Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:9]1[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]1)[CH:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.[C:16]([OH:20])(=O)[CH2:17][OH:18]>C(O)(C)C.C(O)C>[CH2:1]([CH:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:16](=[O:20])[CH2:17][OH:18])[CH2:6][CH2:7]1)[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:17](=[O:18])[CH2:16][OH:20])[CH2:11][CH2:10]1
Reactant: NC1CCC(CC2CCC(N)CC2)CC1
Reactant: O=C(O)CO
Solvent: CC(C)O
Solvent: CCO
Product: O=C(CO)NC1CCC(CC2CCC(NC(=O)CO)CC2)CC1

Procedure:
4,4'-Methylenebis(cyclohexylamine) (56.5 g, 0.27 mole) was dissolved in hot isopropanol (500 ml) and glycolic acid (40.9 g, 0.54 mole) added portion-wise with stirring. Upon cooling, a white gummy solid separated which was isolated by decantation and redissolved in a small volume of ethanol. Crystallization produced a white crystalline, deliquescent solid; m.p. 96°-102° C. Thorough drying under vacuum increased the melting point (m.p. 149°-151° C.) and reduced the deliquescence.
Reaction SMILES: [CH:1]1([C:7]([CH3:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:10][C:11]([F:18])([F:17])[C:12](OCC)=[O:13].C[O-].[Na+].Cl>COCCOC.O.CCOC(C)=O>[F:10][C:11]([F:18])([F:17])[C:12](=[O:13])[CH2:9][C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:8]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)C1CCCCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CC(=O)C(F)(F)F)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of cyclohexylmethylketone (2.75 g, 21.8 mmol) in DME (200 mL) was added ethyl trifluoroacetate (7.79 ml, 65.4 mmol) and sodium methoxide (7.71 g, 131 mmol), and the resulting reaction mixture was stirred at room temperature overnight. EtOAc (500 ml) and water (50 ml) were added, and the pH of the aqueous layer was adjusted to 6 by addition of 1 N HCl solution. The organic layer was washed with brine (50 ml), dried over MgSO4, and concentrated in vacuo to give the title compound in quantitative yield. This was used for the next coupling step without further purification.
Reaction SMILES: [F:1][C:2]1[C:3](/[C:12](/I)=[CH:13]/[C:14](=O)[C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[NH2:22][CH2:23][CH2:24][CH2:25][NH2:26].[H-].[Na+]>>[NH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:12]1[CH:13]=[C:14]([C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)[C:5]2[C:6](=[O:11])[NH:7][C:8]3[C:4]=2[C:3]=1[C:2]([F:1])=[CH:10][CH:9]=3
Reactant: O=C1Cc2c(ccc(F)c2/C(I)=C/C(=O)c2ccc[nH]2)N1
Reactant: NCCCN
Agent: [H-]
Agent: [Na+]
Product: NCCCNc1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
To a suspension of (Z)-5-fluoro-4-[1-iodo-3-oxo-3-(1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-one (from Example 8 above) (118.8 mg, 0.3 mmol) in 1,3-diaminopropane (Aldrich, 3 mL, 35.6 mmol) was added NaH (Aldrich, 90%, 53 mg, 6.6 mmol) in portions at room temperature. After stirring at room temperature for 30 minutes, the reaction mixture was heated to 120° C. for 2.5 hours. The reaction was quenched by pouring the reaction mixture into an ice-cold saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were successively washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 5-(3-amino-propylamino)-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one (Yield 25.3 mg, 26.0%) as the free base which was further purified by RP-HPLC (C-18, eluted with 1% acetonitrile/0.05% acetic acid in H2O) to afford 5-(3-amino-propylamino)-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one acetic acid salt.
Reaction SMILES: [CH2:1]1[C:13]2[N:4]([C:5](=O)[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH:12]=2)[CH2:3][CH2:2]1.[BH4-].[Na+]>P(Cl)(Cl)(Cl)=O.CO>[CH2:1]1[CH:13]2[N:4]([CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH2:12]2)[CH2:3][CH2:2]1
Reactant: O=c1c2ccccc2cc2n1CCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CO
Product: c1ccc2c(c1)CC1CCCN1C2
Temperature: 0 °C
Yield: 41.6 %

