Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([CH3:25])[C:23]=1[OH:24])[CH:19]=O.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C.O>[OH:24][C:23]1[C:22]([CH3:25])=[CH:21][C:18]([C:19]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[C:8]([O:13][CH3:14])[CH:7]=3)[N:1]=2)=[CH:17][C:16]=1[CH3:15]
Reactant: COc1cc(N)c(C(N)=O)cc1OC
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc2nc(-c3cc(C)c(O)c(C)c3)[nH]c(=O)c2cc1OC
Temperature: 150 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
To a solution of 2-amino-4,5-dimethoxybenzamide (0.157 g, 0.8 mmol) in N,N-dimethylacetamide (5 mL) were added 3,5-dimethyl-4-hydroxybenzaldehyde (0.120 g, 0.8 mmol), sodium hydrogen sulphite (58.5%, 0.156 g, 0.88 mmol) and p-toluenesulfonic acid (15 mg, 0.08 mmol). The reaction mixture was stirred at 150° C. for 3 h. The reaction mixture was cooled to room temperature and water (40 mL) was added. A white precipitate was formed and filtered off, washed with water and a small amount of methanol and dried under vacuum to give 2-(4-hydroxy-3,5-dimethylphenyl)-6,7-dimethoxyquinazolin-4(3H)-one (0.230 g, 88% yield) as an off-white solid. Selected data: MS (ES) m/z: 327.12; MP>300° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].[C:14]([C:18]1[O:22][N:21]=[C:20]([OH:23])[CH:19]=1)([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:14]([C:18]1[O:22][N:21]([C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[C:20](=[O:23])[CH:19]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1cc(O)no1
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(=O)n(-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])o1
Reaction time: 0.5 h
Yield: 31.1 %

Procedure:
After mixing 3.7 g of 2,4-dinitrofluorobenzene, 20 ml of dimethylformamide, 2.9 g of 5-t-butyl-3-hydroxyisoxazole, and 2.8 g of potassium carbonate, the reaction was performed for 30 minutes at 80° C. and after cooling the reaction mixture, the product formed was extracted with a mixture of diethyl ether and ethyl acetate. The solvent was distilled off from the extract under reduced pressure and the residue obtained was crystallized from a mixture of diethyl ether and ethyl acetate to provide 1.9 g of the desired compound with a yield of 30.9%. The melting point thereof was 167° C. to 168° C.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:18][C@@H:19]([CH:25]([CH3:27])[CH3:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][NH:18][C@@H:19]([CH:25]([CH3:27])[CH3:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Reactant: CCOC(=O)[C@@H](N)C(C)C
Agent: Cl
Product: CCOC(=O)[C@@H](NCc1cccc(O[Si](C)(C)C(C)(C)C)c1)C(C)C
Yield: 97 %

Procedure:
Prepared as in Example 12-1b from 3-(tert-butyldimethylsilyloxy)benzaldehyde (Example 12-1c) and (S)-ethyl 2-amino-3-methylbutanoate hydrochloride. Yield 97%, colorless liquid. MS 352 (MH+).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([O:13][CH2:14][C@@H:15]2[O:20][C:19]3[C:21]([NH2:26])=[C:22]([NH2:25])[CH:23]=[CH:24][C:18]=3[O:17][CH2:16]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[C:27](C1NC=CN=1)(C1NC=CN=1)=[O:28].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([O:13][CH2:14][CH:15]2[O:20][C:19]3[C:21]4[NH:26][C:27](=[O:28])[NH:25][C:22]=4[CH:23]=[CH:24][C:18]=3[O:17][CH2:16]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(N)c(N)c3O2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4[nH]c(=O)[nH]c4c3O2)cc1
Reaction time: 15 h

