Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([SH:11])[N:4]=1.[CH3:12][N:13]1[C:17](Br)=[C:16]([N+:19]([O-:21])=[O:20])[N:15]=[C:14]1[CH3:22]>[OH-].[Na+].C(O)C>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([S:11][C:17]2[N:13]([CH3:12])[C:14]([CH3:22])=[N:15][C:16]=2[N+:19]([O-:21])=[O:20])[N:6]=1
Reactant: Cc1nc([N+](=O)[O-])c(Br)n1C
Reactant: COc1cc(OC)nc(S)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(OC)nc(Sc2c([N+](=O)[O-])nc(C)n2C)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 57.2 %

Procedure:
4,6-Dimethoxy-2-mercaptopyrimidine (3.0 g) was dissolved in an aqueous solution of sodium hydroxide (0.7 g in 100 ml water). 1,2-Dimethyl-5-bromo-4-nitro-1H-imidazole (3.9 g) dissolved in ethanol (50 ml) was added dropwise, and the mixture was stirred at room temperature for 6 hours. The precipitated product was filtered, washed with water, dried and recrystallised from acetonitrile to give 3.1 g of the desired product, mp 228°-30° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH2:12](O)[CH3:13].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:12]([O:10][C:9](=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[CH3:13]
Reactant: O=C(O)CCCCCCCBr
Reactant: CCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CCCCCCCBr
Reaction time: 12 h
Yield: 76.1 %

Procedure:
To a solution of 8-bromooctanoic acid (0.20 g, 0.89 mmol), DMAP (0.12 g, 0.99 mmol), and ethanol (0.05 g, 0.99 mmol) in methylene chloride (20 mL) was added EDCI (0.19 g, 0.99 mmol) at room temperature. After stirring for 12 h, the reaction mixture was washed with 1 N NaOH aqueous solution (15 mL) and water (30 mL), and the organic layer was dried over Na2SO4 and evaporated to give 8-bromooctanoic acid ethyl ester (0.17 g, 75%). This bromide reacted with 4-(3-adamantan-1-yl-ureido)butyric acid 822 in the same manner as that used for the preparation of 883 to provide 879 (0.19 g, 65%) as a solid: 1H NMR (CDCl3) 1.26 (3H, t, J=6.9 Hz), 1.32-1.35 (6H, m), 1.59-1.66 (10H, m), 1.82 (2H, quint, J=6.9 Hz), 1.94-1.97 (6H, m), 2.05-2.07 (3H, m), 2.28 (2H, t, J=6.9 Hz), 2.36 (2H, t, J=6.9 Hz), 3.16 (2H, q, J=6.9 Hz), 4.05-4.14 (5H, m), 4.31 (1H, s); LC-MS (ESI) m/z calcd for C25H42N2O5 [M+H]+ 451.31. found [M+H]+ 451.20; mp 58-59 C. Anal. (C25H42N2O5) C, H, N.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:12][S:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5])C.[OH-].[K+]>C(O)C.O>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([O:20][C:17]2[CH:16]=[CH:15][C:14]([S:13][CH2:12][C:6]3([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]3)=[CH:19][CH:18]=2)=[CH:26][CH:25]=1
Reactant: CCOC(=O)C1(CSc2ccc(Oc3ccc(Cl)cc3)cc2)CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1(CSc2ccc(Oc3ccc(Cl)cc3)cc2)CCOCC1
Temperature: 25 °C
Yield: 102.5 %

