Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8](=[N:10][OH:11])[NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][CH:13]([CH3:17])[C:14](Cl)=O.C(N(CC)CC)C>CC(C)=O>[CH2:7]([C:8]1[N:9]=[C:14]([CH:13]([Cl:12])[CH3:17])[O:11][N:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(Cl)C(=O)Cl
Reactant: NC(Cc1ccccc1)=NO
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(Cl)c1nc(Cc2ccccc2)no1
Temperature: 0 °C
Yield: 95.2 %

Procedure:
First, 15.0 grams (0.1 mole) of phenyl acetamide oxime was combined with 100 milliliters of dry acetone in a 250 milliliter flask fitted with a thermometer and dropping funnel. The solution was stirred and cooled to 0° C. Next, 12.7 grams (0.1 mole) of 2-chloro propionyl chloride and 10.1 grams (0.1 mole) of triethyl amine was added. During the additions, the temperature was maintained at 0 to 5° C. After the additions were complete, the reaction mass was stirred at room temperature for 30 minutes and then was filtered free of salt. The filtrate was evaporated in vacuo at 50° and the residue was taken up in 300 milliliters of toluene. The toluene solution was charged to a 500 milliliter flask fitted with a Dean Stark water trap, 0.1 gram of toluene sulfonic acid was added, and the solution was heated under reflux until water ceased to be evolved. The toluene solution was then treated with activated carbon, filtered and evaporated in vacuo at 50° C. to yield 21.2 grams (95% of theory) of 3-benzyl-5-(1-chloroethyl)1,2,4-oxadiazole. nD30 1.5040.
Reaction SMILES: N1C=CC=CC=1.C(B1OB(C=C)OB([CH:17]=[CH2:18])O1)=C.[CH2:19]([O:26][C:27]1[N:28]=[N:29][C:30](Cl)=[CH:31][C:32]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH2:19]([O:26][C:27]1[N:28]=[N:29][C:30]([CH:17]=[CH2:18])=[CH:31][C:32]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: C=CB1OB(C=C)OB(C=C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Temperature: 80 °C
Yield: 75.3 %

Procedure:
A vessel containing 2,4,6-triethenyl-1,3,5,2,4,6-trioxatriborinane compound with pyridine (1:1) (1.105 g, 4.59 mmol), 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1, 3 g, 9.18 mmol) and potassium carbonate (3.17 g, 22.95 mmol) was evacuated and flushed with nitrogen. Dioxane (30 ml) and water (3 ml) were added in vacuo and the reaction was degassed before tetrakis(triphenyl-phosphine)palladium(0) (0.530 g, 0.459 mmol) was added. The resulting mixture was then heated at 80° C. for 18 hours and upon cooling, was diluted with ethyl acetate and washed with saturated aqueous sodium carbonate solution. The organics were dried (MgSO4), filtered and solvent removed in vacuo to give a brown oil. This was purified by column chromatography (silica, eluting with 0-30% ethyl acetate in petrol) to afford 3,4-bis(benzyloxy)-6-ethenylpyridazine (1.1 g, 38% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:8]2=[O:9])[CH2:3][CH2:2]1.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl>[NH:24]([C:25]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:8]2=[O:9])[CH2:3][CH2:2]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=C1CCc2ccccc2N1C1CCNCC1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-(4-Piperidinyl)-3,4-dihydrocarbostyril (0.8 g) is dissolved in dichloromethane (20 ml) and thereto is added phenylisocyanate (0.57 ml) and the mixture is stirred at room temperature for 4 hours. The solvent is concentrated and the residue is purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=5:1) and recrystallized from n-hexane/ethanol to give 1-(1-anilinocarbonyl-4-piperidinyl)-3,4-dihydrocarbostyril (0.8 g), as white powder, m.p. 194°-196° C.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[C@H:12]1[C@@H:17]([NH:18][C:19](=[O:27])[O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][C@H:15]2[C@@H:13]1[CH2:14]2.NN>C(O)C>[NH2:3][C@H:12]1[C@@H:17]([NH:18][C:19](=[O:27])[O:20][CH2:21][CH2:22][Si:23]([CH3:25])([CH3:24])[CH3:26])[CH2:16][C@H:15]2[C@@H:13]1[CH2:14]2