Procedure:
To a solution of 0.30 g (0.71 mmole) of [(2R)-7,8-diamino-2,3-dihydro-1,4 benzodioxin-2-yl]methyl 4-methylbenzenesulfonate dihydrochloride in 50 mL of methylene chloride was added 0.50 g (3.0 mmole) of carbonyl diimidazole and 0.65 g (5.0 mmole) of diisopropylethylamine. The reaction mixture was stirred under nitrogen for 15 hours. The mixture was then concentrated in vacuum and 250 mL of ethyl acetate added. This solution was washed with 250 mL portions each of 2 N aqueous HCl, saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on 25 g of silica gel, using a gradient elution commencing with chloroform and ending with 3% methanol in chloroform. The product fractions were combined and evaporated in vacuum to give 0.21 g of the (R)-enantiomer of the title compound as an off-white solid, m.p. 202-204° C.
Reaction SMILES: N1C2C(=CC=CC=2)CC1=O.C(C1OC=C([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([O:23]C)=[O:22])C=1)=O.N1CCCCC1>CCO>[C:21]([OH:23])(=[O:22])[C:20]1[CH:25]=[CH:26][CH:27]=[CH:18][CH:19]=1
Reactant: COC(=O)c1cccc(-c2coc(C=O)c2)c1
Agent: O=C1Cc2ccccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C(O)c1ccccc1
Yield: 184.6 %

Procedure:
A solution of oxindole (400 mg, 2.4 mmol), methyl 3-(5-formylfuran-3-yl)benzoate (518 mg, 2.4 mmol) and piperidine (0.24 mL, 2.4 mmol) in EtOH (10 mL) was stirred at rt 30 min. The resulting precipitate was collected by filtration to yield desired (E)-3-(5-chloro-2-oxoindolin-3-ylidene)methyl)furan-2-yl)benzoic acid (541 mg). LCMS (ES): m/z 366 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[S:3]Cl.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+]>CCOCC.O.CCOCC>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[NH:15][C:16]([S:3][C:2]([F:6])([F:5])[F:1])=[CH:17][CH:18]=2)=[CH:12][CH:13]=1
Reactant: FC(F)(F)SCl
Reactant: Clc1ccc(-c2ccc[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: FC(F)(F)Sc1ccc(-c2ccc(Cl)cc2)[nH]1
Reaction time: 0.5 h

Procedure:
Trifluoromethylsulfenyl chloride is bubbled into a solution of 2-(p-chlorophenyl)pyrrole (0.5 g, 0.00281 mol) and sodium carbonate (0.36 g, 0.00338 mol) in ether at -30° C. under nitrogen. The reaction mixture is stirred for 1/2 hour and diluted with a water/ether mixture. The organic phase is separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title product as a purple solid (0.78 g, mp 34°-39° C.) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: [OH-].[Na+].[OH:3][CH:4]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[N:28]=[CH:27][CH:26]=1)[CH2:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][S:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:9][C@@H:8]1[C:21]([O:23]C)=[O:22].[ClH:37].[Cl:38]CCl.CO>CO.O>[ClH:38].[ClH:37].[OH:3][CH:4]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[N:28]=[CH:27][CH:26]=1)[CH2:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][S:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:9][C@@H:8]1[C:21]([OH:23])=[O:22]
Reactant: ClCCl
Reactant: COC(=O)[C@H]1CN(CCSC2CCCC2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2nccc(C(O)CC[C@@H]3CCN(CCSC4CCCC4)C[C@@H]3C(=O)O)c2c1
Temperature: 60 °C

