Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]1OC2=CC(C(C)(C)CCCCCC)=CC3=C2C(CC(C)(C)O3)C1.[CH3:26][O:27][C:28]1[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][CH2:37][CH2:38][NH:39][CH2:40][CH2:41][CH2:42][CH2:43][NH:44][CH2:45][CH2:46][CH2:47][NH2:48])[CH:31]=[CH:30][C:29]=1[OH:49].[OH:50][CH:51]1[CH:60]2[CH2:61][CH2:62][O:63][C:58]3=[C:59]2[C:54](=[CH:55][C:56]([C:64]([CH3:72])([CH3:71])[CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])=[CH:57]3)[O:53][C:52]1([CH3:74])[CH3:73].C[Mg]I.[Cl-].[NH4+]>C(OCC)C>[CH3:26][O:27][C:28]1[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][CH2:37][CH2:38][NH:39][CH2:40][CH2:41][CH2:42][CH2:43][NH:44][CH2:45][CH2:46][CH2:47][NH2:48])[CH:31]=[CH:30][C:29]=1[OH:49].[OH:50][CH:51]1[CH:60]([CH2:61][CH:62]([OH:63])[CH3:2])[C:59]2[CH:58]=[CH:57][C:56]([C:64]([CH3:72])([CH3:71])[CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])=[CH:55][C:54]=2[O:53][C:52]1([CH3:74])[CH3:73]
Reactant: CCCCCCC(C)(C)c1cc2c3c(c1)OC(C)(C)CC3CC(O)O2
Reactant: CCCCCCC(C)(C)c1cc2c3c(c1)OC(C)(C)C(O)C3CCO2
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Agent: C[Mg]I
Agent: [Cl-]
Solvent: CCOCC
Product: CCCCCCC(C)(C)c1ccc2c(c1)OC(C)(C)C(O)C2CC(C)O
Temperature: 25 °C
Yield: 58.3 %

Procedure:
The hemiacetal obtained in Example 6, dl-5-hydroxy-2,2-dimethyl-8-(1,1dimethylheptyl)-3,3a,4,5-tetrahydro-2H-pyrano[4,3,2-de]benzopyran, (491 mg, 1.42 mmole) was dissolved in 10 ml of diethyl ether and cooled in an ice bath for 15 minutes. From a syringe 1.58 ml of 2.9M methylmagnesium iodide was added slowly with stirring. The reaction mixture was allowed to warm to room temperature and stirred for three hours. Ammonium chloride cyrstals (ca. 100 mg) was added to consume the unreacted Grignard reagent and the mixture stirred for 20 minutes. Ethyl acetate, 75 ml, and water, 50 ml, were added, the mixture stirred for a few minutes, and the layers separated. The aqueous layer was extracted with 50 ml of ethyl acetate and the combined organic layers washed with 50 ml each of water, brine and water again. The organic layer was dried over anhydrous magnesium sulfate and solvent evaporated in vacuo to provide 525 mg of crude oil. The oil was chromatographed on a pair of 2 mm thickness silica gel plates employing an ethyl acetate/pentane (1:3 by volume) solvent system. The region with Rf 0.09-0.21 was extracted with 200 ml of ethyl acetate for 2-3 hours to afford 300 mg of product (58.3%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[O:11]1[CH2:16][CH2:15][CH:14](OS(C)(=O)=O)[CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:14]2[CH2:15][CH2:16][O:11][CH2:12][CH2:13]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(F)ccc1O
Reactant: CS(=O)(=O)OC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(F)ccc1OC1CCOCC1

Procedure:
In a manner similar to the method described in Example 4a, 5-fluoro salicylaldehyde (Aldrich) reacted with methanesulfonic acid tetrahydro-pyran-4-yl ester (Example 32a) and potassium carbonate in dimethylformamide to give a solid. MS (H+), 225.
Reaction SMILES: [NH2:1][C:2](=[O:43])[CH2:3][C:4]1[CH:42]=[CH:41][CH:40]=[CH:39][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[CH:21][C:20]=2[F:38])[N:9]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl>C1COCC1>[F:38][C:20]1[CH:21]=[C:22]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:23]=[CH:24][C:19]=1[NH:18][C:10]1[N:9]=[C:8]([CH2:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[CH:42][C:4]=2[CH2:3][C:2]([NH2:1])=[O:43])[C:13]([C:14]([F:16])([F:15])[F:17])=[CH:12][N:11]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)c(F)c2)CC1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)cc2F)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.1 %