Reactant: C[Si](C)(C)CCOC(=O)N[C@H]1C[C@@H]2C[C@@H]2[C@H]1N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Product: C[Si](C)(C)CCOC(=O)N[C@H]1C[C@@H]2C[C@@H]2[C@H]1N
Temperature: 75 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
To a solution of 2-(trimethylsilyl)ethyl (1S,2R,3S,5S)-2-(1,3-dioxoisoindolin-2-yl)bicyclo[3.1.0]hexan-3-ylcarbamate (1.5 g, 3.886 mmol) in ethanol (20 mL) at room temperature was added hydrazine (1.9 ml, 38.860 mmol), and the resulting mixture was stirred at 75° C. for 2 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:4) to afford the title compound (800 mg, 80%) as a light yellow semi-solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:17][C@H:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]([CH3:19])([CH3:18])[CH2:10]2)[C:5]([F:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:42]=[CH:41][C:25]([O:26][C@H:27]2[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][C@@H:28]2[F:40])=[C:24]([Cl:43])[CH:23]=1.CC1C=CC(S(O)(=O)=O)=CC=1.Cl>CC(O)C.O1CCOCC1>[Cl:43][C:24]1[CH:23]=[C:22]([NH:21][C:2]2[N:7]=[C:6]([NH:8][C@@H:9]3[CH2:17][C@H:16]4[N:12]([CH2:13][CH2:14][CH2:15]4)[C:11]([CH3:19])([CH3:18])[CH2:10]3)[C:5]([F:20])=[CH:4][N:3]=2)[CH:42]=[CH:41][C:25]=1[O:26][C@H:27]1[CH2:32][CH2:31][NH:30][CH2:29][C@@H:28]1[F:40]
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2F)C[C@@H]2CCCN21
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(N)cc2Cl)[C@@H](F)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CC1(C)C[C@H](Nc2nc(Nc3ccc(O[C@H]4CCNC[C@@H]4F)c(Cl)c3)ncc2F)C[C@@H]2CCCN21
Temperature: 100 °C
Yield: 50 %

Procedure:
A mixture of (7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-5,5-dimethyloctahydroindolizin-7-amine (0.2 g, 1.0 eq, 0.6 mmol), tert-butyl (3S,4S)-4-(4-amino-2-chlorophenoxy)-3-fluoropiperidine-1-carboxylate (0.2 g, 1.0 eq, 0.64 mmol) and PTSA (0.1 g, 0.9 eq, 0.6 mmol) was taken in iPrOH (10 mL) and heated at 100° C. for over night. After 18 hours of heating, reaction mixture was cooled to room temperature and PTSA (1.0 eq) was added to complete the deprotection of the Boc group. Then the reaction mixture was heated at 100° C. for 3 hours while stifling and cooled to room temperature. The volatiles were removed under vacuum to leave a crude solid. 4N HCl in dioxane (5 mL) was added to the crude mixture to ensure complete dprotection of the Boc group and the mixture was concentrated to dryness. Work-up and purification conditions used were the same as in Example 89 above for Compound 119, and gave the product as a solid in 50% yield.
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:13]2[N:14]=[C:15]([NH2:18])[N:16]=[CH:17][C:12]=2[CH:11]=[C:10]([C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:26])[C:9]1=[O:27])(C)(C)C.FC(F)(F)C(O)=O.C(OCC)C>C(Cl)Cl>[NH2:18][C:15]1[N:16]=[CH:17][C:12]2[CH:11]=[C:10]([C:19]3[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:26])[C:9](=[O:27])[N:8]([CH2:7][C:6]([OH:28])=[O:5])[C:13]=2[N:14]=1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(N)nc21
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(CC(=O)O)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 52.5 %

Procedure:
To a solution of [2-amino-6-(2,6-dichlorophenyl)-7-oxo-7H-pyrido[2,3-d]pyrimidin-8-yl]-acetic acid tert-butyl ester (157 mg, 0.37 mmol) from Example 36 in 4 mL of methylene chloride was added 2 mL of trifluoroacetic acid. The solution was stirred at room temperature for 5 hours, then concentrated in vacuo. The resultant oil was partitioned between methylene chloride and brine. The aqueous layer was washed with ethyl acetate, and the organic layers were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo to give a gummy solid. Diethyl ether was added, and the resultant precipitate was collected. Hexane was added to the filtrate, and once again the resultant precipitate was collected. The solids were combined and dried in vacuo at 80° C. to give 71 mg (52%) of [2-amino-6-(2,6-dichlorophenyl)-7-oxo-7H-pyrido[2,3-d]pyrimidin-8-yl]-acetic acid that was >97% pure by HPLC; mp 297°-300° C. dec.
