Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3]/[N:4]=[C:5](/[C:9]1[N:10]=[C:11]([NH:14][C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:12][CH:13]=1)\[C:6](O)=[O:7])[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:40][CH:41]1[C:66](=[O:67])[N:43]2[C:44]([C:50]([O:52][CH:53]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)[C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[O:51])=[C:45]([CH2:48][Cl:49])[CH2:46][S:47][C@H:42]12.C([O-])(O)=O.[Na+]>ClCCl>[Cl:49][CH2:48][C:45]1[CH2:46][S:47][C@@H:42]2[CH:41]([NH:40][C:6](=[O:7])/[C:5](/[C:9]3[N:10]=[C:11]([NH:14][C:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[S:12][CH:13]=3)=[N:4]\[O:3][CH2:1][CH3:2])[C:66](=[O:67])[N:43]2[C:44]=1[C:50]([O:52][CH:53]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)=[O:51]
Reactant: CCO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (Z)-2-ethoxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (IVb) (1.095 g, 2.4 mmoles) in dichloromethane (20 mL) was added phosphorus pentachloride (500 mg). After stirring for 1 hour at room temperature, the mixture was added in one portion to an ice-cooled solution of Compound V (1.083 g, 2.4 mmoles) and BSA (1 mL) in dichloromethane (20 mL). After stirring for 0.5 hour the reaction mixture was poured into 10% aqueous NaHCO3 (200 mL) and extracted with CHCl3 (100 mL). The extract was washed with water, dried over MgSO4, and evaporated under reduced pressure. The residue was chromatographed on a silica gel column. Elution with CHCl3 gave VIb as an amorphous powder, 1.76 g (86%).
Reaction SMILES: [OH-].[K+].[CH:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][C:4]=1[OH:13].[CH3:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[O:18][CH2:19][CH2:20]Cl>O>[CH3:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[O:18][CH2:19][CH2:20][O:13][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:3]=1
Reactant: Cc1cccc(OCCCl)c1
Reactant: Oc1ccc2c(c1)CCCC2
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc(OCCOc2ccc3c(c2)CCCC3)c1

Procedure:
4.0 g (0.06 mol) of 85% potassium hydroxide was dissolved in 25 g of distilled water and 7.4 g (0.05 mol) of 5,6,7,8-tetrahydro-β-naphthol was dissolved in the formed solution. 8.5 g (0.05 mol) of 2-(3-methylphenoxy)ethyl chloride was added to the solution and the mixture was stirred under reflux for 3 h.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][CH:9]=2)=[C:5]([CH3:16])[N:4]([C@@H:17]2[O:46][C@H:45]([CH2:47][O:48]CC3C=CC=CC=3)[C@@H:36]([O:37]CC3C=CC=CC=3)[C@H:27]([O:28]CC3C=CC=CC=3)[C@H:18]2[O:19]CC2C=CC=CC=2)[N:3]=1>C(O)C.O1CCCC1.[OH-].[Pd+2].[OH-]>[CH3:1][C:2]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][CH:9]=2)=[C:5]([CH3:16])[N:4]([C@@H:17]2[O:46][C@H:45]([CH2:47][OH:48])[C@@H:36]([OH:37])[C@H:27]([OH:28])[C@H:18]2[OH:19])[N:3]=1
Reactant: CCc1ccc(Cc2c(C)nn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c2C)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1ccc(Cc2c(C)nn([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.6 %

Procedure:
3-(4-ethylphenylmethyl)-2,4-pentanedione 28 (700 mg) and 2,3,4,6-tetra-O-benzyl-α,β-D-glucosehydrazone 29 (1.70 g) (See Schmidt, R. R. et al., Liebigs Ann. Chem. 1981, 2309) were dissolved in tetrahydrofuran (20 ml), and the mixture was stirred at room temperature for 18 hours under argon atmosphere. The solvent was evaporated under reduced pressure, and the residue was dissolved in toluene (20 ml), and the mixture was heated with stirring under reflux for 2 hours. The mixture was left alone until it was cooled, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10-65:35) to give 3,5-dimethyl-4-(4-ethylphenylmethyl)-1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)pyrazole 30 (299 mg) as a pale yellow semisolid. APCI-Mass m/Z 737 (M+H). (2) The above tetrabenzyl compound 30 (294 mg) was dissolved in a mixture of ethanol (5 ml) and tetrahydrofuran (4 ml), and added thereto was palladium hydroxide (100 mg), and the mixture was stirred at room temperature for 16 hours under hydrogen atmosphere under normal pressure. Insoluble materials were filtered off, and the solvent was evaporated under reduced pressure. The residue was crystallized from diethyl ether to give the desired 3,5-dimethyl-4-(4-ethylphenylmethyl)-1-(β-D-glucopyranosyl)pyrazole 31 (118 mg) as colorless powder. APCI-Mass m/Z 377 (M+H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C([N:15]([CH2:26][CH3:27])[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH3:24])C.[CH3:28][CH:29]1[CH2:33][CH:32]([CH3:34])[N:31]([CH2:35]CC#N)[CH:30]1[CH2:39][OH:40].Cl>O1CCCC1>[CH3:28][CH:29]1[CH2:33][CH:32]([CH3:34])[N:31]([CH2:35][CH2:27][C:26]2[NH:15][C:16](=[O:25])[C:17]3[C:18]([CH:24]=2)=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)[CH:30]1[CH2:39][OH:40]
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Reactant: CC1CC(C)N(CCC#N)C1CO
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1cccc2c(=O)[nH]c(CCN3C(C)CC(C)C3CO)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.6 %

Procedure:
Diisopropylamine (3.3 g) was dissolved in tetrahydrofuran (20 mL) and n-butyllithium (1.58M, hexane solution, 19 mL) was is added dropwise under a nitrogen stream at −78° C. After the completion of the dropwise addition, a solution (20 mL) of N,N-diethyl-2,3-dimethylbenzamide (5.2 g) in tetrahydrofuran was added dropwise and the mixture was stirred for 1 hr. A solution (20 mL) of 3-(3,5-dimethyl-2-hydroxymethylpyrrolidin-1-yl)propionitrile (2.3 g) in tetrahydrofuran was added dropwise to the reaction mixture and the temperature of the reaction mixture was raised to room temperature. After the completion of the reaction, the reaction mixture was acidified by adding conc. hydrochloric acid. The reaction mixture was concentrated and washed with hexane. The aqueous layer was basified by adding potassium carbonate and extracted with chloroform. The organic layer was dried over magnesium sulfate. The solvent was concentrated and the obtained residue was purified by silica gel column chromatography The fraction eluted with chloroform:methanol=30:1 was concentrated and the obtained residue was again purified by silica gel column chromatography (NH silica gel, Fuji Silysia Chemical). The fraction eluted with chloroform was concentrated and ether was added to the obtained residue. The precipitated crystals were collected by filtration to give 3-[2-(3,5-dimethyl-2-hydroxymethylpyrrolidin-1-yl)ethyl]-5-methyl-2H-isoquinolin-1-one (0.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)[N:6]=[C:5]([C:18]([OH:20])=O)[CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:33][C:34]1[NH:38][N:37]=[N:36][N:35]=1>CN(C)C=O>[NH:35]1[C:34]([NH:33][C:18]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([C:9]3[CH:10]=[CH:11][C:12]([N:15]([CH3:16])[CH3:17])=[CH:13][CH:14]=3)[N:6]=2)=[O:20])=[N:38][N:37]=[N:36]1
Reactant: Nc1nnn[nH]1
Reactant: COc1cc(C(=O)O)nc(-c2ccc(N(C)C)cc2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Nc2nnn[nH]2)nc(-c2ccc(N(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
To a solution of 4-methoxy-6-(4-dimethylaminophenyl)-2-pyridinecarboxylic acid (0.44 g) in dimethylformamide (6 ml) is added carbonyldiimidazole (0.29 g), and the mixture is agitated at room temperature for one hour. To the mixture is added 5-aminotetrazole (0.15 g), and the mixture is heated at 70° C. for one hour. After cooling, the reaction mixture is poured into ice-water. The resulting precipitates are collected by filtration and washed with water and ethanol to give N-(5-tetrazolyl)-4-methoxy-6-(4-dimethylaminophenyl)-2-pyridinecarboxamide (0.36 g). M.P. 261°-263° C. (recrystallized from dimethylformamide-ethanol)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[NH2:10][C:11]1[C:15]([Br:16])=[C:14]([CH3:17])[O:13][N:12]=1>N1C=CC=CC=1>[Br:16][C:15]1[C:11]([NH:10][S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:8])=[O:7])=[N:12][O:13][C:14]=1[CH3:17]
Reactant: Cc1onc(N)c1Br
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: c1ccncc1
Product: Cc1onc(NS(=O)(=O)c2cccs2)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
Thiophene-2-sulfonyl chloride (183 mg, 1 mmol) was added to a solution of 3-amino-4-bromo-5-methylisoxazole (177 mg,1 mmol) in dry pyridine (0.5 ml). The reaction mixture was stirred at room temperature for 3 h. Pyridine was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with 1N HCl (3×10 ml), brine (10 ml) and dried over anhydrous magnesium sulfate. Evaporation of the solvents left an oily residue which was solidified at -20° C. and then purified by recrystallization from ethyl acetate/hexanes, to give the pure product (51 % yield) as a tan solid, m.p. 156-158° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1Br.C([Li])CCC.[C:15]([O:18][CH2:19][C:20]([CH2:22][O:23][C:24](=[O:26])[CH3:25])=[O:21])(=[O:17])[CH3:16].Cl>C(OCC)C.CCCCCC>[C:24]([O:23][CH2:22][C:20]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([OH:21])[CH2:19][O:18][C:15](=[O:17])[CH3:16])(=[O:26])[CH3:25]
Reactant: CC(=O)OCC(=O)COC(C)=O
Reactant: Fc1ccc(Br)c(F)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(=O)OCC(O)(COC(C)=O)c1ccc(F)cc1F
Temperature: -30 °C
Reaction time: 1 h
Yield: 27.8 %

Procedure:
Under an atmosphere of argon, 22.5 g of 2,4-difluorobromobenzene was dissolved in 200 ml of diethyl ether and to the resulting solution was added dropwise 73 ml of 1.63M n-hexane solution of n-butyllithium at -30° C. The resulting liquid was stirred for 1 hour and stored at -60° C. This liquid was carefully added dropwise using an injection cylinge to 150 ml of diethyl ether solution of 17.4 g of 1,3-diacetoxyacetone which was previously cooled to -30° C. After the resulting liquid was stirred at -60° C. for 2 hours, a temperature thereof was gradually raised to room temperature. Then, the reaction mixture was transferred to 100 ml of 1.2N aqueous solution of hydrochloric acid at 5° C. or below, and the organic layer was separated therefrom and the aqueous layer was extracted twice with 100 ml of ethyl acetate. The organic layers were combined and washed with saturated aqueous solution with sodium chloride, dried over anhydrous magnesium sulfate. The resulting organic layer was filtered and the solvent was removed under reduced pressure. Thus obtained concentrate was purified by column chromatography on silica gel (hexane: ethyl acetate=1:1) to give 8 g of the desired compound.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=C.C(N(CCCC)CCCC)CCC>CC1C=CC(C)=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH:8]=[CH:14][C:13]([O:17][CH2:18][CH3:19])=[O:16])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccc(C)cc1
Product: CCOC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Yield: 55.2 %

Procedure:
The procedure described in Example 1 is repeated, except that 9.28 g (0.05 mol) of 4-nitrobenzoyl chloride, 6.25 g (0.0625 mol) of ethyl acrylate, 8.65 g (0.05 mol) of tri-n-butylamine and 0.1122 g (0.0005 mol) of palladium acetate are used. After a reaction time of 1 hour at 120° C. in 100 ml of p-xylene as the solvent, 6.1 g (0.0276 mol) of ethyl 4-nitrocinnamate are obtained, corresponding to a yield of 55.2% of theory; melting point 137.5° C. Analysis for C11H11NO4 (molecular weight 221: calculated C 59.73%, H 5.01%, N 6.33%; found C 59.47%, H 4.96%, N 6.27%.
Reaction SMILES: [N:1]1([C:7]([C@H:9]2[NH:13][CH2:12][C@@H:11]([S:14][C:15](=[O:17])[CH3:16])[CH2:10]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[S:28](Cl)(=[O:30])=[O:29].OS([O-])(=O)=O.[K+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[S:28]([N:13]1[C@H:9]([C:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:8])[CH2:10][C@H:11]([S:14][C:15](=[O:17])[CH3:16])[CH2:12]1)(=[O:29])=[O:30]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CC(=O)S[C@@H]1CN[C@H](C(=O)N2CCCCC2)C1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)S[C@H]1C[C@@H](C(=O)N2CCCCC2)N(S(=O)(=O)c2ccc3ccccc3c2)C1
Yield: 53.6 %

Procedure:
300 mg (1.17 mmol) (3S,5S)-Thioacetic acid S-[5-(piperidine-1-carbonyl)-pyrrolidin-3-yl] ester in 25 ml CH2Cl2 were treated with 398 mg (1.75 mmol, 1.5 eq) 2-naphthalene sulfonylchloride in the presence of 214 mg (1.75 mmol, 1.5 eq) DMAP at RT for 1.5 h. The solution was added to 1M KHSO4, the phases were separated and the inorganic extracted with CH2Cl2, the combined organic phases were washed with 1M KHSO4, water and brine, dried over Na2SO4 and were concentrated. Flash chromatography yielded 280 mg (54%) (3S,5S)-Thioacetic acid S-[1-(naphthalene-2-sulfonyl)-5-(piperidine-1-carbonyl)-pyrrolidin-3-yl] ester as white crystals.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([OH:12])[CH:11]=1)=[O:5].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH3:3][C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1)=[O:5]
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.2 %

Procedure:
To a mixture of sodium hydride (4.5 g of 80% mineral oil dispersion, 0.15 mol), which had been washed free of mineral oil, in DMF (25 ml) was added, dropwise with cooling, a solution of 3-hydroxyacetophenone (20.5 g, 0.15 mol) in DMF (25 ml). Upon completion of the addition, the mixture was allowed to stir at room temperature for 15 min, at which time was added benzyl bromide (25.6 g, 0.15 mol). The resulting mixture was allowed to stir at room temperature overnight, then was partitioned between EtOAc and 3M HCl. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed successively with 1M NaOH, H2O and saturated aqueous NaCl and dried. The solvent was removed in vacuo to afford the title compound (33 g, 97%), which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:10]O.C=O>CO.O>[NH:1]1[C:2]2([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:8][O:9][CH2:10]1
Reactant: NC1(CO)CCCCC1
Reactant: CO
Agent: C=O
Solvent: O
Product: C1CCC2(CC1)COCN2
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a 500 mL flask containing 1-amino-cyclohexylmethanol (135 g, 1.05 mol) and methanol (50 mL) is added methyl formcel (53 mL of 55% formaldehyde in methanol/water, 1.06 mol) dropwise over a 1 hour period. During the addition, the stirred solution is warmed gently from room temperature to 37° C. After the addition is completed, the mixture is allowed to stir overnight at room temperature. The clear, colorless reaction mixture is stripped on a rotary evaporator (50° C./29″ vacuum). The resulting oil is distilled under vacuum giving a clear, colorless, mobile liquid with a boiling point of 43° C./0.8 torr. A total of 123.4 g is collected (83% yield). A GC analysis indicates 95.6% purity.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18](O)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[OH:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][NH:27][CH2:28]2>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:17]=[C:16]([C:18]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[CH:32][C:23]=4[OH:22])[CH2:28]3)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1cccc2c1CCNC2
Reactant: O=C(O)c1nc(-c2ccc(F)cc2)nc2ccccc12
Agent: Cl
Product: O=C(c1nc(-c2ccc(F)cc2)nc2ccccc12)N1CCc2c(O)cccc2C1
Yield: 24.2 %

Procedure:
Reaction of 2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 5-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 9 (24.2% yield): 1H NMR (300 MHz, DMSO-d6) δ 2.60 and 2.87 (2t, 2H), 3.51 and 4.07 (2t, 2H), 4.45 and 4.96 (2s, 2H), 6.32-6.79 (m, 2H), 6.88 and 7.08 (2t, 1H), 7.37-7.44 (m, 2H), 7.70-7.79 (m, 1H), 7.88-7.99 (2d, 1H), 8.07-8.18 (m, 2H), 8.53-8.62 (m, 2H), 9.50 and 9.55 (2s, 1H); 19F (282 MHz, DMSO-d6) δ −110.0; MS (ESI) m/z 400 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][C@@H:30]2[CH2:32][O:31]2)=[CH:26][CH:25]=1>>[Br:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][N:14]([CH2:32][C@H:30]([OH:31])[CH2:29][O:28][C:27]5[CH:33]=[CH:34][C:24]([Cl:23])=[CH:25][CH:26]=5)[CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1
Reactant: O=C1C(=O)c2ccc(Br)cc2C2=C1SCC1(CCNCC1)O2
Reactant: Clc1ccc(OC[C@@H]2CO2)cc1
Product: O=C1C(=O)c2ccc(Br)cc2C2=C1SCC1(CCN(C[C@H](O)COc3ccc(Cl)cc3)CC1)O2

