Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([Cl:26])=[CH:18][C:17]=2[C:27](=[O:38])[NH:28][C:29]([C:33]([O:35][CH2:36][CH3:37])=[O:34])([CH3:32])[CH2:30][CH3:31])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:36]([O:35][C:33](=[O:34])[C:29]([NH:28][C:27]([C:17]1[CH:18]=[C:19]([Cl:26])[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]=1[O:15][CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:38])([CH3:32])[CH2:30][CH3:31])[CH3:37]
Reactant: CCOC(=O)C(C)(CC)NC(=O)c1cc(Cl)c2ccccc2c1OCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)(CC)NC(=O)c1cc(Cl)c2ccccc2c1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
To a solution of 0.16 g of 4-[4-chloro-2-(1-ethoxycarbonyl-1-methyl-propylcarbamoyl)-naphthalen-1-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester in 8 mL dichloromethane was added 4 mL of TFA at room temperature. This mixture was stirred at room temperature for 1 hour and then concentrated to dryness in vacuo. The residue was treated with 7 M NH3 in MeOH to adjust to pH 9. It was then chromatographed on silica with 7 N NH3 in MeOH/dichloromethane to provide 72 mg 2-{[4-chloro-1-(piperidin-4-yl-methoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-butyric acid ethyl ester.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]([N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)=[O:18])=[CH:20][CH:21]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: CN1CCNCC1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Product: CN1CCN(C(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)CC1
Yield: 93.3 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (2.0 g, 6.98 mmol) and 1-methylpiperazine (0.69 g, 6.98 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethanone as a white solid (2.4 g, 93.3% yield).
Reaction SMILES: [NH2:1][C@H:2]([CH2:19][OH:20])[CH2:3][C:4]([N:6]([CH:16]1[CH2:18][CH2:17]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[Cl:15])=[O:5].[C:21]([O:25][CH3:26])(=[O:24])[CH:22]=[CH2:23]>CO>[CH:16]1([N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=2[Cl:15])[C:4](=[O:5])[CH2:3][C@H:2]([NH:1][CH2:23][CH2:22][C:21]([O:25][CH3:26])=[O:24])[CH2:19][OH:20])[CH2:18][CH2:17]1
Reactant: C=CC(=O)OC
Reactant: N[C@H](CO)CC(=O)N(Cc1cccc(Cl)c1Cl)C1CC1
Solvent: CO
Product: COC(=O)CCN[C@H](CO)CC(=O)N(Cc1cccc(Cl)c1Cl)C1CC1
Temperature: 50 °C

Procedure:
Into a 250 mL round bottom was 4B (10.6 g, 33.4 mmol) and methanol (90 mL). Methyl acrylate (3.16 g, 36.8 mmol, 1.1 eq) was added and the reaction was heated to 50° C. overnight. Solvent was removed under vacuum. The residue was used in the next step without further purification. ESI-MS:m/z 403.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH2:20][CH2:19]3)[C:5]2=[N:6][CH:7]=1.[CH:33]1[CH:38]=[CH:37][C:36]([O:39][C:40](OC2C=CC=CC=2)=[N:41][C:42]#[N:43])=[CH:35][CH:34]=1>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:19][CH2:20][N:21]([C:24](=[O:32])[CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([C:40](=[N:41][C:42]#[N:43])[O:39][C:36]5[CH:37]=[CH:38][CH:33]=[CH:34][CH:35]=5)[CH2:28][CH2:27]4)[CH2:22][CH2:23]3)[C:5]2=[N:6][CH:7]=1
Reactant: O=C(CC1CCNCC1)N1CCN(C2c3ccc(Cl)cc3CCc3cc(Br)cnc32)CC1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: CC(C)O
Product: N#CN=C(Oc1ccccc1)N1CCC(CC(=O)N2CCN(C3c4ccc(Cl)cc4CCc4cc(Br)cnc43)CC2)CC1
Temperature: 80 °C
Yield: 87.4 %

