Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:14]([CH3:25])[CH2:13]1.C(N(CC)CC)C>[Pt].CO.C(Cl)Cl>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C@@H:14]([CH3:25])[CH2:13]2)=[C:2]([Cl:1])[CH:7]=1
Reactant: C[C@H]1CN(Cc2ccc([N+](=O)[O-])cc2Cl)CCN1C(=O)OC(C)(C)C
Agent: [Pt]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccc(N)cc2Cl)CCN1C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 68.4 %

Procedure:
A mixture of 1,1-dimethylethyl (2S)-4-[(2-chloro-4-nitrophenyl)methyl]-2-methyl-1-piperazinecarboxylate (D103) (0.199 g, 0.538 mmol), triethylamine (0.75 mL, 5.38 mmol) and 5% Pt/C catalyst (0.134 g) in MeOH (5 mL) was hydrogenated at room temperature and atmospheric pressure for 3 h. The catalyst was removed by filtration and the filtrate was concentrated to give a colourless oil which was dissolved in DCM. The DCM solution was washed with water (×2) and brine, then dried and concentrated to give the crude product. Purification by column chromatography eluting with 10-40% EtOAc/pentane gave the title compound as a colourless oil (0.125 g). δH (CDCl3, 400 MHz) 7.19 (1H, d), 6.69 (1H, d), 6.54 (1H, dd), 4.18 (1H, br.s), 3.79 (1H, d), 3.70 (2H, br.s), 3.45 (2H, m), 3.07 (1H, td), 2.74 (1H, m), 2.60 (1H, m), 2.19 (1H, dd), 2.03 (1H, m), 1.45 (9H, s), 1.22 (3H, d). MS (ES): MH+ 340/342.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]1([CH2:15][C:16](Cl)=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.N1C=CC=CC=1>ClCCl>[CH:9]1([CH2:15][C:16]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Nc1ccc(O)cc1
Reactant: O=C(Cl)CC1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CC1CCCCC1)Nc1ccc(O)cc1
Reaction time: 8 h

Procedure:
To a solution of 4-aminophenol (3.83 g, 35.1 mmol) in dichloromethane (50 ml) were added cyclohexylacetyl chloride (11.26 g, 70.1 mmol) and pyridine (5.67 ml, 70.1 mmol), while cooling the reaction mixture in an ice bath. After the addition was completed, the cooling bath was removed and stirring was continued overnight at room temperature. The solvent was removed by evaporation and the residue was dissolved in THF (300 ml). 6N NaOH (aq, 41 ml) was added and the mixture was stirred at room temperature for 4 h. The solution was acidified with 1 N hydrochloric acid and the organic phase was removed by evaporation. The solid material was collected by filtration, dried and dissolved in methanol (100 ml). A solution of KOH (5.5 g) in methanol (50 ml) was added. After stirring for 1 h at room temperature water (200 ml) was added and the organic solvent was removed by evaporation. The aqueous phase was acidified with 1 N HCl. The title product was isolated by filtration and dried in vacuo (6.31 g, 77%, pink crystals).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].C[C:13]([CH3:15])=[O:14].CCO[C:19]([CH2:21][SH:22])=O.C(=O)([O-])[O-].[K+].[K+]>CCOCC.O.[I-].[K+]>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][CH2:19][C:21]([O:14][CH2:13][CH3:15])=[S:22])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)=O
Reactant: CCOC(=O)CS
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=S)CCc1ccc([N+](=O)[O-])cc1
Yield: 95 %

Procedure:
43.2 g (0.2 mol) of p-nitrobenzyl bromide, 200 ml of acetone, 0.2 g of potassium iodide, 24 ml of ethyl thioglycollate (that is to say a slight excess) and 27.6 g (0.2 mol) of potassium carbonate are introduced successively into a 1 liter three-necked flask. The mixture is heated under reflux for about 4 hours until the complete disappearance of the bromo derivative; the acetone is evaporated, the oil obtained is taken up in ether and in water, the ether phase is washed with a dilute NaOH solution, so as to eliminate the excess thiol, and then with a dilute HCl solution, and is dried over Na2SO4, and the solvent is evaporated. 49 g (yield: 95%) of the stated product are obtained, which is in the form of an orange-coloured oil.
Reaction SMILES: [Cl:1][CH2:2][S:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[Cl:14])(=[O:5])=[O:4].[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[Cl:14][C:8]1[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=1[N:6]([S:3]([CH2:2][Cl:1])(=[O:4])=[O:5])[C:15](=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: O=S(=O)(CCl)Nc1ccc(F)cc1Cl
Product: CC(=O)N(c1ccc(F)cc1Cl)S(=O)(=O)CCl
Yield: 80 %