Reaction SMILES: [Cl:1][C:2]1[C:7](/[CH:8]=[CH:9]/[O:10]CC)=[CH:6][CH:5]=[C:4]([Cl:13])[N:3]=1.[Na+].[I-].C[Si](Cl)(C)C.C([O-])(O)=O.[Na+]>C(#N)C>[Cl:1][C:2]1[C:7]([CH2:8][CH:9]=[O:10])=[CH:6][CH:5]=[C:4]([Cl:13])[N:3]=1
Reactant: CCO/C=C/c1ccc(Cl)nc1Cl
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: O=CCc1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
To a solution of (E)-2,6-dichloro-3-(2-ethoxyvinyl)pyridine (890 mg, 4.08 mmol) in acetonitrile (10 ml) was added NaI (1.84 g, 12.2 mmol) and TMSCl (887 mg, 8.16 mmol). The resulting mixture was stirred at RT for 4 hours, then treated with NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give the yellow oil 2-(2,6-dichloropyridin-3-yl)acetaldehyde (760 mg, yield: 98%). MS (M+H)+: 190.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][O:18][CH3:19])[C:10]=1[CH3:20].[N:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:22]=[O:23]>C(#N)C.C(Cl)Cl>[CH2:28]([O:27][C:25]([CH2:24][NH:21][C:22]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][O:18][CH3:19])[C:10]=1[CH3:20])=[O:23])=[O:26])[CH3:29]
Reactant: COCCn1ccc(=O)c(O)c1C
Reactant: CCOC(=O)CN=C=O
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)Oc1c(C)n(CCOC)ccc1=O
Reaction time: 0.17 h

Procedure:
5.60 ml of triethylamine are added to a mixture of 5.49 g of 3-hydroxy-1-(2-methoxyethyl)-2-methyl-4(1H)-pyridinone in 150 ml of acetonitrile and 150 ml of methylene chloride, followed by the addition of 6.83 ml of ethyl isocyanatoacetate at room temperature. The slightly exothermic reaction, in the course of which a solution forms within 10 minutes, is complete after 3 hours. The solvent is removed under reduced pressure and the residue is dried under a high vacuum and crystallised from ethyl acetate. The mother liquor is discarded. 1 g of the pale beige product is partitioned between methylene chloride and water. The bulk of the product is present in the aqueous phase, which is concentrated by evaporation. The residue is dissolved in methanol and the solution is treated with activated carbon and concentrated by evaporation. The residue is crystallised from ethyl acetate, to give white crystalline 3-(ethoxycarbonylmethylaminocarbonyloxy)-1-(2-methoxyethyl)-2-methyl-4(1H)-pyridinone with a melting point of 134°-135° C.