Procedure:
1-(3-Bromo-8-chloro-6,11-dihydro-5 H-benzo[5,6]-cyclohepta[1,2-b] pyridin-11-yl)-4-[(4-piperidinyl)acetyl]-piperazine (Formula 47.0) (prepared as described in Preparative Example 11) (2.5 g) (1 equivalent) and diphenylcyanocarbon-imidate (1.38 g) (1.2 equivalents) were dissolved in 2-propanol (65 ml) and the solution was heated at 80° C. under reflux and under nitrogen for 24 h. The mixture was evaporated to dryness and the product was chromatographed on a silica gel column (60×2.5 cm) using neat ethyl acetate as the eluant to give the title compound (Formula 2.0) (2.7921 g; 87%), FABMS: m/z 661 (MH+).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C([OH:15])(C)C.C1(=O)OC(=O)C2=CC=CC=C12>C(O)(C)C>[C:1]([OH:6])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([OH:15])=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)O
Product: O=C(O)c1ccccc1C(=O)O

Procedure:
Phthalamic acids have been prepared by addition of a solution of secondary amine in isopropanol at 78° C. to a phthalic anhydride/isopropanol slurry at 78° C. in a one to one phthalic anhydride/amine molar ratio with subsequent vacuum stripping of the solvent. This method utilizes isopropanol as the solvent for the reaction. Isopropanol, a secondary amine, reacts with phthalic anhydride to yield isopropyl mono ester of phthalic acid. At 78° C., as much as 40% of the product may be this ester.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]([NH:13][C@H:14]1[C@@:23](C(=O)C2C=CC=CC=2)([OH:24])[C@:22](C(=O)C2C=CC=CC=2)([OH:33])[C@@H:21]([CH2:42]O)[O:20][C@@H:15]1[O:16][CH2:17][CH:18]=[CH2:19])(=[O:12])[CH3:11]>COCCOCCOC.C[O-].[Na+].CO>[C:10]([NH:13][C@H:14]1[C@@H:23]([OH:24])[C@H:22]([OH:33])[C@@H:21]([CH2:42][F:7])[O:20][C@@H:15]1[O:16][CH2:17][CH:18]=[CH2:19])(=[O:12])[CH3:11]
Reactant: C=CCO[C@H]1O[C@H](CO)[C@](O)(C(=O)c2ccccc2)[C@@](O)(C(=O)c2ccccc2)[C@@H]1NC(C)=O
Reactant: CCN(CC)S(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: COCCOCCOC
Product: C=CCO[C@H]1O[C@H](CF)[C@@H](O)[C@H](O)[C@@H]1NC(C)=O
Temperature: 40 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a stirred solution of (diethylamino)sulfur trifluoride (0.5 mL) in dry diglyme (2 mL) was added a solution of allyl 2-acetamido-3,4-di-benzoyl-2-deoxy-α-D-mannopyranoside, prepared as described above, (100 mg) in dry diglyme (3 mL) at room temperature, and the reaction mixture was stirred for one hour at room temperature and three hours at 40° C. After the starting material was consumed, the reaction mixture was poured onto ice-water and extracted with ethyl acetate. The extract was dried, concentrated, and the residue was applied to silica gel chromatography. After the impurity was eluted with hexane, the product was eluted with ether to give the fluorinated product in 89 percent yield. The product was then dissolved in 5 mL of 1N sodium methoxide in methanol to remove benzoyl group. After 20 minutes, Dowex 50W X-8[H+] was added to neutralize the reaction mixture. The resin was filtered and the filtrate was concentrated to give allyl 2-acetamido-2,6-dideoxy-6-fluoro-α-D-mannopyranoside in 99 percent yield. The product (50 mg), 1.2 equivalents of palladium (II) acetate, and 2.5 eq of sodium acetate in 95 percent acetic acid (5 mL) were stirred at 50° C. for 18 hours, and the solvent was removed under vacuum. The residue was applied to silica gel chromatography, eluted with ethyl acetate/methanol (2/1) to obtain 2-acetamido-2,6-di-deoxy-6-fluoro-α-D-mannopyranoside in 73 percent yield.
Reaction SMILES: CCCC(O[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])CC.[CH3:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([CH3:27])[C:25]=1[OH:26])[CH:21]=O>>[CH2:9]([O:10][C:14]1[CH:13]=[CH:12][C:11]([C:9](=[O:10])[CH:8]=[CH:21][C:20]2[CH:19]=[C:18]([CH3:17])[C:25]([OH:26])=[C:24]([CH3:27])[CH:23]=2)=[CH:16][CH:15]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCC(CC)OCC(=O)c1ccccc1
Reactant: Cc1cc(C=O)cc(C)c1O
Product: CCCCCCOc1ccc(C(=O)C=Cc2cc(C)c(O)c(C)c2)cc1

