenyl)-ethylene with boron tribromide using procedure analogous to that described in Example 7 yields 2,2-bis-(4-hydroxyphenyl)-1-(1-imidazolyl)-1-(4-cyanophenyl)-ethylene hydrobromide, m.p. 178° dec.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@@H:10]1[C@H:15]2[CH2:16][C@H:12]([C@H:13]([O:17][CH2:18][C@@H:19]([OH:22])CO)[CH2:14]2)[N:11]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:9])#[N:2].[Na]>CO.O.C(OCC)(=O)C>[C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@@H:10]1[C@H:15]2[CH2:16][C@H:12]([C@H:13]([O:17][CH2:18][CH:19]=[O:22])[CH2:14]2)[N:11]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:9])#[N:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2OC[C@@H](O)CO)[C@H]1C(=O)N1CCC[C@H]1C#N
Agent: [Na]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2OCC=O)[C@H]1C(=O)N1CCC[C@H]1C#N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 103.3 %

Procedure:
To a solution of tert-butyl (1R,3S,4S,6R)-3-{[(2S)-2-cyano-1-pyrrolidinyl]carbonyl}-6-{[(2S)-2,3-dihydroxypropyl]oxy}-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 23–1 (250 mg) in methanol (5 mL) and water (5 mL), was added sodium periodinate (522 mg). The mixture was stirred at room temperature for 20 minutes. The reaction mixture was diluted with ethyl acetate, and washed successively with water and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo to give the target compound (238 mg). This compound was used immediately without purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][NH:5][C:6]=1[C:7]([F:10])([F:9])[F:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([O:40][CH3:41])[CH:34]=2)[CH2:29][CH2:28]1)=[O:26].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([N:30]2[CH2:31][CH2:32][N:27]([C:25](=[O:26])[CH2:24][N:5]3[C:6]([C:7]([F:8])([F:10])[F:9])=[C:2]([Br:1])[C:3]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)=[N:4]3)[CH2:28][CH2:29]2)=[CH:34][C:35]=1[O:40][CH3:41]
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Reactant: FC(F)(F)c1[nH]nc(-c2ccccc2)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4ccccc4)c(Br)c3C(F)(F)F)CC2)ccc1Cl