Procedure:
77.5 g (0.3 mol) of 1-chloro-N-(2-chloro-4-fluorophenyl)methanesulfonamide were dissolved in 204.2 g (2 mol) of acetic anhydride and refluxed for 4 hours. The excess acetic anhydride was distilled off under reduced pressure at 100° C. To the still hot residue was added ethanol with stirring and the product precipitated (seeding may aid in crystallization). The crude product was filtered off and washed with cold ethanol and dried to yield 72 g (80%) of the title compound as a solid melting at 89-92° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:37][N:38]([CH3:43])[CH:39]1[CH2:42][NH:41][CH2:40]1.C(N(CC)CC)C>O1CCOCC1>[C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:41]4[CH2:42][CH:39]([N:38]([CH3:43])[CH3:37])[CH2:40]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)n3)sc2c1-c1ccc(Cl)cc1
Reactant: CN(C)C1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CC(N(C)C)C4)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 50 °C

Procedure:
To (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyrimidin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (30.0 mg, 0.058 mmol) and 3-(dimethylamino)azetidine dihydrochloride (30.2 mg. 0.174 mmol) in 1,4-dioxane (1 mL) was added triethylamine (58.8 mg, 81.0 μL, 0.581 mmol). The reaction mixture was heated at 50° C. for 1 h. Upon completion of the reaction, the reaction mixture was filtered through Celite (ethyl acetate eluent), concentrated, and used without further purification. LCMS-ESI+ calc'd for C30H35ClN5O3S (M+H+): 580.2; Found: 580.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:12][CH:11]2[NH:13][CH:7]([CH2:8][O:9][CH2:10]2)[CH2:6]1)=[O:4].[CH3:14][O:15][C:16]([C:18]1[C@H:19]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[Cl:38])[N:20]=[C:21]([C:26]2[S:27][CH:28]=[CH:29][N:30]=2)[NH:22][C:23]=1[CH2:24]Br)=[O:17].CCN(C(C)C)C(C)C>C(Cl)CCl.CCOC(C)=O>[Cl:38][C:32]1[CH:33]=[C:34]([F:37])[CH:35]=[CH:36][C:31]=1[C@H:19]1[C:18]([C:16]([O:15][CH3:14])=[O:17])=[C:23]([CH2:24][N:13]2[CH:7]3[CH2:6][CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:12][CH:11]2[CH2:10][O:9][CH2:8]3)[NH:22][C:21]([C:26]2[S:27][CH:28]=[CH:29][N:30]=2)=[N:20]1
Reactant: COC(=O)C1CC2COCC(C1)N2
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(CN2C3COCC2CC(C(=O)OC)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution 3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic acid methyl ester (90 mg, 0.48 mmol) (PharmaBlock (Nanjing) R&D Co. Ltd, CAS: 1363382-76-6) and (R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (104 mg, 0.24 mmol) in ClCH2CH2Cl (5 mL) was added DIPEA (0.15 mL, 0.48 mmol) at room temperature. The reaction mixture was stirred overnight at room temperature, then diluted with EtOAc (60 mL), washed with sat. NH4Cl, sat. NaHCO3 and brine (20 mL) respectively. The organic layer was dried over Na2SO4, concentrated under reduced pressure to give methyl 9-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylate as a crude product which was used directly in next step.
Reaction SMILES: [OH:1][CH2:2][C:3]([S:5][C@H:6]1[N:9]([C:10]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=2)=[O:31])=[P:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8](=[O:43])[C@@H:7]1[C@H:44]([O:46][C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=1)=[O:48])[CH3:45])=[O:4].N1C=CC=CC=1.[C:66](OC(=O)C)(=[O:68])[CH3:67]>C(Cl)Cl>[C:66]([O:1][CH2:2][C:3]([S:5][C@H:6]1[N:9]([C:10]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=2)=[O:31])=[P:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:8](=[O:43])[C@@H:7]1[C@H:44]([O:46][C:47]([O:49][CH2:50][C:51]1[CH:52]=[CH:53][C:54]([N+:57]([O-:59])=[O:58])=[CH:55][CH:56]=1)=[O:48])[CH3:45])=[O:4])(=[O:68])[CH3:67]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1SC(=O)CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)S[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A stirred solution of 4(R)-hydroxyacetylthio-3(S)-[1(R)-p-nitrobenzyloxycarbonyloxyethyl]-1-(1-p-nitrobenzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)-azetidin-2-one (418 mg, 0.5 mmole) in CH2Cl2 (5 ml) was sequentially treated with pyridine (162 mg) and acetic anhydride (90 mg) and then stirred at room temperature for six hours.
Reaction SMILES: CS([O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][C:15]([CH2:18][CH2:19][CH3:20])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)(=O)=O.[Cl:21][C:22]1[C:23](O)=[CH:24][C:25](=[O:28])[NH:26][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Cl:21][C:22]1[C:23]([O:5][CH:6]2[CH2:11][CH2:10][N:9]([C:12]3[N:17]=[CH:16][C:15]([CH2:18][CH2:19][CH3:20])=[CH:14][N:13]=3)[CH2:8][CH2:7]2)=[CH:24][C:25](=[O:28])[NH:26][CH:27]=1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Reactant: CCCc1cnc(N2CCC(OS(C)(=O)=O)CC2)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1cnc(N2CCC(Oc3cc(=O)[nH]cc3Cl)CC2)nc1
Temperature: 120 °C