Procedure:
To a solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-fluorophenyl)piperidine-1-carboxylate (I61) (0.049 g, 0.081 mmol) in THF (3 mL) was added TFA (0.20 mL, 2.6 mmol). The resulting mixture was then stirred at room temperature for 20 hours then 40° C. for 24 hours. The volatiles were removed by evaporation under reduced and DCM (2 mL) and TFA (1.00 mL, 13.1 mmol) were added. After stirring at 30° C. for 18 hours the mixture was concentrated under reduced pressure and the residue azeotroped twice with toluene (10 mL) to give the title compound (I62) (0.037 g, 91%). LCMS Method C: rt 4.84 min; m/z 502.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=O)[CH2:11][C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F.S(F)(F)(F)[F:26]>C(Cl)Cl>[CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]([F:26])=[CH:11][C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccccc2N(Cc2ccccc2)c2ccccc21
Reactant: FS(F)(F)F
Agent: F
Solvent: ClCCl
Product: FC1=Cc2ccccc2N(Cc2ccccc2)c2ccccc21
Reaction time: 0.5 h

Procedure:
A mixture of 149.7 g (0.5 mole) of 5-benzyl-5,11-dihydro-10H-dibenz[b,f]azepin-10-one (vide British Pat. No. 961 444),27 ml of hydrogen fluoride, 125 g of sulphur tetrafluoride and 400 ml of methylene chloride is heated in a steel autocalve for 16 hours to 70° C. After the mixture has cooled, the bulk of the liquid constituents are filtered off with suction. Then water and aqueous ammonia solution are added until the pH of the aqueous phase is 9-10. The organic phase is separated, washed three times with water, diluted with 200 ml of benzene and concentrated in a rotary evaporator. The black residue is dissolved in methylene chloride and the solution is filtered through 700 g of silica gel (particle size 0.063-0.2 mm) with methylene chloride as eluant. The filtrate is concentrated, the residue dissolved in 1.5 liters of benzene and stirred for 30 minutes with 500 g of magnesium silicate gel. The mixture is filtered and 500 g of magnesium silicate gel are again added to the filtrate. After repeated filtration, the solution is concentrated in vacuo and the black residue is chromatographed over 800 g of silica gel (particle size 0.063-0.2 mm) with hexane/benzene (2:1) as eluant. The homogeneous fractions are combined and concentrated to yield the 5-benzyl-10-fluoro-5H-dibenz[b,f]azepine as a light yellow oil.
Reaction SMILES: CC(C)([O-])C.[Na+].I[C:8]1[CH:9]=[C:10]([Br:14])[CH:11]=[CH:12][CH:13]=1.[CH:15]1[C:27]2[NH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH:24]1[C:25]2[N:26]([C:8]3[CH:9]=[C:10]([Br:14])[CH:11]=[CH:12][CH:13]=3)[C:27]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]=2[CH:21]=[CH:22][CH:23]=1
Reactant: Brc1cccc(I)c1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Product: Brc1cccc(-n2c3ccccc3c3ccccc32)c1
Reaction time: 0.25 h

Procedure:
Mix together 0.4 g Pd2DBA3 (DBA dibenzylideneacetone) and 0.4 g DPPF (DPPF 1,1′-bis(diphenylphosphino)ferrocene) and 4.3 g sodium t-butoxide and dissolve into 200 mL xylenes in glove box. Stir 15 mins then add 25 g of 3-iodo-bromobenzene. Stir 15 mins then add 5 g carbazole and the mix was brought to reflux. Reflux overnight using an air condensor in glove box. The solution immediately is dark purple/brown but on reaching ˜80 C. it is dark reddish brown and cloudy. After heating close to reflux overnight, the solution is dark brown and clear. Evaporated outside the glove box in rotovap and then dissolved in DCM and extracted (soxhlet) through a bed of silica and basic alumina (stacked in soxhlet) using DCM. Collect dark orange solution and evaporate to dryness. Leaves a dark orange oil. Wash with methanol and then dissolve into ether and reprecipitated with methanol—this product is slightly soluble in methanol.
Reaction SMILES: [CH:1]1[C:11]2[C:10](=O)[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1>O1CCCC1>[CH:1]1[C:11]2[CH2:10][NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1Nc2ccccc2Nc2ccccc21
Solvent: C1CCOC1
Product: c1ccc2c(c1)CNc1ccccc1N2
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.7 %