Procedure:
Protocol T was followed using 4-Bromo-3-phenyl-5-trifluoromethyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1, Rf=0.51) afforded the title compound as a white solid. 1H NMR (400 MHz, CDCl3): 7.42-7.52 (m, 5H), 7.18-7.22 (d, 1H), 6.38-6.42 (dd, 1H), 6.46-6.48 (d, 1H), 4.94 (s, 2H), 3.88 (s, 3H), 3.5-3.78 (m, 4H), 3.18 (s, 4H).
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([CH2:28]O)[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[Si:1]([O:18][CH:19]1[CH2:20][N:21]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][N:34]3[C:30](=[O:40])[C:31]4=[CH:39][CH:38]=[CH:37][CH:36]=[C:32]4[C:33]3=[O:35])[N:27]=2)[CH2:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)[Si](OC1CN(c2nc(CO)cs2)C1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OC1CN(c2nc(CN3C(=O)c4ccccc4C3=O)cs2)C1)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 0.1 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-hydroxymethyl-1,3-thiazol-2-yl)azetidine (1.50 g, 3.53 mmol) (obtained as described in Reference Example 2(2)) in tetrahydrofuran (75 ml) were added phthalimide (519 mg, 5.30 mmol), triphenylphosphine (1.39 g, 5.30 mmol) and 40% diethyl azodicarboxylate in toluene solution (2.03 ml, 5.30 mmol) in an ice bath under an atmosphere of nitrogen. The mixture was stirred in an ice bath for 2 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:5) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-(4-phthalimidomethyl-1,3-thiazol-2-yl)azetidine (1.52 mg, yield 78%) as pale yellow oil.
Reaction SMILES: C1(C)CCC(C(C)C)[CH:3]([N:10]([CH:21]2C(C(C)C)CCC(C)C2)[CH:11]2C(C(C)C)CCC(C)C2)C1.[Cl:32][CH2:33][C@H:34]([OH:37])[CH2:35][OH:36]>>[Cl-:32].[OH:37][C@H:34]([CH2:35][OH:36])[CH2:33][N+:10]([CH3:21])([CH3:11])[CH3:3]
Reactant: CC1CCC(C(C)C)C(N(C2CC(C)CCC2C(C)C)C2CC(C)CCC2C(C)C)C1
Reactant: OC[C@@H](O)CCl
Product: C[N+](C)(C)C[C@H](O)CO
Product: [Cl-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
There was added 80 ml of 30 w/v % aqueous solution of trimenthylamine to 20.00 g of (R)-3-chloro-1,2-propanediol (optical purity: 100% e.e., chemical purity: 99%). After stirring for 2 hours at room temperature, the reaction mixture was evaporated to dryness to give 30.40 g of (S)-2,3-dihydroxypropyltrimethylammonium chloride.
Reaction SMILES: Br[CH:2]([C:4]1[CH:5]=[CH:6][C:7]([F:10])=[N:8][CH:9]=1)[CH3:3].[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C.C(Cl)(Cl)Cl.O>[F:10][C:7]1[N:8]=[CH:9][C:4]([CH:2]([N:14]2[CH2:13][CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]2)[CH3:3])=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(Br)c1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CC(c1ccc(F)nc1)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
A mixture of 5-(1-bromoethyl)-2-fluoropyridine (17.65 g, 87 mmol) and tert-butyl piperazine-1-carboxylate (16.92 g, 91 mmol) in acetonitrile (300 mL). was treated with potassium carbonate (14.35 g, 104 mmol) and potassium iodide (2.87 g, 17.30 mmol). The mixture was placed into a pre-heated (70° C.) bath and allowed to stir under inert atmosphere overnight. The reaction mixture was diluted with chloroform (200 mL) and water (100 mL). The organic layer was extracted with chloroform (3×50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica-gel column (330 g) eluting with 50% ethyl acetate/hexanes to give tert-butyl 4-(1-(6-fluoropyridin-3-yl)ethyl)piperazine-1-carboxylate (17.27 g, 55.8 mmol, 64.5% yield) as a yellow oil. m/z (ESI, +ve ion) 310.1 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([O:7][C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14][OH:15])=[CH:10][CH:9]=1)[CH2:5][CH3:6].[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](F)[N:20]=1>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[F:18][C:19]1[N:20]=[C:21]([O:15][CH2:14][CH2:13][O:12][C:11]2[CH:16]=[CH:17][C:8]([O:7][CH:4]([CH3:3])[CH2:5][CH3:6])=[CH:9][CH:10]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: Fc1cccc(F)n1
Reactant: CCC(C)Oc1ccc(OCCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCC(C)Oc1ccc(OCCOc2cccc(F)n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of sodium hydride (0.12 g) in 5 ml of THF and 4 ml of HMPA, cooled in an ice bath, is added, dropwise, a solution of 2-[4-(1-methylpropoxy)phenoxy]ethanol (1.00 g) in 5 ml of THF. The mixture is stirred at RT for 2 hours, after which 2,6-difluoropyridine (0.65 g) is added and the mixture is stirred at RT overnight. The THF is removed by rotoevaporation and the product is isolated by column chromatography on silica gel to give 6-fluoro-2-{2-[4-(1-methylpropoxy)phenoxy]ethoxy}pyridine, MS m/e 306 (M+).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[NH:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[O:16]=[C:14]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)/[CH:13]=[CH:12]/[C:9]1[CH:8]=[CH:7][C:6]([O:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:11][CH:10]=1
Reactant: C1CCN(C[C@@H]2CCCN2)CC1
Reactant: CS(=O)(=O)Oc1ccc(/C=C/C(=O)O)cc1
Product: CS(=O)(=O)Oc1ccc(/C=C/C(=O)N2CCC[C@H]2CN2CCCCC2)cc1

Procedure:
230 mg of the title compound were synthesized as described for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-(4-(methanesulfonyloxy)phenyl)acrylic acid instead of (E)-4-bromocinnamic acid and 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[Cl:21][CH2:22][CH2:23][N:24]1[C:29](=[O:30])[CH2:28][N:27]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[CH2:26][C:25]1=[O:38]>>[ClH:21].[ClH:21].[ClH:21].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:9]2[CH2:10][CH2:11][N:12]([CH2:22][CH2:23][N:24]3[C:25](=[O:38])[CH2:26][N:27]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH2:28][C:29]3=[O:30])[CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Reactant: O=C1CN(Cc2ccccn2)CC(=O)N1CCCl
Product: Cl
Product: O=C1CN(Cc2ccccn2)CC(=O)N1CCN1CCC(=C(c2ccccc2)c2ccc(F)cc2)CC1