Procedure:
A mixture of 1-(5-propylpyrimidin-2-yl)piperidin-4-yl methanesulfonate (800 mg, 2.67 mmol), 5-chloro-4-hydroxypyridin-2(1H)-one (389 mg, 2.67 mmol, AK Scientific) and cesium carbonate (2612 mg, 8.02 mmol) in DMF (20 mL) was heated at 120° C. for 6 h. The reaction was cooled to rt, diluted with EtOAc (30 mL), and washed with H2O (3×). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a yellow solid. The residue was purified by flash chromatography (SiO2, O-10% MeOH/CH2Cl2) to give the desired product as a yellow solid. MS (ESI) 379 (M+H).
Reaction SMILES: [CH3:1][S:2]([Cl:5])(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][N:15]([CH3:33])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([C:22]1[CH:32]=[CH:31][C:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH2:30][C:24]=2[CH:23]=1)=[O:21].C(N(CC)CC)C.O>O1CCCC1>[ClH:5].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][N:15]([CH3:33])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([C:22]1[CH:32]=[CH:31][C:25]2[CH2:26][CH2:27][N:28]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:29][CH2:30][C:24]=2[CH:23]=1)=[O:21]
Reactant: CN(CCCCC(=O)c1ccc2c(c1)CCNCC2)CCc1ccccc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CN(CCCCC(=O)c1ccc2c(c1)CCN(S(C)(=O)=O)CC2)CCc1ccccc1Cl
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methylsulfonyl chloride (45 μl) was added to a solution of 5-[[2-(2-chlorophenyl)ethyl](methyl)amino]-1-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-1-pentanone (223 mg) obtained in Example 205 and triethylamine (139 μl) in tetrahydrofuran (2 ml). After stirring at room temperature for 60 minute, water (10 g) was added, extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give a free base compound of the title compound as a pale yellow oil (230 mg). A solution of the free base compound in ethanol was treated with hydrogen chloride (ethyl acetate solution) to give the title compound as pale yellow amorphous powders (200 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][CH:15]=2)=[CH:4][C:3]=1[CH3:22].F[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1B(O)O>>[CH3:22][C:3]1[CH:4]=[C:5]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][CH:15]=2)[CH:6]=[CH:7][C:2]=1[C:25]1[CH:24]=[CH:29][CH:28]=[C:27]([O:30][CH3:31])[CH:26]=1
Reactant: COC(=O)CCc1cccc(OCc2ccc(Br)c(C)c2)c1
Reactant: COc1ccc(F)c(B(O)O)c1
Product: COC(=O)CCc1cccc(OCc2ccc(-c3cccc(OC)c3)c(C)c2)c1
Yield: 92.9 %

Procedure:
Compound 1.3 (0.070 g, 0.193 mmol) was coupled with 2-fluoro-5-methoxyphenylboronic acid (available from Aldrich) (0.0982 g, 0.578 mmol) according to the method reported for preparation of 1.4 to afford 2.1 (0.070 g, 89%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]([CH3:21])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[CH2:4][CH2:3]1.[CH2:22]([Br:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(OCC)(=O)C>[Br-:29].[CH3:1][N+:2]1([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:7][CH2:6][N:5]([CH2:8][CH:9]([CH3:21])[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:15][CH:16]=2)[CH2:4][CH2:3]1
Reactant: CC(Cc1ccc(C(C)(C)C)cc1)CN1CCN(C)CC1
Reactant: BrCc1ccccc1
Solvent: CCOC(C)=O
Product: CC(Cc1ccc(C(C)(C)C)cc1)CN1CC[N+](C)(Cc2ccccc2)CC1
Product: [Br-]
Yield: 80.2 %