Procedure:
2 cm3 of 5N aqueous sodium hydroxide solution were added, with stirring and under an inert atmosphere, to a solution of 0.48 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-3-carboxylate in 10 cm3 of methanol. After heating the mixture for 16 hours at a temperature in the region of 60° C., the reaction mass was evaporated under reduced pressure (2.9 kPa) at a temperature in the region of 60° C. and the residue obtained was taken up in 4.3 cm3 of distilled water to which had been added 4.3 cm3 of 28% hydrochloric acid. The remaining insoluble material was filtered off and then the filtrate was evaporated under the same conditions as above. The residue obtained was stirred in a dichloromethane/methanol (90/10 by volume) mixture. The resulting precipitate was filtered off and washed with 3 times 2.5 cm3 of the same mixture. The filtrate was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 0.48 g of (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-3-carboxylic acid dihydrochloride was obtained in the form of a foam with a green color melting with softening at a temperature in the region of 156° C.
Reaction SMILES: [F:1][C:2]1[C:10]2[NH:9][C:8](=O)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:8]1[NH:9][C:10]2[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: O=c1[nH]c2cccc(F)c2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1cccc2nc(Cl)[nH]c12
Temperature: 25 °C
Yield: 94.3 %

Procedure:
3-Fluorobenzene-1,2-diamine (0.600 g, 4.76 mmol) was dissolved in THF (14.82 ml) and 1,1′-carbonyldiimidazole (0.848 g, 5.23 mmol) was added at RT. The reaction mixture was stirred overnight at RT and then heated for 24 hours at 50° C. The mixture was cooled to RT and ammonia in MeOH (1.5 ml) was added and the mixture stirred for 30 minutes. The mixture was diluted with water (40 ml) and the resultant brown solid was collected by filtration, washed with water and then dried in vacuo to afford 4-fluoro-1H-benzo[d]imidazol-2(3H)-one (0.700 g, 97%) which was used in the next step without further purification; 1H NMR (400 MHz, DMSO-d6) 6.81 (2H, ddd), 6.88-6.95 (1H, m), 10.82 (1H, s), 11.08 (1H, s); m/z: (ES-) M-H−, 151.19. b) A solution of 4-fluoro-1H-benzo[d]imidazol-2(3H)-one (0.7 g, 4.60 mmol) in phosphorus oxychloride (14.11 ml, 151.39 mmol) was heated at 100° C. for 18 hours. The reaction mixture was cooled to RT and excess phosphorus oxychloride was evaporated in vacuo. The residue was neutralized slowly (Care: exotherm) with saturated sodium bicarbonate solution (10 ml), and the mixture was then extracted with EtOAc (3×20 ml). The combined organic layers were washed with saturated brine and then dried over Na2SO4, filtered and evaporated to afford 2-chloro-7-fluoro-1H-benzo[d]imidazole (0.740 g, 94%) which was used in the next step without further purification; 1H NMR (400 MHz, DMSO-d6) 7.01-7.11 (1H, m), 7.23 (1H, td), 7.32 (1H, s), 13.59 (1H, s); m/z: (ES+) MH+, 171.20. c) 2-Chloro-7-fluoro-1H-benzo[d]imidazole (1.7 g, 9.97 mmol) was charged to a high pressure autoclave PV10832 (Parr 160 ml) with methylamine (40% EtOH solution, 50 ml, 9.97 mmol) and sealed on its trolley and the resulting solution heated to 160° C. in high pressure blast cell 60 for 16 hours. The pressure in the autoclave reached 13 bar. The mixture was evaporated and the residue dissolved in MeOH and then added to an SCX column. The column was eluted with 7N ammonia in MeOH and fractions containing product were evaporated to leave a brown oil. The oil was was purified by flash chromatography on silica, eluting with a gradient of 5 to 20% MeOH in DCM. Pure fractions were evaporated to afford 7-fluoro-N-methyl-1H-benzo[d]imidazol-2-amine (1.230 g, 75%); 1H NMR (400 MHz, DMSO-d6) 2.88 (3H, d), 6.54 (1H, bs), 6.67-6.73 (1H, m), 6.81 (1H, dd), 6.95 (1H, d); m/z: (ES+) MH+, 166.00.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12].Cl.[OH-].[NH4+].[C:16](O)(=O)[CH3:17]>>[CH3:16][C:17]1[NH:1][C:2]2[C:3]([CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=2[N:8]=1
Reactant: Cc1c([N+](=O)[O-])ccc(N)c1N
Reactant: CC(=O)O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: Cc1nc2ccc([N+](=O)[O-])c(C)c2[nH]1
Temperature: 25 °C