Procedure:
This compound was prepared from 4-[(4-fluorophenyl)phenylmethylene]piperidine and 1-(2-chloroethyl)-4-(2-pyridylmethyl)-2,6-piperazinedione according to the process described in Example 6, Stage E.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]2[S:13][C:12]([N:14]([CH3:25])[C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]=[CH:20][CH:19]=[CH:18]4)=[N:11][C:10]=2[C:26]([O:28]CC)=O)=[O:7])=[CH:4][CH:3]=1.[NH3:33].CO>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[S:13][C:12]([N:14]([CH3:25])[C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]=[CH:20][CH:19]=[CH:18]4)=[N:11][C:10]=2[C:26]([NH2:33])=[O:28])=[O:7])=[CH:31][CH:32]=1
Reactant: CCOC(=O)c1nc(N(C)c2ccc3ncccc3c2)sc1NC(=O)c1ccc(F)cc1
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: CN(c1ccc2ncccc2c1)c1nc(C(N)=O)c(NC(=O)c2ccc(F)cc2)s1
Temperature: 80 °C
Yield: 84 %

Procedure:
To a solution of ethyl 5-(4-fluorobenzamido)-2-[methyl(quinolin-6-yl)-amino]thiazole-4-carboxylate (0.14 g, 0.31 mmol) in THF (5 mL) was added 7N NH3-MeOH (5mL), and the mixture was heated at 80° C. for 16 hrs in a sealed tube. The solvent was evaporated in vacuo, and the resulting solids were purified by silica gel chromatography eluted with EtOAc to give 110 mg (84% yield) of the titled compound.
Reaction SMILES: O[C:2]([C:5]1[N:6]=[C:7]([CH2:39][CH2:40][CH3:41])[N:8]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[NH:38][N:37]=[N:36][N:35]=3)=[CH:24][CH:23]=2)[C:9]=1[C:10]([O:12][CH2:13][C:14]1[O:15][C:16](=[O:20])[O:17][C:18]=1[CH3:19])=[O:11])([CH3:4])[CH3:3].CN(C)C(=O)C.S(=O)(=O)(O)O.[OH-].[Na+]>C(Cl)Cl.O>[C:2]([C:5]1[N:6]=[C:7]([CH2:39][CH2:40][CH3:41])[N:8]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[NH:38][N:37]=[N:36][N:35]=3)=[CH:24][CH:23]=2)[C:9]=1[C:10]([O:12][CH2:13][C:14]1[O:15][C:16](=[O:20])[O:17][C:18]=1[CH3:19])=[O:11])([CH3:4])=[CH2:3]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Solvent: O
Product: C=C(C)c1nc(CCC)n(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c1C(=O)OCc1oc(=O)oc1C
Temperature: 40 °C
Yield: 116.7 %

Procedure:
(5-Methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylate [olmesartan medoxomil] (20.0 g) was added into anhydrous N,N-dimethylacetamide (80 ml) under a nitrogen stream, and after dissolution was confirmed, concentrated sulfuric acid (3.0 ml) was poured in and the mixture was reacted at about 100° C. for 2.5 hours. Upon completion of the reaction, the reaction mixture was cooled to about 40° C. and poured into cold water (80 ml). After methylene chloride (80 ml) was poured in, the pH of the reaction mixture was adjusted to 4.2 with 25% sodium hydroxide. The organic layer was separated, washed with brine (80 ml) and concentrated under reduced pressure to obtain 22.58 g of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-isopropenyl-2-propyl-1-[[2′-[1H-tetrazol-5-yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate [crude olmesartan medoxomil dehydrate] as a foam.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:9]([NH:11]N)=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.Cl.CCOCC.N(OC(C)(C)C)=O.N[C@H:37]([C:45]([NH:47][C@H:48]([C:56]([NH:58][C@H:59]([C:66]([NH:68][CH2:69][C:70]([O:72][CH3:73])=[O:71])=[O:67])[CH2:60][O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:57])[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:46])[CH2:38][CH2:39][CH2:40][NH:41][C:42](=[NH:44])[NH2:43]>CN(C)C=O.C(N(CC)CC)C>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:9]([NH:11][C@H:37]([C:45]([NH:47][C@H:48]([C:56]([NH:58][C@H:59]([C:66]([NH:68][CH2:69][C:70]([O:72][CH3:73])=[O:71])=[O:67])[CH2:60][O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:57])[CH2:49][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)=[O:46])[CH2:38][CH2:39][CH2:40][NH:41][C:42](=[NH:43])[NH2:44])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1
Reactant: NNC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Reactant: COC(=O)CNC(=O)[C@H](COC(C)(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CCCNC(=N)N
Agent: CC(C)(C)ON=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)CNC(=O)[C@H](COC(C)(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Reaction time: 20 h

