Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6]([CH2:8][O:9][CH2:10][C:11]([NH:13][NH2:14])=[O:12])=[O:7])[CH3:4].[C:15](=S)=[S:16].CS(C)=O>C(O)C.O>[CH2:3]([O:5][C:6]([CH2:8][O:9][CH2:10][C:11]1[O:12][C:15]([SH:16])=[N:14][N:13]=1)=[O:7])[CH3:4]
Reactant: S=C=S
Reactant: CCOC(=O)COCC(=O)NN
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)COCc1nnc(S)o1

Procedure:
A solution of potassium hydroxide (0.22 g.) in ethanol (2.5 ml.) was added to a suspension of ethoxycarbonylmethoxyacetohydrazide in ethanol (4 ml.), followed by the addition of carbon disulfide (0.95 ml.) and dimethyl sulfoxide (0.54 ml.), respectively. The reaction mixture was then refluxed for a period of 12 hours, cooled and filtered, and the resulting filtrate subsequently evaporated in vacuo. The residual oil so obtained was then dissolved in water, filtered and the filtrate acidified to pH 2.0 with aqueous 2N hydrochloric acid. Extraction of the latter solution with ethyl acetate and subsequent evaporation of the solvent then yielded the desired product, viz., 2-(ethoxycarbonylmethoxymethyl)-1,3,4-oxadiazole-5-thiol, as a white solid material(yield, 0.5 g.), m.p. 101°-103° C.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])/[C:2](=[CH:4]\[CH3:5])/[CH3:3].[CH3:9][C:10]([CH2:14]C)=[CH:11][CH2:12]O.C([O-])(=O)C.C([Sn+2]CCCCCCCC)CCCCCCC.C([O-])(=O)C>C1(C)C=CC=CC=1>[C:1]([O:7][CH2:8][CH:9]=[C:10]([CH3:14])[CH2:11][CH3:12])(=[O:6])/[C:2](=[CH:4]\[CH3:5])/[CH3:3]
Reactant: CCC(C)=CCO
Reactant: C/C=C(/C)C(=O)OC
Agent: CC(=O)[O-]
Agent: CCCCCCCC[Sn+2]CCCCCCCC
Solvent: Cc1ccccc1
Product: C/C=C(/C)C(=O)OCC=C(C)CC

Procedure:
A mixture of 22.8 g. of methyl angelate, 10 g. of 3-methyl-2-pentenol, 80 ml. of toluene and 1 g. of dioctyltin acetate was placed in a 300 ml. glass flask, which was equipped with a Soxhlet extractor filled on the top with molecular sieve 4A and a reflux cooler. The above mixture was heated under continuous reflux while returning the refluxed liquid through the molecular sieve 4A to the flask. The mixture resulted from the heating for a total of 17 hours was subjected to single distillation to give 14.2 g. of a distillate boiling at 115° C. (22 mmHg). The distillate was further subjected to rectification to give 9.70 g. of a distillate boiling at 115° C. (22 mmHg). Analysis of the compound by gaschromatography (Column: Silicone SE-52, 2%/chromosorb GHP) indicated a purity of 99.403% in terms of the area ratio. Refractive index (D ray, 20° C.) was 1.463. Infrared spectrum (liquid film) had absorptions at 2850-3020, 1720, 1670, 1650, 1455, 1385, 1350, 1255, 1225, 1155, 1080, 1040, 960, 845 and 760 cm-1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH:26]=[CH:27][CH2:28]O)[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.S(Cl)([Cl:32])=O>C(Cl)Cl.C(Cl)CCl>[Cl:32][CH2:28][CH:27]=[CH:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][N:17]=[C:16]2[NH:15][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:2]([CH3:1])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(Nc2ncnc3ccc(C=CCO)cc23)ccc1Oc1cccnc1
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1cc(Nc2ncnc3ccc(C=CCCl)cc23)ccc1Oc1cccnc1
Temperature: 100 °C