Procedure:
A suspension of 2,3-dihydropyrrolo[1,2-b]isoquinolin-5(1H)-one (10.8 g, 58.3 mmol) [G. M. Coppola, J. Heterocycl. Chem., 1981, 18, 767] in phosphorus oxychloride (100 ml) was heated at reflux for 1.5 h. Upon cooling, the solvent was removed in vacuo to give an oil. This oil was immediately taken up in cold methanol (275 ml) and sodium borohydride (4.0 g) was added portionwise to this solution while maintaining the reaction mixture at 0° C. The solvent was concentrated and the residue was dissolved in water and washed twice with ethyl acetate. The aqueous solution was made basic with potassium carbonate solution and extracted with ethyl acetate. The organic phase was dried (magnesium sulfate) and concentrated to give an oil. Column chromatography on silica gel gave unreacted starting material (3.57 g, 36%) and the title compound (4.2 g, 63% based on recovered starting material) as a light oil; MS 174 (M+H)+ ; NMR (CDCl3) 7.0-7.2 (broad m, 4H), 4.13 (d, 1H, J=15), 3.40 (d, 1H, J=15), 3.27 (dt, 1H), 2.9-3.1 (M, 1H), 2.71 (t, 1H), 1.4-2.4 (m, 6H).
Reaction SMILES: [CH3:1][CH:2]([CH:4]([OH:7])[CH2:5][CH3:6])[CH3:3].[CH3:8][C:9](=[CH:13][CH3:14])[C:10](O)=[O:11].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:5]([CH:4]([O:7][C:10](=[O:11])[C:9]([CH3:8])=[CH:13][CH3:14])[CH:2]([CH3:3])[CH3:1])[CH3:6]
Reactant: CC=C(C)C(=O)O
Reactant: CCC(O)C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC=C(C)C(=O)OC(CC)C(C)C
Temperature: 120 °C
Yield: 44 %

Procedure:
A reaction flask was charged with ethylmagnesium chloride (CH3CH2MgCl) (2 M, 2.17 L) and cooled to −10° C. Isobutyraldehyde ((CH3)2CHCHO) (295 g) was fed over about 1 hour while the temperature was kept under 15° C. The reaction mixture was aged to room temperature over about 6 hours and then poured into a mixture of ice and acetic acid (293 g). Hexanes (350 mL) were added and aqueous and organic layers were split. The organic layer was separated, washed sequentially with sodium bicarbonate (NaHCO3), brine, and water, and further distilled to provide 2-methyl-pentan-3-ol (336 g). 2-Methyl-pentan-3-ol (153 g), 2-methyl-but-2-enoic acid (100 g), toluene (200 mL), and PTSA (8 g) were charged into to 2-L reaction flask fitted with a Dean-Stark trap. The reaction mixture was heated to reflux at about 120° C. Water was removed. The reaction mixture was aged at reflux for about 13-14 hours till GC analysis showed completion of the reaction. The resulting reaction mixture was washed sequentially with sodium bicarbonate and brine, and further purified by fractional distillation to provide 2-methyl-but-2-enoic acid 1-ethyl-2-methyl-propyl ester (81 g) with a boiling point of 91° C. at 1.1 mmHg.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19].[H-].[Na+]>>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]2[C:3](=[O:2])[NH:19][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[O:12][C:5]=2[CH:6]=1
Reactant: COC(=O)c1ccc(OC)cc1Oc1ccccc1N
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2c(c1)Oc1ccccc1NC2=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 1-2 (47.80 g, 174.9 mmol) in TBF (1 L) was treated with sodium hydride (7.430 g of 60% in oil, 185.7 mmol) in portions and stirred at room temperature for 3 days. The reaction was quenched with aqueous ammonium chloride and extracted three times with diethyl ether. The combined organic extracts were washed with brine and dried (Na2SO4). The solvent was removed in vacuo to afford the crude product 1-3. Recrystallization from ethyl acetate gave 1-3 as white crystals.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:14])[CH3:13])[S:9][CH:10]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:4][CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:14])[CH3:13])[S:9][CH:10]=1
Reactant: CC(=O)Nc1nc(COC(C)=O)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)Nc1nc(CO)cs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
A mixture of (2-(acetylamino)-1,3-thiazol-4-yl)methyl acetate (46 g) and potassium carbonate (30 g) in methanol (640 ml) was stirred for 3 hours at ambient temperature. The reaction mixture was concentrated in vacuo. The residue was diluted with chloroform, and the insoluble material was filtered off. The resulting solution was purified by flash column chromatography on silica-gel with methanol/chloroform (1/99). The resulted solid was collected by filtration with isopropyl ether to give N-(4-(hydroxymethyl)-1,3-thiazol-2-yl)acetamide (35 g) as white crystals.
Reaction SMILES: [Br:1][C@@H:2]([CH2:6][OH:7])[C:3](O)=[O:4].[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([NH:15][C:3](=[O:4])[C@@H:2]([Br:1])[CH2:6][OH:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)[C@@H](Br)CO
Product: O=C(NCc1ccccc1)[C@@H](Br)CO

Procedure:
In one of the embodiments of the present invention, the compound (2S)-2-bromo-3-hydroxypropanoic acid of Formula-XVIII is subjected to react with benzylamine in presence of a base and an activator under mixed anhydride coupling condition to get (2S)-N-benzyl-2-bromo-3-hydroxypropanamide of Formula-XIX. The mixed anhydride coupling reaction conditions as described by Anderson, et al., in JACS, 1967, 89, 5012-5017, the contents of which are incorporated herein by reference. The activators used to activate the carbonyl group are selected from optionally substituted alkyl or aryl chloroformates such as methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, phenyl chloroformate, pivolyl chloride, 1,1-carbonyldiimidazole, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and N,N′-dicyclohexylcarbodiimide. The preferred activator used is alkyl chloroformate selected from methyl chloroformate, ethyl chloroformate and isobutyl chloroformate wherein the most preferred activator used is isobutyl chloroformate. The base used in the reaction is selected from N-methylmorpholine, pyridine, N,N-diisopropylethylamine and triethylamine wherein the preferred base used is N-methylmorpholine. The reaction is carried out in the presence of solvent at temperature in the range of −20° C. to 30° C. The solvent used for the reaction is selected from dichloromethane, ethyl acetate, toluene and tetrahydrofuran. The preferred solvent used for the reaction is ethyl acetate. Accordingly, the compound (2S)-2-bromo-3-hydroxypropanoic acid of Formula-XVIII is taken in ethyl acetate and the isobutyl chloroformate is charged at 20-30° C. Stirred and cooled the reaction mixture to −20° C. Maintaining the temperature at −20° C. charged base N-methylmorpholine and benzylamine to the reaction mass. The reaction is maintained between −20° C. to 30° C. for 4-10 hours. After completion of the reaction, concentrated the reaction mass under reduced pressure, maintaining temperature below 40° C. to get the residual mass. Charged non polar solvent to isolate the compound (2S)-N-benzyl-2-bromo-3-hydroxypropanamide of Formula-XIX. The non polar solvent used for isolation of the compound is selected from hexane, heptane and diisopropyl ether, wherein the preferred non polar solvent used is diisopropyl ether. Stirred and filtered the separated solid product, washed with water and dried to get the compound (2S)-N-benzyl-2-bromo-3-hydroxypropanamide of Formula-XIX.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:29][CH2:30][N:31]([CH3:34])[C:32](=[O:33])[C:10]=12)C1C=CC=CC=1.C1(C2C=CC=CC=2)C=CC=CC=1CC1N2CCN(C)C(=O)C2=C(O)C(=O)N=1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:17]2([CH2:16][C:12]3[N:11]4[CH2:29][CH2:30][N:31]([CH3:34])[C:32](=[O:33])[C:10]4=[C:9]([OH:8])[C:14](=[O:15])[N:13]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:23][CH:24]=1
Reactant: CN1CCn2c(CC3(c4ccc(Cl)cc4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: CN1CCn2c(Cc3ccccc3-c3ccccc3)nc(=O)c(O)c2C1=O
Product: CN1CCn2c(CC3(c4ccc(Cl)cc4)CCCC3)nc(=O)c(O)c2C1=O
Yield: 66.3 %

Procedure:
6-[1-(4-chlorophenyl)-cyclopentylmethyl]-9-hydroxy-2-methyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (32-02) (296 mg, 66.3%) was synthesized from 9-benzyloxy-6-[1-(4-chlorophenyl)cyclopentylmethyl]-2-methyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (31-02) (500 mg, 1.151 mmol) as an off-white solid following the procedure as described for 6-biphenyl-2-ylmethyl-9-hydroxy-2-methyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (12-01).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH3:4].CC[O-].[Na+].[C:10]1([N:16]2[C:22]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=3[NH:20][C:19](=[O:28])[CH2:18][C:17]2=[O:29])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([N:16]2[C:22]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=3[N:20]([CH2:1][CH2:2][CH2:3][CH3:4])[C:19](=[O:28])[CH2:18][C:17]2=[O:29])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCCBr
Reactant: O=C1CC(=O)N(c2ccccc2)c2cc(Cl)ccc2N1
Agent: CC[O-]
Agent: [Na+]
Product: CCCCN1C(=O)CC(=O)N(c2ccccc2)c2cc(Cl)ccc21

Procedure:
In the same manner, by acting butyl bromide in the presence of sodium ethylate, starting from 1-phenyl 8-chloro 1,2,4,5-tetrahydro 2,4 -dioxo 3H-1,5-benzodiazepine, there is obtained 1-phenyl 5-butyl 8-chloro 1,2,4,5-tetrahydro 2,4-dioxo-3H-1,5-benzodiazepine (R1 = H, R2 = Cl, R3 = C4H9, R4 = C6H5) melting at 159°- 161° C., upon recrystallisation in 50% ethanol.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][NH:32]3)=[O:30])[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:37]1[CH2:39][C@@H:38]1[CH2:40][O:41][C:42]1[CH:51]=[CH:50][CH:49]=[C:48]2[C:43]=1[CH:44]=[CH:45][CH:46]=[N:47]2>C(O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][N:32]3[CH2:39][C@@H:38]([OH:37])[CH2:40][O:41][C:42]3[CH:51]=[CH:50][CH:49]=[C:48]4[C:43]=3[CH:44]=[CH:45][CH:46]=[N:47]4)=[O:30])[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCN(C(=O)C2CCCCN2)CC1
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Solvent: CCO
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCN(C(=O)C2CCCCN2C[C@@H](O)COc2cccc3ncccc23)CC1
Temperature: 25 °C
Yield: 69.9 %

Procedure:
1-(Piperidine-2-carbonyl)-piperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (6) (243.4 mg; 0.497 mmol) is dissolved in ethanol (12 mL) at ambient temperature. (R)-5-Oxiranylmethoxy-quinoline (2) (100.0 mg; 0.497 mmol) is added, then the mixture is refluxed for 17 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (50%→100% acetone in hexanes, then 5%→20% ethanol in acetone) affording the desired product (240 mg) as a white solid. ESMS: MH+ 691.4
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C[O-].[Na+].CO[CH:15](OC)[CH2:16][NH2:17].C(O)(=O)C.Cl>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]2[NH:17][CH:16]=[CH:15][N:7]=2)=[CH:4][CH:3]=1
Reactant: COC(CN)OC
Reactant: N#Cc1ccc(Br)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Brc1ccc(-c2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 20.4 %

Procedure:
To a solution of 4-bromobenzonitrile (80.0 g, 440 mmol) in MeOH (800 mL) was added NaOMe (20.1 mL, 87.9 mmol). The mixture was allowed to stir at ambient temperature for 5.5 hours. 2,2-Dimethoxyethanamine (61.6 mL, 571 mmol) was added followed by acetic acid (50.3 mL, 879 mmol). The reaction mixture was heated to 50° C. for 1 hour and then cooled to ambient temperature. MeOH (200 mL) and HCl (200 mL, 1200 mmol) were added, and the reaction mixture was heated to 65° C. for 18 hours. The reaction mixture was then concentrated, and washed with 1:1 H2O:Et2O (2000 mL). The pH of the aqueous layer was adjusted to pH=9 with 6 N NaOH. The resulting solid was filtered and dried to give 2-(4-bromophenyl)-1H-imidazole (20.0 g, 20%). LCMS (APCI+) m/z 223, 224 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:13]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:28](Cl)(=[O:30])[CH3:29]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]([C:18]3[CH:19]=[CH:20][C:21]([S:24]([NH:27][C:28](=[O:30])[CH3:29])(=[O:26])=[O:25])=[CH:22][CH:23]=3)[CH:11]=[C:12]([C:14]([F:16])([F:15])[F:17])[N:13]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CC(=O)Cl
Reactant: Cc1cc(Cl)cc(-c2nc(C(F)(F)F)cn2-c2ccc(S(N)(=O)=O)cc2)c1
Solvent: CC(=O)O
Product: CC(=O)NS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2cc(C)cc(Cl)c2)cc1
Yield: 70 %

Procedure:
To a suspension of 4-[2-(3-chloro-5-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide (0.30 g, 0.72 mmol) in 1.5 mL of acetic acid was added 1.5 mL of acetyl chloride at room temperature. The mixture was heated at reflux for 5 hours. After cooling, the reaction mixture was concentrated under vacuum and the residue was treated with ether to give 0.23 g (70%) of N-[[4-[2-(3-chloro-5-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]phenyl]sulfonyl]acetamide as a white solid: mp (DSC) 232-235° C. Anal. Calc'd. for C19H15ClF3N3O3S: C, 49.84; H, 3.30; N, 9.18; S, 7.00. Found: C, 49.72; H, 3.48; N, 8.81; S, 7.18.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:8][C@@H:7]([O:9][CH:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH2:6][CH2:5][CH2:4]1.[S:25](Cl)([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26].O>N1C=CC=CC=1>[S:25]([O:1][CH2:2][C@@H:3]1[O:8][C@@H:7]([O:9][CH:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH2:6][CH2:5][CH2:4]1)([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26]
Reactant: OC[C@H]1CCC[C@H](OC(Cn2ccnc2)c2ccc(Cl)cc2Cl)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCC[C@H](OC(Cn3ccnc3)c3ccc(Cl)cc3Cl)O2)cc1
Yield: 94.2 %

