Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][CH:5]=2.[OH-].[Na+].Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:18]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[CH3:1][C:2]1[N:3]([C:17]([O:19][C:20]2[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=2)=[O:18])[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][CH:5]=2
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc2cc([N+](=O)[O-])ccc2n1C(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
2-methyl-5-nitroindole (2 g, 8.78 mmol) was dissolved into 80 ml of dichloromethane, and then sodium hydroxide (1.1 g, 26.36 mmol), tetrabutylammonium bromide (32 mg, 0.87 mmol), and 4-nitrophenyl chloroformate (1.86 g, 9.22 mmol) were sequentially added followed by stirring at room temperature for 1 hour. After filtering out the solid made in the reaction, the reaction mixture was washed with dichloromethane. The resultant liquid layer was concentrated and 2-methyl-5-nitro-1-(4-nitrophenoxycarbonyl)indole (2.9 g, 96%) was obtained as yellow solid.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:7]1[CH:28]=[CH:27][C:10]([CH2:11][CH:12]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].Cl.O>C(OCC)C.[Cl-].[Zn+2].[Cl-]>[C:3]([C:7]1[CH:28]=[CH:27][C:10]([CH2:11][CH:12]([CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[OH:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:8]=1)([CH3:4])([CH3:5])[CH3:6]
Reactant: CCOC(=O)C(Cc1ccc(C(C)(C)C)cc1)C(=O)c1cccc(Cl)c1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc(C(C)(C)C)cc1)C(O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of zinc chloride (22.3 g, 163.6 mmol) in diethyl ether (500 ml) was added sodium borohydride (12.4 g, 327.2 mmol), and the mixture was stirred at room temperature for 30 min. Insoluble material was filtered off, and to the filtrate was added a solution of ethyl 2-(4-tert-butylbenzyl)-3-(3-chlorophenyl)-3-oxopropanoate (30.5 g, 81.8 mmol) in diethyl ether. (200 ml) at 0° C. The mixture was stirred for 30 min. and 1N hydrochloric acid was added to stop the reaction. Water (200 ml) was further added, and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine; dried (anhydrous magnesium sulfate) and evaporated under reduced pressure to give the objective substance (26.8 g, 87%).
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][CH2:22][NH2:23].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][CH2:22][N:23]1[CH2:10][C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:3]1=[O:12]
Reactant: COC(=O)c1ccccc1CBr
Reactant: NCCCc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2CN1CCCc1ccccc1Cl
Temperature: 100 °C
Reaction time: 2 h
Yield: 53.2 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (0.115 g, 0.5 mmol), 3-(2-chloro-phenyl)-propylamine (0.102 g, 0.6 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (3 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-[3-(2-chloro-phenyl)-propyl]-2,3-dihydro-isoindol-1-one (0.076 g, 51%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.99 (m, 2H), 2.79 (t, 2H), 3.69 (t, 2H), 4.41 (s, 2H), 7.14-7.58 (m, 7H), 7.88 (d, 1H). GC-MS: m/z 285 (M)+.
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C=CC=CC=1.[Br:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[CH3:36].C1C(=O)N([Br:44])C(=O)C1>CCOC(C)=O>[Br:25][C:26]1[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:28][C:27]=1[CH2:36][Br:44]
Reactant: Cc1ccc(C(F)(F)F)cc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(CBr)c(Br)c1

Procedure:
Solid benzoyl peroxide (1.5 g, 6.3 mmol) was added to a benzene solution (200 mL) of 2-bromo-1-methyl-4-(trifluoromethyl)benzene (10.0 g, 41.8 mmol) and NBS (8.2 g, 46.0 mmol) and the resulting mixture was refluxed. After 16 h the resulting mixture was cooled, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:12][OH:13])[CH:6]=1)=[O:4].O.[C:15]1(C)[CH:20]=CC(S(O)(=O)=O)=C[CH:16]=1.COC(OC)(C)C.C(=O)(O)[O-].[Na+]>CC(C)=O>[Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]2[O:11][C:15]([CH3:20])([CH3:16])[O:13][CH2:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(CBr)c1ccc(O)c(CO)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: COC(C)(C)OC
Solvent: O
Product: CC1(C)OCc2cc(C(=O)CBr)ccc2O1
Yield: 6402.1 %