Procedure:
This compound was synthesized from 4-hexyloxyacetophenone and 3,5-dimethyl-4-hydroxybenzaldehyde according to general method 1 described earlier.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]([CH2:9][C:10](OCC)=[O:11])#N.Cl[C:16]([Cl:24])([C:22]#[N:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(C=C)=O>C(OCC)(=O)C>[Cl:24][C:16]([C:22]#[N:23])([CH2:7][CH2:9][CH:10]=[O:11])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C(Cl)(Cl)C#N
Reactant: CCOC(=O)CC#N
Agent: C=CC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cl)(C#N)CCC=O
Temperature: 5 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a suspension of finely ground K2CO3 (4.26 g, 30 mmol) in 100 mL of ethyl acetate were added sequentially 5.65 g of ethyl cyanoacetate (50 mmol) and 9.1 g of ethyl dichlorocyanoacetate (50 mmol) at 0° C. Acrolein (6.72 g, 120 mmol) was added within a period of 1 h using a syringe pump. The resulting mixture was stirred at 5° C. for 3 hours, filtered through Celite with the aid of CH2Cl2, concentrated (25° C., 25 mm Hg), and distilled to give 15.6 of the title compound (77%).
Reaction SMILES: [OH:1][CH2:2][CH:3]=[C:4]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])[CH3:5].[C:17]1([CH2:23][C:24](Cl)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([CH2:23][C:24]([O:1][CH2:2][CH:3]=[C:4]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])[CH3:5])=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCO
Product: CC(C)=CCCC(C)=CCCC(C)=CCOC(=O)Cc1ccccc1
Yield: 54 %

Procedure:
A mixture of farnesol (440 mg, 2 mmol) and phenylacetyl chloride (584 mg, 7.8 mmol) was refluxed for 2.5 hours. Extraction with hexane, and purification yielded 368 mg (yield: 54%) of oil having the following physical properties.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[C:8]([O:13][C:14]1[C:15]([C:20]([OH:23])([CH3:22])[CH3:21])=[N:16][CH:17]=[CH:18][CH:19]=1)=[CH:7]2.[CH3:24]I.[H-].[Na+]>CN(C)C=O>[CH3:24][O:23][C:20]([C:15]1[C:14]([O:13][C:8]2[C:9]([CH3:12])=[N:10][C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[F:1])=[CH:19][CH:18]=[CH:17][N:16]=1)([CH3:21])[CH3:22]
Reactant: CI
Reactant: Cc1nc2c(F)cccc2cc1Oc1cccnc1C(C)(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(C)(C)c1ncccc1Oc1cc2cccc(F)c2nc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 28.7 %

Procedure:
0.50 g of 2-[(8-fluoro-2-methylquinolin-3-yloxy)pyridin-2-yl]propan-2-ol and 0.45 g of methyl iodide were dissolved in 10 ml of dimethylformamide. 64 mg of sodium hydride (60% oil suspension) were added thereto while cooling with ice followed by stirring the reaction solution for 2 hours while continuing to cool with ice. Subsequently, the reaction solution was poured in ice water followed by extraction with ethyl acetate. The extract was washed with saturated saline and dried with magnesium sulfate followed by distilling off the solvent under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 0.15 g of 3-[2-(2-methoxy-2-propyl)pyridin-3-yloxy]-8-fluoro-2-methylquinoline.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=O.[IH:11].[NH2:12][NH:13][C:14]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[NH:15]>C(O)C>[IH:11].[CH2:17]([NH:16][C:14]([NH:13][N:12]=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([CH3:10])=[C:2]([CH3:1])[CH:3]=1)=[NH:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N=C(NN)NCc1ccccc1
Reactant: Cc1ccc(C=O)cc1C
Agent: I
Solvent: CCO
Product: Cc1ccc(C=NNC(=N)NCc2ccccc2)cc1C