Procedure:
To a stirred solution of 4.3 g of 5,11-dihydro-10H-dibenz[b,e][1,4]diazepin-11-one in 50 ml of tetrahydrofuran, under nitrogen and cooled to 0° C. is added 4.0 ml of 10N methyl sulfide-borane complex. The ice bath is removed after 30 minutes and the reaction mixture stirred at room temperature for 18 hours. The reaction mixture is cooled in an ice bath and 30 ml of anhydrous methanol added dropwise and evaporated to dryness in vacuo. Another 30 ml of methanol is added and evaporated to a residue. The residue is quenched with 30 ml of 40% sodium hydroxide followed by heating at 110° C. for 45 minutes and cooling to room temperature. The reaction mixture is diluted with 200 ml of water and extracted with methylene chloride (3×100 ml). The combined extracts are washed with 1N HCl, water and 0.5N NaOH. The organic layer is dried and evaporated in vacuo to give 3.2 g of the desired product, m.p. 114°-116° C.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([NH:10][C:11]2[N:16]=[C:15]([NH:17][CH3:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[CH:13][N:12]=2)=[C:4]([Cl:23])[CH:3]=1.[CH3:24][N:25]1[C:29]([Sn](CCCC)(CCCC)CCCC)=[CH:28][N:27]=[N:26]1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:23][C:4]1[CH:3]=[C:2]([C:29]2[N:25]([CH3:24])[N:26]=[N:27][CH:28]=2)[C:7]([O:8][CH3:9])=[CH:6][C:5]=1[NH:10][C:11]1[N:16]=[C:15]([NH:17][CH3:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[CH:13][N:12]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnnn1C
Reactant: CNc1nc(Nc2cc(OC)c(Br)cc2Cl)ncc1C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: CNc1nc(Nc2cc(OC)c(-c3cnnn3C)cc2Cl)ncc1C(F)(F)F
Temperature: 100 °C
Yield: 44.3 %

Procedure:
A mixture of N2-(4-bromo-2-chloro-5-methoxyphenyl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (50 mg, 0.12 mmol), 1-methyl-5-(tributylstannyl)-1H-1,2,3-triazole (68 mg, 0.18 mmol) and Pd(dppf)2Cl2 (10 mg, 0.012 mmol) in dioxane (4 mL) was degassed under a stream of nitrogen for 10 min. The reaction mixture was heated to 100° C. for 18 h. Further amounts of 1-methyl-5-(tributylstannyl)-1H-1,2,3-triazole (68 mg, 0.18 mmol) and Pd(dppf)2Cl2 (10 mg, 0.012 mmol) were added and the mixture maintained at 100° C. for another 24 h, after which further amounts of 1-methyl-5-(tributylstannyl)-1H-1,2,3-triazole (68 mg, 0.18 mmol) and Pd(dppf)2Cl2 (10 mg, 0.012 mmol) were added. The mixture was maintained at 100° C. for another 48 h. The mixture was cooled and concentrated to dryness under vacuum, and the residue partitioned between DCM and water. The separated organic phase was concentrated to dryness under vacuum and the residue purified by RP-HPLC; the product was isolated as a cream solid (22 mg, 44%). LCMS (ESCI_Formic_MeCN): [MH+]=414 at 3.45 min. 1H NMR δ (DMSO-d6): 8.58 (s, 1H); 8.16 (s, 1H); 7.98 (s, 1H); 7.71 (s, 1H); 7.42 (s, 1H); 7.24 (d, J=5.1, 1H); 3.82 (s, 3H); 3.76 (s, 3H); 2.87 (d, J=4.4, 3H).
Reaction SMILES: C([O-])=O.[NH4+].C([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][N:21]2[C:25]3=[N:26][C:27]([N:31]4[CH2:37][CH:36]5[O:38][CH:33]([CH2:34][CH2:35]5)[CH2:32]4)=[CH:28][C:29](=[O:30])[N:24]3[CH2:23][C@@:22]2([CH3:43])[C:39]([F:42])([F:41])[F:40])=[CH:15][CH:14]=1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[OH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][N:21]2[C:25]3=[N:26][C:27]([N:31]4[CH2:32][CH:33]5[O:38][CH:36]([CH2:35][CH2:34]5)[CH2:37]4)=[CH:28][C:29](=[O:30])[N:24]3[CH2:23][C@@:22]2([CH3:43])[C:39]([F:42])([F:41])[F:40])=[CH:15][CH:14]=1
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CC4CCC(C3)O4)cc2=O)N1CCc1ccc(OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CC4CCC(C3)O4)cc2=O)N1CCc1ccc(O)cc1
Temperature: 25 °C