Procedure:
2-Bromo-4'-hydroxy-3'-hydroxymethylacetophenone (17.7 g), p-toluenesulfonic acid monohydrate (124 mg) and acetone dimethyl acetal (256 ml) were dissolved in acetone (256 ml), and the solution was heated under reflux for 30 minutes. After cooling, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate, then the solvent was removed in vacuo. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: hexane/ethyl acetate=7/1) gave 2-bromo-1-(2,2-dimethylbenzo[1,2-d]-1,3-dioxan-6-yl)-1-ethanone (11.9 g) having a melting point of 52-54° C.
Reaction SMILES: [F:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:14]([C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[O:18][CH2:19][CH:20]1[O:22][CH2:21]1)#[N:15]>C(O)(C)C.CCCCCC>[C:14]([C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[O:18][CH2:19][CH:20]([OH:22])[CH2:21][N:11]1[CH2:10][CH2:9][N:8]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:13][CH2:12]1)#[N:15]
Reactant: Fc1cccnc1N1CCNCC1
Reactant: N#Cc1ccccc1OCC1CO1
Solvent: CC(C)O
Solvent: CCCCCC
Product: N#Cc1ccccc1OCC(O)CN1CCN(c2ncccc2F)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
To a solution of 1-(3-fluoro-2-pyridyl)piperazine (453 mg, 2.5 mmol) in 5 ml of isopropanol stirred at 70° C. under nitrogen was added portionwise 2-cyanophenoxy-2,3-epoxypropane (438 mg, 2.5 mmol) and the mixture stirred for 21/2 hours at 70° C. The solvent was removed in vacuo at room temperature and the residual oil was chromatographed on silica gel eluting with 5% methanol-chloroform. The product was obtained as a colorless oil which slowly solidified upon trituration in hexane to yield 0.66 g of 1-[3-(2-cyanophenoxy)-2-hydroxypropyl]-4-(3-fluoro-2-pyridyl)piperazine; m.p. 68°-70° C. Analysis satisfactory for C19H21FN4O2.
Reaction SMILES: [C:1]12([CH2:8][O:9][C:10]3[C:22](Cl)=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:12]([F:24])[CH:11]=3)[CH2:7][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2]2.[CH:25]1(B(O)O)[CH2:27][CH2:26]1.F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]12([CH2:8][O:9][C:10]3[C:22]([CH:25]4[CH2:27][CH2:26]4)=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:12]([F:24])[CH:11]=3)[CH2:7][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2]2
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC23CCCCC2C3)cc1F
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC23CCCCC2C3)cc1F
Temperature: 140 °C
Yield: 75 %

Procedure:
In a sealed tube containing tert-butyl 4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-chloro-2-fluorobenzoate (1.30 g, 3.70 mmol), cyclopropylboronic acid (0.47 g, 5.50 mmol), tricyclohexylphosphine tetrafluoroborate (0.27 g, 0.74 mmol) and palladium acetate (0.08 g, 0.37 mmol) and potassium phosphate (3.13 g, 14.8 mmol) in toluene (20 mL) and water (2.0 mL) was bubbled with a nitrogen atmosphere for 10 minutes. The reaction mixture was heated to 140° C. for 6 hours and cooled to ambient temperature. The solvent was concentrated in vacuo to dryness. The crude residue was purified column chromatography (10% gradient ethyl acetate in hexanes) afforded the title compound as a colorless solid (1.00 g, 75%): 1H NMR (300 MHz, CDCl3) 7.37 (d, J=8.5 Hz, 1H), 6.42 (d, J=12.8 Hz, 1H), 3.61 (d, J=9.1 Hz, 1H), 3.78 (d, J=9.1 Hz, 1H), 1.96-1.52 (m, 7H), 1.55 (s, 9H), 0.92-0.82 (m, 4H), 0.67-0.61 (m, 4H), 0.38-0.33 (m, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1.O=S(Cl)[Cl:19]>ClCCCl>[O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([Cl:19])=[O:13])=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccc(-n2ccccc2=O)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: O=C(Cl)c1ccc(-n2ccccc2=O)cc1

Procedure:
4-(2-oxopyridin-1(2H)-yl)benzoic acid (1 g, 4.6 mmol) was ]mixed with 10 mL of 1,2-dichloroethane. To this suspension was added SOCl2 (6 mL), and the mixture was refluxed for 1.5 h. The mixture was reduced in vacuo. The remaining traces of SOCl2 were removed by adding 1,2-dichloroethane (2×5 mL) and evaporating to dryness to yield 4-(2-oxopyridin-1(2H)-yl)benzoyl chloride as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH3:19][O:20][NH2:21]>>[CH2:19]([O:20][NH:21][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][N:17]=[CH:18][C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[Cl:1])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1Cl
Reactant: CON
Product: O=C(NOCc1ccccc1)c1ccncc1Nc1ccc(I)cc1Cl