Procedure:
A mixture of 2.68 g. of 3,4-dimethylbenzaldehyde and 5.84 g. of 1-amino-3-benzylguanidine hydroiodide [W. J. Finnegan, R. A. Henry and E. Lieber, J. Org. Chem., 18, 779 (1953)] in 30 ml. of 66% aqueous ethanol is heated under reflux for 3 hours and then allowed to cool and crystallize. Filtration gives nearly colorless crystals which are recrystallized from aqueous ethanol, giving the desired product as cream-colored crystals, m.p. 183°-185° C.
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][C:5]1=[N:6][C:7](=[O:17])[S:8]/[C:9]/1=[CH:10]\[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[Cs+].[Cs+].F[C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[C:33]([F:36])([F:35])[F:34].O>CS(C)=O>[CH3:3][NH:4][C:5]1=[N:6][C:7](=[O:17])[S:8]/[C:9]/1=[CH:10]\[CH:11]1[CH2:16][CH2:15][N:14]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=2[C:33]([F:34])([F:36])[F:35])[CH2:13][CH2:12]1
Reactant: CNC1=NC(=O)S/C1=C\C1CCNCC1
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CNC1=NC(=O)S/C1=C\C1CCN(c2ccc(C#N)cc2C(F)(F)F)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 11 %

Procedure:
To a solution of (5Z)-4-(methylamino)-5-(piperidin-4-ylmethylidene)-1,3-thiazol-2(5H)-one dihydrochloride (100 mg) in dimethyl sulfoxide (2 mL) were added cesium carbonate (327 mg) and 4-fluoro-3-(trifluoromethyl)benzonitrile (76 mg), and the mixture was stirred at 100° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/methanol) to give the title compound (14.5 mg).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16](O)=[O:17])=[N:4][NH:3]1.ON1C2C=CC=CC=2N=N1.[CH3:32][NH:33][C:34]([C:36]1[N:37]=[C:38]([C:45]([F:48])([F:47])[F:46])[N:39]2[CH2:44][CH2:43][NH:42][CH2:41][C:40]=12)=[O:35].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C=O>[CH3:32][NH:33][C:34]([C:36]1[N:37]=[C:38]([C:45]([F:48])([F:46])[F:47])[N:39]2[CH2:44][CH2:43][N:42]([C:16](=[O:17])[C:15]3[CH:19]=[CH:20][CH:21]=[C:13]([CH2:12][C:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:2](=[O:1])[NH:3][N:4]=4)[CH:14]=3)[CH2:41][C:40]=12)=[O:35]
Reactant: CNC(=O)c1nc(C(F)(F)F)n2c1CNCC2
Reactant: O=C(O)c1cccc(Cc2n[nH]c(=O)c3ccccc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)c1cccc(Cc3n[nH]c(=O)c4ccccc34)c1)CC2
Reaction time: 12 h
Yield: 89.9 %