Procedure:
A solution of 14.4 g of 1-methyl-4-[3-(4-tert.-butylphenyl)-2-methylpropyl]-piperazine and 10.3 g of benzyl bromide in 200 ml of ethyl acetate was refluxed for 6 hours, after which the mixture was evaporated down to 80 ml and then cooled to +5° C. The precipitated product was filtered off under suction, washed with ether and dried. 18.4 g of 1-methyl-1-benzyl-4-[3-(4-tert.-butylphenyl)-2-methylpropyl]-piperazinium bromide were obtained in the form of colorless crystals of melting point 216° C. (compound 3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C([Mg]Br)C.[CH3:15][C:16]1([CH3:24])[C:18]([CH3:20])([CH3:19])[CH:17]1[C:21](Cl)=[O:22]>ClCCl.[Cl-].[Zn+2].[Cl-]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:21]([CH:17]1[C:18]([CH3:20])([CH3:19])[C:16]1([CH3:24])[CH3:15])=[O:22]
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Reactant: Fc1ccc2[nH]ccc2c1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC1(C)C(C(=O)c2c[nH]c3ccc(F)cc23)C1(C)C
Yield: 40 %

Procedure:
A mixture of 5-fluoroindole (0.34 g. 2.5 mmol), ethylmagnesium bromide (1.0 M solution in THF, 3.0 mL, 3.0 mmol), zinc chloride (1.0 M solution in Et2O, 3.0 mL, 3.0 mmol) and the product of Example 1A (3.7 mmol) in 25 mL of dichloromethane was processed as described in Example 1B to provide the title compound (0.26 g, 1.0 mmol, 40% yield). MS (DCI/NH3) m/z 260 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(C=O)C.O1CCOCC1.[Br:23][CH2:24][C:25](Br)=[O:26]>O>[Cl:11][C:10]1[C:2]([NH:1][C:25](=[O:26])[CH2:24][Br:23])=[C:3]([CH:7]=[CH:8][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(Br)CBr
Reactant: Nc1c(Cl)cccc1C(=O)O
Solvent: C1COCCO1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CBr)Nc1c(Cl)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
A solution of 2-amino-3-chlorobenzoic acid (7 g, 0.041 mol), anhydrous DMF (20 mL) and anhydrous dioxane (20 mL) was cooled to 0° C. in a 250 mL 3-necked flask, fitted with a magnetic stirrer and constant additional funnel. Bromoacetyl bromide was added dropwise over a 27 min period, keeping the internal temperature between 0° to 2° C. After the addition was complete, the solution was allowed to warm to room temperature and stirring was continued for 4 hours. The reaction mixture was cooled in an ice-bath and diluted with water (100 mL). The resulting yellow precipitate was filtered, washed with water and dried in vacuum oven for 2 days, affording 7.7 g (65%) of the title compound as a light yellow crystals, mp 173-175° C.; 1H NMR (CD3OD) δ 7.88 (dd, 1H, J=1.6, J=6), 7.68 (dd, 1H, J=1.2, J=6.8), 7.39 (t, 1H, J=8); 13C NMR (CD3OD) δ 176.37, 168.38, 134.84, 134.40, 131.95, 130.53, 129.15, 129.05, 28.66; MS (EI, m/z) 293 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.CN([CH2:15][CH2:16]N(C)C)C.[Li][CH2:21][CH2:22]CC>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:15][CH3:16])([CH2:21][CH3:22])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CN(C)CCN(C)C
Reactant: [Li]CCCC
Product: CCC1(CC)C(=O)Nc2cc(Cl)ccc21
Yield: 23.2 %