Procedure:
N-Benzyloxy-3-(2-chloro-4-iodo-phenylamino)-isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.25 mmol of 3-[(2-chloro-4-iodophenyl)amino]isonicotinic acid (intermediate 2) and 0.36 mmol of O-methyl-hydroxylamine. LC/MS [10.01 min; 480 (M+1)]
Reaction SMILES: O1CCCC1.[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22](Cl)=[N:23][OH:24])=[CH:17][CH:16]=2)=[N:11][CH:12]=1.[C:26]([C:28]1[C:29]([NH2:35])=[N:30][C:31]([NH2:34])=[CH:32][CH:33]=1)#[CH:27].C(N(CC)CC)C>O>[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]3[CH:27]=[C:26]([C:28]4[C:29]([NH2:35])=[N:30][C:31]([NH2:34])=[CH:32][CH:33]=4)[O:24][N:23]=3)=[CH:17][CH:16]=2)=[N:11][CH:12]=1
Reactant: Cc1ccc(OCc2ccc(CC(Cl)=NO)cc2)nc1
Reactant: C#Cc1ccc(N)nc1N
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(OCc2ccc(Cc3cc(-c4ccc(N)nc4N)on3)cc2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.6 %

Procedure:
To a tetrahydrofuran (5.00 mL) solution of (4-(5-methyl-pyridin-2-yloxymethyl)-phenyl)-acetohydroximoyl chloride (130 mg, 0.447 mmol) described in Manufacturing Example 44-1-5 and 3-ethynyl-pyridin-2,6-diamine (30.0 mg, 0.226 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (126 μL, 0.903 mmol) at room temperature, which was stirred for 2 hours at room temperature. Water was added to the reaction solution at room temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane=2:1) to obtain the title compound (57.4 mg, 65.6%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:20])[N:8]([C:12]3[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH2:19])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.O>C(O)(C)(C)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:20])[N:8]([C:12]3[CH:17]=[C:16]([N:25]4[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]4)[N:15]=[C:14]([NH2:19])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(Cl)nc(N)n1
Solvent: CC(C)(C)O
Solvent: O
Product: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 120 °C

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-chloropyrimidin-2-amine (2.3 g, 6.5 mmol) and 1-methyl piperazine (3.61 mL, 32.6 mmol) in tert-butyl alcohol (10 mL) and was heated at 120° C. for 20 h. The reaction mixture was cooled to r.t., poured into water, extracted with AcOEt, washed with sat'd NaHCO3 aqueous solution and brine, dried with MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 10% methanol in methylene chloride to afford the desired compound. LCMS (M+H)+: m/z=417.1.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.Br[CH2:14][C:15]#[CH:16].C(N(C(C)C)C(C)C)C.C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCCC.ClCCl>[CH2:16]([NH:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=1)[C:15]#[CH:14]
Reactant: C#CCBr
Reactant: Nc1ccc(OC(F)(F)F)cc1
Solvent: CCCCCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C#CCNc1ccc(OC(F)(F)F)cc1
Yield: 66.2 %

Procedure:
A solution of 8.86 g (50 mmol) of 4-(trifluoromethoxy)benzenamine, 8.18 g (55 mmol) of an 80% solution of 3-bromo-1-propyne in toluene, and 8.72 ml (50 mmol) of N-ethyl-N-(1-methylethyl)-2-propanamine in 200 ml of toluene is heated at 90° C. for eighteen hours. The suspension is cooled and treated with ethyl acetate. The suspension is washed several times with water. The ethyl acetate layer is separated, dried (magnesium sulfate), and concentrated to give a brown liquid. This is applied to a column of 1 kg of flash silica gel packed in n-heptane-dichloromethane (2:1). Elution with the same solvent gives 7.12 g (66.2%) of the product as a brown liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[CH2:7][CH2:8][C:9]3[C:10]([CH3:21])=[N:11][N:12]([C:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=4)[C:13]=3[C:5]=2[CH:4]=1.Cl[CH2:25][CH2:26][CH2:27][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.[H-].[Na+].[I-].[Na+]>CN(C)C=O.C(=O)(O)[O-].[Na+]>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[CH2:7][CH2:8][C:9]3[C:10]([CH3:21])=[N:11][N:12]([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:25][CH2:26][CH2:27][N:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)=[CH:16][CH:15]=4)[C:13]=3[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)-c1c(c(C)nn1-c1ccc(O)cc1)CC2
Reactant: ClCCCN1CCCC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)-c1c(c(C)nn1-c1ccc(OCCCN3CCCC3)cc1)CC2
Temperature: 70 °C
Yield: 20.6 %