Procedure:
To a solution of 4-[4-(4-chlorophenoxy)phenylthiomethyl]tetrahydropyran-4-carboxylic acid ethyl ester (70 mg, 0.17 mmol) in ethanol (2 mL) containing two drops of water, was added potassium hydroxide (58.3 mg, 1.04 mmol). The mixture was refluxed for 13 hours, cooled to room temperature, acidified to pH 4, and extracted with ethyl acetate (4×50 mL). The combined organic layers were dried over magnesium sulfate, and concentrated to afford 4-[4-(4-chlorophenoxy)phenylthiomethyl]-tetrahydropyran-4-carboxylic acid (66 mg, 100%), which is spectroscopically identical to that isolated from the prior procedure of Example 7D.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=2[O:19][CH3:20])[C:12]([NH2:23])=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([N:33]=[C:34]=[S:35])(=O)C1C=CC=CC=1>CC(C)=O>[C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=2[O:19][CH3:20])[C:12]([NH:23][C:34]([NH2:33])=[S:35])=[CH:11][N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(N)c2c1
Solvent: CC(C)=O
Product: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(NC(N)=S)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.6 %

Procedure:
(4-Amino-6,8-dimethoxy-isoquinolin-1-ylmethyl)carbamic acid tert-butyl ester (225 mg, 0.675 mmol) was taken up in 10 mL of dry acetone, and benzoylisothiocyanate (121 mg, 0.742 mmol) was added dropwise. The reaction was stirred at room temperature for 2 h, and was then concentrated to a yellow solid. This solid was triturated with 50% aqueous EtOH, filtered, and suspended in 10% NaOH (5.0 mL). The reaction mixture was placed in an oil bath that was pre-heated to 98° C. for 1 h, (the solid was dissolved in 10 min). The mixture was cooled, acidified to pH 6-7 by 2.0 N aqueous HCl solution, and filtered. The yellow solid was washed with water, and dried in vacuo to give 126 mg (48%) of (6,8-dimethoxy-4-thioureido-isoquinolin-1-ylmethyl)carbamic acid tert-butyl ester. 1H-NMR (CDCl3): δ, 8.34 (s, 1H), 7.60 (s, 1H), 6.78 (d, 1H, J=2.1 Hz), 6.63 (d, 1H, J=1.9 Hz), 5.06 (d, 2H, J=3.7 Hz), 4.00 (s, 3H), 3.96 (s, 3H), 3.65 (s, 2H), 1.51 (s, 9H); MS: calculated for C18H24N4O4S+H 393.0; found: 393.0.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH3:7])[N:6]=1.Br[CH2:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18]>CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>[CH3:20][O:19][C:17]([C:16]1[CH:21]=[CH:22][CH:23]=[CH:24][C:15]=1[CH2:14][S:1][C:2]1[S:3][C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH3:7])[N:6]=1)=[O:18]
Reactant: COC(=O)Cc1sc(S)nc1C
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1sc(SCc2ccccc2C(=O)OC)nc1C
Reaction time: 1 h
Yield: 79 %

Procedure:
4.1 g of methyl 2-mercapto-4-methyl-1,3-thiazol-5-yl-acetate were dissolved in 50 ml of DMF and, in the presence of 5 g of ground potassium carbonate, 5.1 g of methyl 2-bromomethylbenzoate were added dropwise. After the evolution of heat had subsided, the mixture was stirred for 1 h, filtered, and DMF was removed in a rotary evaporator. The residue was taken up in ethyl acetate and washed 2× with water. The organic phase was dried, and the solvent was removed in vacuo. 5.6 g of an oil were obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([O-:16])=O)=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[NH2:22][C:23]1[CH:40]=[CH:39][C:26]2[N:27]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([N:36]([CH3:38])[CH3:37])=[CH:32][CH:31]=3)[NH:29][C:25]=2[CH:24]=1>>[CH3:37][N:36]([CH3:38])[C:33]1[CH:32]=[CH:31][C:30]([C:28]2[NH:27][C:26]3[CH:39]=[CH:40][C:23]([NH:22][C:14](=[O:16])[C:13]4[CH:12]=[CH:11][C:10]([NH:9][C:7](=[O:8])[C:6]5[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:21])=[CH:20][CH:19]=5)=[CH:18][CH:17]=4)=[CH:24][C:25]=3[N:29]=2)=[CH:35][CH:34]=1
Reactant: CN(C)c1ccc(-c2nc3ccc(N)cc3[nH]2)cc1
Reactant: CN(C)c1ccc(C(=O)Nc2ccc(C(=O)[O-])cc2)cc1
Product: CN(C)c1ccc(C(=O)Nc2ccc(C(=O)Nc3ccc4[nH]c(-c5ccc(N(C)C)cc5)nc4c3)cc2)cc1