Procedure:
Following similar methods to those described in Preparation 321 starting from 6-chloro-1,3-dihydro-indol-2-one (4 g, 25 mmol), TMEDA(11.2 mL, 79 mmol), BuLi (1.6M in hexane, 30 mL, 48 mmol) and Etl (2.9 mL, 36 mmol) gave the title compound (1.3 g). MS: [M+H]+=224.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](S(C3C=CC=CC=3)=O)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C1([Mg]Br)C=CC=CC=1.[Br:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1.[NH4+].[Cl-]>C1COCC1>[Br:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]([C:7]2[C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=[CH:9][CH:8]=2)[OH:35])=[CH:32][CH:31]=1
Reactant: COc1ccc2c(S(=O)c3ccccc3)ccnc2c1
Reactant: O=Cc1ccc(Br)cc1
Agent: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc2c(C(O)c3ccc(Br)cc3)ccnc2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
In a 100 mL round bottom flask under N2, was dissolved 7-methoxy-4-(phenylsulfinyl)quinoline (650 mg, 2.29 mmol) in 10 mL of THF and then the solution was cooled to −78° C. and treated with PhMgBr (3M in Et2O) (1.50 mL, 4.59 mmol). The reaction mixture was then warmed to rt. After 30 min, the mixture was cooled again to −78° C., and solid 4-bromobenzaldehyde (1.27 g, 6.88 mmol) was added. Then, the reaction mixture was warmed to rt. After 2 h the reaction mixture was neutralized with aqueous NH4Cl (sat). The aqueous phase was extracted three times with dichloromethane, and then the organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was purified by MPLC (ISCO dichloromethane:MeOH 100:0 to 90:10) to afford (4-bromophenyl)(7-methoxyquinolin-4-yl)methanol (540 mg, 68.4% yield) as a yellow solid. MS (ESI pos. ion) m/z: 345 (M2H+). Calc'd exact mass for C17H14BrNO2: 343. 1H NMR (400 MHz, CDCl3) 8.83 (d, J=4.42 Hz, 1H), 7.81 (d, J=9.35 Hz, 1H), 7.53 (d, J=4.42 Hz, 1H), 7.44-7.49 (m, 3H), 7.25 (d, J=8.34 Hz, 2H), 7.14 (dd, J=9.28, 2.59 Hz, 1H), 6.43 (s, 1H), 3.93 (s, 3H).
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:25]=[C:26]([N:30]([CH3:37])[C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(O)C.ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:33][C:32]([F:34])([F:35])[C:31]([N:30]([C:26]1[CH:27]=[C:28]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C@@H:3]([CH3:14])[C@H:2]([OH:1])[CH2:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:6][CH:7]=2)[CH:29]=[CH:24][CH:25]=1)[CH3:37])=[O:36]
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Reactant: CN(C(=O)C(F)(F)F)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: C[C@H](Oc1ccc(-c2cccc(N(C)C(=O)C(F)(F)F)c2)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.150 g, Example 33), N-(3-bromo-phenyl)-2,2,2-trifluoro-N-methylacetamide (0.282 g), 2M aqueous sodium carbonate (0.50 ml) and tetrakis(triphenylphosphine)palladium (0) (0.020 g) in ethanol (3 ml) with heating at 90° C. for 2 hours. After work up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane. The product obtained was dissolved in dichloromethane (3 ml), and cooled to 0° C. Trifluoroacetic anhydride (0.09 ml) was added dropwise, the reaction mixture stirred for 1 hour at room temperature, before concentrating under reduced pressure. Methanol (10 ml) and water (10 ml) were added and the resulting mixture was stirred for 30 minutes at room temperature. The product was extracted with ethyl acetate, and the combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as an oil (0.148 g).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:12]1([C:18]2(C3C=CC=CC=3)[CH:26]3[CH:22]([CH2:23][NH:24][CH2:25]3)[C:21](=[O:27])[CH:20]=[CH:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N([CH2:39][CH3:40])CC)C>ClCCl>[C:12]1([CH:18]2[C:26]3([C:40]4[CH:39]=[CH:3][CH:2]=[CH:1][CH:6]=4)[CH:22]([CH2:23][N:24]([C:8](=[O:9])[CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:25]3)[C:21](=[O:27])[CH:20]=[CH:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)Cc1ccccc1
Reactant: O=C1C=CC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: ClCCl
Product: O=C1C=CC(c2ccccc2)C2(c3ccccc3)CN(C(=O)Cc3ccccc3)CC12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phenylacetyl chloride (0.82 cc) is added to a solution, cooled to +5° C., of 7,7-diphenyl-2,3,3a,4,7,7a-hexahydro-1H-isoindol-4-one hydrochloride (2 g) and triethylamine (1.7 cc) in dry dichloromethane (20 cc). The reaction mixture is stirred for 1 hour at +5° C. and for 1 hour at room temperature; it is washed with distilled water (2×20 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in acetonitrile (15 cc). The crystals are drained, washed with isopropyl ether (10 cc), dried and then recrystallized in acetonitrile (20 cc). The crystals obtained are drained and dried. (3aRS, 7aRS)-7,7a-Diphenyl-2-(phenylacetyl)-2,3,3a,4,7,7a-hexahydro-1H-isoindol-4-one (2.7 g), m.p. 188° C., is obtained.