Procedure:
700 mg (11.10 mmol) of ammonium formate and 156 mg (0.22 mmol) of 20% palladium hydroxide are added at 0° C. to a solution of 1.20 g (2.22 mmol) of (S)-1-[2-(4-benzyloxyphenyl)ethyl]-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one in 15 mL of methanol. The mixture is refluxed for 1 hour and then allowed to cool to room temperature. The reaction medium is filtered through Celite and the filtrate is then evaporated to dryness. After purification by chromatography on silica gel (eluent A/B: DCM/MeOH, gradient A/B: t 0 min 0% B, t 25 min 10% B, t 30 min 10% B), 732 mg of (S)-1-[2-(4-hydroxyphenyl)ethyl]-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one were obtained, corresponding to the following characteristics:
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][CH2:9][CH:8]2[C:12]([NH2:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]1([CH:7]2[CH2:11][CH2:10][CH2:9][CH:8]2[CH2:12][NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)C1CCCC1c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC1CCCC1c1ccccc1
Reaction time: 2.5 h

Procedure:
A solution of 2-phenylcyclopentane carboxamide (900 mg, 4.76 mmol) in THF (15 mL) was added dropwise to a cold (0° C.) suspension of LAH (271 mg, 7.13 mmol) in THF (15 mL). The cooling bath was removed and the mixture was stirred for 2.5 h. The reaction was quenched with MeOH (2 mL) and then 1N HCl (2 mL). The mixture was filtered through Celite. The filtrate was diluted with EtOAc and washed with sat'd sodium bicarbonate (3×), washed with brine, dried over potassium carbonate. and concentrated to give (2-phenylcyclopentyl)methanamine as a clear oil. (760 mg, 91.2%). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.37-7.14 (m, 5H), 2.76 (dd, J=12.5, 4.8 Hz, 1H), 2.67-2.51 (m, 2H), 2.18-1.96 (m, 3H), 1.92-1.65 (m, 3H), 1.53-1.33 (m, 3H). LCMS: M+1=176.18.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].C([Li])CCC.[Br:9][C:10]1[C:15]2[O:16][CH2:17][C@@H:18]3[C@@H:23]([CH2:24]OS(C)(=O)=O)[CH2:22][N:21]([CH3:30])[CH2:20][C@H:19]3[C:14]=2[CH:13]=[C:12]([O:31][CH3:32])[CH:11]=1.[ClH:33].C(OCC)(=O)C>O1CCCC1.C(O)(C)C.O>[Br:9][C:10]1[C:15]2[O:16][CH2:17][C@@H:18]3[C@@H:23]([CH2:24][S:3][CH2:1][CH3:2])[CH2:22][N:21]([CH3:30])[CH2:20][C@H:19]3[C:14]=2[CH:13]=[C:12]([O:31][CH3:32])[CH:11]=1.[ClH:33]
Reactant: COc1cc(Br)c2c(c1)[C@@H]1CN(C)C[C@H](COS(C)(=O)=O)[C@H]1CO2
Reactant: CCS
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)O
Product: CCSC[C@H]1CN(C)C[C@H]2c3cc(OC)cc(Br)c3OC[C@H]12
Reaction time: 2 h