Procedure:
4-(8-Methoxy-3-methyl-4,5-dihydrobenzo[g]indazol-1-yl)-phenol (0.1 mmol) was dissolved in N,N-dimethylformamide (1 mL), and -(3-chloropropyl)pyrrolidine (15 mg, 0.1 mmol), sodium hydride (4 mg, 60% dispersion in mineral oil, 0.1 mmol) and sodium iodide (15 mg, 0.1 mmol) were added. The reaction was heated at 70° C. for 3 hours. The solution was diluted with saturated sodium bicarbonate and extracted with ethyl acetate. The extracts were dried over MgSO4 and concentrated. SiO2 chromatography with 2% triethylamine/10% methanol/ethyl acetate gave 8.6 mg of the desired product. LC-MS (C26H31N3O2 calculated 417) m/z 418 (M+H). 1H NMR (300 MHz, CDCl3) δ 7.41-7.36 (m, 2H), 7.17 (d, J=8.7 Hz, 1H), 6.99-6.94 (m, 2H), 6.67 (dd, J=8.7 Hz, 2.4 Hz, 1H), 6.40 (d, J=2.4 Hz, 1H), 4.07 (t, J=6.3 Hz, 2H), 3.52 (s, 3H), 2.91 (m, 2H), 2.72-2.58 (m, 8H), 2.30 (s, 3H), 2.12-2.04 (m, 2H), 1.86-1.81 (m, 4H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:23])[CH:6]([C:13]1[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:24]I>CN(C=O)C.[NH4+].[Cl-]>[CH3:3][O:4][C:5](=[O:23])[C:6]([C:13]1[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21])([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:24]
Reactant: CI
Reactant: COC(=O)C(c1ccccc1)c1cc(Br)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(c1ccccc1)c1cc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
NaH (562 mg, 23.4 mmol) is added portion wise to a solution of (5-Bromo-2-nitro-phenyl)-phenyl-acetic acid methyl ester (6.8 g, 19.5 mmol) in DMF (100 mL) at room temperature and stirred at room temperature for 3 hours. MeI (8.3 g, 58.5 mmol) is added to the above mixture at 0° C. The mixture is warmed to room temperature slowly and stirred overnight. The mixture is diluted with saturated aqueous NH4Cl solution and extracted with ethyl acetate (3×100 mL). The combined organic phase is washed with water and brine, dried over Na2SO4, filtered and concentrated to give the product.
Reaction SMILES: Cl.[C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[C:12]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH:11]=1)=[O:9])([CH3:5])([CH3:4])[CH3:3].[BH4-].[Na+].[CH3:31][S:32](O)(=[O:34])=[O:33]>CO>[CH3:31][S:32]([O:9][CH:8]([CH2:7][NH:6][C:2]([CH3:5])([CH3:3])[CH3:4])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[C:12]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH:11]=1)(=[O:34])=[O:33]
Reactant: CC(=O)OCc1cc(C(=O)CNC(C)(C)C)ccc1Oc1ccccc1C
Reactant: CS(=O)(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)OCc1cc(C(CNC(C)(C)C)OS(C)(=O)=O)ccc1Oc1ccccc1C

Procedure:
Proceeding in a manner similar to that described above in part B of Example 151, 22 g. of 3-(acetoxymethyl)-4-(o-toluyloxy)phenyl tert-butylaminomethyl ketone hydrochloride was reduced in anhydrous methyl alcohol with 1.13 g. of sodium borohydride and the reduction product was treated with methanesulfonic acid to yield 3-(acetoxymethyl)-4-(o-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate as a white solid which melted at 116°-118° C. (uncorr.).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][N:14]([CH3:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][C:22]([OH:24])=O.Cl.[Cl:27][C@@H:28]1[C@@H:36]2[C@@H:32]([CH2:33][NH:34][CH2:35]2)[C:31]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:30][CH2:29]1.Cl>ClCCl.C(#N)C.C(OCC)C.C(N(CC)CC)C>[ClH:27].[Cl:27][C@@H:28]1[C@@H:36]2[C@@H:32]([CH2:33][N:34]([C:22](=[O:24])[CH2:21][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]([CH3:13])[CH3:25])[CH2:35]2)[C:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:30][CH2:29]1
Reactant: Cl[C@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@@H]21
Reactant: CN(C)c1ccccc1CC(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1ccccc1CC(=O)N1C[C@H]2[C@@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@H]2Cl
Reaction time: 1 h
Yield: 13 %