Procedure:
A mixture of 2,3-diamino-6-nitrotoluene (0.945 g, 5.65 mmol), conc. hydrochloric acid (5 mL) and glacial acetic acid (30 mL) is heated to reflux for 2 hours. The mixture is cooled to room temperature, then poured in a mixture of crushed ice (100 mL) and ammonium hydroxide (100 mL) and extracted with 20% methanol in chloroform (2×400 mL). The combined extracts are dried over potassium carbonate and rotary evaporated to afford 2,4-dimethyl-5-nitrobenzimidazole as a brown solid. The product is used in the following step without further purification.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([NH2:40])[CH:31]=[CH:32][C:33]=1[N:34]1[CH:38]=[N:37][C:36]([CH3:39])=[N:35]1.[CH2:41]([C:48]1[CH:53]=[C:52]([CH3:54])[N:51]=[C:50](Cl)[N:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.O>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:41]([C:48]1[CH:53]=[C:52]([CH3:54])[N:51]=[C:50]([NH:40][C:30]2[CH:31]=[CH:32][C:33]([N:34]3[CH:38]=[N:37][C:36]([CH3:39])=[N:35]3)=[C:28]([O:27][CH3:26])[CH:29]=2)[N:49]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: COc1cc(N)ccc1-n1cnc(C)n1
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(Nc2nc(C)cc(Cc3ccccc3)n2)ccc1-n1cnc(C)n1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 29.8 %

Procedure:
Palladium(II) acetate (5.9 mg, 0.026 mmol) and 2-(dicyclohexylphosphino)biphenyl (19 mg, 0.052 mmol) were dissolved under an atmosphere of nitrogen in dioxane (2 mL). The reaction was stirred for 25 minutes at room temperature. Sodium tert.-butylate (48 mg, 0.49 mmol), 3-methoxy-4-(3-methyl-[1,2,4]triazol-1-yl)-phenylamine (67 mg, 0.33 mmol) dissolved in dioxane (1.5 mL) and 4-benzyl-2-chloro-6-methyl-pyrimidine (79 mg, 0.36 mmol) were added. The reaction was heated three times for 30 minutes to 200° C. in a microwave oven. Water was added and the reaction was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using methylenechloride/methanol (19:1 v/v) as eluent to yield the title compound as a yellow gum (38 mg, 30%). MS ISP (m/e): 387.3 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.49 (s, 1H), 7.97 (s, 1H), 7.56 (d, 1H), 7.26-7.33 (m, 5H), 6.98 (d, 1H), 6.51 (s, 1H), 3.97 (s, 2H), 3.83 (s, 3H), 2.48 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]([CH:13]1[CH2:15][CH2:14]1)[C:7]2=[O:16].[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18]>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:21][C:17]([CH3:20])([CH3:19])[CH3:18])[N:8]([CH:13]1[CH2:15][CH2:14]1)[C:7]2=[O:16]
Reactant: O=c1c2cccc(Br)c2nc(Cl)n1C1CC1
Reactant: CC(C)(C)N
Product: CC(C)(C)Nc1nc2c(Br)cccc2c(=O)n1C1CC1
Temperature: 90 °C
Yield: 92.8 %