Procedure:
To a stirred solution of 0.46 ml ethanethiol in 40 ml dry tetrahydrofuran (THF) under nitrogen at -10° is added dropwise 2.3 ml n-butyllithium (2.28M in hexane). This solution is added to a solution of 1.91 g (±)-[4R*,4aS*,10bR*]-7-bromo-4-(methylsulfonyloxymethyl)-1,3,4,4a,5,10b-hexahydro-9-methoxy-2-methyl-2H-[1]benzopyrano[4,3-c]pyridine in 25 ml THF. After stirring 2 h at 25°, 5 ml H2O is added and the reaction mixture concentrated under reduced pressure. The residue is partitioned between 25 ml H2O and 50 ml CH2Cl2. The CH2Cl2 phase is washed with 20 ml H2O, dried over Na2SO4, filtered and concentrated. Flash chromatography with CH2Cl2 /MeOH (40:1) yields an oil which is dissolved in 40 ml isopropyl alcohol. The solution is warmed at 50° and 1 ml 3.4N HCl/ethyl acetate is added. After cooling overnight the product is filtered, washed with isopropyl alcohol/ether (1:1) and dried to afford the title compound, m.p. 268°-269° dec (HCl salt).
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=1)=[O:4].[Br:15]N1C(=O)CCC1=O>N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:12][C:8]1[N:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:14])([CH3:13])[CH3:1])[CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(NC(=O)C(C)(C)C)n1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)Nc1cccc(CBr)n1
Yield: 35.3 %

Procedure:
Carbon tetrachloride (CCl4, 300 mL) and the product from Example 1 (50.6 g, 0.26 mol) were placed in a 1-L flask equipped with a N2 inlet The solution was stirred until all solid dissolved. N-bromosuccinimide (NBS, 46.8 g, 0.26 mol) was then added to the reaction flask, followed by 2,2'-azobisisobutyronitrile (AIBN, 0.02 g). The reaction was heated to reflux for 7 h with a 500 watt reflector spot lamp. After cooling the reaction to room temperature, it was filtered and all solvent was removed under reduced pressure. Flash chromatography (15/85 ethyl acetate (EtOAc)/Hex) provided 24.89 g (37%) of title product.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[CH2:28](O)[CH2:29][CH3:30]>>[CH2:28]([O:14][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:17][CH:16]=1)[CH2:29][CH3:30]
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Reactant: CCCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCCOC(=O)c1ccc(C(=O)c2ccccc2)cc1
Yield: 76.3 %

Procedure:
A mixture of 10.0 grams (0.044 mole) of p-benzoylbenzoic acid, 100 milliliters of n-propanol and 0.25 milliliters of concentrated sulfuric acid was stirred under reflux for 5 hours. Aqueous sodium bicarbonate solution was then added. The organic layer was separated, dried over anhydrous magnesium sulfate and filtered. Volatiles were removed under vacuum with warming to provide 9.0 grams (76.3% yield) of n-propyl-p-benzoylbenzoate. The infrared spectrum revealed carbonyl absorption bands at 1670 and 1730 cm-1.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:24][CH2:23][C@@H:22]3[C@@H:18]([CH2:19][NH:20][CH2:21]3)[C@@H:17]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:34]1(=O)[CH2:38][CH2:37][C:36](=[O:39])[CH2:35]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:24][CH2:23][C@@H:22]3[C@@H:18]([CH2:19][N:20]([C:34]4[CH2:38][CH2:37][C:36](=[O:39])[CH:35]=4)[CH2:21]3)[C@@H:17]2[C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: C[C@@H](O[C@H]1CC[C@H]2CNC[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C[C@@H](O[C@H]1CC[C@H]2CN(C3=CC(=O)CC3)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
To a solution of 12.3 mg (0.26 mmol) of (3aR,4R,5S,7aR)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}4-(4-fluorophenyl)octahydro-1H-isoindole (Example 2) in -2 mL dry toluene was added 2.7 mg (0.028 mmol) cyclopentane-1,3-dione and a catalytic amount (˜0.5 mg) of PTSA. The resulting mixture was heated at reflux for 16 hr. The solvent was removed vacuum and the residue was purified by prep TLC eluting with EtOAc/MeOH (95/5) to afford the title compound. 1H-NMR (CDCl3): δ: 7.73 (1H, s), 7.20 (2H, s), 7.03-6.90 (2H, m), 4.98, 4.80 (1H, s), 4.50 (1H, m), 3.62-3.18 (2H, m), 3.30-3.18 (3H, m), 3.15, 2.97 (1H, d, J=11.2 Hz), 2.68 (2H, m), 2.55-2.40 (4H, m), 2.17 (1H, m), 2.20 (1H, m), 2.00 (1H, m), 1.85 (1H, m), 1.62 (1H, m), 1.33 (3H, d, J=6.2 Hz). MS: (MH)+556.0.
Reaction SMILES: B(Br)(Br)Br.[C:5]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:21]3[C:16](=[C:17]([O:28]C)[CH:18]=[CH:19][C:20]=3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:15][CH2:14][C:13]2=[O:30])=[CH:7][CH:6]=1>ClCCl>[C:5]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=[CH:7][C:8]([CH2:11][N:12]2[C:21]3[C:16](=[C:17]([OH:28])[CH:18]=[CH:19][C:20]=3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:15][CH2:14][C:13]2=[O:30])=[CH:9][CH:10]=1
Reactant: COc1ccc(-c2ccccc2)c2c1CCC(=O)N2Cc1ccc(-c2ccccc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1CCc2c(O)ccc(-c3ccccc3)c2N1Cc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 103.7 %