Procedure:
0.39 g of carbonyldiimidazole is added to a solution, cooled to +4° C., of 0.43 g of (2-dimethylaminophenyl)-acetic acid in 15 cm3 of dry dichloromethane. The mixture is stirred for one hour at +4° C. and then a solution of 0.84 g of (3aR,7S,7aR)-7-chloro-4,4-diphenylperhydro-isoindole hydrochloride in 10 cm3 of dry dichloromethane is then added followed by a solution of 0.34 cm3 of triethylamine in 10 cm3 of dry dichloromethane. The reaction mixture is stirred at room temperature for 20 hours and then diluted with 100 cm3 of dichloromethane, washed with 50 cm3 of water and then with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 23 cm), eluting under a nitrogen pressure of 0.4 bar with an ethyl acetate and cyclohexane mixture (25/75 by volume) and collecting fractions of 80 cm3. Fraction 2 is concentrated to dryness under reduced pressure (2.7 kPa). The product, which is obtained in the form of a base, is converted to the hydrochloride by dissolving in 4 cm3 of acetonitrile followed by the addition of 6 cm3 of a 3.2N solution of hydrochloric acid in ethyl ether, washing with isopropyl ether and drying. 0.08 g of (3aR,7S,7aR)-7-chloro-2-[(2-dimethylamino-phenyl)acetyl]-4,4-diphenylperhydroisoindole hydrochloride is obtained in the form of a beige solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:24])=[C:8]([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4]>O1CCCC1>[C:15]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13][C:12]([NH:11][CH2:10][C:8]2[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[O:6][C:7]=2[CH3:24])=[CH:17][CH:16]=1
Reactant: COC(=O)c1cc(CNc2ccc(-c3ccccc3)cc2)c(C)o1
Solvent: C1CCOC1
Product: Cc1oc(C(=O)O)cc1CNc1ccc(-c2ccccc2)cc1
Reaction time: 3 h
Yield: 40.2 %

Procedure:
A solution of 4-(biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carboxylic acid methyl ester (158) (91 mg, 0.283 mmoles) in dry tetrahydrofuran (5 ml) was treated with potassium trimethylsilanoate (182 mg, 1.42 mmoles) and the mixture stirred under an argon atmosphere for 3 hours. After evaporation of the solvent, the residue was purified by HPLC (gradient: 15% acetonitrile/85% water containing 0.1% trifluoroacetic acid to 55% acetonitrile/45% water at a rate of 1%/min) to afford compound 160(35 mg) as a white solid. LC/MS System D; Rt=7.64 mins, m/z (ES+)=308 (M+H for C19H17NO3).
Reaction SMILES: [C:1]([N:11]1[CH2:18][C:17](=[O:19])[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:20](O)[CH2:21][OH:22].C1C=CC=CC=1>O>[C:1]([N:11]1[CH2:18][C:17]2([O:22][CH2:21][CH2:20][O:19]2)[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: OCCO
Reactant: O=C1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Solvent: c1ccccc1
Solvent: O
Product: O=C(O)[C@@H]1CC2(CN1C(=O)OCc1ccccc1)OCCO2
Reaction time: 8 h
Yield: 97 %

Procedure:
A stirred mixture of 12.8 g (0.049 mole) of N-carbobenzyloxy-4-keto-L-proline, 53 ml (0.095 mole) of ethylene glycol, and 0.35 g of p-toluenesulfonic acid H2O in 1.31 l. of benzene is heated and the resulting solution is refluxed for 7 hours (water formed is collected in a Dean-Stark apparatus). After standing overnight at room temperature, the lower glycol layer is separated and the benzene solution is washed with 150 ml of saturated sodium chloride, dried (MgSO4), and the solvent evaporated to give 14.6 g of N-carbobenzyloxy-4,4-ethylenedioxy-L-proline as a syrupy residue. The latter is dissolved in 60 ml of ethanol, filtered, treated with 5 g of cyclohexylamine, and diluted with ether. On seeding and rubbing, the crystalline cyclohexylamine salt separates; weight after cooling overnight, 9.0 g., m.p. 179°-180° (s. 173°). The material is recrystallized from acetonitrile, m.p. 182°-184° (s. 179°), [α]D26 -21° (c, 1 % in EtOh).