Procedure:
8-bromo-2-chloro-3-cyclopropylquinazolin-4(3H)-one (723) (213 mg, 0.711 mmol) was treated with tert-butylamine (0.90 mL, 8.56 mmol) and heated at 90° C. in a sealed tube for 24 h. The reaction mixture was concentrated to remove the excess t-BuNH2 and the crude residue was chromatographed on an ISCO Combiflash RF (12 g Redisep column, using a gradient of 0-5% MeOH in DCM) affording 8-bromo-2-(tert-butylamino)-3-cyclopropylquinazolin-4(3H)-one (224 mg, 0.66 mmol, 94% yield) as an off-white crystalline solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.02 (1H, dd, J=8.0, 1.4 Hz), 7.82 (1H, dd, J=7.7, 1.5 Hz), 6.94 (1H, t, J=7.7 Hz), 5.42 (1H, s), 2.62-2.71 (1H, m), 1.61 (9H, s), 1.28-1.35 (2H, m), 0.87-0.95 (2H, m). m/z (ESI, +ve) 335.9/337.9 (M+1)+.
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[CH3:13][Si](C=[N+]=[N-])(C)C>CO.ClCCl>[CH2:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:13])=[O:9])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(C(=O)O)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: CCCc1ccc(C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 96.7 %

Procedure:
To a 0° C. solution of 4-propylbenzoic acid (2 g, 12.18 mmol) in methanol (3.00 mL) and dichloromethane (10 mL) was added trimethylsilyldiazomethane (7.92 mL, 15.83 mmol), dropwise over a period of 5 min. Towards the end of the addition, the reaction mixture was pale yellow. The reaction was stirred at 0° C. for 30 min. and the excess diazo reagent was quenched by the slow addition of acetic acid at 0° C. (˜1.5 mL). The colorless solution was concentrated and partitioned between ether (20 mL) and sat. aq. sodium bicarbonate (10 mL). The ether layer was washed with brine (10 mL), dried over sodium sulfate and concentrated to yield methyl 4-propylbenzoate (2.1 g, 11.78 mmol, 97% yield) as a liquid. 1H NMR (400 MHz, CDCl3) δ ppm 7.95 (d, J=8.28 Hz, 2H) 7.24 (d, J=8.53 Hz, 2H) 3.90 (s, 3H) 2.61-2.67 (m, 2H) 1.59-1.71 (m, 1H) 0.94 (t, J=7.40 Hz, 1H).
Reaction SMILES: [CH:1]([N:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[C:7](Cl)[C:6]1=[O:13])([CH2:3][CH3:4])[CH3:2].Cl.[Cl:15][C:16]1[CH:17]=[C:18]([O:25][CH3:26])[CH:19]=[C:20]2[C:24]=1[NH:23][CH2:22][CH2:21]2>>[Cl:11][C:9]1[N:8]=[C:7]([N:23]2[C:24]3[C:20](=[CH:19][C:18]([O:25][CH3:26])=[CH:17][C:16]=3[Cl:15])[CH2:21][CH2:22]2)[C:6](=[O:13])[N:5]([CH:1]([CH3:2])[CH2:3][CH3:4])[CH:10]=1
Reactant: CCC(C)n1cc(Cl)nc(Cl)c1=O
Reactant: COc1cc(Cl)c2c(c1)CCN2
Agent: Cl
Product: CCC(C)n1cc(Cl)nc(N2CCc3cc(OC)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 1-sec-butyl-3,5-dichloro-2(1H)-pyrazinone and 7-chloro-5-methoxyindoline hydrochloride as the starting materials. mp 143-145° C.; 1H NMR (300 MHz, CDCl3): δ 6.89 (s, 1 H), 6.77-6.72 (m, 2 H), 4.96-4.89 (m, 1 H), 4.34 (t, J=7.9 Hz, 2 H), 3.76 (s, 3 H), 3.07 (t, J=7.7 Hz, 2 H), 1.74-1.64 (m, 2 H), 1.33 (d, J=7.0 Hz, 3 H), 0.89 (t, J=7.6 Hz, 3 H); HRMS (ESI) calcd for C17H20N3O2Cl2 (M+H)+: 368.0933; found m/z 368.0927.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(C#N)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C[Mg]I.CC[O:19][CH2:20][CH3:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:20](=[O:19])[CH3:21])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: N#CC1(c2ccc(Cl)cc2)CCC1
Reactant: CCOCC
Agent: C[Mg]I
Product: CC(=O)C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A solution of 1-(4-chlorophenyl)cyclobutanecarbonitrile (238 g) in ether (500 ml) was added at reflux temperature under nitrogen over 40 minutes to stirred ethereal methylmagnesium iodide solution (3M; 701 ml). After the addition was complete, the mixture was stirred at reflux temperature for 3 hours and at ambient temperature for 60 hours. The resulting solid was collected by filtration, washed well with ether, and added in portions to a stirred mixture of crushed ice (1 l) and concentrated hydrochloric acid (1 l). The resulting mixture was stirred at 95° C. for 1 hour then cooled to ambient temperature. The product was extracted into dichloromethane (3×250 ml), and the combined extracts were washed with water (3×200 ml), dried (MgSO4), and the solvent was removed in vacuo. The residue was distilled to give 1-[1-(4-chlorophenyl)cyclobutyl]ethanone as a brown oil (198.1 g), b.p. 95-100° C. at 0.3 mbar.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH2:14][C:15](Cl)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[C:19]1([C:25]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH:33]3[CH:29]([CH2:30][NH:31][CH2:32]3)[C:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])([OH:34])[CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[C:43]1([C:25]2([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:33]3[CH:29]([CH2:30][NH:31][CH:32]3[C:15](=[O:16])[CH2:14][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])([OH:34])[CH2:27][CH2:26]2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: COc1ccccc1C1(O)CCC(c2ccccc2)(c2ccccc2)C2CNCC21
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1C1(O)CCC(c2ccccc2)(c2ccccc2)C2C(C(=O)Cc3ccccc3)NCC21
Reaction time: 24 h