Procedure:
To a suspension of 0.035 g (0.091 mmol) of 3-{4-[3-methyl-4-(pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl}-prop-2-en-1-ol in 0.5 mL of methylene chloride and 1 mL of ethylene dichloride was added 1 mL of thionyl chloride. The reaction was heated at 100° C. for 1 hour and the solvents were evaporated to provide [6-(3-chloro-propenyl)-quinazolin-4-yl]-[3 methyl-4-(pyridin-3-yloxy)-phenyl]-amine [MS: M+ 403.1] which was dissolved in THF and used directly in the next reaction. To the solution of [6-(3-chloro-propenyl)-quinazolin-4-yl]-[3-methyl-4-(pyridin-3-yloxy)-phenyl]-amine was added 0.10 mL of morpholine and 0.044 mL of triethylamine. The mixture was heated at 85° C. for 16 hours, cooled to room temperature, and partitioned between 10% aqueous potassium carbonate and ethyl acetate. The aqueous layer was further extracted with ethyl acetate and the combined organics were dried and evaporated to yield 57 mg of material. The product was purified on a silica gel prep plate, eluting with 96:4:0.1 chloroform/methanol/concentrated ammonium hydroxide to afford 26 mg of the title compound; 1H NMR (CDCl3): δ 8.71 (s, 1), 8.33 (m, 2), 7.94 (s, 1), 7.80 (m, 2), 7.69 (s, 1), 7.58 (m, 1), 7.20 (m, 1), 6.94 (d, J=8.7 Hz, 1), 6.68 (d, J=15.8 Hz, 1), 6.46 (m, 1), 3.79 (m, 4), 3.26(m, 2), 2.63 (m, 4), 2.25 (s, 3).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH2:13][CH2:14]1)[CH2:11][CH2:10]2.[F:22][C@@H:23]1[CH2:27][N:26]([C:28](=[O:40])[CH2:29]OS(C2C=CC=CC=2)(=O)=O)[C@H:25]([C:41]#[N:42])[CH2:24]1.[I-].[K+]>>[CH2:20]([O:19][C:17]([C:12]12[CH2:11][CH2:10][C:9]([NH:8][CH2:29][C:28]([N:26]3[CH2:27][C@@H:23]([F:22])[CH2:24][C@H:25]3[C:41]#[N:42])=[O:40])([CH2:16][CH2:15]1)[CH2:14][CH2:13]2)=[O:18])[CH3:21]
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)COS(=O)(=O)c1ccccc1
Reactant: CCOC(=O)C12CCC(N)(CC1)CC2
Agent: [I-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Yield: 72.7 %

Procedure:
Using ethyl 4-aminobicyclo[2.2.2]octane-1-carboxylate trifluoroacetate (685 mg), (2S,4S)-4-fluoro-1-[2-(benzenesulfonyloxy)acetyl]pyrrolidine-2-carbonitrile (625 mg) and potassium iodide (33.2 mg), the same procedure was followed as in Example 7 to give (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]ac etyl]-4-fluoropyrrolidine-2-carbonitrile (511 mg, 73% yield). This compound was identical to the compound obtained in Example 7.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]([CH:17]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[OH:16])=[O:8]>C(O)(C)C.CCCCCCC>[Br:1][C:2]1[C:3]([O:22][CH2:23][C:24]([F:25])([F:26])[F:27])=[N:4][C:5]([C:18]([F:21])([F:19])[F:20])=[C:6]([CH:17]=1)[C:7]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[OH:16])=[O:8]
Reactant: O=C(NC1CCCCC1O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Solvent: CCCCCCC
Solvent: CC(C)O
Product: O=C(N[C@@H]1CCCC[C@@H]1O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F

Procedure:
5-Bromo-N-((1RS,2SR)-2-hydroxy-cyclohexyl)-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinamide (103 g) was subjected to chiral chromatography on ChiralPak AD with 5% isopropanol/n-heptane as eluent. The product eluted as second peak to give after evaporation of the solvent the title compound (43.3 g) as a white solid, MS (ISP) 465.0, 467.0 (M+H)+; [α]D20+19.1°.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[Cl:12][C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=1)=[O:14]>C(Cl)Cl>[ClH:12].[CH3:25][O:24][C:22]([C:19]1[CH:20]=[CH:21][C:16]([O:15][C:13]([N:9]2[CH2:10][CH2:11][N:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH2:7][CH2:8]2)=[O:14])=[CH:17][CH:18]=1)=[O:23]
Reactant: COC(=O)c1ccc(OC(=O)Cl)cc1
Reactant: CCC(CC)N1CCNCC1
Solvent: ClCCl
Product: CCC(CC)N1CCN(C(=O)Oc2ccc(C(=O)OC)cc2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
To a stirred mixture of 1-(1-ethylpropyl)piperazine (350 μl, 2.0 mmol) and dry DCM (15 ml) was added 4-methoxycarbonylphenyl chloroformate (430 mg, 2.0 mmol). The mixture was stirred overnight at room temperature and then diluted with DCM (50 ml). The reaction mixture was washed with 1 N NaOH (3×25 ml) and water (2×25 ml). The organic solution was concentrated and re-evaporated twice with acetonitrile. The residue was dissolved in a 0.5 N HCl solution (15 ml) and a small portion of acetonitrile. The acidic solution was concentrated and stirred with ethyl acetate (15 ml). The solid was isolated and dried to give 670 mg (90%) of the title compound as a solid. M.p. 248° C. decomp.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=O)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.N1C2C(=CC(C=O)=CC=2)C=N1.[S:35]=[C:36]1[NH:40][C:39](=[O:41])[CH2:38][S:37]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:38]4[S:37][C:36](=[S:35])[NH:40][C:39]4=[O:41])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:20]([F:21])([F:23])[F:22])[CH:3]=1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Reactant: O=C1CSC(=S)N1
Agent: O=Cc1ccc2[nH]ncc2c1
Product: O=C1NC(=S)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-thioxo-thiazolidin-4-one was prepared from 1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde was prepared from 1H-indazole-5-carbaldehyde and 2-thioxo-thiazolidin-4-one following General Procedure B.
Reaction SMILES: O[C:2]1[CH:15]=[C:14]([OH:16])[CH:13]=[C:12]([OH:17])[C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[C:31](=[O:34])([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CN(C)C(=O)C.[I-].[K+]>[OH:17][C:12]1[CH:13]=[C:14]([O:16][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:15]=[C:2]([O:34][CH2:31][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:4][CH2:3][CH2:2][CH2:15][CH3:14])[C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: O=C([O-])[O-]
Reactant: O=C(c1ccccc1)c1c(O)cc(O)cc1O
Reactant: CCCCCCCCCCCCBr
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOc1cc(O)c(C(=O)c2ccccc2)c(OCCCCCCCCCCCC)c1
Temperature: 110 °C
Reaction time: 7 h
Yield: 72.3 %

Procedure:
A mixture of 4.5 g (20 mmol) of 2,4,6-trihydroxybenzophenone, 9.8 g (40 mmol) of 1-bromododecane, 2.7 g (20 mmol) of potassium carbonate and 30 mg (0.2 mmol) of potassium iodide in 50 ml of toluene and 20 ml of N,N-dimethylacetamide is stirred at 110° C. for 7 h. The reaction mixture is cooled and then neutralized with 10% HCI. The organic solution is washed with water and then with saturated sodium chloride solution. The residue which remains after drying over MgSO4, filtering and concentrating by evaporation is purified by chromatography over silica gel (toluene/hexane 3:2). The product is recrystallized from isopropyl alcohol. 4.1 g of the compound are obtained as pale yellow crystals having a melting point of 37°-38° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([N:7]=[C:8]=[O:9])=[N:4][CH:3]=1.C1C=CC=CC=1.[Cl:16][CH2:17][NH:18][CH2:19][CH:20]=[O:21]>C(O)C.O>[Cl:16][CH2:17][N:18]([CH2:19][CH:20]=[O:21])[C:8]([NH:7][C:5]1[S:6][C:2]([Br:1])=[CH:3][N:4]=1)=[O:9]
Reactant: O=CCNCCl
Reactant: O=C=Nc1ncc(Br)s1
Solvent: O
Solvent: CCO
Solvent: c1ccccc1
Product: O=CCN(CCl)C(=O)Nc1ncc(Br)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Bromothiazol-2-yl isocyanate dimer (17.0 grams), benzene (70 ml) and the dimethyl acetal of 2-chloromethylaminoacetaldehyde (13.5 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is then stirred at room temperature for a period of about 1 hour. After this time the reaction mixture is filtered, and the filtrate is stripped of solvent under reduced pressure, leaving an oil. This oil is dissolved in an ethanol-water mixture, and the solution is filtered. The filtrate is then stripped of solvents under vacuum to yield the desired product the dimethyl acetal of 2-[1-chloromethyl-3-(5-bromothiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.C([Li])CCC.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#N)=[CH:16][CH:15]=1.CC[O:24]CC>>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]([C:2]2[CH:6]=[CH:5][S:4][CH:3]=2)=[O:24])=[CH:16][CH:15]=1
Reactant: COc1ccc(C#N)cc1
Reactant: CCOCC
Reactant: Brc1ccsc1
Agent: [Li]CCCC
Product: COc1ccc(C(=O)c2ccsc2)cc1
Temperature: -75 °C
Reaction time: 0.17 h

Procedure:
To 4.0 g (0.0246 m) of 3-bromothiophene in 70 ml ether cooled to -75° C. under N2 was added dropwise 0.0246 m of n-butyllithium (in hexane) at such a rate that the temperature was <-70° C. After addition was complete the reaction mixture was stirred at -75° C. for 10 minutes and then a solution of 4-methoxybenzonitrile (3.46 g, 0.026 m) in 20 ml ether was added dropwise at <-70° C. The resulting suspension was stirred at -75° C. for 45 minutes and then allowed to warm to -10° C. over 2 hours. The reaction mixture was cooled, quenched with 15 ml H2O and then with 40 ml of 2N HCl. The phases were separated and the aqueous extract was washed with 50 ml ether, and then heated at reflux for 2 hours. This solution was cooled and extracted with 2×60 ml ether. The organic phases were washed with brine, dried and evaporated to give an oil which was triturated with petroleum ether to give the product as a solid, m.p. 58°-61° C.
Reaction SMILES: FC1C=CC=CC=1[N:8]1[C:12]2[N:13]([CH3:18])[C:14](=[O:17])[CH:15]=[CH:16][C:11]=2[CH:10]=[N:9]1.[C:19]([N:23]1[C:27]2[N:28]([CH3:33])[C:29](=[O:32])[CH:30]=[CH:31][C:26]=2[CH:25]=[N:24]1)([CH3:22])([CH3:21])[CH3:20].[Br:34]Br.[OH-:36].[Na+]>CC(O)=O.O>[C:19]([N:23]1[C:27]2[N:28]([CH3:33])[C:29](=[O:32])[CH:30]=[CH:31][C:26]=2[CH:25]=[N:24]1)([CH3:22])([CH3:21])[CH3:20].[C:14]([OH:17])(=[O:36])[CH3:15].[Br:34][C:15]1[C:14](=[O:17])[N:13]([CH3:18])[C:12]2[NH:8][N:9]=[CH:10][C:11]=2[CH:16]=1
Reactant: BrBr
Reactant: Cn1c(=O)ccc2cnn(-c3ccccc3F)c21
Reactant: [OH-]
Agent: Cn1c(=O)ccc2cnn(C(C)(C)C)c21
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(=O)c(Br)cc2cn[nH]c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Tert-butyl-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one was prepared in a fashion similar to that described for 1-(2-fluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (155 mg) as a light yellow crystalline solid (Example 1-step 3). To a solution of 1-tert-butyl-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (240 mg, 1.17 mmol) in glacial AcOH (5.5 mL) at RT was added bromine (0.060 mL, 1169 μmol) slowly. An orange suspension resulted and it was allowed to stir at RT for 1 h. 5.0 mL water was added, and the pH was adjusted to pH 6 using 5 N NaOH. It was extracted with 2×50 mL EtOAc, dried over MgSO4, filtered and concentrated in vacuo (rotovap) affording 5-bromo-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one acetic acid adduct (305 mg) as a beige solid. MS (ESI, pos.ion) m/z: 227.9 (M+1) and 229.9 (M+1). This crude product was used in the next step.
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[O:23][CH2:24][C:25]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=1[F:32].[C:33]([O:38][CH2:39][CH3:40])(=[O:37])[C:34]#[C:35][CH3:36].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:39]([O:38][C:33]([C:34]1[C:35]([CH3:36])=[N:14][N:15]2[C:16]([O:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=3[F:32])=[CH:17][C:18]([O:21][CH3:22])=[CH:19][C:20]=12)=[O:37])[CH3:40]
Reactant: CC#CC(=O)OCC
Reactant: COc1cc[n+](N)c(OCc2c(F)cccc2F)c1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cc(OC)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 12 %

Procedure:
A solution of 3.99 g (6.15 mmol, 72% purity) of 1-amino-2-[(2,6-difluorobenzyl)oxy]-4-methoxypyridinium 2,4,6-trimethylbenzenesulphonate (Example 161A) in 70 ml of N,N-dimethylformamide was admixed with 1.38 g (12.31 mmol) of ethyl 2-butynoate (CAS: 4341-76-8) and 2.55 g (18.46 mmol) of potassium carbonate. The reaction mixture was stirred at room temperature for 18 hours and added dropwise to 150 ml of water. The resulting precipitate was filtered off and dried under reduced pressure, which gave 477 mg (12% yield, 57% purity) of product.
Reaction SMILES: CN(C)P(N(C)C)(N(C)C)=[O:4].[CH:12]1[C:17]2[C:18]([O:20][C:21](=[O:22])[C:16]=2[CH:15]=[C:14]2[C:23]([O:25][C:26](=[O:27])[C:13]=12)=[O:24])=[O:19].[OH2:28]>>[C:26]([OH:25])(=[O:27])[C:13]1[C:14](=[CH:15][C:16](=[C:17]([CH:12]=1)[C:18]([OH:20])=[O:19])[C:21]([OH:4])=[O:22])[C:23]([OH:24])=[O:28]
Reactant: O
Reactant: O=c1oc(=O)c2cc3c(=O)oc(=O)c3cc12
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(O)c1cc(C(=O)O)c(C(=O)O)cc1C(=O)O
Temperature: 0 °C

Procedure:
To 20 ml of hexamethylphosphoramide solution of 0.654 g (3.00 mmol) of pyromellitic acid dianhydride (the solution became green) was added dropwise 15 ml of hexamethylphosphoramide solution of 1.8 g (6.00 mmol) of the monoester synthesized in the above step with stirring at 0° C. in a nitrogen gas atmosphere (the solution became light ashy) and then the mixture was allowed to stand for more than 3 days at room temperature to provide a colorless solution. A small amount of the solution thus formed was poured in water to form white precipitates. By 1HNMR and IR spectra of the white solid obtained, it was confirmed that the desired half ester formed.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[C:9]2=[O:28])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(N(CC)CC)C>ClCCl>[F:35][C:32]1[CH:33]=[CH:34][C:29]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:9]2=[O:28])=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCN2CCC(c3ccc(F)cc3)(c3ccc(F)cc3)C2=O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1N(CCN2CCNCC2)CCC1(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
The product from Example 63B (2.00 g, 4.12 mmol) was dissolved in dichloromethane (40 mL) and treated with trifluoroacetic acid (7.40 g, 64.9 mmol) at 0° C. The reaction was allowed to come to room temperature and stirred for 1 hour. The reaction was neutralized with triethylamine and concentrated. The residue was taken into ethyl acetate, and then it was washed with water and brine, dried with MgSO4, filtered and concentrated to give the title compound. MS (DCI) m/z 386.2 (M+H)+.
Reaction SMILES: C([Li])CCC.[C:6]1([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:17][C:18]1[CH:32]=[CH:31][CH:30]=[CH:29][C:19]=1[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1>CCCCCC.O1CCCC1>[Cl:17][C:18]1[CH:32]=[CH:31][CH:30]=[CH:29][C:19]=1[CH2:20][CH2:21][N:22]1[CH2:23][CH2:24][C:25]([CH:14]([CH3:15])[C:13]([NH:12][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:16])([OH:28])[CH2:26][CH2:27]1
Reactant: CCC(=O)Nc1ccccc1
Reactant: O=C1CCN(CCc2ccccc2Cl)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C(=O)Nc1ccccc1)C1(O)CCN(CCc2ccccc2Cl)CC1
Reaction time: 2 h