Procedure:
Compound 442 was prepared from 4-(4-dimethylaminobenzamido)benzoate and 5-amino-2-(4-dimethylaminophenyl)benzimidazole by standard conditions. [M+H]+ calcd for C31H30N6O2: 519.24; found: 518.99.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([N:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)=[O:15])[C:9]2=[O:29])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14](=[O:15])[N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:9]2=[O:29])=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CN2CCC(c3ccc(Cl)cc3)(c3ccc(Cl)cc3)C2=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CN1CCC(c2ccc(Cl)cc2)(c2ccc(Cl)cc2)C1=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Example 25E (0.920 g, 1.73 mmol) in CH2Cl2 (20 mL) was added trifluoroacetic acid (2.66 mL, 34.6 mmol) under nitrogen. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated to remove excess trifluoroacetic acid and then diluted with CH2Cl2 (150 ml). The organic layer was washed with saturated aqueous NaHCO3 solution, water, and brine, dried with MgSO4, filtered, and concentrated. Purification by chromatography on silica gel, eluting with 7N NH3 in CH3OH/CH2Cl2, 3:97) yielded the title compound: 1H NMR (300 MHz, DMSO-d6) δ ppm 7.42-7.30 (m, 8H), 4.16 (s, 2H), 3.40-3.29 (m, 7H), 2.75-2.59 (m, 6H).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].[OH-].[K+].[CH3:14][N:15]([CH3:21])[NH:16][C:17](=[O:20])[CH2:18][Cl:19].O1CCOCCOCCOCCOCCOCC1>C1(C)C=CC=CC=1>[CH3:14][N:15]([CH3:21])[NH:16][C:17](=[O:20])[CH:18]([O:6][C:4](=[O:5])[C:3]1[C:7]([Cl:11])=[CH:8][CH:9]=[CH:10][CH:2]=1)[Cl:19]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: CN(C)NC(=O)CCl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN(C)NC(=O)C(Cl)OC(=O)c1ccccc1Cl
Yield: 99.8 %