Procedure:
7.6 g of Z-His-NH-NH2 (25 mmols) are suspended in 60 ml of dimethylformamide, 31 ml of hydrogen chloride in ether (2.43 N,. 75.3 mmols) are added at -16°C and the clear yellowish solution thereby obtained is mixed, at -18°C, with 3.2 ml of t-butyl nitrite (95 % strength, 26.5 mmols) in 10 ml of dimethylformamide. After 10 minutes 10.4 ml of triethylamine (75 mmols) in 25 ml of pre-cooled dimethylformamide, and 8.5 g of H-Arg-Phe-Ser(tBu)-Gly-OCH3. 2 HCl (14 mmols) in 50 ml of pre-cooled dimethylformamide are added. The mixture is diluted with 40 ml of dimethylformamide and four portions each of 1.0 ml of triethylamine (a total of 28.7 mmols) are added in intervals of 5 minutes. The mixture is allowed to stand for a further 3 hours at 0°C and for 20 hours at room temperature, the precipitated salts are then filtered off, and the reaction solution is concentrated in vacuo to about three-fourths of its volume. On repeatedly stirring the product into a large amount of ethyl acetate a crude product is obtained which is purified by counter-current distibution in the system methanol-buffer-chloroform-carbon tetrachloride (9:3.5:8:2) through 130 stages (buffer as under 18); rmax = 54; K = 0.7. The pure fractions are combined, evaporated, freed of ammonium acetate in a high vacuum at 40°C, and lyophilised after solution in water.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].CN[C:14]([NH:21][CH3:22])=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[CH2:23](N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:4](/[C:15](=[CH:14]/[N:21]([CH3:22])[CH3:23])/[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:5])=[CH:7][CH:8]=[C:9]([Cl:11])[N:10]=1
Reactant: CCOC(=O)C=C(NC)NC
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccc(Cl)nc1Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(=C\N(C)C)C(=O)c1ccc(Cl)nc1Cl

Procedure:
A solution of 2,6-dichloronicotinoyl chloride (62.5 g), ethyl 3,3-dimethylaminoacrylate (58.8 g) and triethylamine (69 g) in toluene (600 mL) was stirred at 90° C. for 1 hour then cooled and concentrated. The concentrate was dissolved in dichloromethane (60 mL), diluted with diethyl ether, and filtered. The filtrate was concentrated, and the concentrate was crystallized from dichloromethane/diethyl ether/hexanes.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:22])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][C:19](O)=[O:20])([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:26])=O>C1C=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([CH3:22])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][C:19]([Cl:26])=[O:20])([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(CC(=O)O)O2
Solvent: c1ccccc1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(CC(=O)Cl)O2
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
In a dry flask, a solution of 15.32 g. (50 mmol.) of (±)-(6-acetoxy-2,5,7,8-tetramethylchroman-2-yl) acetic acid in 100 ml. of benzene was heated under N 2 to 50° C. as 21.15 ml. (0.25 mol.) of oxalyl chloride was added over 20 minutes. The solution was stirred at 50° C. for another 20 minutes, cooled and stripped of solvent to produce (±)-(6-acetoxy-2,5,7,8-tetramethylchroman -2-yl) acetyl chloride. To a solution of this acid chloride in 200 ml. of dry toluene was added 15 g. of sodium acetate and 1.5 g. of 10% by weight palladium on 90% by weight carbon and 0.30 ml. of quinoline. This mixture was hydrogenated in a Parr apparatus. After 12 hours, the uptake of H 2 (about 55 mmole) had virtually ceased. The catalyst was removed by filtration and the filtrates wee stripped of solvent. The residue was taken up in ether, washed with 2N aqueous HCl, saturated aqueous sodium bicarbonate solution and saturated brine, dried over sodium sulfate and stripped of solvent to give 15.4 g. of light yellow solid which was chromatographed on 1 kg. of 0.063-0.2 mm silica gel. Elution with 95:5 parts by volume benzene-ethyl acetate gave 11.0 g. of light yellow resin. The material from two such reactions was combined and crystallized from acetone-petroleum ether (b.p. 30°-60° C.) to give (±)-(6-acetoxy-2,5,7,8-tetramethylchroman-2-yl)-acetaldehyde as a white powder, sint 66.5° C., m.p. 68°-70° C.