Procedure:
0.35 cm3 of triethylamine and then 0.33 cm3 of phenylacetyl chloride are added to a suspension of 1.1 g of (3aRS,4RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)-perhydroisoindol-4-ol hydrochloride in 25 cm3 of dry methylene chloride at room temperature. The reaction mixture is stirred at this temperature for 24 hours, diluted with 200 cm3 of methylene chloride, washed with 100 cm3 of a saturated solution of sodium bicarbonate, with 100 cm3 of water (twice) and then with an aqueous saturated solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed over a Merck silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 22 cm) by eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (55/45 by volume) and collecting fractions of 20 cm3. Fractions 11 to 18 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is crystallised in 70 cm3 of acetonitrile and the crystals are filtered off and dried. 0.5 g of (3aRS,4RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-phenylacetyl-perhydroisoindol-4-ol is obtained in the form of a white solid.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH2:15]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[CH2:16][CH3:17].[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:15][CH2:16][CH3:17])=[CH:19][CH:20]=1
Reactant: CCCc1ccc(O)cc1
Reactant: OCCCCCCBr
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1ccc(OCCCCCCBr)cc1
Temperature: 25 °C
Yield: 66.8 %

Procedure:
A solution of diisopropylazodicarboxylate (2.12 g, 10.5 mmol) in THF (25 mL) was added via syringe pump over 1.5 h to a mixture of 4-propylphenol (purchased from Aldrich Chemical Co.) (1.36 g, 10.0 mmol), 6-bromo-1-hexanol (purchased from Aldrich Chemical Co.) (1.81 g, 10.0 mmol), and triphenylphosphine (2.75 g, 10.5 mmol) in THF (25 mL) at 0° C. under argon. The slightly yellow reaction was stirred at 0° C. for 30 min, whereupon additional triphenylphosphine (262 mg, 1.00 mmol) was added, followed by addition of diisopropylazodicarboxylate (200 mL, 1.0 mmol) over 30 min. The reaction was allowed to warm to RT, at which time silica gel (15 g) was added. The mixture was concentrated in vacuo and the white powder obtained was purified by flash chromatography on silica gel (150 g) eluted with a step gradient of hexane to 2:98 EtOAc/hexane. The slightly impure product obtained was rechromatographed on silica gel (150 g) eluted with 1:99 EtOAc/hexane to give title compound (2.00 g, 67%) as a colorless oil.