Procedure:
This compound was prepared in the manner of Example I, using 12.2 grams (0.064 mole) of 2,6-dichlorobenzoic acid, 4.2 grams (0.064 mole) of potassium hydroxide, 8.7 grams (0.064 mole) of chloroacetic acid 2,2-dimethylhydrazide, and 1.7 grams of 1,4,7,10,13,16-hexaoxacyclooctadecane in 180 ml of dry toluene. The crude product was recrystallized twice from ethyl acetate using decolorizing carbon to give 18.6 grams of 2,6-dichlorobenzoyloxyacetic acid 2,2-dimethylhydrazide; mp 160°-162°. The ir and the nmr spectra were consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)[C:6]([CH:21]([NH:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][CH:30]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:5]2.O1CCCC1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)[C:6]([CH:21]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([C:33]([OH:35])=[O:34])=[CH:37][CH:38]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:5]2
Reactant: CCCCCCC(Nc1ccc(C(=O)OC)cc1)c1cc2cc(Cl)ccc2n1-c1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCC(Nc1ccc(C(=O)O)cc1)c1cc2cc(Cl)ccc2n1-c1cccc(C(F)(F)F)c1
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a mixture of methyl 4-[(1-{5-chloro-1-[3-(trifluoromethyl)phenyl]-1H-indol-2-yl}heptyl)amino]benzoate (645 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (5.00 mL), and the mixture was stirred overnight with heating under reflux, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (5.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (589 mg, 94%) as a white solid.
Reaction SMILES: [S:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([O:14][CH2:15][C:16]3[N:17]=[N:18][N:19]([CH2:21][C:22]([N:24]([CH2:36][C:37]([O:39]CC)=[O:38])[CH2:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)=[O:23])[CH:20]=3)[CH:11]=[CH:10][C:8]=2[N:9]=1)(=[O:4])(=[O:3])[NH2:2].[Li+].[OH-]>C1COCC1.O>[S:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([O:14][CH2:15][C:16]3[N:17]=[N:18][N:19]([CH2:21][C:22]([N:24]([CH2:36][C:37]([OH:39])=[O:38])[CH2:25][C:26]4[CH:27]=[CH:28][C:29]([C:32]([F:34])([F:35])[F:33])=[CH:30][CH:31]=4)=[O:23])[CH:20]=3)[CH:11]=[CH:10][C:8]=2[N:9]=1)(=[O:3])(=[O:4])[NH2:2]
Reactant: CCOC(=O)CN(Cc1ccc(C(F)(F)F)cc1)C(=O)Cn1cc(COc2ccc3nc(S(N)(=O)=O)sc3c2)nn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NS(=O)(=O)c1nc2ccc(OCc3cn(CC(=O)N(CC(=O)O)Cc4ccc(C(F)(F)F)cc4)nn3)cc2s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 20 mL round bottomed flask equipped with a magnetic stir bar containing THF:H2O (1:1, 10 mL) was placed 139 (176 mg, 0.29 mmol). To this solution LiOH (61 mg, 1.45 mmol) was added and the reaction was allowed to stir at RT for 3 h. After the reaction was done, THF was removed and the aqueous layer was acidified to pH=3 with 6 M HCl. The reaction was then poured into brine (50 mL) and extracted into CHCl3 (3×20 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried over MgSO4 and concentrated in vacuo to afford BD336 (yield not determined) as a colorless solid.
Reaction SMILES: C(=O)(O)[O-:2].[Na+].Cl.NO.[CH:9]1([C:12]2[N:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=2)[CH2:11][CH2:10]1>C(O)C>[CH:9]1([C:12]2[N:17]=[C:16]([C:18]([NH2:19])=[O:2])[CH:15]=[C:14]([C:20]([F:23])([F:21])[F:22])[CH:13]=2)[CH2:11][CH2:10]1
Reactant: N#Cc1cc(C(F)(F)F)cc(C2CC2)n1
Reactant: O=C([O-])O
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cc(C(F)(F)F)cc(C2CC2)n1
Reaction time: 4 h
Yield: 92.2 %

Procedure:
To 7 ml of ethanol were added 0.58 g of sodium bicarbonate and 0.48 g of hydroxylamine hydrochloride, and the mixture was heated to reflux for 1 hour. After allowing to cool, 0.6 g of 6-cyclopropyl-4-trifluoromethylpyridine-2-carbonitrile was added at 0° C., and the mixture was stirred for 4 hours, and concentrated. To the residue was added water, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.6 g of 6-cyclopropyl-4-trifluoromethylpyridine-2-carboxamide=oxime.
Reaction SMILES: [S:1](=[O:5])(=O)(O)[OH:2].[C:6]1([OH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[OH:12][C:6]1[CH:11]=[CH:10][C:9]([S:1]([C:9]2[CH:10]=[CH:11][C:6]([OH:12])=[CH:7][CH:8]=2)(=[O:5])=[O:2])=[CH:8][CH:7]=1
Reactant: Oc1ccccc1
Reactant: O=S(=O)(O)O
Product: O=S(=O)(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 180 °C
Reaction time: 0.03 h
Yield: 57.9 %