Procedure:
48 cc of n-butyl-lithium in hexane are added dropwise at 0°, in an atmosphere of nitrogen with stirring, to a solution of 9 g of N-phenylpropionamide in 90 cc of anhydrous tetrahydrofuran. The mixture is stirred at 45°-48° for 21/2 hours and a solution of 10.5 g of N-o-chlorophenethyl-4-piperidone in 25 cc of anhydrous tetrahydrofuran is added dropwise within 50 minutes. The heating (oil bath) is removed and the reaction mixture is stirred for a further hour while cooling slowly. 10 cc of a 20% potassium carbonate solution are subsequently added to the reaction solution while stirring and cooling with ice, dilution is effected with ether and the organic phase is decanted, dried over magnesium sulphate and concentrated by evaporation at reduced pressure. The resulting crude compound is filtered over silica gel resulting crude compound is filtered over silica gel (eluant: chloroform containing 3% of methanol) and an equivalent amount of fumaric acid is added to the resulting title compound in ethanol whereby this crystallizes as hydrogen fumarate. The hydrogen fumarate form of the title compound has a M.P. of 159°-161°.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[CH2:3][NH:4][C@H:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]([NH2:8])=[O:7].C(N(CC)CC)C.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>ClCCl.C(=O)(O)[O-].[Na+]>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:4]([CH2:3][C:2]([CH3:16])([CH3:15])[CH3:1])[C@H:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([NH2:8])=[O:7])(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)CN[C@@H](C(N)=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CN([C@@H](C(N)=O)c1ccccc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 50 °C
Yield: 3 %

Procedure:
(R)-2-(2,2-Dimethyl-propylamino)-2-phenyl-acetamide (700 mg, 3.2 mmol) was dissolved in dichloromethane (15 mL) and chilled in an ice bath. The solution was treated with triethylamine (553 uL, 4.0 mmol) followed by 4-chlorobenzenesulfonyl chloride (671 mg, 3.2 mmol). After heating at 50° C. for 18 h, the mixture was cooled, diluted with aqueous sodium bicarbonate and extracted with dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated to an oil. Purification on a silica gel flash column (40% EtOAc in hexanes, eluent) afforded the title compound in 3% yield. 13CNMR (100 MHz, CDCl3) 28.6, 33.2, 62.7, 70.0, 128.8, 129.0, 121.1, 129.2, 130.7, 133.6, 138.7, 139.0, 172.7. MS 395.1 m/z (M+1).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]([NH:49][CH2:50][CH3:51])[CH3:48]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([N:49]([CH2:50][CH3:51])[CH2:47][CH3:48])=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCNCC
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(CC)CC)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with diethylamine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C40H52Cl2N5O3 [(M+H)+] 720.3442, observed 720.3440.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[OH:28])/[CH:5]=[CH:6]/[C:7]1[N:15]([CH3:16])[C:14]2[C:13](=[O:17])[N:12]([CH2:18][CH2:19][CH3:20])[C:11](=[O:21])[N:10]([CH2:22][CH2:23][CH3:24])[C:9]=2[N:8]=1.C(N(C(C)C)CC)(C)C.Cl[CH2:39][O:40][CH3:41].[O:42]1[CH2:46]CC[CH2:43]1>>[CH3:39][O:40][CH2:41][O:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH2:43][O:42][CH3:46])/[CH:5]=[CH:6]/[C:7]1[N:15]([CH3:16])[C:14]2[C:13](=[O:17])[N:12]([CH2:18][CH2:19][CH3:20])[C:11](=[O:21])[N:10]([CH2:22][CH2:23][CH3:24])[C:9]=2[N:8]=1
Reactant: CCCn1c(=O)c2c(nc(/C=C/c3ccc(O)c(O)c3)n2C)n(CCC)c1=O
Reactant: COCCl
Reactant: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCn1c(=O)c2c(nc(/C=C/c3ccc(OCOC)c(OCOC)c3)n2C)n(CCC)c1=O
Yield: 57 %

Procedure:
Compound 53 (300 mg, 0.78 mmol) obtained in Reference Example 46 was dissolved in 6 ml of tetrahydrofuran. To the solution were added 1.64 ml (9.41 mmol) of diisopropylethylamine and 1.64 ml (7.12 mmol) of chloromethylmethyl ether under ice-cooling in a stream of argon, and the mixture was heated under reflux for 3 hours. Ice was added to the reaction solution and the mixture was separated with chloroform-a saturated aqueous saline solution. The organic layer was dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) and recrystallized from hexane/ethyl acetate to give 211 mg (yield 57%) of Compound 189 as white needles.