Procedure:
A solution of 5.10 g of 1-[trans-β-(6-hydroxymethyltetrahydropyran-2-yloxy)-2,4-dichlorophenethyl]imidazole in 40 ml of dry pyridine was stirred overnight at room temperature with 2.88 g of tosyl chloride. The reaction mixture was poured into water and extracted with diethyl ether. The ethereal extract was washed with aqueous sodium chloride and dried over anhydrous sodium sulphate, and the solvent was removed by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel eluted with a 20:20:1 by volume mixture of benzene, ethyl acetate and ethanol, to give 6.8 g of the title compound, as a colourless liquid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=2)=[N:4][C:5]([CH3:10])=[C:6]([Br:9])[C:7]=1[CH3:8].[C:21](Cl)(=[O:26])[CH2:22][CH2:23][CH2:24][CH3:25]>>[C:21]([O:20][CH2:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([N:11]2[C:3]3=[N:4][C:5]([CH3:10])=[C:6]([Br:9])[C:7]([CH3:8])=[C:2]3[N:1]=[C:10]2[CH2:5][CH2:6][CH2:7][CH3:2])=[CH:13][CH:14]=1)(=[O:26])[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCC(=O)Cl
Reactant: Cc1nc(Nc2ccc(CCO)cc2)c(N)c(C)c1Br
Product: CCCCC(=O)OCCc1ccc(-n2c(CCCC)nc3c(C)c(Br)c(C)nc32)cc1

Procedure:
The title compound was prepared according to the procedure described in step 5 of Example 1 from 2-{4-[(3-amino-5-bromo-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol (step 4 of Example 9) and pentanoyl chloride.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:50][CH2:51][CH3:52])[N:8]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30]([C:31]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:9]=1[C:10]([OH:12])=[O:11])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:62][C:63]1[O:64][C:65](=[O:69])[O:66][C:67]=1[CH3:68]>CC(C)=O.C1(C)C=CC=CC=1>[CH3:52][CH2:51][CH2:50][C:7]1[N:8]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:21]([C:26]4[N:30]([C:31]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)([C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)[C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)[N:29]=[N:28][N:27]=4)=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:19]=2)[C:9]([C:10]([O:12][CH2:68][C:67]2[O:66][C:65](=[O:69])[O:64][C:63]=2[CH3:62])=[O:11])=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[N:6]=1
Reactant: Cc1oc(=O)oc1CCl
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
4-(1-Hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylic acid dehydrate (100 g) was suspended in acetone (1 L) & heated to reflux; the solution obtained was added to suspension of potassium carbonate (15 g), potassium iodide (6 g) & 4-chloromethyl-5-methyl-1,3-dioxol-2-one (35 g) in acetone (500 mL) at reflux temperature. Reaction mass was refluxed for 2-6 hrs. After competition of reaction, the reaction mass was filtered & the acetone was distilled from combined mother liquor. The residue obtained was dissolved in toluene (1 L) toluene layer was washed with brine (3×250 mL). Toluene was removed under reduced pressure & residue thus obtained was recrystallized from methanol to give trityl Olmesartan
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][CH2:9][C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2Br)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:26]([N:33]=[C:34]=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[CH2:9][C:10]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:16])[CH:15]=3)[N:33]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:34]2=[O:35])=[CH:5][CH:4]=1
Reactant: O=C=NCc1ccccc1
Reactant: COc1ccc(CNCc2cc(Cl)ccc2Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2Cc3cc(Cl)ccc3N(Cc3ccccc3)C2=O)cc1
Temperature: 120 °C

Procedure:
To a stirring mixture of N-(4-methoxybenzyl)(2-bromo-5-chlorophenyl)methanamine (0.94 g, 2.77 mmol), Pd(PPh3)4 (0.32 g, 0.277 mmol), and K2CO3 (0.77 g, 5.55 mmol) was added DMF (5.0 mL), followed by slow addition of benzyl isocyanate (0.38 mL, 3.05 mmol) at 0° C. The mixture was heated at 120° C. for 4 hrs. The resulting mixture was concentrated and passed through a short path of silica gel and eluted with DCM until the product eluted. The combined organic layers were concentrated to give the product 3-(4-methoxybenzyl)-1-benzyl-6-chloro-3,4-dihydroquinazolin-2(1H)-one as a pale yellow foam. MS m/e 340 (M+H)+.