Procedure:
3-[(4-Oxo-3H-phthalazin-1-yl)methyl]benzoic acid 15a (186 mg, 0.67 mmol) was dissolved in 20 mL of N,N-dimethylformamide, followed by addition of 1-hydroxybenzotriazole (98 mg, 0.73 mmol), crude N-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide 13a (150 mg, 0.61 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (173 mg, 0.91 mmol) and triethylamine (253 μL, 1.82 mmol). After stirring for 12 hours, the reaction mixture was was concentrated under reduced pressure, added with 50 mL of H2O and extracted with ethyl acetate (50 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain N-methyl-7-[3-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxamide 21 (280 mg, yield 90.0%) as a light yellow solid.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:28])[C:13]2[NH:19][C:18]3[C:20]([Cl:24])=[CH:21][CH:22]=[CH:23][C:17]=3[CH2:16][S:15](=[O:26])(=[O:25])[C:14]=2[CH:27]=1)=[O:9].[N+:29]([O-])([OH:31])=[O:30]>O>[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:28])[C:13]2[NH:19][C:18]3[C:20]([Cl:24])=[CH:21][C:22]([N+:29]([O-:31])=[O:30])=[CH:23][C:17]=3[CH2:16][S:15](=[O:25])(=[O:26])[C:14]=2[CH:27]=1)=[O:9]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cccc(Cl)c1N2
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc([N+](=O)[O-])cc(Cl)c1N2
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Cooled sulfuric acid (1 mL) was added to a solution of compound of Example 37e (0.3 g, 0.85 mmol) in concentrated nitric acid (10 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1.5 h. The reaction mixture was slowly poured in cold water (100 mL), solid obtained was filtered, washed with water till pH was neutral. Solid obtained was crystallized using ethyl acetate/pet. ether 60-80° C. to obtain the title compound. Yield: 0.31 g, (91.70%); 1H NMR (DMSO-d6, 300 MHz): δ 2.70 (s, 3H, CH3), 3.90 (s, 3H, OCH3), 5.30 (s, 2H, CH2), 8.10 (s, 1H, Ar), 8.15 (s, 1H, Ar), 8.35 (s, 1H, NH), 8.55 (s, 2H, Ar); MS: m/e (EI) 396 (M+).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=[O:2].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][O:2][C:1]([C:4]23[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]2)[CH2:6][CH2:5]3)=[O:3])=[CH:27][CH:26]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)OCc3ccc(Cl)cc3)(CC1)CC2
Yield: 61.4 %

Procedure:
In a similar manner to Example 8, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (30.0 mg) and 4-chlorobenzyl bromide (21.0 mg) were used to obtain (2S,4S)-1-[[N-[4-(4-chlorobenzyl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (25.5 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1.CN1CCN(C)CC1.ClN1C(=O)CCC1=O.[Cl:30][CH2:31][CH2:32][CH2:33][OH:34].ClC(Cl)(Cl)C(O)=O>ClCCl>[Cl:30][CH2:31][CH2:32][CH2:33][O:34][C:2]1[NH:1][C:9]2[C:4]([C:3]=1[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: OCCCCl
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: CN1CCN(C)CC1
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: COC(=O)c1c(OCCCCl)[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A mixture of methyl indole-3-carboxylate and dichloromethane is cooled to 0° C. 1,4-dimethylpiperazine (0.55 eq.) and N-chlorosuccinimide (1.1 eq) are added and the mixture left to stir for two hours to give a slurry containing the compound of formula (C) above. The resulting slurry is added to a solution of 3-chloropropanol (1.1 eq) and trichloroacetic acid (0.12 eq) in dichloromethane, maintaining the temperature below 0° C. The reaction mixture is left to stir for half an hour, then washed with 10% aqueous sodium carbonate, 0.5 M hydrochloric acid and water. The organic solution is dried over sodium sulphate, filtered and the solvent evaporated. Toluene is added and the mixture stirred at 0-5° C. for one hour. The product is then filtered, washed with toluene and dried to give the title product in 83% yield.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[N+:13]([C:16]1[S:20][C:19]([CH:21]=O)=[CH:18][CH:17]=1)([O-:15])=[O:14]>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:21][C:19]1[S:20][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=1
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: NNC(=S)NC1CC2C=CC1C2
Product: O=[N+]([O-])c1ccc(C=NNC(=S)NC2CC3C=CC2C3)s1

Procedure:
The title compound was prepared from a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (100 mg, 0.56 mmol) and 5-nitrothiophene-2-carboxaldehyde (88 mg, 0.56 mmol) similar to Example 3 and isolated as an orange solid (67 mg, 37%). 1H NMR (CDCl3): 10.13 (s, 1H), 7.96 (s, 1H), 7.86 (d, J=4.2 Hz, 1H), 7.37 (d, J=7.5 Hz, 1H), 7.17 (d, J=4.2 Hz, 1H), 6.26-6.13 (m, 2H), 4.26-4.20 (m, 1H), 3.05 (s, 1H), 3.00 (s, 1H), 1.95-1.87 (m, 1H), 1.70 (d, J=9.0 Hz, 1H), 1.49 (d, J=9.0 Hz, 1H), 1.46-1.39 (m, 1H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]1([C:11]2[C:12](=[O:19])[CH:13]3[CH:17]([CH:18]=2)[CH2:16][CH2:15][CH2:14]3)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>ClCCl>[C:1]([C:8]1[CH:7]=[CH:6][C:5]([C:11]2[C:12](=[O:19])[CH:13]3[CH:17]([CH:18]=2)[CH2:16][CH2:15][CH2:14]3)=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: O=C1C(c2ccccc2)=CC2CCCC12
Solvent: ClCCl
Product: CC(=O)c1ccc(C2=CC3CCCC3C2=O)cc1

Procedure:
A solution of Perrier complex was prepared from acetyl chloride (663mg, 8.45 mmol) and aluminimum chloride (1.13 g, 8.45 mmol) in dichloromethane (5 ml) and 4,5,6,6a-tetrahydro-2-phenyl-1(3aH)pentalenone (335 mg, 1.69mmol) in dichloromethane (95 ml) was added at 0° C. The mixture was heated under reflux for 48 h, then poured onto ice, extracted with dichloromethane and the extract washed with aqueous potassium carbonate and dried (MgSO4). After removal of solvent the residue was chromatographed. Ethyl acetate—n-hexane (1:2) eluted unreacted starting ketone (17 mg) followed by the title product (277 mg, 68%), yellowish crystals, m.p. 76-77° C.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][CH2:12][NH2:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH2:14][C:15](=[O:28])[CH2:16][C:17]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][CH:23]2[O:25][CH2:24]2)=[CH:19][CH:18]=1>CO>[NH2:14][C:15](=[O:28])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:21][CH2:22][CH:23]([OH:25])[CH2:24][NH:13][CH2:12][CH2:11][CH2:10][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[CH:2]2)=[CH:26][CH:27]=1
Reactant: NC(=O)Cc1ccc(OCC2CO2)cc1
Reactant: NCCCn1cnc2ccccc21
Solvent: CO
Product: NC(=O)Cc1ccc(OCC(O)CNCCCn2cnc3ccccc32)cc1

Procedure:
A mixture of 9.8 grams of 1H-benzimidazole-1-propanamine and 12.16 grams of 1-[4-(2-amino-2-oxoethyl)phenoxy]-2,3-epoxypropane in 400 ml of 95% methanol was refluxed for 17 hours. The solvent was then evaporated under reduced pressure and the residue was chromatographed on a silica gel column packed in chloroform and eluted with solutions containing increasing percentages of methanol in chloroform. The fractions eluted with 30% methanol were combined and the solvent evaporated under reduced pressure. The solid residue was triturated with ether and then separated and dried at reduced pressure and room temperature to give N-{3-[4-(2-amino-2-oxoethyl)phenoxy]-2-hydroxypropyl}-1H-benzimidazole-1-propanamine melting at about 92°-96° C. This compound has the following structural formula: ##STR12##
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24](=[O:34])[C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=3[O:32][CH3:33])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)([CH3:8])[C:3](OCC)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH3:8][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24](=[O:34])[C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=3[O:32][CH3:33])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)([CH3:1])[CH2:3][OH:4]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(-c2ccc(CNC(=O)c3cc(Cl)ccc3OC)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1ccc(Cl)cc1C(=O)NCc1ccc(-c2ccc(OC(C)(C)CO)cc2)cc1

Procedure:
1.8 gm (3.74 millimols) of ethyl 2-methyl-2-{4-[(2-methoxy-5-chloro-benzamido)-methyl]-biphenyl-4'-oxy}-propionate were reduced to the alcohol by heating in 50 ml of ether with 0.1 gm (3.8 millimols) of lithium aluminum hydride at the boiling point of the solvent for 15 minutes. After decomposition with water, drying of the ether phase over sodium sulfate, and distilling off the ether, the alcohol was purified on a silicagel column with benzene/ethyl acetate (6:4) as the eluant. Yield: 0.5 gm (30% of theory); m.p. 109° C.