Procedure:
Compound 190 was synthesized using 9-bromospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-[(4-chlorophenoxy)methyl]oxirane and conditions outlined in procedure Y. M.p.=150-152° C.; 400 MHz 1H NMR (CDCl3) δ: 7.92-7.89 (m, 1H), 7.87-7.85 (m, 1H), 7.65-7.62 (m, 1H), 7.27-7.22 (m, 2H), 6.88-6.84 (m, 2H), 4.20-4.08 (m, 1H), 4.03-3.95 (m, 2H), 2.96 (s, 3H), 2.85-2.74 (m, 2H), 2.74-2.60 (m, 2H), 2.60-2.50 (m, 1H), 2.21-2.12 (m, 2H), 2.00-1.85 (m, 2H); LCMS: 564 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][C:9](=[O:11])[C:8]2[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=2[O:2][CH3:1])[C:12]([NH2:14])=[O:13])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: Nc1cccc(Cl)c1
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1cccc(Cl)c1

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 3-chloroaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH3:11][C:12]([CH3:26])([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][OH:23])[CH2:13][OH:14]>N1C=CC=CC=1>[C:2]([O:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:12]([CH3:26])([CH3:11])[CH2:13][O:14][C:2](=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: CC(C)(CO)CCCCCCC(C)(C)CO
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(CCCCCCC(C)(C)COC(=O)c1cccnc1)COC(=O)c1cccnc1
Yield: 65 %

Procedure:
106.2 Grams (0.6 mole) of nicotinoyl chloride hydrochloride in 300 ml of anhydrous pyridine were reacted with 23.0 grams (0.1 mole) of 2,2,9,9-tetramethyl-1,10-decanediol, according to the procedure described in Example 1. 28.8 Grams of product, recrystallized from ethanol, were obtained, having m.p. 68°-69° C. Yield: 65,5% of theoretical.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].C(N(CC)CC)C>ClCCl>[CH3:12][C:11]([Si:8]([CH3:10])([CH3:9])[O:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1NCC[C@@H]1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCNC1=O
Reaction time: 8 h
Yield: 72.1 %

Procedure:
A mixture of 14 g of (S)-3-hydroxy-2-pyrrolidinone, 45 g of tert-butyldimethylsilyl chloride, 50 ml of triethylamine and 500 ml of dichloromethane was stirred overnight. The solution was washed four times with water, once with brine, dried and concentrated in vacuo. The residue was dissolved in 500 ml of methanol, refluxed overnight and concentrated in vacuo. The residue was purified by chromatography (silica gel), giving 21.5 g of (S)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2-pyrrolidinone; [α]D26° =-52° (dichloromethane); mp 48°-49° C.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[C:17](N1C=CN=C1)([N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)=[O:18]>C(Cl)Cl>[C:4]([C:3]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:2]=1[NH:1][C:17]([N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)=[O:18])(=[O:5])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cc(Cl)ccc1NC(=O)n1ccnc1
Temperature: 45 °C
Yield: 69.9 %

Procedure:
To a solution of 2-amino-5-chlorobenzophenone (40 g, 172.7 mmol) in CH2Cl2 (175 μL) was added carbonyldiimidazole (30.8 g, 189.9 mmol). The reaction was heated to 45° C. for 16 h resulting in a white precipitate. The reaction was cooled in an ice bath and the precipitate collected by vacuum filtration and dried to give 39.3 g (69.9%) of N-(2-benzoyl-4-chlorophenyl)-1H-imidazole-1-carboxamide as a white solid. 1H NMR (CDCl3, 400 MHz) 8.66 (s, 1H); 7.46 (m, 4H); 7.25 (s, 1H); 7.19 (d, J=6.96 Hz, 2H); 7.15 (s, 1H); 6.94 (m, 2H); 6.76 (d, J=2.29 Hz, 1H). MS (Electrospray): m/z 348.0 (M+Na).
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([O-:8])=[O:7].[C:16]([C:18]1[CH:23]=[C:22]([S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[CH:21]=[CH:20][C:19]=1[F:30])#[CH:17]>>[Cl:15][C:13]1[CH:12]=[CH:11][C:3]([O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7])=[C:2]([C:17]#[C:16][C:18]2[CH:23]=[C:22]([S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[CH:21]=[CH:20][C:19]=2[F:30])[CH:14]=1
Reactant: CC(C)(Oc1ccc(Cl)cc1Br)C(=O)[O-]
Reactant: C#Cc1cc(S(=O)(=O)CCC)ccc1F
Product: CCCS(=O)(=O)c1ccc(F)c(C#Cc2cc(Cl)ccc2OC(C)(C)C(=O)O)c1

Procedure:
Following the general method as outlined in Example 168, starting from 2-(2-bromo-4-chlorophenoxy)-2-methylpropanoate (Intermediate 264), and 2-ethynyl-1-fluoro-4-(propane-1-sulfonyl)-benzene (Intermediate 109) the title compound was obtained as a brown sticky solid after purification by preparative HPLC.