Reaction SMILES: [C:1]1(=[O:20])[N:5]([O:6][CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])[C:4](=[O:15])[C:3]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:2]12.FC(F)(F)C(O)=O>ClCCl>[C:4]1(=[O:15])[N:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])[C:1](=[O:20])[C:2]2=[CH:19][CH:18]=[CH:17][CH:16]=[C:3]12
Reactant: CC(C)(C)OC(=O)CON1C(=O)c2ccccc2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
tert-Butyl phthalimidooxyacetate (compound 8) (0.5 g, 1.8 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1.5 mL) was added, as illustrated in FIG. 6. The mixture was stirred at RT for one hour and evaporated to dryness. The residue was azeotroped with chloroform (3 times) to yield a white solid weighing 0.393 g (100% yield). The compound was characterized by NMR and MS as follows: 1) C-NMR (d-DMSO): 73.73, 124.13, 129.43, 135.65, 163.46, 168.87 ppm; and 2) H-NMR (d-DMSO): 4.76 (s, 2H); 7.86 (s, 4H) ppm; and 3) MS (ESI): 220.0 [M−H]−, 463.1 [2M-2H+Na]−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:12]#[N:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[H][H]>[Ni].C(O)C>[CH2:1]([O:3][C:4]([C:6]1([CH2:12][NH2:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C#N)CCCCC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)C1(CN)CCCCC1
Reaction time: 8 h
Yield: 80 %

Procedure:
Excess Raney Nickel in an ethanol slurry was added to a solution of 1-cyano-cyclohexanecarboxylic acid ethyl ester in ethanol under a nitrogen atmosphere. The nitrogen atmosphere was replaced with excess hydrogen gas and the mixture was allowed to stir overnight. The reaction mixture was filtered through celite and the solvent was removed. The compound was clean enough to continue without purification. 80% yield. MH+=186.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH:7]([CH2:11][C:12]1([C:17](=[O:33])[NH:18][CH:19]([C:29](=[O:32])[NH:30][CH3:31])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:8][CH2:9]O)([CH3:4])([CH3:3])[CH3:2].[O:35]=[C:36]1[C:44]2[CH:43]=[C:42]3[CH:45]=[CH:46][CH:47]=[CH:48][C:41]3=[CH:40][C:39]=2[C:38](=[O:49])[NH:37]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:1]([O:5][C:6](=[O:34])[CH:7]([CH2:11][C:12]1([C:17](=[O:33])[NH:18][CH:19]([C:29](=[O:32])[NH:30][CH3:31])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:13][CH2:14][CH2:15][CH2:16]1)[CH2:8][CH2:9][N:37]1[C:38](=[O:49])[C:39]2[CH:40]=[C:41]3[CH:48]=[CH:47][CH:46]=[CH:45][C:42]3=[CH:43][C:44]=2[C:36]1=[O:35])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1NC(=O)c2cc3ccccc3cc21
Reactant: CNC(=O)C(Cc1ccc(OC)cc1)NC(=O)C1(CC(CCO)C(=O)OC(C)(C)C)CCCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CNC(=O)C(Cc1ccc(OC)cc1)NC(=O)C1(CC(CCN2C(=O)c3cc4ccccc4cc3C2=O)C(=O)OC(C)(C)C)CCCC1
Reaction time: 240 h

Procedure:
To a solution of 4-hydroxy-2-{1-[2-(4-methoxyphenyl)-1-(methylcarbamoyl)ethylcarbamoyl]cyclopentylmethyl}butyric acid tert-butyl ester (500 mg, 1.05 mmol) in dry tetrahydrofuran (20 mL) was added 1,3-dioxo-1,3-dihydrobenzo[f]isoindole (414 mg, 2.1 mmol), triphenylphosphine (550 mg, 2.1 mmol) and diethylazodicarboxylate (0.33 mL, 2.1 mmol) and the resulting mixture was stirred for 10 days. The solvent was evaporated under vacuum and the residue was chromatographed on silica gel eluting with 30% ethyl acetate in hexane. Fractions containing the two diastereomeric products were combined and evaporated to leave a solid which was recrystallized from ethyl acetate to afford 4-(1,3-dioxo-1,3-dihydrobenzo[f]isoindol-2-yl)-2-{1-[2-(4-methoxyphenyl)-1-(methylcarbamoyl)ethylcarbamoyl]cyclopentylmethyl}butyric acid tert-butyl ester (diastereomer A) as a white solid, 45 mg (7%). The mother liquor from the recrystallization was concentrated under vacuum to afford an oil which was taken up in 25% ethyl acetate in hexane and allowed to stand overnight. A small amount of solid was removed by filtration and the solvent was evaporated to give an oil highly enriched in diastereomer B, 60 mg (9%).