Procedure:
102 g (1.0 mole) of 96% sulfuric acid and 546 g (6.0 moles) of phenol were simultaneously fed dropwise over a period of 30 minutes to a vertical glass tube (length 80 cm, diameter 4 cm) heated at 180° C. and packed with glass balls (diameter 4 mm). The residence time of the reaction mixture in the packed column was about 1 to 3 minutes. The effluent reaction mixture was collected and excess phenol was distilled off. The residue was dissolved in 5-10% sodium hydroxide solution and bis(4-hydroxyphenyl) sulfone was then precipitated therefrom by the addition of sulfuric acid to a pH of from 6.5 to 7.0. After filtration and drying, there were obtained 145 g (58%) of bis(4-hydroxyphenyl) sulfone 98.5% pure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:28])[CH2:9][CH:10]([CH:17]([C:23]([O:25]CC)=[O:24])[C:18]([O:20]CC)=[O:19])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:28])[CH2:9][CH:10]([CH:17]([C:23]([OH:25])=[O:24])[C:18]([OH:20])=[O:19])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)C(CC(=O)c1ccc(Cl)cc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(CC(c1ccccc1)C(C(=O)O)C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 64.5 %

Procedure:
The solution of diethyl 2-[3-(4-chlorophenyl)-3-oxo-1-phenylpropyl]malonate (0.9 g) and 3M NaOH (7.5 ml) in ethanol (30 ml) was heated to reflux for 4 h. The mixture was cooled to rt, poured into water (30 ml), and acidified with 10% HCl. The aqueous layer was extracted three times with ethyl acetate (20 ml) and the combined organic layers were washed with brine and dried (magnesium sulfate). After evaporation of the solvent the residue was recrystallised from benzene to give 2-[3-(4-chlorophenyl)-3-oxo-1-phenylpropyl]malonic acid (0.5 g) as colourless solid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9](OS(C(F)(F)F)(=O)=O)=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)=[CH:15][C:14]([Cl:25])=[CH:13][CH:12]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[C:1]([O:5][C:6]([C:8]1[C:9]([N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)=[CH:15][C:14]([Cl:25])=[CH:13][CH:12]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2ccc(Cl)cc2c1-c1cccc(Cl)c1
Product: CC(C)(C)OC(=O)c1c(N2CCCCC2)nc2ccc(Cl)cc2c1-c1cccc(Cl)c1

Procedure:
The title compound was prepared in analogy to example 92 step A from 6-chloro-4-(3-chloro-phenyl)-2-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid tert-butyl ester (prepared as described in example 91 step C, 150 mg, 0.29 mmol) and piperidine (0.057 ml, 0.58 mmol). Pale yellow solid (95 mg, 72%). LC-MS (ESI): 457 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][O:7][C:8]([C:10]2C(C3C=CC=C([N+]([O-])=O)C=3)C(C(OC(C)C)=O)=C(C)[NH:14][C:15]=2[CH3:16])=[O:9])=[CH:4][CH:3]=1.C(O)C>C(O)(C)C>[Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][O:7][C:8](=[O:9])/[CH:10]=[C:15](\[NH2:14])/[CH3:16])=[CH:4][CH:3]=1
Reactant: CC1=C(C(=O)OCc2ccc(Cl)cc2)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)C)=C(C)N1
Solvent: CCO
Solvent: CC(C)O
Product: C/C(N)=C/C(=O)OCc1ccc(Cl)cc1
Yield: 78 %

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 3'-nitrobenzylideneacetoacetic acid isopropyl ester and 75 mmols of β-aminocrotonic acid 4-chlorobenzyl ester in 120 ml of isopropanol gave 2,6-dimethyl-3-isopropoxycarbonyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid 4-chlorobenzyl ester of melting point 137° C (from ethanol).
Reaction SMILES: [OH:1][C:2]12[CH2:6][C:4]([NH:7][C:8](=[O:10])[CH3:9])([CH2:5]1)[CH2:3]2.[H-].[Na+].I[CH2:14][CH3:15]>C1COCC1>[CH2:14]([O:1][C:2]12[CH2:6][C:4]([NH:7][C:8](=[O:10])[CH3:9])([CH2:5]1)[CH2:3]2)[CH3:15]
Reactant: CC(=O)NC12CC(O)(C1)C2
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC12CC(NC(C)=O)(C1)C2

Procedure:
To a anhydrous THF (5 mL) solution of N-(3-hydroxybicyclo[1.1.1]pentan-1-yl)acetamide (1) (1 mmol) is added NaH (60% dispersion in mineral oil, 3 mmol) portionwise at 0° C. After addition, the mixture is stirred until the evolution of gas stops. Iodoethane (1 mmol) is then added by syringe slowly. The reaction is monitored by LCMS and TLC. After consumption of starting material, the reaction mixture is quenched by adding water (3 mL) and extracted with ethyl acetate (3×). The organic layers are combined, dried (magnesium sulfate), filtered, and concentrated. The crude residue is subjected to flash chromatography (silica gel, EtOAc/hexanes) to afford N-(3-ethoxybicyclo[1.1.1]pentan-1-yl)acetamide (2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14](O)[CH2:15][CH2:16][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.N>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH2:16][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCN(CC)CCC(O)c1ccc(C2CCCCC2)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: O
Solvent: Cc1ccccc1
Product: CCN(CC)CC=Cc1ccc(C2CCCCC2)c(Cl)c1
Yield: 86.3 %

Procedure:
81 g of the compound produced in step (b) were dissolved in 500 ml of toluene and, to the solution so produced, was added a solution of 76 g of p-toluenesulphonic acid in the minimum quantity of water. The mixture was heated under reflux for about 20 hours, continuously removing the water formed. At the end of this time, the solution was cooled and poured into 2 liters of water, to which ammonia was added until the solution became alkaline. The organic phase was then separated, washed with water and dried with sodium sulphate. 66 g (yield 86%) of 3-chloro-4-cyclohexyl-1-(3-diethylamino-propen-1-yl)-benzene (hereinafter referred to as compound 933 CB) were obtained in the form of a light brown oil. This was dissolved in ether and reacted with a sufficient quantity of hydrochloric acid dissolved in the same solvent to produce 67 g of the hydrochloride having a melting point of 161° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:23][O-:24].[Na+].O>C1(C)C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH3:22])[N:12]=[CH:11][CH:10]=[C:9]2[O:8][C:5]1[CH:6]=[N:7][C:2]([O:24][CH3:23])=[CH:3][CH:4]=1
Reactant: COc1cc2nccc(Oc3ccc(Cl)nc3)c2cc1OC
Reactant: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cn1
Temperature: 25 °C
Yield: 61.5 %

Procedure:
4-(6-Chloro-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 206) (145 mg) and sodium methoxide (87 mg) were suspended in toluene (1.2 ml), and the suspension was heated under reflux for 20 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (88 mg, yield 61%).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([CH2:23][O:24]C(=O)C)[C@@H:12]([CH2:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:11][C@@H:10]1[O:37][CH2:38][C@H:39]1[O:46][C@H:43]([O:44][CH3:45])[C@H:42]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:41]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C@@H:40]1[O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C1(C)C=CC=CC=1.C[O-].[Na+]>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:13]([CH2:23][OH:24])[C@@H:12]([CH2:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:11][C@@H:10]1[O:37][CH2:38][C@H:39]1[O:46][C@H:43]([O:44][CH3:45])[C@H:42]([O:47][CH2:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C@@H:41]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C@@H:40]1[O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@H]1O[C@H](CO[C@H]2O[C@H](COCc3ccccc3)[C@@H](COC(C)=O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CO[C@H]1O[C@H](CO[C@H]2O[C@H](COCc3ccccc3)[C@@H](CO)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 6-O-(2,3,6-tri-O-benzyl-4-deoxy-4-acetyloxymethyl-α-D-glucopyranosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside (2.469 g, 2.593 mmol) is dissolved in hot toluene (20 mL) and methanol (80 mL) is added, followed by a few drops of 1 M methanolic sodium methoxide. The mixture is stirred at room temperature during 2 h. The reaction mixture is made neutral with Amberlite IR 120 (H+) resin, filtered and concentrated under reduced pressure so as to afford methyl 6-O-(2,3,6-tri-O-benzyl-4-deoxy-4-hydroxymethyl-α-D-glucopyranosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside as an amorphous solid.