Procedure:
A dichloromethane solution (12 ml) of 2N boron tribromide was added dropwise at −20° C. to a dichloromethane solution (50 ml) of 1-(biphenyl-4-ylmethyl)-5-methoxy-8-phenyl-3,4-dihydro-1H-quinolin-2-one (5.00 g). After stirring for 4 hours, the reaction mixture was poured into ice water and separated into layers. The organic layer was washed twice with water, washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from a dichloromethane-diisopropyl ether mixed solvent to thereby obtain 5.01 g (yield: quantitative) of 1-(biphenyl-4-ylmethyl)-5-hydroxy-8-phenyl-3,4-dihydro-1H-quinolin-2-one as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:12][CH3:13])=[N:7][CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1.Cl>C(O)(=O)C.[Fe]>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([CH:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=3)[C:8]([NH:12][CH3:13])=[N:7][CH2:6]2)=[CH:19][CH:18]=1
Reactant: CNC1=NCC(c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc21
Agent: [Fe]
Agent: Cl
Solvent: CC(=O)O
Product: CNC1=NCC(c2ccc(N)cc2)c2cc(Cl)ccc21
Reaction time: 2 h

Procedure:
135.2 mg of iron powder were added to a solution of 255 mg of 6-chloro-1-methylamino-4-(4-nitrophenyl)-3,4-dihydroisoquinoline in 4.5-5 ml of glacial acetic acid and then 1.8 ml of concentrated hydrochloric acid were added dropwise, and the mixture was boiled under reflux conditions for 2 hours. The solvent was removed by distillation, and the residue was mixed with water and made alkaline with 2N NaOH. This aqueous phase was extracted with ethyl acetate and purified by MPLC chromatography using an MPRC cartridge with a mixture of 10 parts by volume of ethyl acetate, 5 parts by volume of n-heptane, 5 parts by volume of dichloromethane, 5 parts by volume of methanol and 1 part by volume of concentrated aqueous ammonia solution. Amorphous product.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH:15]([CH:22]2[CH2:24][CH2:23]2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:10][N:9]=1)(C)(C)C.FC(F)(F)C(O)=O.CCOC(C)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH:22]1([CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][C:12]2[CH:11]=[CH:10][N:9]=[C:8]([NH2:7])[CH:13]=2)[CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)Nc1cc(CC(c2ccccc2)C2CC2)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1cc(CC(c2ccccc2)C2CC2)ccn1
Reaction time: 16 h
Yield: 102.5 %

Procedure:
The crude [4-(2-cyclopropyl-2-phenyl-ethyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (97 mg) is dissolved in DCM (1.5 mL) and trifluoroacetic acid (0.5 mL) is added. After the mixture is stirred for 16 hrs, EtOAc (25 mL) is added followed by the addition of saturated NaHCO3 aqueous solution (10 mL) and water (15 mL). The mixture is stirred for 15 min and the aqueous layer is separated and extracted with EtOAc (2×25 ml). All the organic layers are combined and concentrated to give 70 mg of the crude product which is used in the next step without purification.