Reaction SMILES: ClC1C=CC(C(N)C(N)CCC)=CC=1.Cl.C(OC1C=C(OC)C=CC=1C(=N)OCC)C.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[NH:43][C:42]([C:44]3[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][C:45]=3[O:52][CH2:53][CH3:54])=[N:41][CH:40]2[CH2:55][CH:56]2CCC[CH2:57]2)=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([CH:39]2[NH:43][C:42]([C:44]3[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][C:45]=3[O:52][CH2:53][CH3:54])=[N:41][CH:40]2[CH2:55][CH2:56][CH3:57])=[CH:37][CH:38]=1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1
Agent: CCCC(N)C(N)c1ccc(Cl)cc1
Agent: CCOC(=N)c1ccc(OC)cc1OCC
Agent: Cl
Product: CCCC1N=C(c2ccc(OC)cc2OCC)NC1c1ccc(Cl)cc1

Procedure:
5-(4-Chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-propyl-4,5-dihydro-1H-imidazole was prepared from 1-(4-chloro-phenyl)-pentane-1,2-diamine and ethyl 2-ethoxy-4-methoxy-benzimidate hydrochloride in an analogous manner as described for the preparation of 5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (Example 9). HR-MS (ES, m/z) observed 373.1680, calculated for C21H26N2O2Cl [(M+H)+]373.1678.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][NH:8]3)=[CH:4][C:3]=2[O:2]1.C([Mg]Br)C.Br[C:18]1[C:23](=[O:24])[NH:22][C:20](=[O:21])[C:19]=1[Br:25].[Cl-].[NH4+]>C1(C)C=CC=CC=1.O1CCCC1>[Br:25][C:19]1[C:20]([NH:22][C:23](=[O:24])[C:18]=1[C:6]1[C:5]2[C:9](=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[NH:8][CH:7]=1)=[O:21]
Reactant: c1cc2cc3c(cc2[nH]1)OCO3
Reactant: O=C1NC(=O)C(Br)=C1Br
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1NC(=O)C(c2c[nH]c3cc4c(cc23)OCO4)=C1Br
Yield: 56.8 %

Procedure:
6.44 g (40 mmol) 5,6-methylenedioxyindole are dissolved in 300 ml anhydrous toluene and mixed dropwise at 60° C. with 20 ml of a 2M solution of ethyl magnesium bromide in tetrahydrofuran (Aldrich). After completion of the addition, there is added dropwise thereto a solution of 1.7 g (6.67 mmol) dibromomaleinimide in 50 ml toluene, with the addition of the minimum amount of tetrahydrofuran required for solution, and then heated under reflux for 18 hours. After cooling, the reaction mixture is mixed with a saturated aqueous solution of ammonium chloride, the organic phase is separated off and the aqueous phase is extracted three times with toluene and once with ethyl acetate. The combined organic phases are dried, rotary evaporated and chromatographed in silica gel (elution agent: dichloromethane/ethyl acetate 30:1 v/v). There is obtained 1.27 g (56% of theory) 2-bromo-3-(5,6-methylenedioxy-1H-indol-3-yl)maleinimide; m.p. about 185° C. (decomp.); RF=0.50 (dichloromethane/ethyl acetate 3:1 v/v); and 0.63 g (22.5% of theory) 2,3-bis-(5,6-methylenedioxy-1H-indol-3-yl)-maleinimide in the form of red crystals; m.p, about 270° C. (decomp.), after recrystallisation from propanol; RF=0.36 (dichloromethane/ethyl acetate 3:1 v/v).
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].[F:47][C:48]1[CH:53]=[CH:52][C:51]([C@H:54]([NH2:56])[CH3:55])=[CH:50][CH:49]=1>>[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]([NH:56][C@@H:54]([C:51]4[CH:52]=[CH:53][C:48]([F:47])=[CH:49][CH:50]=4)[CH3:55])=[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: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])([CH3:2])[CH3:3]
Reactant: C[C@@H](N)c1ccc(F)cc1
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[C@H](C)c2ccc(F)cc2)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 reacted with (R)-1-(4-fluorophenyl)ethylamine (Alfa) to give the title product. LC-MS (ES+) 786 [(M+H)+].
