Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]#[N:15])=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]#[N:15])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccccc1-c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
A solution of 5.59 g of 4'-methyl-2-cyanobiphenyl, 29 mmol of N-bromosuccinimide, 0.9 mmol of benzoylperoxide and 500 mL of carbon tetrachloride was refluxed for 3 hours. After cooling to room temperature, the resulting suspension was filtered and then concentrated in vacuo to provide the crude 4'-bromomethyl-2-cyanobiphenyl. The product was recrystallized from ether to yield 4.7 g of product; m.p. 114.5°-120.0°. NMR (200 MHz, CDCl3) δ 7.82-7.37 (m, 8H); 4.50 (s, 2H). Anal. Calcd. for C14H10BrN: C, 61.79, H, 3.70; N, 5.15. Found: C, 62.15; H, 3.45; N, 4.98.
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][NH:17][C:18](=[O:26])[C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)[N:15]=2)[CH:7]=[CH:8][C:9]=1[OH:10].[CH2:28](Br)[CH:29]=[CH2:30]>>[CH2:30]([O:10][C:9]1[CH:8]=[CH:7][C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][NH:17][C:18](=[O:26])[C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)[N:15]=2)=[CH:5][C:4]=1[O:3][CH:2]([F:1])[F:27])[CH:29]=[CH2:28]
Reactant: Cc1cccnc1C(=O)NCc1coc(-c2ccc(O)c(OC(F)F)c2)n1
Reactant: C=CCBr
Product: C=CCOc1ccc(-c2nc(CNC(=O)c3ncccc3C)co2)cc1OC(F)F

Procedure:
Using the compound obtained in Example 367 and allyl bromide, white powdery N-[2-(4-allyloxy-3-difluoromethoxy phenyl)oxazol-4-ylmethyl]-3-methylpicolinamide was obtained following the procedure of Example 98.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[N+:28]([C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1)([O-:30])=[O:29].O>CN(C)C=O>[CH3:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][C:34]1[CH:35]=[CH:36][C:31]([N+:28]([O-:30])=[O:29])=[CH:32][CH:33]=1
Reactant: COCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCCOCCc1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 77.1 %

Procedure:
A portion of 13 (9.0 g, 28.3 mmol) was dissolved in 50 mL of dimethylformamide. Potassium carbonate (11.75 g, 85.0 mmol) and 4-nitrophenol (3.82 g, 27.5 mmol) were added. The solution was stirred at 80° C. for 16 hours. After cooling to room temperature, the solution was poured into water and extracted three times with methylene chloride. The combined organic layers were washed with water, then brine, dried over magnesium sulfate, filtered, and the solvent was removed by distillation at reduced pressure. Chromatography (silica, hexane:ethyl acetate, 1:2) was employed to isolate the product (5.71 g, 73% yield). IR (neat) 3109.2, 3078.2, 2878.5, 1726.3, 1588.1, 1511.2, 1337.1, 1106.7, 1050.3, 932.6, 845.5, 753.3, 656.1 cm−1. 1H NMR (CDCl3) δ 8.07 (d, J=9.3 Hz, 2H), 6.88 (d, J=9.3 Hz, 2H), 4.12 (app t, 2H), 3.79 (app t, 2H), 3.62 (m, 2H), 3.58 to 3.53 (m, 4H), 3.44 to 3.42 (m, 2H), 3.26 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.29, 141.93, 126.24, 114.99, 72.29, 71.29, 71.03, 70.98, 69.77, 68.60, 59.44.
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[O:20]([C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[C:1]([CH2:9][CH2:10][C:11]([O:13][CH2:30][C:29]1[CH:32]=[CH:33][CH:34]=[C:27]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:28]=1)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Reactant: O=C(O)CCC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCC(=O)c1ccccc1)OCc1cccc(Oc2ccccc2)c1
Reaction time: 4 h

Procedure:
To 12 g of 3-benzoylpropionic acid and 9.3 g of potassium carbonate in 100 ml of dimethylformamide (DMF), under nitrogen, is added m-phenoxybenzyl bromide (17.1 g). The reaction is stirred about 4 hr and then water added followed by extraction with ether. The combined extracts are washed with water, saturated sodium chloride, dried over calcium sulfate and rotoevaporated to give m-phenoxybenzyl 3-benzoylpropionate which can be further purified by prep. TLC eluting with 15% ethyl acetate/hexane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:13]=1.C[O-].[Na+].Cl.[C:18](=O)([O:21]C)[O:19][CH3:20]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][CH:8]([C:18]([O:19][CH3:20])=[O:21])[C:7](=[O:12])[C:6]=2[CH:13]=1
Reactant: O=C1CCCSc2ccc(Br)cc21
Reactant: COC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: COC(=O)C1CCSc2ccc(Br)cc2C1=O

Procedure:
To a solution of 7-bromo-2,3,4,5-tetrahydro-1-benzothiepin-5-one (13.5 g) in dimethyl carbonate (200 ml) was added at room temperature sodium methoxide (14.2 g), and the mixture was refluxed for 8 hours under nitrogen atmosphere. To the mixture was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give brown prism of methyl 7-bromo-5-oxo-2,3,4,5-tetrahydro-1-benzothiepine-4-carboxylate (11.5 g).
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].C([Li])CCC.CO[C:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1>C1COCC1>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[O:5][N:4]=[C:2]([CH3:3])[CH:1]=2)=[CH:15][CH:16]=1
Reactant: CC(C)=NO
Reactant: COC(=O)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(Br)cc2)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetone oxime (4.85 g, 66.4 mmol) was dissolved in THF (100 mL) and cooled to 0° C. n-Butyllithium (1.6M in hexanes, 81 mL, 129.6 mmol) was added and the reaction was stirred at room temperature for 1 hour. 4-Bromo-benzoic acid methyl ester (9.4 g, 43.7 mmol) in THF (30 mL) and the reaction stirred for 24 hours. The mixture was submitted to standard aqueous workup then dried over MgSO4 and evaporated. The residue was taken up in EtOH and HCl (4N in dioxane, 1 mL) was added. The reaction was heated to 60° C. and monitored by analytical TLC. When completed, the reaction mixture was concentrated to dryness to afford the title compound, which was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[C:13]#[C:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1>C(OCC)(=O)C.C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1/[CH:13]=[CH:14]\[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1
Reactant: COc1ccc2c(c1C#CC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc2c(c1/C=C\C1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.6 %

Procedure:
A solution of tert-butyl 4-[(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)-ethynyl]piperidine-1-carboxylate (0.157 g, 0.423 mmol) synthesized in Example B55, Step 1 in ethyl acetate/ethanol (1:1, 3 mL) was added with 5% palladium/carbon (wetted with 50% water, 0.0500 g), and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through Celite, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl (Z)-4-[2-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)vinyl]piperidine-1-carboxylate (0.0610 g, 39%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:14]1)=[O:11].CI.[C:40](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:40][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:14]1)=[O:11]
Reactant: O=C([O-])[O-]
Reactant: CC(C)CN(C(=O)c1nc2ccccc2[nH]1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)CN(C(=O)c1nc2ccccc2n1C)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
tert-Butyl (3S,5R)-3-{(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (205 mg) was dissolved in dimethylformamide (5 ml), methyl iodide (75 μl) and cesium carbonate (391 mg) were added and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and a fraction eluted with ethyl acetate-hexane (6:4) was concentrated under reduced pressure to give the object product (184 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)[Cl:21].[CH3:25][O:26][CH2:27][O:28][C:29]1[C:30]([CH3:44])=[C:31]2[C:36](=[C:37]([CH3:40])[C:38]=1[CH3:39])[O:35][C:34]([CH3:43])([CH:41]=O)[CH2:33][CH2:32]2>C(Cl)Cl.[Zn]>[Cl:21][C:20]([Cl:24])=[CH:41][C:34]1([CH3:43])[CH2:33][CH2:32][C:31]2[C:36](=[C:37]([CH3:40])[C:38]([CH3:39])=[C:29]([O:28][CH2:27][O:26][CH3:25])[C:30]=2[CH3:44])[O:35]1
Reactant: ClC(Cl)(Cl)Cl
Reactant: COCOc1c(C)c(C)c2c(c1C)CCC(C)(C=O)O2
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCOc1c(C)c(C)c2c(c1C)CCC(C)(C=C(Cl)Cl)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
A mixture of triphenylphosphine (524 mg, 2.0 mmol), carbon tetrachloride (193 ul, 2.0 mmol), Zinc dust (130 mg, 2.0 mmol) and 6-methoxymethoxy-2,5,7,8-tetramethyl-chroman-2-carbaldehyde (0.25 gram, 0.95 mmol) in 4 ml of DCM was stirred overnight at room temperature. The mixture was rinsed with hexane times and the combined solutions were dried over MgSO4. The solution was concentrated and the residue was purified via flash column chromatography on silica gel (10% ethyl acetate in hexane) to afford 320 mg of 2-(2,2-dichloro-vinyl)-6-methoxymethoxy-2,5,7,8-tetramethyl-chroman.
Reaction SMILES: Cl.[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5].C(N(C(C)C)CC)(C)C.[I:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CN(C=O)C>[I:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][C:3]2([O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]2[NH2:5])[OH:2])=[CH:26][CH:25]=1
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: BrCc1ccc(I)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)OC1(O)Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 9.4 %

Procedure:
Thus, a slurry of glucosamine hydrochloride (0.7 g) and diisopropylethylamine (0.6 mL) in DMF (2.0 mL) was stirred at 80° C. for 30 minutes. A solution of 4-iodobenzylbromide (0.4 g) in DMF (2 mL) was added to the reaction mixture, and the resulting mixture stirred for 18 hours. After the reaction mixture was cooled to room temperature, the precipitated solid was removed from the supernatant by decanting. Volatiles were removed from the supernatant, and the resulting residue was separated on a si-gel column using 10% aqueous MeCN as the eluent to yield 50 mg of pure 4-iodobenzyl glucosamine (compound TP012 in the scheme above). The purity of 4-iodobenzyl bromide, which can vary greatly from batch to batch if obtained from commercial suppliers, will affect the yields of this reaction accordingly. The compound 4-Iodobenzyl galactosamine can be prepared using a similar reaction scheme, starting from galactosamine hydrochloride and iodobenzyl bromide.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]32[N:15]=[C:14]([CH3:16])[C:13](=S)[NH:12]3)=[CH:4][CH:3]=1.[NH3:18]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]32[N:12]=[C:13]([NH2:18])[C:14]([CH3:16])=[N:15]3)=[CH:4][CH:3]=1
Reactant: CC1=NC2(CCCc3ccc(Br)cc32)NC1=S
Reactant: N
Product: CC1=NC2(CCCc3ccc(Br)cc32)N=C1N
Temperature: 110 °C
Yield: 65.6 %

Procedure:
7′-Bromo-4-methyl-3′,4′-dihydro-2′H-spiro[imidazole-2,1′-naphthalene]-5(1H)-thione (Example 51 Step 3, 1 g, 3.23 mmol) was taken up in ammonia (7M in MeOH, 15 mL, 105 mmol) and the resulting mixture was heated in the microwave reactor at 110° C. for 30 min. The solvent was evaporated. Ammonia (7M in MeOH, 15 mL, 105 mmol) was added and the reaction was heated again using MW for 30 min at 110° C. The solvent was evaporated. Ammonia (7M in MeOH, 15 mL, 105 mmol) was added and the reaction was heated again using MW for 30 min at 110° C. The solvent was evaporated and the residue was dissolved in EtOAc (20 mL). The resulting mixture was extracted with 0.1 M citric acid (2×10 mL). The organic layer was discarded while the aqueous phase was basified to pH 12 by addition of 50% NaOH (aq) and extracted with DCM (3×20 mL). The organic phase was dried with a phase separator and concentrated in vacuo to give the title compound (0.619 g, 65% yield). 20 mg of the product was purified using flash chromatography (4 g SiO2, DCM in 0.1M NH3 in MeOH) to give the title compound (10 mg). 1 H NMR (500 MHz, CDCl3) δ ppm 1.88-1.99 (m, 2 H), 2.07-2.16 (m, 1 H), 2.20 (dqd, 1 H), 2.31-2.37 (m, 3 H), 2.92 (t, 2 H), 6.68 (d, 1 H), 7.04 (d, 1 H), 7.25 (dd, 1 H); 1 H NMR (500 MHz, CD3OD) δ ppm 1.84 (ddd, 1 H), 1.94 (ddd, 1 H), 2.03-2.12 (m, 1 H), 2.15 (dtd, 1 H), 2.34 (s, 3 H), 2.91 (t, 2 H), 6.69 (d, 1 H), 7.11 (d, 1 H), 7.29 (dd, 1 H), MS (ES+) m/z 292 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:9])[CH:8]=CC=CC=1.[CH3:10][O:11][CH:12]([O:20][CH3:21])[CH2:13][NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18].C(Br)C=C>O>[CH2:9]([N:14]([CH2:13][CH:12]([O:11][CH3:10])[O:20][CH3:21])[C:15](=[O:19])[O:16][CH2:17][CH3:18])[CH:3]=[CH2:8]
Reactant: Cc1ccccc1
Reactant: CCOC(=O)NCC(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C=CCBr
Product: C=CCN(CC(OC)OC)C(=O)OCC
Temperature: 80 °C
Reaction time: 1 h

Procedure:
20 g of sodium hydride (80% strength in paraffin oil) are initially introduced into 500 ml of toluene and 89 g (0.5 mol) of ethyl N-(2,2-dimethoxyethyl)-carbamate are added dropwise at 80° C. The mixture is stirred at 80° C. for one hour and 73 g (0.6 mol) of allyl bromide are then added dropwise in the course of three hours. The mixture is stirred at 80° C. overnight, the salts are dissolved with water and the organic phase is separated off. The aqueous phase is extracted with toluene, the organic phases are dried over potassium carbonate and concentrated and the residue is distilled.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:13])[C:10]([OH:12])=O.Cl.[C:16]1([C:22]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@H:30]3[C@H:26]([CH2:27][NH:28][CH2:29]3)[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[CH3:14][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:13])[C:10]([N:28]1[CH2:27][C@H:26]2[C@H:30]([C:22]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH2:24][C:25]2=[O:31])[CH2:29]1)=[O:12]
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Reactant: CC(C(=O)O)c1ccccc1N(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C(=O)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1)c1ccccc1N(C)C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
N,N'-carbonyldiimidazole (0.85 g) is added to a solution, cooled to 5° C., of (RS)-2-(2-dimethylaminophenyl)propionic acid (1 g) in dichloromethane (30 cc), and the mixture is stirred for 30 minutes at this temperature. A solution of (3aR, 7aR)-7,7-diphenylperhydro-4-isoindolone hydrochloride (1.7 g) and triethylamine (1.4 cc) in dichloromethane (30 cc) is added. The reaction mixture is stirred at 20° C. for 16 hours, washed with water (2×100 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.2-0.063 mm, diameter 3 cm, height 50 cm), eluting under a nitrogen pressure of 0.5 bar with ethyl acetate and collecting 125-cc fractions. Fractions 4 to 6 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aR, 7aR)-2-[(RS)-2-(2-dimethylaminophenyl)propionyl]-7,7-diphenylperhydro-4-isoindolone (1.4 g) in the form of white meringue-like product;
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24](I)=[CH:23][C:3]=1[N:4]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.C([Mg]Cl)(C)C.CON(C)[C:36]([C:38]1([CH3:41])[CH2:40][CH2:39]1)=[O:37]>C1COCC1.C(OCC)C>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:3]2[CH:23]=[C:24]([C:36]([C:38]3([CH3:41])[CH2:40][CH2:39]3)=[O:37])[CH:25]=[CH:26][C:2]=2[Cl:1])=[CH:7][CH:8]=1
Reactant: CON(C)C(=O)C1(C)CC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(I)ccc2Cl)cc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(C(=O)C3(C)CC3)ccc2Cl)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Under argon, 7.587 g (15.37 mmol) of 2-chloro-5-iodo-N,N-bis(4-methoxybenzyl)aniline were dissolved in 100 ml of THF and cooled to −78° C. 7.65 ml (15.27 mmol) of a 2 M solution of isopropylmagnesium chloride in diethyl ether were then slowly added dropwise. The reaction solution was then slowly warmed to −40° C. and stirred at this temperature for 30 min. 2 g (13.97 mmol) of N-methoxy-N,1-dimethylcyclopropanecarboxamide [R. Shintani et al., Chem. Eur. J., 15 (35), 8692-8694 (2009)], dissolved in 20 ml of THF, were then slowly added dropwise to the reaction solution. The reaction mixture obtained was then slowly warmed to room temperature and stirred at this temperature overnight. 50 ml of an ice-cold saturated aqueous ammonium chloride solution were then added to the reaction mixture. After separation of the phases, the aqueous phase was extracted three more times with ethyl acetate, and the combined organic phases were dried over magnesium sulphate, filtered and evaporated to dryness. The crude product obtained was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 3.977 g (63% of theory) of the title compound.
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.[H-].[Na+].Br[CH2:14][C:15]([O:17][CH3:18])=[O:16]>O1CCCC1>[CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH:6][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:4][C:3]=2[O:2]1
Reactant: COC(=O)CBr
Reactant: Nc1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CNc1ccc2c(c1)OCO2

Procedure:
3,4-Methylenedioxyaniline (30.7 g) was dissolved in 300 ml of dry tetrahydrofuran, followed by the addition of 10.7 g of sodium hydride (in oil, 60%) and 22.7 ml of methyl bromoacetate under ice cooling. Under an argon stream, the resultant mixture was stirred at room temperature for 2 days. The reaction mixture was extracted with ether. The organic layer so obtained was washed with water, shaken together with a saturated aqueous NaCl solution and then dried over anhydrous sodium sulfate. The solvent was distilled off, whereby reddish brown crystals were obtained. The crude crystals were decolored and then recrystallized from methanol, whereby 28.0 g of methyl 2-[N-(3,4-methylenedioxyphenyl)amino]acetate were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)[CH:7]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:14][C:15]2[CH:23]=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)[S:32]([C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc3c(c2)OCO3)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc3c(c2)OCO3)S(=O)(=O)c2ccc(F)cc2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step A of Examples 1 from 3-(3-{[(benzo[1,3]dioxol-5-ylmethyl)-amino]-methyl}-phenyl)-propionic acid methyl ester, prepared in Step A of Example 15a, and 4-fluorobenzenesulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.82 (m, 2H), 7.17 (m, 3H), 7.05 (d, 1H), 6.89 (d, 1H), 6.83 (s, 1H), 6.64 (d, 1H), 6.56 (s, 1H), 6.48 (m, 1H), 5.91 (s, 2H), 4.27 (s, 2H), 4.19 (s, 2H), 3.67 (s, 3H), 2.83 (t, 2H), 2.52 (t, 2H).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][N:17]3[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:24]([Li])([CH3:27])([CH3:26])[CH3:25]>C1C=CC=CC=1>[C:24]([C:20]1([OH:23])[CH2:21][CH2:22][N:17]([CH2:16][CH:6]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]2=3)[CH2:18][CH2:19]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C1CCN(CC2c3ccccc3CCc3ccccc32)CC1
Reactant: [Li]C(C)(C)C
Solvent: c1ccccc1
Product: CC(C)(C)C1(O)CCN(CC2c3ccccc3CCc3ccccc32)CC1
Reaction time: 2 h

Procedure:
Solution of 5 parts of 1-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methyl]-4-piperidinone in 150 parts by volume of benzene is added dropwise over a period of 50 minutes to a stirred, cooled solution of tert-butyllithium (33.8 parts by volume of 1.9 M ethyl ether solution) in 150 parts by volume of benzene under a nitrogen atmosphere. The resultant solution is stirred at ambient temperature for about 1 hour and quenched with the addition of 100 parts by volume of 10% ammonium chloride. The solution is stirred for additional 2 hours, the organic layer separated, washed with brine, dried with magnesium sulfate and concentrated in vacuo to give clear yellow oil. This oil is chromatographed on silica gel using 1% ethanol/methylene chloride as eluent to afford 4-tert-butyl-1-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-methyl]-4-piperidinol melting at about 96°-98.5° C. This compound is represented by the following general formula ##STR27##