Reaction SMILES: C(Cl)(Cl)Cl.[F:5][C:6]([F:24])([F:23])[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[C:18]([OH:19])=[C:17]([C:20]([CH3:22])=[O:21])[CH2:16][S:15]2)=[CH:10][CH:9]=1.S(Cl)(Cl)(=O)=O>O>[F:24][C:6]([F:5])([F:23])[O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[S:15][CH:16]=[C:17]([C:20]([CH3:22])=[O:21])[C:18]=2[OH:19])=[CH:12][CH:13]=1
Reactant: CC(=O)C1=C(O)C(c2ccc(OC(F)(F)F)cc2)SC1
Solvent: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(=O)c1csc(-c2ccc(OC(F)(F)F)cc2)c1O
Temperature: -15 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
A chloroform (45 mL) solution of 2-(4-trifluoromethoxyphenyl)-3-hydroxy-4-methylcarbonyl-2,5-dihydrothiophene (4.5 g, 12.6 mmol, purity: 85%) was cooled to −5° C., and to this solution, a chloroform (90 mL) solution of sulfuryl chloride (1.1 mL, 1.1 equivalent amounts) was dropwise added over a period of 30 minutes, followed by stirring at −15° C. for 1 hour. The temperature of the solution was raised to 0° C., and water (11 mL) was dropwise added, followed by liquid separation. The obtained chloroform solution was sequentially washed with water, a saturated salt solution, a sodium hydroxide aqueous solution, a saturated sodium thiosulfate aqueous solution and a saturated salt solution, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off to obtain a crude product. The obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to give the desired product as a yellow solid (3.15 g, yield: 83%).
Reaction SMILES: [OH:1][CH:2]1[C:8]2[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=2[N:6]([C:14](=[O:32])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][C:16]=2[CH3:31])[CH2:5][CH2:4][CH2:3]1.CN(C1C=CC=CN=1)C.Cl.CN(C1C=CC=CN=1)C.C(OC([NH:62][C@H:63]([C:67](O)=[O:68])[CH:64]([CH3:66])[CH3:65])=O)C1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl.C(O)(=O)C.C(OCC)(=O)C.[Pd].CO>[NH2:62][C@H:63]([C:67]([O:1][CH:2]1[C:8]2[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=2[N:6]([C:14](=[O:32])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][C:16]=2[CH3:31])[CH2:5][CH2:4][CH2:3]1)=[O:68])[CH:64]([CH3:66])[CH3:65]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3cc(Cl)ccc32)c(C)c1
Agent: [Pd]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OC(=O)[C@@H](N)C(C)C)c3cc(Cl)ccc32)c(C)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 38.5 %

Procedure:
To a solution of 5-hydroxy-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.0 g), dimethylaminopyridine (1.26 g) and dimethylaminopyridine hydrochloride (1.10 g) in chloroform (20 ml) are added N-benzyloxycarbonyl-L-valine (672 mg) and dicyclohexylcarbodiimide (1.42 g), and the mixture is stirred at room temperature for 7 hours. To the mixture are added methanol (3 ml) and acetic acid (0.7 ml), and the mixture is stirred at room temperature for 30 minutes. The insoluble materials are removed by filtration, and to the filtrate is added 5% aqueous sodium hydrogen sulfate solution, and further extracted with dichloromethane. The extract is washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure to give crude 5-N-benzyloxycarbonyl-L-valyloxy-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (2.0 g). This product is dissolved in a mixture of acetic acid (15 ml) and ethyl acetate (15 ml), and thereto is added 5% Pd-C (0.3 g). The mixture is subjected to hydrogenation at ordinary room temperature under atmospheric pressure. After hydrogenation, the catalyst is removed by filtration, and the filtrate is concentrated. The resulting residue is purified by silica gel column chromatography (eluent; ethyl acetate) to give Isomer A (0.48 g) and Isomer B (0.47 g) of 5-L-valyloxy-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine.